U.S. patent application number 09/526143 was filed with the patent office on 2001-11-08 for heteroaromatic glucokinase activators.
Invention is credited to Bizzarro, Fred Thomas, Corbett, Wendy Lea, Grippo, Joseph Francis, Haynes, Nancy-Ellen, Holland, George William, Kester, Robert Francis, Sarabu, Ramakanth.
Application Number | 20010039344 09/526143 |
Document ID | / |
Family ID | 26824957 |
Filed Date | 2001-11-08 |
United States Patent
Application |
20010039344 |
Kind Code |
A1 |
Bizzarro, Fred Thomas ; et
al. |
November 8, 2001 |
Heteroaromatic glucokinase activators
Abstract
2,3-Di-substituted N-heteroaromatic propionamides with said
substitution at the 2-position being a substituted phenyl group and
at the 3-position being a cycloalkyl ring, said propionamides being
glucokinase activators which increase insulin secretion in the
treatment of type II diabetes.
Inventors: |
Bizzarro, Fred Thomas;
(Colonia, NJ) ; Corbett, Wendy Lea; (Randolph,
NJ) ; Grippo, Joseph Francis; (Stirling, NJ) ;
Haynes, Nancy-Ellen; (Cranford, NJ) ; Holland, George
William; (North Caldwell, NJ) ; Kester, Robert
Francis; (Hackensack, NJ) ; Sarabu, Ramakanth;
(Cedar Grove, NJ) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
26824957 |
Appl. No.: |
09/526143 |
Filed: |
March 15, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60126707 |
Mar 29, 1999 |
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60165944 |
Nov 17, 1999 |
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Current U.S.
Class: |
544/332 |
Current CPC
Class: |
C07C 275/50 20130101;
C07D 285/135 20130101; C07D 261/14 20130101; C07D 213/75 20130101;
C07C 2601/04 20170501; C07D 263/48 20130101; C07C 2601/10 20170501;
C07D 213/80 20130101; C07C 2601/08 20170501; C07D 233/88 20130101;
C07D 239/42 20130101; C07C 2601/02 20170501; C07C 323/62 20130101;
C07D 253/07 20130101; A61P 3/10 20180101; C07D 277/46 20130101;
C07C 2601/14 20170501; C07D 241/20 20130101; C07C 317/44 20130101;
C07D 213/82 20130101; C07D 277/56 20130101; C07D 277/58 20130101;
C07D 237/22 20130101 |
Class at
Publication: |
544/332 |
International
Class: |
C07D 239/02 |
Claims
What is claimed is:
1. A compound comprising an amide of the formula: 139wherein, the *
indicates an asymmetric carbon atom, R.sup.1 and R.sup.2 are
independently hydrogen, halo, amino, hydroxyamino, cyano, nitro,
lower alkyl, --OR.sup.5, 140 perfluoro-lower alkyl, lower alkyl
thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl,
perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or
sulfonamido, R.sup.3 is cycloalkyl having from 3 to 7 carbon atoms;
R.sup.4 is an unsubstituted or mono-substituted five- or
six-membered heteroaromatic ring connected by a ring carbon atom to
the amine group shown, which five- or six-membered heteroaromatic
ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen
or nitrogen, with one heteroatom being nitrogen which is adjacent
to the connecting ring carbon atom; said mono-substituted
heteroaromatic ring being monosubstituted at a position on a ring
carbon atom other than adjacent to said connecting carbon atom with
a substituent selected from the group consisting of lower alkyl,
halo, nitro, cyano, --(CH.sub.2).sub.n-OR.sup.6,
141--(CH.sub.2).sub.n-NHR.sup- .6 n is 0, 1, 2, 3 or 4; R.sup.1 is
hydrogen, lower alkyl, or perfluoro-lower alkyl and R.sup.6,
R.sup.7 and R.sup.8 are independently hydrogen or lower alkyl; or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R.sup.3 is cyclopentyl.
3. The compound of claim 2, wherein R.sup.4 is unsubstituted
thiazole.
4. The compound of claim 3, wherein the amide is the R
configuration at the asymmetric carbon shown.
5. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
hydrogen, halogen, perfluoro-lower alkyl and the other of said
R.sup.1 and R.sup.2 is halo, nitro or perfluoro-lower alkyl.
6. The compound of claim 5, wherein said amide is
2-(3-chloro-phenyl)-3-cy-
clopentyl-N-thiazol-2-yl-propionamide.
7. The compound of claim 5, wherein said amide is
2-(4-bromo-phenyl)-3-cyc- lopentyl-N-thiazol-2-yl-propionamide.
8. The compound of claim 5, wherein said amide is
2-(4-chloro-phenyl)-3-cy-
clopentyl-N-thiazol-2-yl-propionamide.
9. The compound of claim 5, wherein said amide is
3-cyclopentyl-2-(3,4-dic-
hlorophenyl)-N-thiazol-2-yl-propionamide.
10. The compound of claim 5, wherein said amide is
3-cyclopentyl-N-thiazol-
-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide.
11. The compound of claim 5, wherein said compound is
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propio-
namide.
12. The compound of claim 5, wherein said compound is
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propio-
namide.
13. The compound of claim 5, wherein said compound is
3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide.
14. The compound of claim 9, wherein said amide is
3-cyclopentyl-2(R)-(3,4-
-dichloro-phenyl)-N-thiazol-2-yl-propionamide.
15. The compound of claim 5, wherein one of R.sup.1 and R.sup.2 is
amino, nitro, halo or hydrogen and the other of said R.sup.1 and
R.sup.2 is amino, cyano or nitro.
16. The compound of claim 15, wherein said amide is
3-cyclopentyl-2-(4-nitrophenyl)-N-thiazol-2-yl-propionamide.
17. The compound of claim 15, wherein said amide is
2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
18. The compound of claim 15, wherein said amide is
2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
19. The compound of claim 15, wherein said amide is
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
20. The compound of claim 15, wherein said amide is
2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide.
21. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
lower alkylthio, perfluoro-lower alkyl thio, halo or hydrogen and
the other is perfluoro-lower alkylthio, lower alkylsulfinyl or
lower alkylthio.
22. The compound of claim 21, wherein said amide is
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propion-
amide.
23. The compound of claim 21, wherein said amide is
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide.
24. The compound of claim 21, wherein said amide is
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-y-
l-propionamide.
25. The compound of claim 21, wherein said amide is
3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide.
26. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
lower alkyl sulfonyl, hydrogen, nitro, amino, cyano, hydroxylamino,
sulfonamido or halo, and the other of said R.sup.1 and R.sup.2 is
lower alkyl sulfonyl.
27. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.
28. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propiona-
mide.
29. The compound of claim 26, wherein said amide is
2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propion-
amide.
30. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl--
propionamide.
31. The compound of claim 26, wherein said amide is
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propion-
amide.
32. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide.
33. The compound of claim 26, wherein said amide is
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionam-
ide.
34. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide.
35. The compound of claim 26, wherein said amide is
2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamid-
e.
36. The compound of claim 26, wherein said amide is
3-cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]-N-thiazol-2-yl-propionami-
de.
37. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
lower alkyl sulfonyl, and the other is halo or perfluoro-lower
alkyl.
38. The compound of claim 37, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2--
yl-propionamide.
39. The compound of claim 37, wherein said amide is
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-pro-
pionamide.
40. The compound of claim 37, wherein said amide is
2-[3-chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propio-
namide.
41. The compound of claim 37, wherein said amide is
2-(3-bromo-4-nmethanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propio-
namide.
42. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
perfluoro-lower alkyl sulfonyl or hydrogen and the other is
perfluoro-lower alkyl sulfonyl.
43. The compound of claim 42, wherein said amide is
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propio-
namide.
44. The compound of claim 42, wherein said amide is
3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propio-
namide.
45. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
--OR.sup.5, or 142and the other of said R.sup.1 and R.sup.2 is
hydrogen or --OR.sup.5; and R.sup.5 is as above.
46. The compound of claim 45, wherein said amide is
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide.
47. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide.
48. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.
49. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide.
50. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide.
51. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide.
52. The compound of claim 45, wherein said amide is
3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.
53. The compound of claim 45, wherein said amide is
4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid
methyl ester.
54. The compound of claim 3, wherein one of R.sup.1 and R.sup.2 is
--OR.sup.5 and the other is halo.
55. The compound of claim 54, wherein said amide is
3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide.
56. The compound of claim 54, wherein said amide is
3-cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide.
57. The compound of claim 3, wherein R.sup.4 is a mono-substituted
thiazole with said substituent.
58. The compound of claim 57, wherein said substituent is
--(CH.sub.2).sub.n-OR.sup.6 and n and R.sup.6 are as above.
59. The compound of claim 58, wherein one of R.sup.1 and R.sup.2 is
halo and the other of said R.sup.1 and R.sup.2 is hydrogen or
halo.
60. The compound of claim 59, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-pro-
pionamide.
61. The compound of claim 59, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]--
propionamide.
62. The compound of claim 59, wherein said amide is
2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propio-
namide.
63. The compound of claim 59, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-pro-
pionamide.
64. The compound of claim 58, wherein one of R.sup.1 and R.sup.2 is
lower alkyl sulfonyl, and the other of said R.sup.1 and R.sup.2 is
lower alkyl sulfonyl or hydrogen.
65. The compound of claim 64 wherein said amide is
3-cyclopentyl-N-(4-hydr-
oxymethyl-thiazol-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide.
66. The compound of claim 64, wherein said amide is
3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-ph-
enyl)-propionamide.
67. The compound of claim 57, wherein said substituent is lower
alkyl, one of R.sup.1 and R.sup.2 is hydrogen or halogen and the
other of said R.sup.1 and R.sup.2 is halogen.
68. The compound of claim 67, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methyl-thiazol-2-yl)-propionami-
de.
69. The compound of claim 67, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-thiazol-2-yl)-propionami-
de.
70. The compound of claim 57, wherein said substituent is
143wherein n is 0 or 1 and R.sup.1 is hydrogen, or lower alkyl.
71. The compound of claim 70, wherein one of R.sup.1 and R.sup.2 is
hydrogen and the other is halo.
72. The compound of claim 71, wherein said amide is
{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceti-
c acid ethyl ester.
73. The compound of claim 71, wherein said amide is
{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceti-
c acid methyl ester.
74. The compound of claim 71, wherein said amide is
2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxyli-
c acid methyl ester.
75. The compound of claim 71, wherein said amide is
2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxyli-
c acid ethyl ester.
76. The compound of claim 71, wherein said amide is
{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceti-
c acid ethyl ester.
77. The compound of claim 71, wherein said amide is
2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxyli-
c acid methyl ester.
78. The compound of claim 71, wherein said amide is
2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxyli-
c acid ethyl ester.
79. The compound of claim 71, wherein said amide is
{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceti-
c acid methyl ester.
80. The compound of claim 70, wherein R.sup.1 and R.sup.2 are each
independently halo.
81. The compound of claim 80, wherein said amide is
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ac-
etic acid.
82. The compound of claim 80, wherein said amide is
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ac-
etic acid ethyl ester.
83. The compound of claim 80, wherein said amide is
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carbox-
ylic acid.
84. The compound of claim 80, wherein said amide is
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carbox-
ylic acid.
85. The compound of claim 80, wherein said amide is
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ac-
etic acid methyl ester.
86. The compound of claim 80, wherein said amide is
(2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4--
carboxylic acid methyl ester.
87. The compound of claim 80, wherein said amide is
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carbox-
ylic acid methyl ester.
88. The compound of claim 80, wherein said amide is
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carbox-
ylic acid ethyl ester.
89. The compound of claim 70, wherein one of R.sup.1 or R.sup.2 is
nitro, amino or hydrogen and the other of said R.sup.1 and R.sup.2
is nitro or amino.
90. The compound of claim 89, wherein said amide is
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic
acid ethyl ester.
91. The compound of claim 89, wherein said amide is
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic
acid methyl ester.
92. The compound of claim 89, wherein said amide is
2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic
acid methyl ester.
93. The compound of claim 89, wherein said amide is
2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic
acid ethyl ester.
94. The compound of claim 89, wherein said amide is
{2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic
acid methyl ester.
95. The compound of claim 89, wherein said amide is
2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic
acid methyl ester.
96. The compound of claim 70, wherein one of R.sup.1 and R.sup.2 is
lower alkyl sulfonyl, perfluoro-lower alkyl, halogen or hydrogen
and the other of said R.sup.1 and R.sup.2 is lower alkyl
sulfonyl.
97. The compound of claim 96, wherein said amide is
{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4-
-carboxylic acid ethyl ester.
98. The compound of claim 96, wherein said amide is
{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4--
yl}-4-acetic acid methyl ester.
99. The compound of claim 96, wherein said amide is
{2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propiony-
lamino]-thiazol-4-yl}-acetic acid methyl ester.
100. The compound of claim 96, wherein said amide is
2-[3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionyl-
amino]-thiazole-4-carboxylic acid methyl ester.
101. The compound of claim 57, wherein said substituent is
144wherein R.sup.8 is as above.
102. The compound of claim 101, wherein one of R.sup.1 and R.sup.2
are hydrogen and the other of said R.sup.1 and R.sup.2 is nitro or
amino.
103. The compound of claim 102, wherein said amide is
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-ac-
etic acid ethyl ester.
104. The compound of claim 101, wherein one of R.sup.1 and R.sup.2
is halo or perfluoro-lower alkyl and the other of said R.sup.1 and
R.sup.2 is perfluoro-lower alkyl, halogen or hydrogen.
105. The compound of claim 104, wherein said amide is
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]thiazol-5-yl}-oxo-
-acetic ethyl ester.
106. The compound of claim 104, wherein said amide is
{2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-t-
hiazol-4-yl}-oxo-acetic acid ethyl ester.
107. The compound of claim 101, wherein said one of R.sup.1 and
R.sup.2 is hydrogen or halogen and the other of said R.sup.1 and
R.sup.2 is lower alkyl sulfonyl.
108. The compound of claim 107, wherein said compound is
{2-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-t-
hiazol-4-yl}-oxo-acetic acid ethyl ester.
109. The compound of claim 57, wherein said substitutent is
nitro.
110. The compound of claim 109, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro-thiazol-2-yl)-propionamid-
e.
111. The compound of claim 2, wherein R.sup.4 is unsubstituted
pyridine.
112. The compound of claim 111, wherein one of R.sup.1 and R.sup.2
are halo, perfluoro-lower alkyl or hydrogen and the other of said
R.sup.1 and R.sup.2 is halo, perfluoro-lower alkyl, amino, cyano or
nitro.
113. The compound of claim 112, wherein said amide is
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propio-
namide.
114. The compound of claim 112, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide.
115. The compound of claim 112, wherein said amide is
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-2-propionamide.
116. The compound of claim 112, wherein said amide is
3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide.
117. The compound of claim 112, wherein said amide is
2-(3-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
118. The compound of claim 112, wherein said amide is
2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
119. The compound of claim 112, wherein said amide is
2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
120. The compound of claim 112, wherein said amide is
2-(4-chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
121. The compound of claim 112, wherein said amide is
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
122. The compound of claim 112, wherein said amide is
3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide.
123. The compound of claim 111, wherein one of R.sup.1 and R.sup.2
is lower alkyl thio, perfluoro-lower alkyl thio or cyano, and the
other is hydrogen.
124. The compound of claim 123, wherein said amide is
2-(4-cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide.
125. The compound of claim 123, wherein said amide is
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide.
126. The compound of claim 123, wherein said amide is
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propion-
amide.
127. The compound of claim 111, wherein one of R.sup.1 and R.sup.2
is lower alkyl sulfonyl, halo, cyano, nitro or hydrogen and the
other is lower alkyl sulfonyl.
128. The compound of claim 127, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propiona-
mide.
129. The compound of claim 127, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.
130. The compound of claim 127, wherein said amide is
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propion-
amide.
131. The compound of claim 127, wherein said amide is
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propion-
amide.
132. The compound of claim 127, wherein said amide is
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide.
133. The compound of claim 127, wherein said amide is
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionam-
ide.
134. The compound of claim 127, wherein said amide is
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propio-
namide.
135. The compound of claim 111, wherein one of R.sup.1 and R.sup.2
is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen
and the other is perfluoro-lower alkyl sulfonyl, or perfluro-lower
alkyl.
136. The compound of claim 135, wherein said amide is
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2--
yl-propionamide.
137. The compound of claim 135, wherein said amide is
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propio-
namide.
138. The compound of claim 2, wherein R.sup.4 is a pyridine ring
mono-substituted with one of said substituents.
139. The compound of claim 138, wherein said substitutent is
145wherein n and R.sup.7 are as above.
140. The compound of claim 139, wherein R.sup.1 and R.sup.2 are
each independently halo.
141. The compound of claim 140, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-pro-
pionamide.
142. The compound of claim 140, wherein said amide is
6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic
acid methyl ester.
143. The compound of claim 139, wherein one of R.sup.1 and R.sup.2
is hydrogen and the other is halo, amino, cyano or nitro.
144. The compound of claim 143, wherein said amide is
6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic
acid.
145. The compound of claim 143, wherein said amide is
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid
methyl ester.
146. The compound of claim 143, wherein said amide is
6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid
methyl ester.
147. The compound of claim 143, wherein said amide is
6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid
methyl ester.
148. The compound of claim 143, wherein said amide is
6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid
methyl ester.
149. The compound of claim 143, wherein said amide is
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic
acid.
150. The compound of claim 143, wherein said amide is
6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic
acid.
151. The compound of claim 139, wherein one of R.sup.1 and R.sup.2
is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen
and the other is perfluoro-lower alkyl sulfonyl or lower alkyl
sulfonyl.
152. The compound of claim 151, wherein said amide is
6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-ni-
cotinic acid methyl ester.
153. The compound of claim 151, wherein said amide is
6-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-ni-
cotinic acid.
154. The compound of claim 151, wherein said amide is
6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic
acid methyl ester.
155. The compound of claim 138, wherein said substituent is
--(CH.sub.2).sub.n-OR.sup.6 wherein n and R.sup.6 are as above.
156. The compound of claim 155, wherein one of R.sup.1 and R.sup.2
are halo and the other is hydrogen or halo.
157. The compound of claim 156, wherein said amide is
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)
propionamide.
158. The compound of claim 156, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propiona-
mide.
159. The compound of claim 156, wherein said amide is
2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propio-
namide.
160. The compound of claim 155, wherein one of R.sup.1 and R.sup.2
is lower alkyl sulfonyl or hydrogen and the other is lower alkyl
sulfonyl.
161. The compound of claim 160, wherein said amide is
3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-pheny-
l)-propionamide.
162. The compound of claim 138, wherein said substituent is halo or
perfluoro-lower alkyl.
163. The compound of claim 162, wherein one of R.sup.1 and R.sup.2
is halo or hydrogen and the other is halo.
164. The compound of claim 163, wherein said amide is
N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionam-
ide.
165. The compound of claim 163, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-brompyridin)-2-yl-propionamide-
.
166. The compound of claim 163, wherein said amide is
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-y-
l)-propionamide.
167. The compound of claim 163, wherein said amide is
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propion-
amide.
168. The compound of claim 162, wherein one of R.sup.1 and R.sup.2
is halo, nitro or hydrogen and the other is perfluoro-lower alkyl
sulfonyl or lower alkyl sulfonyl.
169. The compound of claim 168, wherein said amide is
N-(5-chloro-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phe-
nyl)-propionamide.
170. The compound of claim 168, wherein said amide is
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phen-
yl)-propionamide.
171. The compound of claim 168, wherein said amide is
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-pheny-
l)-propionamide.
172. The compound of claim 168, wherein said amide is
2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopent-
yl-propionamide.
173. The compound of claim 168, wherein said amide is
N-(5-bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopen-
tyl-propionamide.
174. The compound of claim 168, wherein said amide is
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl--
pyridin-2-yl)-propionamide.
175. The compound of claim 168, wherein said amide is
N-(5-chloro-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclope-
ntyl-propionamide.
176. The compound of claim 138, wherein said substituent is
nitro.
177. The compound of claim 176, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyridin)-2-yl-propionamid-
e.
178. The compound of claim 138, wherein said substituent is lower
alkyl.
179. The compound of claim 178, wherein one of R.sup.1 and R.sup.2
is halo or hydrogen and the other of said R.sup.1 and R.sup.2 is
halo, perfluoro-lower alkyl or perfluoro-lower alkyl sulfonyl.
180. The compound of claim 179, wherein said substituent is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylpyridin)-2-yl-propionami-
de.
181. The compound of claim 179, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylpyridin)-2-yl-propionami-
de.
182. The compound of claim 179, wherein said amide is
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylpyridin)-2-yl-propionami-
de.
183. The compound of claim 179, wherein said amide is
3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phe-
nyl)-propionamide.
184. The compound of claim 179, wherein said amide is
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-methyl-pyridin-2-
-yl)-propionamide.
185. The compound of claim 138, wherein said substituent is
146wherein n and R.sup.6 are as above.
186. The compound of claim 185, wherein one of R.sup.1 and R.sup.2
are independently selected from the group consisting of halo or
hydrogen and the other of said R.sup.1 and R.sup.2 is halo, or
lower alkyl sulfonyl.
187. The compound of claim 186, wherein said amide is
6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotin-
amide.
188. The compound of claim 2, wherein R.sup.4 is unsubstituted
imidazolyl.
189. The compound of claim 188, wherein one of R.sup.1 and R.sup.2
is selected from the group consisting of halo and hydrogen and the
other of said R.sup.1 and R.sup.2 is halo, or lower alkyl
sulfonyl.
190. The compound of claim 189, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide.
191. The compound of claim 2, wherein R.sup.4 is an isoxazolyl
ring.
192. The compound of claim 191, wherein said ring is substituted
with a lower alkyl substituent.
193. The compound of claim 192, wherein one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl
and the other of said R.sup.1 or R.sup.2 is hydrogen or halo.
194. The compound of claim 193, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionam-
ide.
195. The compound of claim 2, wherein R.sup.4 is unsubstituted
oxazolyl.
196. The compound of claim 195, wherein one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and
the other of said R.sup.1 or R.sup.2 is hydrogen or halo.
197. The compound of claim 196, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide.
198. The compound of claim 2, wherein R.sup.3 is cyclopentyl and
R.sup.4 is unsubstituted pyridazinyl ring.
199. The compound of claim 198, wherein one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and
the other of said R.sup.1 or R.sup.2 is hydrogen or halo.
200. The compound of claim 199, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide.
201. The compound of claim 2, wherein R.sup.4 is unsubstituted
pyrimidinyl.
202. The compound of claim 201, wherein one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and
the other is hydrogen or halo.
203. The compound of claim 202, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide.
204. The compound of claim 202, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-6-yl-propionamide.
205. The compound of claim 202, wherein said amide is
3-cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamide.
206. The compound of claim 2, wherein R.sup.4 is an unsubstituted
thiadiazolyl ring.
207. The compound of claim 206, wherein one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl or lower alkyl sulfonyl and
the other of said R.sup.1 and R.sup.2 is hydrogen or halo.
208. The compound of claim 207, wherein said amide is
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamid-
e.
209. The compound of claim 1, wherein R.sup.3 is cyclohexyl.
210. The compound of claim 209, wherein R.sup.4 is unsubstituted
thiazolyl.
211. The compound of claim 210, wherein one of R.sup.1 and R.sup.2
is halo, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl,
perfluoro-lower alkyl, and the other of said R.sup.1 and R.sup.2 is
halo, perfluoro-lower alkyl or hydrogen.
212. The compound of claim 211, wherein said amide is
2-[4-methanesulfonyl phenyl]-3-cyclohexyl
N-thiazol-2-yl-propionamide.
213. The compound of claim 1, wherein R.sup.3 is cycloheptyl.
214. The compound of claim 213, wherein R.sup.4 is unsubstituted
thiazolyl.
215. The compound of claim 214, wherein one of R.sup.1 and R.sup.2
is halo, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl,
perfluoro-lower alkyl, and the other of said R.sup.1 and R.sup.2 is
halo, perfluoro-lower alkyl or hydrogen.
216. The compound of claim 215, wherein said amide is
2-[4-methanesulfonyl phenyl]-3-cycloheptyl
N-thiazol-2-yl-propionamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 60/126,707, filed Mar. 29, 1999 and No.
60/165,944, filed Nov. 17, 1999.
BACKGROUND OF THE INVENTION
[0002] Glucokinase (GK) is one of four hexokinases that are found
in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.)
Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases
catalyze the first step in the metabolism of glucose, i.e., the
conversion of glucose to glucose-6-phosphate. Glucokinase has a
limited cellular distribution, being found principally in
pancreatic .beta.-cells and liver parenchymal cells. In addition,
GK is a rate-controlling enzyme for glucose metabolism in these two
cell types that are known to play critical roles in whole-body
glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N.
B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and
Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration
of glucose at which GK demonstrates half-maximal activity is
approximately 8 mM. The other three hexokinases are saturated with
glucose at much lower concentrations (<1 mM). Therefore, the
flux of glucose through the GK pathway rises as the concentration
of glucose in the blood increases from fasting (5 mM) to
postprandial (.about.10-15 mM) levels following a
carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and
Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M.
Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto,
Calif., pages 463-496, 1993]. These findings contributed over a
decade ago to the hypothesis that GK functions as a glucose sensor
in .beta.-cells and hepatocytes (Meglasson, M. D. and Matschinsky,
F. M. Amer. J Physiol. 246, E1-E13, 1984). In recent years, studies
in transgenic animals have confirmed that GK does indeed play a
critical role in whole-body glucose homeostasis. Animals that do
not express GK die within days of birth with severe diabetes while
animals overexpressing GK have improved glucose tolerance (Grupe,
A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie,
T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An
increase in glucose exposure is coupled through GK in .beta.-cells
to increased insulin secretion and in hepatocytes to increased
glycogen deposition and perhaps decreased glucose production.
[0003] The finding that type II maturity-onset diabetes of the
young (MODY-2) is caused by loss of function mutations in the GK
gene suggests that GK also functions as a glucose sensor in humans
(Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173,
1995). Additional evidence supporting an important role for GK in
the regulation of glucose metabolism in humans was provided by the
identification of patients that express a mutant form of GK with
increased enzymatic activity. These patients exhibit a fasting
hypoglycemia associated with an inappropriately elevated level of
plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New
England J. Med. 338, 226-230, 1998). While mutations of the GK gene
are not found in the majority of patients with type II diabetes,
compounds that activate GK and, thereby, increase the sensitivity
of the GK sensor system will still be useful in the treatment of
the hyperglycemia characteristic of all type II diabetes.
Glucokinase activators will increase the flux of glucose metabolism
in .beta.-cells and hepatocytes, which will be coupled to increased
insulin secretion. Such agents would be useful for treating type II
diabetes.
SUMMARY OF THE INVENTION
[0004] This invention provides a compound, comprising an amide of
the formula: 1
[0005] wherein R.sup.1 and R.sup.2 are independently hydrogen,
halo, amino, hydroxyamino, cyano, nitro, lower alkyl, --OR.sup.5,
2
[0006] perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower
alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl,
lower alkyl sulfinyl, or sulfonamido; R.sup.3 is cycloalkyl having
from 3 to 7 carbon atoms;
[0007] R.sup.4 is an unsubstituted or mono-substituted five- or
six-membered heteroaromatic ring connected by a ring carbon atom to
the amine group shown, which five- or six-membered heteroaromatic
ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen
or nitrogen, with one heteroatom being nitrogen which is adjacent
to the connecting ring carbon atom; said mono-substituted
heteroaromatic ring being monosubstituted at a position on a ring
carbon atom other than adjacent to said connecting carbon atom with
a substituent selected from the group consisting of lower alkyl,
halo, nitro, cyano, 3
[0008] --(CH.sub.2).sub.n-NHR.sup.6
[0009] n is 0, 1, 2, 3 or 4;
[0010] R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl
and R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or
lower alkyl;
[0011] or a pharmaceutically acceptable salt thereof.
[0012] The compounds of formula I have been found to activate
glucokinase in vitro. Glucokinase activators are useful for
increasing insulin secretion in the treatment of type II
diabetes.
DETAILED DESCRIPTION OF THE INVENTION
[0013] This invention provides a compound, comprising an amide of
the formula: 4
[0014] wherein R.sup.1 and R.sup.2 are independently hydrogen,
halo, amino, hydroxyamino, cyano, nitro, lower alkyl, --OR.sup.5,
5
[0015] perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower
alkyl thio, lower alkyl sulfinyl, lower alkyl sulfonyl,
perfluoro-lower alkyl sulfonyl, or sulfonamido; R.sup.3 is
cycloalkyl having from 3 to 7 carbon atoms;
[0016] R.sup.4 is an unsubstituted or mono-substituted
five-membered heteroaromatic ring connected by a ring carbon atom
to the amine group shown, which five- or six-membered
heteroaromatic ring contains from 1 to 3 heteroatoms selected from
sulfur, oxygen or nitrogen, with one heteroatom being nitrogen
which is adjacent to the connecting ring carbon atom; said
mono-substituted heteroaromatic ring being monosubstituted at a
position on a ring carbon atom other than adjacent to said
connecting carbon atom with a substituent selected from the group
consisting of lower alkyl, halo, nitro, cyano, 6
[0017] --(CH.sub.2).sub.n-NHR.sup.6
[0018] n is 0, 1, 2, 3 or 4;
[0019] R.sup.5 is hydrogen, lower alkyl, or perfluoro-lower alkyl
and R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen or
lower alkyl;
[0020] or a pharmaceutically acceptable salt thereof.
[0021] Therefore, in the compound of formula I, the "*" illustrates
the asymmetric carbon atom in this compound. The compound of
formula I may be present either as a racemate or in the "R"
configuration at the asymmetric carbon shown. The "R" enantiomers
are preferred.
[0022] As used throughout this application, the term "lower alkyl"
includes both straight chain and branched chain alkyl groups having
from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
preferably methyl and ethyl. As used herein, the term "halogen or
halo" unless otherwise stated, designates all four halogens, i.e.
fluorine, chlorine, bromine and iodine. As used herein,
"perfluoro-lower alkyl" means any lower alkyl group wherein all of
the hydrogens of the lower alkyl group are substituted or replaced
by fluoro. Among the preferred perfluoro-lower alkyl groups are
trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
[0023] As used herein the term "aryl" signifies aryl mononuclear
aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can
be unsubstituted or substituted in one or more positions with
halogen, nitro, lower alkyl, or lower alkoxy substituents and
polynuclear aryl groups, such as naphthyl, anthryl, and
phenanthryl, which can be unsubstituted or substituted with one or
more of the aforementioned groups. Preferred aryl groups are the
substituted and unsubstituted mononuclear aryl groups, particularly
phenyl. As used herein, the term "lower alkoxy" includes both
straight chain and branched chain alkoxy groups having from 1 to 7
carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy,
preferably methoxy and ethoxy. The term "arylalkyl" denotes an
alkyl group, preferably lower alkyl, in which one of the hydrogen
atoms can be replaced by an aryl group. Examples of arylalkyl
groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl,
4-methoxybenzyl and the like.
[0024] As used herein, the term "lower alkanoic acid" denotes lower
alkanoic acids containing from 2 to 7 carbon atoms such as
propionic acid, acetic acid and the like. The term "lower alkanoyl"
denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms
such as propionoyl, acetyl and the like. The term "aroic acids"
denotes aryl alkanoic acids where aryl is as defined above and
alkanoic contains from 1 to 6 carbon atoms. The term "aroyl"
denotes aroic acids wherein aryl is as defined hereinbefore, with
the hydrogen group of the COOH moiety removed. Among the preferred
aroyl groups is benzoyl.
[0025] During the course of the reaction the various functional
groups such as the free carboxylic acid or hydroxy groups will be
protected via conventional hydrolyzable ester or ether protecting
groups. As used herein the term "hydrolyzable ester or ether
protecting groups" designates any ester or ether conventionally
used for protecting carboxylic acids or alcohols which can be
hydrolyzed to yield the respective hydroxyl or carboxyl group.
Exemplary ester groups useful for those purposes are those in which
the acyl moieties are derived from a lower alkanoic, aryl lower
alkanoic, or lower alkane dicarboxcyclic acid. Among the activated
acids which can be utilized to form such groups are acid
anhydrides, acid halides, preferably acid chlorides or acid
bromides derived from aryl or lower alkanoic acids. Example of
anhydrides are anhydrides derived from monocarboxylic acid such as
acetic anhydride, benzoic acid anhydride, and lower alkane
dicarboxcyclic acid anhydrides, e.g. succinic anhydride as well as
chloro formates e.g. trichloro, ethylchloro formate being
preferred. A suitable ether protecting group for alcohols are, for
example, the tetrahydropyranyl ethers such as
4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are
aroylmethylethers such as benzyl, benzhydryl or trityl ethers or
.alpha.-lower alkoxy lower alkyl ethers, for example, methoxymethyl
or allylic ethers or alkyl silylethers such as
trimethylsilylether.
[0026] The term "amino protecting group" designates any
conventional amino protecting group which can be cleaved to yield
the free amino group. The preferred protecting groups are the
conventional amino protecting groups utilized in peptide synthesis.
Especially preferred are those amino protecting groups which are
cleavable under mildly acidic conditions from about pH 2.0 to 3.
Particularly preferred amino protecting groups such as t-butoxy
carbamate (BOC), benzyloxy carbamate (CBZ), 9-flurorenylmethoxy
carbamate (FMOC).
[0027] The heteroaromatic ring defined by R.sup.4 can be an
unsubstituted or mono-substituted five- or six-membered
heteroaromatic ring having from 1 to 3 heteroatoms selected from
the group consisting of oxygen, nitrogen, or sulfur and connected
by a ring carbon to the amine of the amide group shown. The
heteroaromatic ring contains a first nitrogen heteroatom adjacent
to the connecting ring carbon atom and if present, the other
heteroatoms can be sulfur, oxygen or nitrogen. Such heteroaromatic
rings include, for example, pyrazinyl, pyridazinyl, isoxazolyl,
isothiazolyl, and pyrazolyl. Among the preferred heteroaromatic
rings are included pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, and
imidazolyl. These heteroaromatic rings which constitute R.sup.4 are
connected via a ring carbon atom to the amide group to form the
amides of formula I. The ring carbon atom of the heteroaromatic
ring which is connected via the amide linkage to form the compound
of formula I cannot contain any substituent.
[0028] When R.sup.4 is an unsubstituted or mono-substituted
five-membered heteroaromatic ring, the preferred rings are those
which contain a nitrogen heteroatom adjacent to the connecting ring
carbon and a second heteroatom adjacent to the connecting ring
carbon or adjacent to said first heteroatom.
[0029] The preferred five-membered heteroaromatic rings contain 2
or 3 heteroatom with thiazolyl, imidazolyl, oxazolyl and
thiadiazolyl being especially present. When the heteroaromatic ring
is a six-membered heteroaromatic, the ring is connected by a ring
carbon to the amine group shown, with one nitrogen heteroatom being
adjacent to the connecting ring carbon atom. The preferred
six-membered heteroaromatic rings include, for example, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
[0030] The term "pharmaceutically acceptable salts" as used herein
include any salt with both inorganic or organic pharmaceutically
acceptable acids such as hydrochloric acid, hydrobromic acid,
nitric acid, sulfuric acid, phosphoric acid, citric acid, formic
acid, maleic acid, acetic acid, succinic acid, tartaric acid,
methanesulfonic acid, para-toluene sulfonic acid and the like. The
term "pharmaceutically acceptable salts" also includes any
pharmaceutically acceptable base salt such as amine salts, trialkyl
amine salts and the like. Such salts can be formed quite readily by
those skilled in the art using standard techniques.
[0031] In accordance with one embodiment of this invention, R.sup.3
is cyclopentyl (the compound I-D). The embodiments of the compound
I-D are those compounds where R.sup.4 is an unsubstituted thiazole
(Compound I-D1). Among the various embodiments of the compound of
I-D1 are included those compounds where:
[0032] a) one of R.sup.1 and R.sup.2 is hydrogen, halogen,
perfluoro-lower alkyl and the other of said R.sup.1 and R.sup.2 is
halo or perfluoro-lower alkyl;
[0033] b) one of R.sup.1 and R.sup.2 is amino, nitro, halo, nitro
or hydrogen and the other of said R.sup.1 and R.sup.2 is amino,
cyano or nitro;
[0034] c) one of R.sup.1 and R.sup.2 is lower alkylthio,
perfluoro-lower alkyl thio, halo or hydrogen and the other of said
R.sup.1 and R.sup.2 is perfluoro-lower alkylthio, lower
alkylsulfinyl or lower alkylthio;
[0035] d) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl,
hydrogen, nitro, cyano, amino, hydroxyamino, sulfonamido or halo,
and the other of said R.sup.1 and R.sup.2 is lower alkyl
sulfonyl;
[0036] e) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, and
the other of said R.sup.1 and R.sup.2 is halo or perfluoro-lower
alkyl;
[0037] f) one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl
sulfonyl or hydrogen and the other of said R.sup.1 and R.sup.2 is
perfluoro-lower alkyl sulfonyl; and
[0038] g) one of R.sup.1 and R.sup.2 is --OR.sup.5, or 7
[0039] and the other of said R.sup.1 and R.sup.2 is hydrogen or
--OR.sup.5; and R.sup.5 is as above
[0040] h) one of R.sup.1 and R.sup.2 is --OR.sup.1 and the other is
halo.
[0041] In accordance with another embodiment of this invention
where R.sup.3 is cyclopentyl, the embodiments are those compounds
where R.sup.4 is a mono-substituted thiazole (compounds I-D2).
Among the embodiments of compounds I-D2, are those compounds where
the mono-substitution is --(CH.sub.2).sub.n-OR.sup.6 and n and
R.sup.6 are as above (compounds I-D2(a)). Among the embodiments of
compounds I-D2 (a) are those compounds where:
[0042] a) one of R.sup.1 and R.sup.2 is halo and the other of said
R.sup.1 and R.sup.2 is hydrogen or halo;
[0043] b) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, and
the other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl or
hydrogen; and
[0044] c) one of R.sup.1 and R.sup.2 is hydrogen and the other of
said R.sup.1 and R.sup.2 is lower alkyl or perfluoro-lower
alkyl.
[0045] In accordance with another embodiment of the invention where
R.sup.3 is cyclopentyl and R.sup.4 is a mono-substituted thiazole
(Compounds I-D2), are those compounds where the mono-substitution
is lower alkyl and one of R.sup.1 and R.sup.2 are hydrogen or
halogen and the other of R.sup.1 and R.sup.2 is halogen (Compounds
I-D2(b)).
[0046] Among another embodiment of the compounds I-D are those
compounds where the mono-substituted thiazole is substituted with
8
[0047] wherein n is 0 or 1 and R.sup.7 is hydrogen, or lower alkyl
(Compounds of I-D2(c)). Among the embodiments of compounds of
formula I-D2(c) are those compounds where:
[0048] a) one of R.sup.1 and R.sup.2 is hydrogen and the other of
said R.sup.1 and R.sup.2 is halo;
[0049] b) R.sup.1 and R.sup.2 are each independently halo;
[0050] c) one of R.sup.1 or R.sup.2 is nitro, amino or hydrogen and
the other of said R.sup.1 and R.sup.2 is nitro or amino; and
[0051] d) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl,
perfluoro-lower alkyl, halogen or hydrogen and the other of said
R.sup.1 and R.sup.2 is lower alkyl sulfonyl.
[0052] In accordance with another embodiment of this invention,
where R.sup.3 and cyclopentyl and R.sup.4 is a mono-substituted
thiazole (Compounds I-D2) are those compounds where the
mono-substituted thiazole is substituted with 9
[0053] wherein R.sup.8 is as above (Compounds I-D2(d)).
[0054] Among the embodiments of compound I-D2(d) are those
compounds where:
[0055] a) one of R.sup.1 and R.sup.2 are hydrogen and the other of
said R.sup.1 and R.sup.2 is nitro or amino;
[0056] b) one of R.sup.1 and R.sup.2 is halo or perfluoro-lower
alkyl and the other of said R.sup.1 and R.sup.2 is perfluoro-lower
alkyl, halogen or hydrogen; and
[0057] c) one of R.sup.1 and R.sup.2 is hydrogen or halogen and the
other of said R.sup.1 and R.sup.2 is lower alkyl sulfonyl.
[0058] In accordance with another embodiment of this invention,
where R.sup.3 is cyclopentyl and R.sup.4 is a mono-substituted
thiazole, compounds I-D2, are those compounds where the
mono-substitution on the thiazole ring is a nitro group and one of
R.sup.1 and R.sup.2 are hydrogen and halogen and the other of
R.sup.1 and R.sup.2 is halogen or lower alkyl sulfonyl (compound of
formula I-D2(e)).
[0059] In accordance with another embodiment of this invention,
where R.sup.3 is cyclopentyl (Compound I-D) and R.sup.4 is an
unsubstituted pyridine (Compounds I-D3). Among the embodiments of
compound I-D3 are those compounds where:
[0060] a) one of R.sup.1 and R.sup.2 are halo, perfluoro-lower
alkyl or hydrogen and the other of said R.sup.1 and R.sup.2 is
halo, perfluoro-lower alkyl, amino, cyano or nitro;
[0061] b) one of R.sup.1 and R.sup.2 is lower alkyl thio,
perfluoro-lower alkyl thio or cyano, and the other is hydrogen;
[0062] c) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl, halo,
cyano, nitro or hydrogen and the other of said R.sup.1 and R.sup.2
is lower alkyl sulfonyl; and
[0063] d) one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl
sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said
R.sup.1 and R.sup.2 is perfluoro-lower alkyl sulfonyl,
perfluoro-lower alkyl.
[0064] In accordance with another embodiment of the invention,
where R.sup.3 is cyclopentyl (Compounds I-D) are those compounds
where R.sup.4 is a mono-substituted pyridine ring. Among the
embodiments of the mono-substituted pyridine (Compounds I-D4) are
those compounds where the mono-substitution is 10
[0065] wherein n and R.sup.7 are as above
[0066] (compound I-D4(a)). Among the embodiments of compounds
I-D4(a) are those compounds where:
[0067] a) wherein R.sup.1 and R.sup.2 are each independently
halo;
[0068] b) wherein one of R.sup.1 and R.sup.2 is hydrogen and the
other of said R.sup.1 and R.sup.2 is halo, amino, cyano or nitro;
and
[0069] c) one of R.sup.1 and R.sup.2 is perfluoro-lower alkyl
sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said
R.sup.1 and R.sup.2 is perfluoro-lower alkyl sulfonyl or lower
alkyl sulfonyl.
[0070] Other embodiments of the compounds of formula I-D4(b) are
those compounds where the pyridine ring is mono-substituted with
--(CH.sub.2).sub.n-OR.sup.6 wherein n and R.sup.6 are as above
(Compounds I-D4(b)). Among the embodiments of the compound I-D4(b)
are those compounds where:
[0071] a) one of R.sup.1 and R.sup.2 are halo and the other of said
R.sup.1 and R.sup.2 is hydrogen or halo; and
[0072] b) one of R.sup.1 and R.sup.2 is lower alkyl sulfonyl or
hydrogen and the other of said R.sup.1 and R.sup.2 is lower alkyl
sulfonyl.
[0073] Another embodiment of compounds where R.sup.3 is cyclopentyl
and R.sup.4 is a mono-substituted pyridine ring are those compounds
where the pyridine ring is mono-substituted with a halo or
perfluoro-lower alkyl substituent, the compound of formula I-D4(c).
Among the embodiments of the compound of formula I-D4(c) are those
compounds where:
[0074] a) one of R.sup.1 and R.sup.2 is halo or hydrogen and the
other is halo; and
[0075] b) one of R.sup.1 and R.sup.2 is halo, nitro or hydrogen and
the other is perfluoro-lower alkyl sulfonyl or lower alkyl
sulfonyl.
[0076] In accordance with another embodiment of this invention are
compounds of where R.sup.3 is cyclopentyl and R.sup.4 is a
mono-substituted pyridine are those compounds where the pyridine is
mono-substituted with a nitro substituent, (Compound I-D4(d)). The
embodiments of the compound I-D4(d) include compounds where one of
R.sup.1 and R.sup.2 is halo and other of said R.sup.1 or R.sup.2 is
hydrogen, halo, or lower alkyl sulfonyl.
[0077] In accordance with another embodiment of this invention are
compounds of formula I where R.sup.3 is cyclopentyl and R.sup.4 is
mono-substituted pyridine and the mono-substitution is a lower
alkyl group (Compounds I-D4(e)). Among the embodiments of compounds
I-D4(e) are those compounds where one of R.sup.1 and R.sup.2 is
halo or hydrogen and the other of said R.sup.1 and R.sup.2 is halo,
perfluoro-lower alkyl, perfluoro-lower alkyl sulfonyl, or lower
alkyl sulfonyl.
[0078] In accordance with another embodiment of this invention
where R.sup.3 is cyclopentyl and R.sup.4 is a mono-substituted
pyridine are those compounds where the mono-substituent is 11
[0079] wherein n and R are as above
[0080] (Compound I-D4(f)). Among the embodiments of compound
I-D4(f) are those compounds wherein one of R.sup.1 and R.sup.2 are
independently selected from the group consisting of halo or
hydrogen and the other of said R.sup.1 and R.sup.2 is halo, or
lower alkyl sulfonyl.
[0081] Another embodiment of this invention where R.sup.3 is
cyclopentyl are those compounds where R.sup.4 is an unsubstituted
imidazolyl (Compound I-D5). Among the embodiments of compounds I-D5
are those compounds wherein one of R.sup.1 and R.sup.2 is selected
from the group consisting of halo and hydrogen and the other of
said R.sup.1 and R.sup.2 is halo, or lower alkyl sulfonyl.
[0082] Another embodiment of the compounds of this invention are
those compounds where R.sup.3 is cyclopentyl and R.sup.4 is an
isoxazolyl ring (the compound I-D6). The embodiments of compound
I-D6 are those compounds where the isoxazolyl ring is unsubstituted
or substituted, preferably mono-substituted. Among the
mono-substituted substituents, the preferred substituents
substituted on the isoxazolyl ring is lower alkyl. An embodiment of
the compound I-D6, either where the isoxazolyl ring is
unsubstituted or substituted with a lower alkyl substituent are
those compounds where one of R.sup.1 and R.sup.2 is halo, nitro or
perfluoro-lower alkyl, lower alkyl sulfonyl and the other of
R.sup.1 and R.sup.2 is hydrogen or halo.
[0083] Another embodiment of this invention where R.sup.3 is
cyclopentyl are those compounds where R.sup.4 is either an
unsubstituted oxazolyl, or an oxazolyl mono-substituted with a
lower alkyl group. Another embodiment with respect to either of
those compounds are those compounds where one of R.sup.1 or R.sup.2
is halo, nitro or perfluoro-lower alkyl, lower alkyl sulfonyl and
the other is of R.sup.1 or R.sup.2 is hydrogen or halo.
[0084] Another embodiment of this invention where R.sup.3 is
cyclopentyl are those compounds where R.sup.4 is pyridazinyl which
is either unsubstituted or substituted with a lower alkyl group
(Compound I-D7). Embodiments of the compound I-D7 are encompassed
by this invention include those compounds where one of R.sup.1 or
R.sup.2 is halo, nitro or perfluoro-lower alkyl, lower alkyl
sulfonyl and the other of said R.sup.1 or R.sup.2 is hydrogen or
halo.
[0085] Another embodiment of this invention where R.sup.3 is
cyclopentyl include compounds where R.sup.4 is unsubstituted
pyrimidinyl. The embodiments of those compounds where R.sup.3 is
cyclopentyl and R.sup.4 is unsubstituted pyrimidinyl include those
compounds where one of R.sup.1 or R.sup.2 is halo, nitro or
perfluoro-lower alkyl, lower alkyl sulfonyl and the other is
hydrogen or halo.
[0086] Another embodiment of this invention includes compounds
where R.sup.3 is cyclopentyl where R.sup.4 is an unsubstituted
thiadiazolyl ring. Among the embodiments included within those
compounds where R.sup.3 is cyclopentyl and R.sup.4 is an
unsubstituted thiadiazolyl ring are those compounds wherein one of
R.sup.1 or R.sup.2 is halo, nitro or perfluoro-lower alkyl, lower
alkyl sulfonyl and the other of said R.sup.1 and R.sup.2 is
hydrogen or halo.
[0087] In accordance with other embodiments of this invention,
R.sup.3 in the compound of formula I can be cycloheptyl or
cyclohexyl. The embodiments of the compound of formula I where
R.sup.3 is cycloheptyl or cyclohexyl include those compounds where
R.sup.4 is thiazolyl which can be mono-substituted or
unsubstituted. Embodiments included within such compounds where
R.sup.3 is cycloheptyl or cyclohexyl and R.sup.4 is an
unsubstituted thiazolyl include those compounds wherein one of
R.sup.1 and R.sup.2 is halo, lower alkyl sulfinyl, perfluoro-lower
alkyl sulfinyl, perfluoro-lower alkyl, lower alkyl sulfonyl and the
other is of said R.sup.1 and R.sup.2 with halo, perfluoro-lower
alkyl or hydrogen.
[0088] The compound of formula I can be prepared starting from the
compound of formula V by the following Reaction Scheme: 12
[0089] wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
above.
[0090] The carboxylic acids and their lower alkyl esters of formula
V wherein one of R.sup.1 and R.sup.2 is nitro, cyano, thio, amino,
chloro, bromo, or iodo and the other is hydrogen are commercially
available. In cases, where only the carboxylic acids are available,
they can be converted to the corresponding esters of lower alkyl
alcohols using any conventional esterification methods. All the
reactions hereto forward are to be carried out on lower alkyl
esters of the carboxylic acids of formula V. The amino substituted
compounds of formula V can be converted to other substituents
either before or after conversion to the compounds of formula 1-a'.
In this respect, the amino groups can be diazotized to yield the
corresponding diazonium compound, which in situ can be reacted with
the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for
example, Baleja, J. D. Synth. Comm. 1984, 14, 215; Giam, C. S.;
Kikukawa, K., J. Chem. Soc, Chem. Comm. 1980, 756; Kau, D.;
Krushniski, J. H.; Robertson, D. W, J. Labelled Compd Rad. 1985,
22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn.
1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164)
to yield corresponding compounds of formula V, where one of the
substituents is lower alkyl thio, perfluoro-lower alkyl thio and
the other is hydrogen. If desired, the lower alkyl thio or
perfluoro-lower alkyl thio compounds can then be converted to the
corresponding lower alkyl sulfonyl or perfluoro-lower alkyl
sulfonyl substituted compounds of formula V by oxidation. Any
conventional method of oxidizing alkyl thio substituents to
sulfones can be utilized to effect this conversion. If it is
desired to produce compounds of lower alkyl or perfluoro-lower
alkyl groups of compounds of formula V, the corresponding halo
substituted compounds of formula V can be used as starting
materials. Any conventional method of converting an aromatic halo
group to the corresponding alkyl group (see for example, Katayama,
T.; Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam.,
Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A.,
Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.; Tamboroski, C.,
J. Org. Chem. 1984, 49, 478; Chen, Q, -Y.; Duan, J. -X. J. Chem.
Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone,
C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett.
1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013)
can be utilized to effect this conversion. On the other hand, the
thio substituent can be oxidized to a --SO.sub.3H group which then
can be converted to --SO.sub.2Cl which is reacted with ammonia form
the sulfonamide substituent --S(O).sub.2--NH.sub.2. If the
compounds of formula V wherein one or both of R.sup.1 and R.sup.2
is hydroxyamino, the corresponding nitro compounds can be used as
starting material and can be converted to the corresponding
compounds where R.sup.1 and/or R.sup.2 are hydroxyamino. Any
conventional method of converting a nitro group to the
corresponding aromatic hydroxyamino compound can be used to affect
this conversion.
[0091] The carboxylic acids or esters of formula V wherein both of
R.sup.1 and R.sup.2 are chloro, or fluoro are commercially
available. In cases, where only the carboxylic acids are available,
they can converted to the corresponding esters of lower alkyl
alcohols using any conventional esterification method. To produce
the compound of formula V where both R.sup.1 and R.sup.2 are nitro,
3,4-dinitrotoluene can be used as starting material. This compound
can be converted to the corresponding 3,4-dinitrophenyl acetic
acid. This conversion can take place either before or after the
compound of formula V is converted to the compound of formula 1-a'.
Any conventional method of converting an aryl methyl group to the
corresponding aryl acetic acid can be utilized to effect this
conversion (see for example, Clark, R. D.; Muchowski, J. M.;
Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M, Synthesis,
1991, 871). The compounds of formula V where both R.sup.1 and
R.sup.2 substituents are amino can be obtained from the
corresponding dinitro compound of formula V, described above. Any
conventional method of reducing a nitro group to an amine can be
utilized to effect this conversion. The compound of formula V where
both R.sup.1 and R.sup.2 are amine groups can be used to prepare
the corresponding compound of formula V where both R.sup.1 and
R.sup.2 are iodine or bromine via a diazotization reaction. Any
conventional method of converting amino group to an iodo or bromo
group (see for example, Lucas, H. J.; Kennedy, E. R. Org. Synth.
Coil. Vol, II 1943, 351) can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where both
R.sup.1 and R.sup.2 are lower alkyl thio or perfluoro-lower alkyl
thio groups, the compound of formula V where R.sup.1 and R.sup.2
are amino can be used as starting material. Any conventional method
of converting aryl amino group to aryl thioalkyl group can be
utilized to effect this conversion. If it is desired to produce
compound of formula V where R.sup.1 and R.sup.2 are lower alkyl
sulfonyl or lower perfluoro alkyl sulfonyl, the corresponding
compounds of formula V where R.sup.1 and R.sup.2 are lower alkyl
thio or perfluoro-lower alkyl thio can be used as starting
material. Any conventional method of oxidizing alkyl thio
substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of formula V, where both
R.sup.1 and R.sup.2 are substituted with lower alkyl or
perfluoro-lower alkyl groups, the corresponding halo substituted
compounds of formula V can be used as starting materials. Any
conventional method of converting an aromatic halo group to the
corresponding alkyl or perfluoro-lower alkyl group can be utilized
to effect this conversion.
[0092] The carboxylic acids corresponding to the compounds of
formula V where one of R.sup.1 and R.sup.2 is nitro and the other
is halo are known from the literature (see for
4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.;
Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical
Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid,
Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J.
Org. Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J.
Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be
converted to the corresponding lower alkyl esters using any
conventional esterification methods. Thus, if it is desired to
produce the compound of formula V where one of R.sup.1 and R.sup.2
is nitro and the other is lower alkyl thio or perfluoro-lower alkyl
thio, the corresponding compound where one of R.sup.1 and R.sup.2
is nitro and the other is chloro can be used as starting material.
In this reaction, any conventional method of nucleophilic
displacement of aromatic chlorine group with a lower alkyl thiol
can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J.
Chem. Res.-S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh,
I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.;
Yamada, A, Synthesis, 1993, 194; Sufter, M.; Kunz, W, U.S. patent,
U.S. Pat. No. 5,169,951). Once the compounds of formula V where one
of R.sup.1 and R.sup.2 is nitro and the other is lower alkyl thio
or perfluoro-lower alkyl thio are available, they can be converted
to the corresponding compounds of formula V where one of R.sup.1
and R.sup.2 is nitro and the other is lower alkyl sulfonyl or
perfluoro-lower alkyl sulfonyl using conventional oxidation
procedures. If it is desired to produce compounds of formula V
where one of R.sup.1 and R.sup.2 is amino and the other is lower
alkyl thio or perfluoro-lower alkyl thio, the corresponding
compound where one of R.sup.1 and R.sup.2 is nitro and the other is
lower alkyl thio or perfluoro-lower alkyl thio can be used as
starting materials. Any conventional method of reducing an aromatic
nitro group to an amine can be utilized to effect this conversion.
If it is desired to produce compounds of formula V where one of
R.sup.1 and R.sup.2 is lower alkyl thio and the other is
perfluoro-lower alkyl thio, the corresponding compound where one of
R.sup.1 and R.sup.2 is amino and the other is lower alkyl thio or
perfluoro-lower alkyl thio can be used as starting materials. Any
conventional method of diazotizing aromatic amino group and
reacting it in situ with the desired lower alkyl thiol can be
utilized to effect this conversion. If it is desired to produce
compounds of formula V where one of R.sup.1 and R.sup.2 is lower
alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl, the
corresponding compounds where one of R.sup.1 and R.sup.2 is lower
alkyl thio and the other is perfluoro-lower alkyl thio, can be used
as starting materials. Any conventional method of oxidizing an
aromatic thio ether group to the corresponding sulfone group can be
utilized to effect this conversion. If it is desired to produce
compounds of formula V where one of R.sup.1 and R.sup.2 is halo and
the other is lower alkyl thio or perfluoro-lower alkyl thio, the
corresponding compounds where one of R.sup.1 and R.sup.2 is amino
and the other is lower alkyl thio or perfluoro-lower alkyl thio can
be used as starting materials. Any conventional method of
diazotizing an aromatic amino group and conversion of it in situ to
an aromatic halide can be utilized to effect this conversion. If it
is desired to produce compounds of formula V where one of R.sup.1
and R.sup.2 is halo and the other is lower alkyl sulfonyl or
perfluoro-lower alkyl sulfonyl, the corresponding compounds where
one of R.sup.1 and R.sup.2 is halo and the other is lower alkyl
thio or perfluoro-lower alkyl thio can be used as starting
materials. Any conventional method of oxidizing an aromatic thio
ether to the corresponding sulfone can be utilized to effect this
conversion. If it is desired to produce compounds of various
combinations of lower alkyl and perfluoro-lower alkyl groups of
compounds of formula V, the corresponding halo substituted
compounds of formula V can be used as starting materials. Any
conventional method of converting an aromatic halo group to the
corresponding alkyl group can be utilized to effect this
conversion. If one wishes to prepare the compound formula V where
one of R.sup.1 and R.sup.2 is nitro and the other is amino, the
compound of formula V where one of R.sup.1 and R.sup.2 is nitro and
other is chloro can be used as a starting material. The chloro
substituent on the phenyl ring can be converted to an iodo
substituent (see for example, Bunnett, J. F.; Conner, R. M.; Org.
Synth. Coll Vol V, 1973, 478; Clark, J. H.; Jones, C. W. J. Chem.
Soc. Chem. Commun. 1987, 1409), which in turn can be reacted with
an azide transferring agent to form the corresponding azide (see
for example, Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Chem. Soc.
Jpn, 1980, 53, 1765). This azide can then be reduced in a
conventional manner to form the amine substituent by reducing it
with commonly used reducing agent for converting azides to amines
(see for example, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis,
1987, 48).
[0093] If it is desired to produce the compound of formula V where
both R.sup.1 and R.sup.2 are cyano, this compound can be prepared
as described hereinbefore from compounds where R.sup.1 and R.sup.2
are amino via diazotization to produce the diazonium salt followed
by reaction with cyano group transferring agent. If it is desired
to convert the commercially available compound to the compound of
formula V where one of R.sup.1 and R.sup.2 is cyano and the other
is not cyano, the compound of formula V where one of R.sup.1 and
R.sup.2 is nitro and the other is chloro is used as a starting
material. Using this starting material, the nitro is converted to
the cyano and the halo is converted to any other desired R.sup.1
and R.sup.2 substituent as described hereinbefore.
[0094] If it is desired to produce the compound of formula V
wherein one of R.sup.1 or R.sup.2 is a 13
[0095] this compound can be formed from the corresponding compound
where R.sup.1 and R.sup.2 is an amino group by converting the amino
group to a diazonium salt reacting the diazonium salt with a
hydrohalic acid to form the corresponding halide and then reacting
this halide with a Grignard reagent to produce the corresponding
acid which can be esterified. On the other hand, if one wants to
produce the compound of formula V where both R.sup.1 and R.sup.2
are carboxylic acid groups. This compound can be produced as
described above from the corresponding compound of formula V where
both R.sup.1 and R.sup.2 are amino groups. In the same manner, the
amino groups in the compound of formula V can be converted to the
corresponding compound where R.sup.1 or both of R.sup.1 or R.sup.2
is OR.sub.5 by simply reacting the amino group with sodium nitrate
in sulfuric acid to convert the amino group to a hydroxy group and
thereafter etherifying, if desired, the hydroxy group.
[0096] The substituents which form R.sup.1 and R.sup.2 can be added
to the ring after condensation after the compound of formula XII
with the compound of formula VIII to form the compound of formula
I-a'. Hence, all of the reactions described to produce various
substituents of R.sup.1 and R.sup.2 in the compound of formula I
can be carried out on the compound of formula I-a'after its
formation by the reaction of compound of formula XII and VIII to
form the compound of formula I-a'.
[0097] In the first step of this Reaction Scheme, the alkyl halide
of formula VI is reacted with the compound of formula V, to produce
the compound of formula VII. In this reaction, if in the compounds
of formula V, R.sup.1 or R.sup.2 is an amino group, such amino
group(s) have to be protected before carrying out the alkylation
reaction with the alkyl halide of formula VI. The amino group can
be protected with any conventional acid removable group (see for
example, for t-butyloxycarbonyl group see, Bodanszky, M. Principles
of Peptide Chemistry, Springer -Verlag, New York, 1984, p 99). The
protecting group has to be removed from the amino groups after
preparing the corresponding amine protected compounds of formula
I-a' to obtain the corresponding amines. The compound of formula V
is an organic acid having an alpha carbon atom and the compound of
formula VI is an alkyl halide so that alkylation occurs at the
alpha carbon atom of this carboxylic acid. This reaction is carried
out by any conventional means of alkylation of the alpha carbon
atom of a lower alkyl ester of a carboxylic acid. Generally, in
these alkylation reactions any alkyl halide is reacted with the
anion generated from any acetic acid ester. The anion can be
generated by using a strong organic base such as lithium
diisopropylamide, n-butyl lithium as well as other organic lithium
bases. In carrying out this reaction, low boiling ether solvents
are utilized such as tetrahydrofuran at low temperatures from
-80.degree. C. to about -10.degree. C. being preferred. However any
temperature from -80.degree. C. to room temperature can be
used.
[0098] The compound of formula VII can be converted to the compound
of formula XII by any conventional procedure to convert a
carboxylic acid ester to an acid. The compound of formula XII is
condensed with the compound of formula VIII via conventional
peptide coupling to produce the compound of formula I-a'. In
carrying out this reaction, any conventional method of condensing a
primary amine with a carboxylic acid can be utilized to effect this
conversion. The required amino heteroaromatic compounds of formula
VIII, are commercially available or can be prepared from the
reported literature. The heteroaromatics of formula VIII, wherein
one of the substitutions is --(CH.sub.2).sub.nCOOR.sup.7, where
n=0, 1, 2, 3, or 4 can be prepared from the corresponding
carboxylic acid. Any conventional carbon homologation methods to
convert a lower carboxylic acid to its higher homologs, (see for
example, Skeean, R. W.; Goel, O. P. Synthesis, 1990, 628) which
then can be converted to the corresponding lower alkyl esters using
any conventional esterification methods. The heteroaromatics of
formula VIII, wherein one of the claimed substitutions is
--(CH.sub.2).sub.nOR.sup.6, where n=0, 1, 2, 3, or 4 can be
prepared from the corresponding carboxylic acid. Any conventional
carbon homologation methods to convert a lower carboxylic acid to
its higher homologs, which then can be converted to the
corresponding alcohols using any conventional ester reduction
methods. The heteroaromatics of formula VIII, wherein one of the
substituents is --COCOOR.sup.8, can be prepared from the
corresponding halogen. Any conventional acylation method to convert
an aromatic or heteroaromatic halogen to its oxoacetic acid lower
ester derivative (see for example, Hayakawa, K.; Yasukouchi, T.;
Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895) can be
utilized.
[0099] The compound of formula VII has an asymmetric carbon atom
through which the group --CH.sub.2R.sup.3 and the acid amide
substituents are connected. In accordance with this invention, the
preferred stereoconfiguration of this group is R.
[0100] If it is desired to produce the R or the S isomer of the
compound of formula I, this compound can be separated into these
isomers by any conventional chemical means. Among the preferred
chemical means is to react the compound of formula XII with an
optically active base. Any conventional optically active base can
be utilized to carry out this resolution. Among the preferred
optically active bases are the optically active amine bases such as
alpha-methylbenzylamine, quinine, dehydroabietylamine and
alpha-methylnaphthylamine. Any of the conventional techniques
utilized in resolving organic acids with optically active organic
amine bases can be utilized in carrying out this reaction.
[0101] In the resolution step, the compound of formula XII is
reacted with the optically active base in an inert organic solvent
medium to produce salts of the optically active amine with both the
R and S isomers of the compound of formula XII. In the formation of
these salts, temperatures and pressure are not critical and the
salt formation can take place at room temperature and atmospheric
pressure. The R and S salts can be separated by any conventional
method such as fractional crystallization. After crystallization,
each of the salts can be converted to the respective compounds of
formula XII in the R and S configuration by hydrolysis with an
acid. Among the preferred acids are dilute aqueous acids, i.e.,
from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or
aqueous hydrochloric acid. The configuration of formula XII which
is produced by this method of resolution is carried out throughout
the entire reaction scheme to produce the desired R or S isomer of
formula I. The separation of R and S isomers can also be achieved
using an enzymatic ester hydrolysis of any lower alkyl esters
corresponding to the compound of the formula XII (see for example,
Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053),
which results in the formation of corresponding chiral acid and
chiral ester. The ester and the acid can be separated by any
conventional method of separating an acid from an ester. The
preferred method of resolution of racemates of the compounds of the
formula XII is via the formation of corresponding diastereomeric
esters or amides. These diastereomeric esters or amides can be
prepared by coupling the caboxylic acids of the formula XII with a
chiral alcohol, or a chiral amine. This reaction can be carried out
using any conventional method of coupling a carboxylic acid with an
alcohol or an amine. The corresponding diastereomers of compounds
of the formula XII can then be separated using any conventional
separation methods. The resulting pure diastereomeric esters or
amides can then be hydrolyzed to yield the corresponding pure R or
S isomers. The hydrolysis reaction can be carried out using
conventional known methods to hydrolyze an ester or an amide
without racemization.
[0102] All of the compounds of formula I which include the
compounds set forth in the Examples, activated glucokinase in vitro
by the procedure of Example A. In this manner, they increase the
flux of glucose metabolism which causes increased insulin
secretion. Therefore, the compounds of formula I are glucokinase
activators useful for increasing insulin secretion.
[0103] The following compounds were tested and found to have
excellent glucokinase activator in vivo activity when administered
orally in accordance with the assay described in Example B:
[0104]
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionam-
ide
[0105]
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propiona-
mide
[0106]
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)--
propionamide
[0107]
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamid-
e
[0108]
6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotin-
ic acid methyl ester
[0109]
N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)--
propionamide
[0110]
3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)--
propionamide
[0111]
3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfon-
yl-phenyl)-propionamide
[0112]
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-
-2-yl) propionamide
[0113]
6-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylami-
no]-nicotinic acid methyl ester
[0114]
3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl--
propionamide
[0115]
3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-pr-
opionamide
[0116]
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-p-
ropionamide
[0117]
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-p-
ropionamide
[0118]
2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionami-
de
[0119]
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl--
propionamide
[0120]
N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cy-
clopentyl-propionamide
[0121]
2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl--
propionamide
[0122]
(2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propi-
onamide
[0123]
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-p-
ropionamide
[0124]
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-p-
ropionamide
[0125]
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionami-
de
[0126]
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thia-
zol-2-yl-propionamide
[0127]
N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-
-cyclopentyl-propionamide
[0128] This invention will be better understood from the following
examples, which are for purposes of illustration and are not
intended to limit the invention defined in the claims which follow
thereafter.
EXAMPLE 1
(A)
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide:
[0129] 14
[0130] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 2.0 g, 6.96 mmol),
benzotriazol-1-yloxy-tris(dim- ethylamino)phosphonium
hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05
g, 10.44 mmol) in methylene chloride (50 mL) at 25.degree. C. was
treated with triethylamine (2.9 mL, 20.88 mmol). The reaction
mixture was stirred for 14 h. The reaction mixture was then diluted
with water (10 mL) and extracted with methylene chloride
(3.times.10 mL). The combined organic layers were sequentially
washed with water (1.times.10 mL), a 1N aqueous sodium hydroxide
solution (1.times.10 mL), a 1N aqueous hydrochloric acid solution
(1.times.10 mL), and a saturated aqueous sodium chloride solution
(1.times.10 ML). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-th- iazol-2-yl-propionamide
(2.48 g, 96%) as a white solid: mp 143.5-145.5.degree. C.; EI-HRMS
m/e calcd for C.sub.17H.sub.18Cl.sub.2N.s- ub.2OS (M.sup.+)
368.0516, found 368.0516.
[0131] (B) In an analogous manner, there were obtained:
[0132] (a) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-(amino-thiazol-4-yl)-oxo-acetic acid ethyl ester:
{2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazol-4-yl}-o-
xo-acetic acid ethyl ester as a white solid: mp 134-136.degree. C.;
FAB-HRMS m/e calcd for C.sub.21H.sub.22Cl.sub.2N.sub.2O.sub.4S
(M+H).sup.+ 469.0755, found 469.0746.
[0133] (b) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-(amino-thiazol-5-yl)-oxo-acetic acid ethyl ester:
{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-5-yl}-ox-
o-acetic acid ethyl ester as a white solid: mp 129-131.degree. C.;
FAB-HRMS m/e calcd for C.sub.21H.sub.22Cl.sub.2N.sub.2O.sub.4S
(M+H).sup.+ 469.0755, found 469.0765.
[0134] (c) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and (2-amino-thiazol-4-yl)-acetic acid ethyl ester:
{2-[3-Cyclopentyl-2-(3,4--
dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl
ester as a yellow solid: mp 138-139.degree. C.; FAB-HRMS m/e calcd
for C.sub.21H.sub.24Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+ 455.0963,
found 455.0960.
[0135] (d) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-5-methylthiazole:
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methy-
l-thiazol-2-yl)-propionamide as a white solid: mp 142-143.degree.
C.; EI-HRMS m/e calcd for C.sub.18H.sub.20Cl.sub.2N.sub.2OS
(M.sup.+) 382.0673, found 382.0679.
[0136] (e) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-4-methylthiazole:
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-methy-
l-thiazol-2-yl)-propionamide as a white foam: mp 151-152.degree.
C.; FAB-HRMS m/e calcd for C.sub.18H.sub.20Cl.sub.2N.sub.2OS
(M+H).sup.+ 383.0751, found 383.0758.
[0137] (f) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-thiazole-4-carboxylic acid ethyl ester:
2-[3-Cyclopentyl-2-(3,4-d-
ichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl
ester as a white solid: mp 104-107.degree. C.; FAB-HRMS m/e calcd
for C.sub.20H.sub.22Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+ 441.0807,
found 441.0808.
[0138] (g) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-thiazole-5-carboxylic acid ethyl ester:
2-[3-Cyclopentyl-2-(3,4-d-
ichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl
ester as a light yellow solid: mp 136-137.degree. C.; FAB-HRMS m/e
calcd for C.sub.20H.sub.22Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+
441.0807, found 441.0803.
[0139] (h) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-5-nitrothiazole:
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-nitro--
thiazol-2-yl)-propionamide as an orange solid: mp 67-71.degree. C.;
FAB-HRMS m/e calcd for C.sub.17H.sub.17Cl.sub.2N.sub.3O.sub.3S
(M+H).sup.+ 414.0446, found 414.0442.
[0140] (i) From 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid
and 2-amino-thiazole-4-carboxylic acid amide:
2-[3-Cyclopentyl-2-(3,4-dichlor-
ophenyl)-propionylamino]-thiazole-4-carboxylic acid amide as a
light orange solid: mp 120-122.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.19Cl.sub.2N.sub.3O.sub.2S (M.sup.+) 411.0575, found
411.0572.
EXAMPLE 2
2-(4-Bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0141] 15
[0142] A solution of diisopropylamine (7.7 mL, 54.88 mmol) in dry
tetrahydrofluran (23 mL) and
1,3-dimnethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (10 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (22.0 mL, 54.88 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-bromophenylacetic acid (5.62 g, 26.13 mmol) in dry
tetrahydrofliran (23 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The
reaction mixture turned dark in color and was allowed to stir at
-78.degree. C. for 1 h, at which time, a solution of
iodomethylcyclopentane (5.76 g, 27.44 mmol) in a small amount of
dry tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 24 h. The
reaction mixture was quenched with water and then concentrated in
vacuo to remove tetrahydrofliran. The aqueous residue was acidified
using a 10% aqueous hydrochloric acid solution. The resulting
aqueous layer was extracted with ethyl acetate (2.times.100 mL).
The combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
2-(4-bromo-phenyl)-3-cyclopenty- l-propionic acid (3.88 g, 50%) as
a light yellow solid: mp 91-93.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17BrO.sub.2 (+) 296.0412, found 296.0417.
[0143] A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic
acid (1.01 g, 3.39 mmol) in methylene chloride (8.5 mL) was treated
with 2 drops of dry N,N-dimethylformamide. The reaction mixture was
cooled to 0.degree. C. and then treated with oxalyl chloride (3 mL,
33.98 mmol). The reaction mixture was stirred at 0.degree. C. for
10 min and then stirred at 25.degree. C. for 15 h. The reaction
mixture was concentrated in vacuo. The resulting yellow oil was
dissolved in a small amount of methylene chloride and slowly added
to a cooled solution (0.degree. C.) of 2-aminothiazole (680.6 mg,
6.79 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.79 mmol) in
methylene chloride (17 mL). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then at 25.degree. C. for 15
h. The reaction mixture was concentrated in vacuo to remove
methylene chloride. The resulting residue was diluted with ethyl
acetate (200 mL). The organic phase was washed with a 10% aqueous
hydrochloric acid solution (2.times.100 mL), washed with a
saturated aqueous sodium bicarbonate solution (2.times.100 mL), and
washed with a saturated aqueous sodium chloride solution
(1.times.100 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated in vacuo to afford
2-(4-bromo-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (1.23
g, 95%) as an orange solid which was used in subsequent reactions
without further purification. An analytical sample was
recrystallized from ethyl acetate to provide a cream solid: mp
201-202.degree. C.; EI-HRMS m/e calcd for
C.sub.17H.sub.19BrN.sub.2OS (M.sup.+) 378.0401, found 378.0405.
EXAMPLE 3
(A)
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
[0144] 16
[0145] A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry
tetrahydrofuran (50 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (10 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a lOM
solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small
amount of dry tetrahydrofuran. After approximately one-half of the
4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added,
a precipitate formed. Upon further addition of the remaining
4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the
reaction mixture became thick in nature. After complete addition of
the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the
reaction mixture was very thick and became difficult to stir. An
additional amount of dry tetrahydrofuran (20 mL) was added to the
thick reaction mixture, and the reaction mixture was stirred at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 15 h. The
reaction mixture was quenched with water (100 mL), and the
resulting yellow reaction mixture was concentrated in vacuo to
remove tetrahydrofuran. The aqueous residue was acidified to pH=2
using concentrated hydrochloric acid. The aqueous layer was
extracted with ethyl acetate. The organic phase was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/3
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g,
52%) as a white solid: mp 152-154.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.4S (M.sup.+) 296.1082, found 296.1080.
[0146] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g,
16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in
methylene chloride (41 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small
portions. The reaction mixture color changed from light yellow to a
darker yellow then to brown. After the complete addition of
N-bromosuccinimide, the reaction mixture was allowed to warm to
25.degree. C. over 30 min. The brown reaction mixture was then
treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 19 h. The
reaction mixture was then concentrated in vacuo to remove methylene
chloride. The remaining black residue was diluted with a 10%
aqueous hydrochloric acid solution (400 mL) and then extracted with
ethyl acetate (3.times.200 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl-
)-N-thiazol-2-yl-propionamide (4.49 g, 72%) as a white solid: mp
216-217.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.22N.sub.2O.sub.3S- .sub.2(M.sup.+) 378.1072, found
378.1071.
[0147] (B) In an analogous manner, there were obtained:
[0148] (a) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic
acid and 2-aminothiazole-4-carboxylic acid methyl ester:
2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4--
carboxylic acid methyl ester as a tan solid: mp 126-128.degree. C.;
EI-HRMS m/e calcd for C.sub.20H.sub.24N.sub.2O.sub.5S.sub.2 (M)
436.1127, found 436.1119.
[0149] (b) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic
acid and 2-aminothiazole-4-carboxylic acid ethyl ester:
2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazole-4--
carboxylic acid ethyl ester as a light yellow solid: mp
101-103.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.26N.sub.2O.sub.5S.sub.2 (M.sup.+) 450.1283, found
450.1284.
[0150] (c) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic
acid and methyl 2-amino-4 thiazoleacetate:
{2-[3-Cyclopentyl-2-(4-methanesulfo-
nyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester
as a yellow solid: mp 63-65.degree. C.; EI-HRMS mn/e calcd for
C.sub.21H.sub.26N.sub.2O.sub.5S.sub.2 (M.sup.+) 450.1283, found
450.1294.
[0151] (d) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic
acid and ethyl 2-amino-4-thiazoleacetate:
{2-[3-Cyclopentyl-2-(4-methanesulfon-
yl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester as
a light yellow solid: mp 61-63.degree. C.; EI-HRMS m/e calcd for
C.sub.22H.sub.28N.sub.2O.sub.5S.sub.2 (M.sup.+) 464.1440, found
464.1431.
EXAMPLE 4
2-(4-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0152] 17
[0153] A solution of
3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propi- onamide
(prepared in Example 22, 345 mg, 1.0 mmol) in ethyl acetate (100
mL) was treated with 10% palladium on activated carbon (34.5 mg).
The reaction mixture was stirred under hydrogen gas at 60 psi at
25.degree. C. for 6 h. The catalyst was then filtered off through a
pad of celite (ethyl acetate). The filtrate was concentrated in
vacuo to give
2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3
mg, 91.4%) as a yellow solid: mp 102-107.degree. C.; EI-HRMS m/e
calcd for C.sub.17H21N.sub.3OS (M.sup.+) 315.1405, found
315.1401.
EXAMPLE 5
2-(3-Amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0154] 18
[0155] A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6
mmol) in methanol (50 mL) was treated with a catalytic amount of
sulfuric acid. The reaction mixture was refluxed for 48 h. The
reaction was then concentrated in vacuo. The residue was dissolved
in methylene chloride (50 mL) and washed with a saturated aqueous
sodium bicarbonate solution (2.times.25 mL), water (1.times.50 mL),
and a saturated aqueous sodium chloride solution (1.times.50 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic
acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp
29-30.degree. C.; EI-HRMS m/e calcd for C.sub.9H.sub.9NO.sub.4
(M.sup.+) 195.0531, found 195.0532.
[0156] A solution of freshly prepared lithium diisopropylamide
(43.3 mL of a 0.3M stock solution, 12.99 mmol) cooled to
-78.degree. C. was treated with (3-nitro-phenyl)-acetic acid methyl
ester (2.45 g, 12.56 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(32 mL, 3:1). The resulting solution was stirred at -78.degree. C.
for 45 min. Iodomethylcyclopentane (2.78 g, 13.23 mmol) was then
added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78
mL), and the mixture was stirred at -78.degree. C. for 3 h. The
reaction was warmed to 25.degree. C. and was stirred at 25.degree.
C. for 16 h. The reaction mixture was then quenched by the dropwise
addition of a saturated aqueous ammonium chloride solution (25 mL)
and was concentrated in vacuo. The residue was diluted with water
(50 mL) and extracted with ethyl acetate (3.times.50 mL). The
organics were washed with a saturated aqueous lithium chloride
solution (2.times.25 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63
g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.19NO.sub.4 (M.sup.+) 277.1314, found 277.1317.
[0157] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic
acid methyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (10
mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol).
The reaction was stirred at 25.degree. C. for 48 h. The
tetrahydrofuran was then removed in vacuo. The residue was diluted
with water (25 mL) and extracted with ether (1.times.20 mL). The
aqueous layer was acidified to pH=2 with a 3N aqueous hydrochloric
acid solution. The product was extracted into methylene chloride
(3.times.25 mL), washed with a saturated aqueous sodium chloride
solution (2.times.25 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo to give 3-cyclopentyl-2-(3-nitro-phen-
yl)-propionic acid (0.48 g, 91.9%) as a tan solid: mp 95-99.degree.
C.; EI-HRMS m/e calcd for C.sub.14H.sub.17NO.sub.4 (M.sup.+)
263.1157, found 263.1156.
[0158] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic
acid (432 mg, 1.64 mmol) in methylene chloride (16 mL) was cooled
to 0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.90 mL, 1.80 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 1.2 h. The
reaction mixture was then treated with a solution of
2-aminothiazole (361.4 mg, 3.61 mmol) in tetrahydrofuran (16 mL)
and N,N-diisopropylethylamine (0.70 mL, 3.93 mmol). The reaction
mixture was stirred at 25.degree. C. for 6 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (409.3
mg, 72.2%) as a tan solid: mp 171-174.degree. C.; EI-HRMS m/e calcd
for C.sub.17H.sub.19N.sub.3O.sub.3S (M.sup.+) 345.1147, found
345.1153.
[0159] A solution of
3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propiona- mide (327.8
mg, 0.95 mmol) in ethyl acetate (25 mL) was treated with 10%
palladium on activated carbon. The reaction mixture was stirred
under hydrogen gas at 60 psi at 25.degree. C. for 3 h. The catalyst
was then filtered off through a pad of celite (ethyl acetate). The
filtrate was concentrated in vacuo to give
2-(3-amino-phenyl)-3-cyclopentyl-N-thiazol-- 2-yl-propionamide (310
mg, 100%) as a white solid: mp 158-160.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.21N.sub.3OS (M.sup.+) 315.1405, found
315.1405.
EXAMPLE 6
2-(3-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0160] 19
[0161] (3-Chloro-phenyl)-acetic acid (6.03 g, 0.03 mol) was
dissolved in ethanol (37.7 mL) and treated with a catalytic amount
of sulfuric acid. The reaction mixture was refluxed for 12 h. The
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
(3-chloro-phenyl)-acetic acid ethyl ester (6.10 g, 86.8%) as a
clear oil: EI-HRMS m/e calcd for C.sub.10H.sub.11ClO.sub.2
(M.sup.+) 198.0448, found 198.0442.
[0162] A solution of freshly prepared lithium diisopropylamide (23
mL of 0.31M stock solution, 7.13 mmol) cooled to -78.degree. C. was
treated with (3-chloro-phenyl)-acetic acid ethyl ester (1.28 g,
6.48 mmol) in tetrahydrofiran/hexamethylphosphoramide (16.1 mL,
3:1). The resulting solution was stirred at -78.degree. C. for 45
min. At this time, the reaction was treated with a solution of
iodomethylcyclopentane (1.50 g, 7.13 mmol) in
hexamethylphosphoramide (1 mL). The reaction mixture was stirred at
-78.degree. C. for 4 h. The reaction was warmed to 25.degree. C.
and stirred at 25.degree. C. for 16 h. The reaction mixture was
then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (20 mL). This mixture was poured into
water (100 mL) and extracted with ethyl acetate (3.times.50 mL).
The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 75/25 hexanes/ethyl acetate) afforded
2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70
g, 93%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21ClO.sub.2 (M.sup.+) 280.1230, found 280.1238.
[0163] A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic
acid ethyl ester (1.70 g, 6.05 mmol) and methyl urea (673 mg, 9.08
mmol) in a solution of magnesium methoxide in methanol (7.4 wt %,
17.3 mL, 12.1 mmol) was refluxed at 100.degree. C. for 6 h. The
reaction mixture was then concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 75/25
hexanes/ethyl acetate) afforded
1-[2-(3-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea
(149.1 mg, 8%) as a white solid: mp 52-55.degree. C.; EI-HRMS m/e
calcd for C.sub.16H.sub.21ClN.sub.2O.sub.2 (M.sup.+) 308.1292,
found 308.1287. The methyl ester of the starting material was
recovered from the reaction mixture due to transesterification.
[0164] A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic
acid methyl ester (113 mg, 0.42 mmol) and 2-aminothiazole (84 mg,
0.84 mnuol) in a solution of magnesium methoxide in methanol (7.4
wt %, 2.4 mL, 1.69 mmol) was refluxed at 100.degree. C. for 20 h.
The reaction mixture was then concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (87
mg, 53%) as a white solid: mp 138.8-141.2.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.19ClN.sub.2OS (M.sup.+) 334.0906, found
334.0907.
EXAMPLE 7
2-(4-Chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0165] 20
[0166] A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03
mol) in ethanol (38.4 mL) was treated with a catalytic amount of
sulfuric acid. The reaction mixture was refluxed for 12 h. The
reaction was then concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)
afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as
a pale yellow solid: mp 39-41.degree. C.; EI-HRMS m/e calcd for
C.sub.10H.sub.11C.sub.2 (M.sup.+) 198.0448, found 198.0452.
[0167] A solution of freshly prepared lithium diisopropylamide
(23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to -78.degree.
C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28
g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL,
3:1). The resulting solution was stirred at -78.degree. C. for 45
min. At this time, the reaction was treated with a solution of
iodomethylcyclopentane (1.50 mg, 7.13 mrmol) in
hexamethylphosphoramide (1 mL). The reaction mixture was stirred at
-78.degree. C. for 4 h. The reaction was warmed to 25.degree. C.
and stirred at 25.degree. C. for 16 h. The reaction mixture was
then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (20 mL). This mixture was poured into
water (100 mL) and extracted with ethyl acetate (3.times.50 mL).
The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 75/25 hexanes/ethyl acetate) afforded
2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65
g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21Cl.sub.2O.sub.2 (M.sup.+) 280.1230, found
280.1227.
[0168] A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic
acid ethyl ester (1.65 g, 5.89 mmol) and methyl urea (654 mg, 8.83
mmol) in a solution of magnesium methoxide in methanol (7.4 wt %,
16.9 mL, 11.78 mmol) was refluxed at 100.degree. C. for 6 h. The
reaction mixture was then concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 75/25
hexanes/ethyl acetate) afforded
1-[2-(4-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea
(105.3 mg, 5.8%) as a white solid: mp 145-147.degree. C.; EI-HRMS
m/e calcd for C.sub.16H.sub.21ClN.sub.2O.sub.2 (M.sup.+) 308.1292,
found 308.1291. The methyl ester of the starting material was
recovered from the reaction mixture due to transesterification.
[0169] A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic
acid methyl ester (648 mg, 2.43 mmol) and 2-aminothiazole (487 mg,
4.86 mmol) in a solution of magnesium methoxide in methanol (7.4 wt
%, 14.0 mL, 9.72 mmol) was refluxed at 100.degree. C. for 20 h. The
reaction mixture was then concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (286
mg, 35%) as a white solid: mp 156.6-159.8.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.19ClN.sub.2OS (M.sup.+) 334.0906, found
334.0910.
EXAMPLE 8
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide
[0170] 21
[0171] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.31M stock solution, 7.13 mmol) cooled to -78.degree. C.
was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg,
3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1).
The resulting solution was stirred at -78.degree. C. for 30 min.
Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in
hexamethylphosphoramide (1 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (10 mL). The excess solvent was removed
in vacuo. The residue was acidified to pH=1 with a 1N aqueous
hydrochloric acid solution. The mixture was then poured into water
(150 mL) and extracted with ethyl acetate (3.times.100 mL). The
organics were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
75/25 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9
mg, 65%) as a white solid: mp 94-95.degree. C.; EI-HRMS m/e calcd
for C.sub.15H.sub.17F.sub.3O.sub.2 (M.sup.+) 309.1079, found
309.1072.
[0172] A solution of
3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (185 mg,
0.64 mmol) in methylene chloride (6.5 mL) was cooled to 0.degree.
C. and was treated with a 2.0M solution of oxalyl chloride in
methylene chloride (0.35 mL, 0.71 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (142 mg, 1.42 mmol) in tetrahydrofuran (3.23 mL)
and N,N-diisopropylethylamine (0.27 mL, 1.55 mmol). The solution
was stirred at 25.degree. C. for 5 h. At this time, the reaction
was concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide
(127 mg, 53.3%) as a white solid: mp 210-212.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.19F.sub.3N.sub.2OS (M.sup.+) 368.1175,
found 368.1170.
EXAMPLE 9
3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide
[0173] 22
[0174] A solution of diisopropylamine (3.2 mL, 23.16 mnmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a lOM
solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (2.55 g, 12.13
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was stirred at -78.degree. C. for 30 min and
then allowed to warm to 25.degree. C. where it was stirred for 24
h. The reaction mixture was quenched with water and then
concentrated in vacuo to remove tetrahydrofuran. The remaining
aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric
acid solution and then extracted with ethyl acetate (200 mL). The
organic layer was washed with a saturated aqueous sodium chloride
solution (1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g,
35%) as a cream solid: mp 91-93.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.2S (M.sup.+) 264.1184, found 264.1177.
[0175] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg,
0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene
chloride (2 mL) was cooled to 0.degree. C. and then treated with
N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the
complete addition of N-bromosuccinimide, the reaction mixture was
allowed to warm to 25.degree. C. over 30 min. The reaction mixture
was then treated with 2-aminothiazole (160 mg, 1.60 mmol), and the
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The reaction mixture was then concentrated in vacuo to remove
methylene chloride. The remaining residue was diluted with water
and ethyl acetate. The organic layer was further washed with a 1N
aqueous hydrochloric acid solution, washed with a saturated aqueous
sodium bicarbonate solution, dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded
crude 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiaz-
ol-2-yl-propionamide as a yellow solid. Recrystallization from 2/1
hexanes/ethyl acetate afforded pure
3-cyclopentyl-2-(4-methylsulfanyl-phe-
nyl)-N-thiazol-2-yl-propionamide (114 mg, 44%) as a white solid: mp
195-196.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.22N.sub.2OS.sub.2 (M.sup.+) 346.1174, found
346.1171.
EXAMPLE 10
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propiona-
mide
[0176] 23
[0177] A solution of duisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(300 mL). The organic layer was washed with a saturated aqueous
sodium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-trifluoromethylsulfany-
l-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp
69-71.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0178] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(60 mg, 0.19 mmol) and triphenylphosphine (49.4 mg, 0.19 mmol) in
methylene chloride (471 .mu.L) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (36.9 mg, 0.21 mmol) in small
portions. After the complete addition of N-bromosuccinimide, the
reaction mixture was allowed to warm to 25.degree. C. over 30 min.
The bright orange reaction mixture was then treated with
2-aminothiazole (39.6 mg, 0.40 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 18 h. The reaction mixture
was then concentrated in vacuo to remove methylene chloride. The
remaining residue was diluted with ethyl acetate (50 mL). The
organic layer was washed with a 10% aqueous hydrochloric acid
solution (1.times.50 mL), washed with a saturated aqueous sodium
bicarbonate solution (1.times.50 mL), washed with water (1.times.50
mL), dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-sulfa-
nyl-phenyl)-propionamide (49.9 mg, 66%) as a white foam: mp
58-60.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.19F.sub.3N.sub.2OS.sub.2 (M.sup.+) 400.0890, found
400.0895.
EXAMPLE 11
(A)
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-pro-
pionamide
[0179] 24
[0180] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(300 mL). The organic layer was washed with a saturated aqueous
sodium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-trifluoromethylsulfany-
l-phenyl)propionic acid (1.47 g, 58%) as a cream solid: mp
69-71.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0181] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(1.33 g, 4.18 miol) in methanol (10 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 36 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (200 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 97/3
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trif-
luoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g,
99%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.2S (M.sup.+) 332.1058, found
332.1052.
[0182] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
methyl ester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was
treated with 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based
on 80%, 9.26 mmol). The reaction mixture was stirred at 25.degree.
C. for 17 h, at which time, thin layer chromatography showed the
presence of two new lower R.sub.f products. An additional 2.00 g of
3-chloroperoxybenzoic acid was added to the reaction mixture to
drive the conversion of the sulfoxide to the sulfone, and the
resulting reaction mixture was stirred at 25.degree. C. for 3 d.
The reaction mixture was concentrated in vacuo to remove methylene
chloride. The resulting residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
bicarbonate solution (3.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 19/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-rifluoromethanesulfony- l-phenyl)propionic acid
methyl ester (1.19 g, 95%) as a light yellow oil: EI-HRMS mie calcd
for C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956, found
364.0965.
[0183] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
methyl ester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 ML) was
treated with a 0.8M aqueous lithium hydroxide solution (3.6 mL,
2.92 mmol). The reaction mixture was stirred at 25.degree. C. for
23 h and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo to afford
a cream solid. This solid was purified by triturating with diethyl
ether/petroleum ether to provide pure
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid
(527.0 mg, 77%) as a white solid: mp 143-145.degree. C.; EI-HRMS
m/e calcd for C.sub.15H.sub.17F.sub.3O.sub.4S (M.sup.+) 350.0800,
found 350.0816.
[0184] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
(164.0 mg, 0.47 mmol) and triphenylphosphine (184.2 mg, 0.70 mmol)
in methylene chloride (1.2 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (141.6 mg, 0.80 mmol) in small
portions. After the complete addition of N-bromosuccinimide, the
reaction mixture was allowed to warm to 25.degree. C. where it was
stirred for 1 h. The reaction mixture was then treated with
2-aminothiazole (140.6 mg, 1.40 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 22 h. The reaction mixture
was then concentrated in vacuo. Flash chromatography (Merck Silica
gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfo-
nyl-phenyl)-propionamide (47.9 mg, 24%) as a cream solid: mp
189-191.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.19F.sub.3N.sub.2O- .sub.3S.sub.2 (M.sup.+) 432.0789,
found 432.0791.
[0185] (B) In an analogous manner, there were obtained:
[0186] (a) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and 2-aminothiazole-4-carboxylic acid methyl ester:
2-[3-Cyelopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-th-
iazole-4-carboxylic acid methyl ester as a gray solid: mp
122-125.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.21F.sub.3N.sub.2O.sub.5S.sub.2 (M.sup.+) 490.0844,
found 490.0844.
[0187] (b) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and 2-aminothiazole-4-carboxylic acid ethyl ester:
2-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-th-
iazole-4-carboxylic acid ethyl ester as a white solid: mp
132-134.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.23F.sub.3N.sub.2O.sub.5S.sub.2 (M.sup.+) 504.1000,
found 504.0988.
[0188] (c) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and methyl 2-amino-4-thiazoleacetate: {2-[3-Cyclopentyl-2-(4-trifl-
uoromethanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic
acid methyl ester as a yellow foam: mp 48-52.degree. C.; EI-HRMS
m/e calcd for C.sub.21H.sub.23F.sub.3N.sub.2O.sub.5S.sub.2
(M.sup.+) 504.1000, found 504.0998.
EXAMPLE 12
2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propion-
amide
[0189] 25
[0190] A solution of anhydrous aluminum chloride (5.00 g, 37.50
mmol) in chloroform (15 mL) was cooled to 0.degree. C. and stirred
for 30 min under a nitrogen atmosphere. A solution of ethyl oxalyl
chloride (3.91 g, 28.64 mmol) in chloroform (5 mL) was then added,
and the resulting reaction mixture was stirred at 0.degree. C. for
an additional 30 min. A solution of 2-chlorothioanisole (4.08 g,
25.58 mmol) in chloroform (20 mL) was then slowly added to the
cooled reaction mixture. The solution became red in color and
slowly became gum-like over a period of 30 min. The resulting
reaction mixture was then stirred for an additional 3.5 h, and
during this period, the reaction mixture was allowed to warm to
25.degree. C. The reaction mixture was then quenched by the
addition of water (25 mL). The aqueous layer was extracted with
chloroform (3.times.25 mL). The combined organic layers were
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
(3-chloro-4-methylsulfanyl-phenyl)-oxo-ac- etic acid ethyl ester
(4.32 g, 65.3%) as a yellow oil.
[0191] A solution of (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic
acid ethyl ester (3.93 g, 15.19 mmol) in methanol (30 mL) was
cooled to 0.degree. C. and then treated with sodium borohydride
(530.9 mg, 14.03 mmol). The reaction mixture changed from yellow to
colorless. The mixture was stirred for 15 min and then quenched
with a 1N aqueous hydrochloric acid solution (10 mL). The resulting
reaction mixture was then extracted with methylene chloride
(2.times.30 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.30 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 9/1 then 4/1
hexanes/ethyl acetate) afforded
(3-chloro-4-methylsulfanyl-phenyl)-hydrox- y-acetic acid ethyl
ester (1.43 g, 38%) as a white solid: mp 56-57.degree. C.; EI-HRMS
m/e calcd for C.sub.11H.sub.13ClO.sub.3S (M.sup.+) 260.0273, found
260.0276.
[0192] A solution of
(3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester
(1.43 g, 5.49 mmol) in pyridine (2 mL) was treated with acetic
anhydride (2 mL) and 4-dimethylaminopyridine (50 mg, 0.41 mmol).
The reaction mixture was stirred at 25.degree. C. for 16 h. The
reaction mixture was then diluted with methylene chloride (100 mL).
The organic layer was washed with a 1N aqueous hydrochloric acid
solution (2.times.30 mL), washed with a saturated aqueous sodium
chloride solution (1.times.30 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
acetoxy-(3-chloro-4-methylsulfanyl-phenyl- )-acetic acid ethyl
ester (1.51 g, 91%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.13H.sub.15ClO.sub.4S (M) 302.0379, found 302.0387.
[0193] A solution of
acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester
(1.47 g, 4.87 mmol) in hexamethylphosphoramide (7.2 mL) and
methanol (20 .mu.L) was treated with a 0.1M solution of samarium
iodide in tetrahydrofuran (146 mL, 14.6 mmol). The reaction mixture
was stirred at 25.degree. C. under nitrogen for 6 min. During this
time period, the reaction mixture changed from purple to white. The
reaction mixture was diluted with water (150 mL) and then extracted
with methylene chloride (3.times.100 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
4/1 hexanes/ethyl acetate) afforded
(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.71 g,
60%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.11H.sub.13ClO.sub.2S (M.sup.+) 244.0324, found 244.0332.
[0194] A solution of diisopropylamine (457 .mu.L, 3.26 mmol) in
tetrahydrofuran (5 mL) was cooled to -78.degree. C. under a
nitrogen atmosphere and then treated with a 2.5M solution of
n-butyllithium in hexanes (1.3 mL, 3.26 mmol). The mixture was
stirred at -78.degree. C. for 30 min, at which time, a solution of
(3-chloro-4-methylsulfanyl-pheny- l)-acetic acid ethyl ester (0.67
g, 2.75 mmol) in tetrahydrofuran (8 mL) was slowly added to the
reaction mixture. The reaction mixture turned deep yellow in color.
The reaction mixture was then further stirred at -78.degree. C. for
30 min, at which time, a solution of iodomethylcyclopentane (0.65
g, 3.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrah- ydro-2(1H)-pyrimidone
(1 mL) was added via syringe. The reaction mixture was then allowed
to warm to 25.degree. C., where it was stirred for 16 h. The
reaction mixture turned red in color during this time period. The
reaction mixture was quenched with a 6N aqueous hydrochloric acid
solution (5 mL) and further diluted with water (20 mL). The
reaction mixture was then extracted with methylene chloride
(3.times.20 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.25 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 4/1
hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsul-
fanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (0.50 g,
56%) as a light yellow oil.
[0195] A solution of
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-pr- opionic acid
ethyl ester (0.45 g, 1.39 mmol) in ethanol (3 mL) was treated with
a 10% aqueous potassium hydroxide solution (2 mL). The reaction
mixture was stirred under nitrogen at 25.degree. C. for 16 h. The
reaction mixture was then acidified with a 1N aqueous hydrochloric
acid solution (5 mL). The reaction mixture was then extracted with
methylene chloride (3.times.15 mL). The combined organic layers
were dried over sodium sulfate, filtered, and concentrated in vacuo
to afford
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid
(0.29 g, 70%) as a white solid: EI-HRMS m/e calcd for
C.sub.15H.sub.19ClO.sub.2- S (M.sup.+) 298.0794, found
298.0798.
[0196] A solution of
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (0.62 g, 1.41 mmol) and
2-(3-chloro-4-methylsulfanyl-- phenyl)-3-cyclopentyl-propionic acid
(0.29 g, 0.95 mmol) in methylene chloride (10 mL) was treated with
N,N-diisopropylethylamine (500 .mu.L, 2.87 mmol) and
2-aminothiazole (140 mg, 1.27 mmol). The mixture was stirred under
nitrogen at 25.degree. C. for 14 h. The reaction mixture was then
washed with a 6N aqueous hydrochloric acid solution (1.times.15 mL)
and washed with a saturated aqueous sodium chloride solution
(1.times.25 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propion-
amide (0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for
C.sub.18H.sub.21ClN.sub.2OS.sub.2 (M.sup.+) 380.0783, found
380.0792.
[0197] A solution of
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N--
thiazol-2-yl-propionamide (187 mg, 0.49 mmol) in methylene chloride
(10 mL) was cooled to 0.degree. C. under nitrogen and then treated
with 3-chloroperoxybenzoic acid (456.8 mg based on 50% purity). The
reaction mixture was stirred for 3 h, and during this period, the
temperature was allowed to warm to 25.degree. C. The reaction
mixture was then diluted with methylene chloride (50 mL). The
organic layer was washed with a saturated aqueous sodium carbonate
solution (1.times.20 mL), washed with a saturated aqueous sodium
chloride solution (1.times.20 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propio-
namide (102 mg, 50%) as a white solid: EI-HRMS m/e calcd for
C.sub.18H.sub.21ClN.sub.2O.sub.3S.sub.2 (M.sup.+) 412.0682, found
412.0674.
EXAMPLE 13
[0198]
(2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propi-
onamide 26
[0199] A solution of 4-(methanesulfonyl)phenyl acetic acid (43.63
g, 0.204 mol) in methanol (509 mL) was treated slowly with
concentrated sulfuric acid (2 mL). The resulting reaction mixture
was heated under reflux for 19 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (800 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.200 mL), washed with a saturated
aqueous sodium chloride solution (1.times.200 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 1/1 hexanes/ethyl
acetate) afforded 4-(methanesulfonyl)phenyl acetic acid methyl
ester (45.42 g, 98%) as a yellow oil which solidified to a cream
colored solid upon sitting over time at 25.degree. C.: mp
78-80.degree. C.; EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.4S
(M.sup.+) 228.0456, found 228.0451.
[0200] A mechanical stirrer was used for this reaction. A solution
of diisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186
mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL)
was cooled to -78.degree. C. and then treated with a 2.5M solution
of n-butyllithium in hexanes (83.4 mL, 0.21 mol). The yellow-orange
reaction mixture was stirred at -78.degree. C. for 35 min and then
slowly treated with a solution of 4-(methanesulfonyl)phenyl acetic
acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186
mL) and 1,3-dimethyl-3,4,5,6-tetrah- ydro-2(1H)-pyrimidinone (62
mL). The reaction mixture turned dark in color. The reaction
mixture was then stirred at -78.degree. C. for 50 min, at which
time, a solution of iodomethylcyclopentane (50.08 g, 0.24 mol) in a
small amount of dry tetrahydrofuran was added slowly. The reaction
mixture was then stirred at -78.degree. C. for 50 min, and then
allowed to warm to 25.degree. C., where it was stirred for 36 h.
The reaction mixture was quenched with water (100 mL), and the
resulting reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The remaining residue was diluted with ethyl
acetate (1.5 L). The organic phase was washed with a saturated
aqueous sodium chloride solution (1.times.500 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylphenyl)-
propionic acid methyl ester (41.79 g, 68%) as a yellow viscous oil:
EI-HRMS m/e calcd for C.sub.16H.sub.22O.sub.4S (M.sup.+) 310.1239,
found 310.1230.
[0201] A solution of
3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl
ester (50.96 g, 0.16 mol) in methanol (410 mL) was treated with a
1N aqueous sodium hydroxide solution (345 mL, 0.35 mol). The
reaction mixture was stirred at 25.degree. C. for 24 h. The
reaction mixture was concentrated in vacuo to remove methanol. The
resulting aqueous residue was acidified to pH=2 with concentrated
hydrochloric acid and then extracted with ethyl acetate
(5.times.200 mL). The combined organic layers were dried over
sodium sulfate, filtered, and concentrated in vacuo to afford pure
3-cyclopentyl-2-(4-methanesulfonylphenyl)propioni- c acid (43.61 g,
90%) as a white solid which was used without further purification:
mp 152-154.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.4S (M.sup.+) 296.1082, found 296.1080.
[0202] Two separate reactions were setup in parallel: (1) A
solution of (R)-(+)-4-benzyl-2-oxazolidinone (3.67 g, 20.73 mmol)
in dry tetrahydrofuran (35 mL) was cooled to -78.degree. C. and
then treated with a 2.5M solution of n-butyllithium in hexanes (7.9
mL, 19.86 mmol). The resulting reaction mixture was stirred at
-78.degree. C. for 30 min and then allowed to warm to 25.degree.
C., where it was stirred for 1.5 h. (2) A solution of racemic
3-cyclopentyl-2-(4-methanesulfonylphenyl)pro- pionic acid (5.12 g,
17.27 mmol) in dry tetrahydrofuran (35 mL) was cooled to 0.degree.
C. and then treated with triethylamine (2.8 mL, 19.86 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated dropwise with trimethylacetyl chloride (2.6 mL, 20.73
mmol). The resulting reaction mixture was stirred at 0.degree. C.
for 2 h and then cooled to -78.degree. C. for the addition of the
freshly prepared chiral oxazolidinone. The reaction mixture
containing the oxazolidinone was then added to the cooled
(-78.degree. C.) mixed anhydride solution. The resulting reaction
mixture was stirred as -78.degree. C. for 1 h and allowed to
gradually warm to 25.degree. C. The reaction mixture was then
stirred at 25.degree. C. for 3 d. The resulting reaction mixture
was quenched with water (100 mL) and then concentrated in vacuo to
remove tetrahydrofuran. The resulting aqueous residue was diluted
with ethyl acetate (600 mL). The organic layer was washed with a
saturated aqueous sodium chloride solution (1.times.300 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Thin
layer chromatography using 13/7 hexanes/ethyl acetate as the
developing solvent indicated the presence of two products. The
higher moving product had a R=0.32 and the lower moving product had
a R.sub.f=0.19. Flash chromatography (Merck Silica gel 60, 230-400
mesh, 9/1 then 13/7 hexanes/ethyl acetate) afforded two products:
(1) The higher R.sub.f product (4R,
2'S)-4-benzyl-3-[3-cyclopentyl-2-(4-m-
ethanesulfonylphenyl)propionyl]-oxazolidin-2-one (2.12 g, 54%) as a
white foam: mp 62-64.degree. C.; [.alpha.].sup.23.sub.589=+6.30
(c=0.24, chloroform); EI-HRMS m/e calcd for
C.sub.25H.sub.29NO.sub.5S (M.sup.+) 455.1766, found 455.1757. (2)
The lower R.sub.f product (4R,
2'R)-4-benzyl-3-[3-cyclopentyl-2-(4-methanesulfonylphenyl)propionyl]-oxaz-
olidin-2-one (3.88 g, 99%) as a white foam: mp 59-61.degree. C.;
[.alpha.].sup.23.sub.589=-98.3.degree. (c=0.35, chloroform);
EI-HRMS m/e calcd for C.sub.25H.sub.29NO.sub.5S (M.sup.+) 455.1766,
found 455.1753. The combined mass recovery from the two products
was 6.00 g, providing a 76% conversion yield for the reaction.
[0203] An aqueous solution of lithium hydroperoxide was freshly
prepared from mixing a solution of anhydrous lithium hydroxide
powder (707.3 mg, 16.86 mmol) in 5.27 mL of water with a 30%
aqueous hydrogen peroxide solution (3.44 mL, 33.71 mmol). This
freshly prepared aqueous lithium hydroperoxide solution was cooled
to 0.degree. C. and then slowly added to a cooled (0.degree. C.)
solution of (4R, 2'R)-4-benzyl-3-[3-cyclopenty-
l-2-(4-methanesulfonylphenyl)propionyl]-oxazolidin-2-one (3.84 g,
8.43 mmol) in tetrahydrofuran (33 mL) and water (11 mL). The
reaction mixture was stirred 0.degree. C. for 1.5 h. The reaction
mixture was then quenched with a 1.5N aqueous sodium sulfite
solution (25 mL). The reaction mixture was further diluted with
water (300 mL). The resulting aqueous layer was continuously
extracted with diethyl ether until thin layer chromatography
indicated the absence of the recovered chiral oxazolidinone in the
aqueous layer. The aqueous layer was then acidified to pH=2 with a
10% aqueous hydrochloric acid solution and extracted with ethyl
acetate (300 mL). The organic extract was dried over sodium
sulfate, filtered, and concentrated in vacuo to afford
(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid as a
white solid (2.23 g, 89%) which was used without further
purification. Flash chromatography (Merck Silica gel 60, 70-230
mesh, 30/1 methylene chloride/methanol then 10/1 methylene
chloride/methanol) was used to obtain a purified sample for
analytical data and afforded pure
(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid as a
white foam: mp 62-64.degree. C. (foam to gel);
[.alpha.].sup.23.sub.589-50.0.de- gree. (c=0.02, chloroform);
EI-HRMS m/e calcd for C.sub.15H.sub.20O.sub.4S (M.sup.+) 296.1082,
found 296.1080.
[0204] A solution of triphenylphosphine (3.35 g, 12.79 mmol) in
methylene chloride (19 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (2.28 g, 12.79 mmol) in
small portions. The reaction mixture was stirred at 0.degree. C.
for 30 min, and during this time period, the color of the reaction
mixture changed from light yellow to a darker yellow then to a
purple color. The cooled purple reaction mixture was then treated
with the (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)p- ropionic
acid (2.23 g, 7.52 mmol). The resulting reaction mixture was then
allowed to warm to 25.degree. C. over 45 min, at which time, the
reaction mixture was then treated with 2-aminothiazole (1.88 g,
18.81 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 12 h. The reaction mixture was then concentrated
in vacuo to remove methylene chloride. The remaining black residue
was diluted with ethyl acetate (300 mL) and then washed well with a
10% aqueous hydrochloric acid solution (2.times.100 mL), a 5%
aqueous sodium bicarbonate solution (3.times.100 mL), and a
saturated aqueous sodium chloride solution (1.times.200 mL). The
organic layer was then dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate)
afforded
(2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamid-
e (2.10 g, 74%) as a white foam: mp 78-80.degree. C. (foam to gel);
[.alpha.].sup.23.sub.589=-70.4.degree. (c=0.027, chloroform);
EI-HRMS m/e calcd for C.sub.18H.sub.22N.sub.2O.sub.3S.sub.2
(M.sup.+) 378.1072, found 378.1081.
EXAMPLE 14
3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionam-
ide
[0205] 27
[0206] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenyla- cetic acid
methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found 229.0146.
[0207] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitrophenyl)-3-cy- clopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0208] A solution of
2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl
ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53
mmol) in dimethyl sulfoxide (3 mL) was heated at 130.degree. C. for
5 h. The black reaction mixture was then poured over ice (20 g),
resulting in the formation of a brown sticky substance. The
resulting mixture was then treated with ethyl acetate (50 mL) and
water (50 mL), and the layers were separated. The aqueous layer was
further extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propi- onic acid
methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.6S (M+H).sup.+ 356.1169, found 356.1175.
[0209] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-pro- pionic acid
methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL,
3.65 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting aqueous residue was diluted with
water (25 mL) and then treated with a 1N aqueous hydrochloric acid
solution (10 mL). The resulting aqueous layer was then extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/4
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfo-
nyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam.
Analytical data indicated the presence of a small impurity;
however, the
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
was used without further purification in subsequent reactions.
[0210] A solution of triphenylphosphine (138 mg, 0.53 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small
portions. The reaction mixture was stirred at 0.degree. C. for 10
min and then treated with
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
(150 mg, 0.44 mmol). The resulting reaction mixture was stirred at
0.degree. C. for 5 min and then allowed to warm to 25.degree. C.,
where it was stirred for 25 min. The reaction mixture was then
treated with 2-aminothiazole (97 mg, 0.97 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 15 h. The crude
reaction mixture was directly purified by flash chromatography,
(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate), to
afford 3-cyclopentyl-2-(4-methanesulfonyl-3-ni-
trophenyl)-N-thiazol-2-yl-propionamide (96 mg, 52%) as a pale
yellow solid: mp 121-124.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.21N.sub.3O.sub.5S.sub.2 (M+H).sup.+ 424.1001, found
424.1000.
EXAMPLE 15
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-prop-
ionamide
[0211] 28
[0212] A solution of
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamin-
o]-thiazole-5-carboxylic acid ethyl ester (prepared in Example 1
(B)(g), 110 mg, 0.25 mmol) in diethyl ether (2 mL) at 0.degree. C.
was slowly treated with lithium aluminum hydride (12 mg, 0.31
mmol). The resulting reaction mixture continued to stir at
0.degree. C. and was allowed to gradually warm to 25.degree. C. The
reaction mixture was then stirred at 25.degree. C. over a period of
14 h. The reaction mixture was slowly quenched by the dropwise
addition of water (5 mL). The resulting reaction mixture was
partitioned between water and ethyl acetate. A saturated aqueous
sodium chloride solution was added to break up the emulsions. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/3 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichloroph-
enyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide (52.9 mg, 53%)
as a light yellow solid: mp 128-130.degree. C.; EI-HRMS m/e calcd
for C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.2S (M.sup.+) 398.0623,
found 398.0623.
EXAMPLE 16
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-p-
ropionamide
[0213] 29
[0214] A solution of
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylami-
no]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 1
(B)(c), 129 mg, 0.28 mmol) in tetrahydrofuran (1.4 mL) at
25.degree. C. was slowly treated with sodium borohydride (22.5 mg,
0.59 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 10 h. After 10 h at 25.degree. C., a substantial
amount of starting material still remained. An additional amount of
sodium borohydride powder (21.4 mg, 0.57 mmol) was added to the
reaction mixture, and the reaction mixture was heated under reflux
for 14 h. The reaction mixture was allowed to cool to 25.degree.
C., and then slowly quenched by the dropwise addition of water. The
resulting reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting residue was diluted with ethyl
acetate (100 mL) and washed with a saturated aqueous sodium
chloride solution (1.times.50 mL). The organic layer was dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 then 1/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]--
propionamide (68.1 mg, 58%) as a white foam: mp 85-86.degree. C.;
FAB-HRMS m/e calcd for C.sub.19H.sub.22Cl.sub.2N.sub.2O.sub.2S
(M+H).sup.+ 413.0858, found 413.0838.
EXAMPLE 17
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-prop-
ionamide
[0215] 30
[0216] A solution of
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamin-
o]-thiazole-4carboxylic acid ethyl ester (prepared in Example
1(B)(f), 200 mg, 0.45 mmol) in tetrahydrofuran (3 mL) at 25.degree.
C. was slowly treated with sodium borohydride (26.0 mg, 0.68 mmol).
The reaction mixture was heated under reflux for 48 h. The reaction
mixture was allowed to cool to 25.degree. C. and then slowly
quenched by the dropwise addition of water. The resulting reaction
mixture was partitioned between water and ethyl acetate. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(4-hydroxymethyl-thiazol-2-yl)-pro-
pionamide (44.9 mg, 25%) as a white solid: mp 88-90.degree. C.;
EI-HRMS m/e calcd for C.sub.18H.sub.20Cl.sub.2N.sub.2O.sub.2S
(M.sup.+) 398.0623, found 398.0631.
EXAMPLE 18
{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ace-
tic Acid
[0217] 31
[0218] A solution of
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylami-
no]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example
1(B)(c), 198.1 mg, 0.44 mmol) in absolute ethanol (2.2 mL) was
treated with a 1N aqueous sodium hydroxide solution (910 .mu.L,
0.91 mmol). The reaction mixture was heated under reflux for 2 h.
The reaction mixture was allowed to cool to 25.degree. C. and then
concentrated in vacuo to remove absolute ethanol. The resulting
residue was acidified to pH=2 with a 10% aqueous hydrochloric acid
solution and extracted with ethyl acetate (1.times.150 mL). The
organic layer was washed with a saturated aqueous sodium chloride
solution (1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. The resulting white residue was washed well
with cold water and dried to afford {2-[3-cyclopentyl-2-(3,4--
dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid (150 mg,
81%) as a white solid: mp 100-102.degree. C.; FAB-HRMS m/e calcd
for C.sub.19H.sub.20Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+ 427.0650,
found 427.0633.
EXAMPLE 19
2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxy-
lic Acid
[0219] 32
[0220] A solution of
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamin-
o]-thiazole-5-carboxylic acid ethyl ester (prepared in Example
1(B)(g), 1.0 g, 2.27 mmol) in absolute ethanol (10 mL) was treated
with a 1N aqueous sodium hydroxide solution (4.77 mL, 4.77 mmol).
The reaction mixture was heated under reflux for 15 h. The reaction
mixture was allowed to cool to 25.degree. C. and then concentrated
in vacuo to remove absolute ethanol. The resulting yellow residue
was acidified to pH=2 with concentrated hydrochloric acid and
extracted with ethyl acetate (2.times.75 mL). The combined organic
layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Recrystallization from ethyl acetate
afforded 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionyla-
mino]-thiazole-5-carboxylic acid (210 mg, 22%) as a white solid: mp
269-270.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.18Cl.sub.2N.sub.- 2O.sub.3S (M+H).sup.+ 413.0493,
found 413.0483.
EXAMPLE 20
2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxy-
lic Acid
[0221] 33
[0222] A solution of
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamin-
o]-thiazole-4-carboxylic acid ethyl ester (prepared in Example
1(B)(f), 600 mg, 1.36 mmol) in absolute ethanol (6 mL) was treated
with a 1N aqueous sodium hydroxide solution (2.85 mL, 2.85 mmol).
The reaction mixture was heated under reflux for 15 h. The reaction
mixture was allowed to cool to 25.degree. C. and then concentrated
in vacuo to remove absolute ethanol. The resulting yellow residue
was acidified to pH=2 with concentrated hydrochloric acid and
extracted with ethyl acetate (2.times.100 mL). The combined organic
layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo. Precipitation from 1/1 hexanes/ethyl acetate
afforded 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-pr-
opionylamino]-thiazole-4-carboxylic acid (399 mg, 71%) as a white
solid: mp 285-287.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.18Cl.sub.2N.s- ub.2O.sub.3S (M+H).sup.+ 413.0493,
found 413.0481.
EXAMPLE 21
(A)
{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-
-acetic acid methyl ester
[0223] 34
[0224] A solution of
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylami-
no]-thiazol-4-yl}-acetic acid (prepared in Example 18, 95.4 mg,
0.223 mmol) in methanol (1.1 mL) was treated with 1 drop of
concentrated sulfuric acid. The reaction mixture was heated under
reflux for 15 h. The reaction mixture was allowed to cool to
25.degree. C. and then concentrated in vacuo to remove methanol.
The resulting residue was diluted with ethyl acetate (100 mL). The
organic phase was washed with a saturated aqueous sodium chloride
solution (1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
{2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-ac-
etic acid methyl ester (77.2 mg, 78%) as a yellow viscous oil:
FAB-HRMS m/e calcd for C.sub.20H.sub.22Cl.sub.2N.sub.2O.sub.3S
(M+H).sup.+ 441.0807, found 441.0804.
[0225] (B) In an analogous manner, there were obtained:
[0226] (a) From
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-th-
iazole-4-carboxylic acid (prepared in Example 20):
2-[3-Cyclopentyl-2-(3,4-
-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid methyl
ester as a white solid: mp 153-155.degree. C.; FAB-HRMS m/e calcd
for C.sub.19H.sub.20Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+ 427.0650,
found 427.0659.
[0227] (b) From
2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-th-
iazole-5-carboxylic acid (prepared in Example 19):
2-[3-Cyclopentyl-2-(3,4-
-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid methyl
ester as a white solid: mp 150-151.degree. C.; FAB-HRMS m/e calcd
for C.sub.19H.sub.20Cl.sub.2N.sub.2O.sub.3S (M+H).sup.+ 427.0650,
found 427.0650.
EXAMPLE 22
(A)
3-Cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide
[0228] 35
[0229] A solution of freshly prepared lithium diisopropylamide
(430.55 mL of a 0.3M stock solution, 129.16 mmol) cooled to
-78.degree. C. was treated with (4-nitro-phenyl)-acetic acid ethyl
ester (26.32 g, 125.83 mmol) in
tetrahydrofaranlhexamethylphosphoramide (312.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 45 min.
Iodomethylcyclopentane (27.75 g, 132.1 mmol) was then added in
hexamethylphosphoramide (27.75 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (250 mL). This mixture was concentrated,
diluted with water (250 mL), and extracted with ethyl acetate
(3.times.300 mL). The organics were washed with a saturated aqueous
lithium chloride solution (2.times.250 mL), dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-nitro-pheny- l)-propionic acid ethyl
ester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.4 (M.sup.+) 291.1470, found 291.1470.
[0230] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid ethyl ester (14.1 g, 48.06 mmol) in tetrahydrofuran/water (300
mL, 3:1) was treated with lithium hydroxide (4.35 g, 103.67 mmol).
The reaction was stirred at 25.degree. C. for 21 h. The
tetrahydrofuran was then removed in vacuo. The residue was diluted
with water (75 mL) and extracted with ether (3.times.75 mL). The
aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric
acid solution. The product was extracted into methylene chloride
(3.times.75 mL), washed with a saturated aqueous sodium chloride
solution (2.times.100 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo to give 3-cyclopentyl-2-(4-nitro-phen-
yl)-propionic acid (11.97 g, 93.6%) as a yellow solid: mp
119-125.degree. C.; EI-HRMS m/e calcd for C.sub.14H.sub.17NO.sub.4
(M.sup.+) 263.1157, found 263.1162.
[0231] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (131 mg, 0.5 mmol) in methylene chloride (5.0 mL) was cooled
to 0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (1.0 mL, 2.0 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (110 mg, 1.0 mmol) in tetrahydrofuran (5 mL) and
N,N-diisopropylethylamine (0.28 mL, 0.55 mmol). The solution was
stirred at 25.degree. C. for 24 h. At this time, the reaction was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazo- l-2-yl-propionamide (38
mg, 22.4%) as a yellow solid: mp 186-187.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.19N.sub.3O.sub.3S (M.sup.+) 345.1147, found
345.1148.
[0232] (B) In an analogous manner, there was obtained:
[0233] (a) From ethyl 2-amino-4-thiazole glyoxylate and
3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid:
{2-[3-Cyclopentyl-2-(4-n-
itro-phenyl)-propionylamino]-thiazol-4-yl}-oxo-acetic acid ethyl
ester (57.5%) as a white solid: mp 134-136.degree. C.; FAB-HRMS m/e
calcd for C.sub.21H.sub.23N.sub.3O.sub.6S (M+H).sup.+ 446.1400,
found 446.1386.
EXAMPLE 23
{2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylaminol-thiazol-4-yl}-acetic
Acid Ethyl Ester
[0234] 36
[0235] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (prepared in Example 22A, 263.0 mg, 1.0 mmol) in
N,N-dimethylformamide (10 mL) was treated with
0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (379 mg, 1.0 mmol),
(2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol)
and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction
mixture was stirred at 25.degree. C. for 5 h. The reaction mixture
was then poured into a 2N aqueous hydrochloric acid solution (25
mL) and extracted with ethyl acetate (3.times.25 mL). The organic
layers were combined and washed with water (1.times.75 mL), a
saturated aqueous sodium bicarbonate solution (1.times.75 mL), a
saturated aqueous sodium chloride solution (3.times.75 mL), dried
over sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 70/30
hexanes/ethyl acetate) afforded
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic
acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS
m/e calcd for C.sub.21H.sub.25N.sub.3O.sub.5S (M+H).sup.+ 432.1593,
found 432.1595.
EXAMPLE 24
{2-13-Cyclopentyl-2-(4-nitro-phenyl)-propionylaminol-thiazol-4-yl}-acetic
Acid Methyl Ester
[0236] 37
[0237] A solution of
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]--
thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 23, 160
mg, 0.37 mmol) in methanol (10 mL) was treated with a catalytic
amount of sulfuric acid. The reaction mixture was refluxed for 68
h. The reaction was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate)
afforded
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic
acid methyl ester (82.3 mg, 53.3%) as a pale yellow oil: FAB-HRMS
m/e calcd for C.sub.20H.sub.23N.sub.3O.sub.5S (M+H).sup.+ 418.1436,
found 418.1424.
EXAMPLE 25
{2-[2-(4-Amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic
Acid Methyl Ester
[0238] 38
[0239] A solution of
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]--
thiazol-4-yl}-acetic acid methyl ester (prepared in Example 24,
75.3 mg, 0.18 mmol) in ethyl acetate (25 mL) was treated with 10%
palladium on activated carbon. The reaction mixture was stirred
under hydrogen gas at 60 psi at 25.degree. C. for 4 h. The catalyst
was then filtered off through a pad of celite (ethyl acetate). The
filtrate was concentrated in vacuo to give
{2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazo-
l-4-yl}-acetic acid methyl ester (64.5 mg, 93.3%) as a tan oil:
EI-HRMS m/e calcd for C.sub.20H.sub.25N.sub.3O.sub.3S (M.sup.+)
387.1616, found 387.1612.
EXAMPLE 26
2-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic
Acid methyl ester
[0240] 39
[0241] A solution of
2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-t-
hiazole-4-carboxylic acid ethyl ester (prepared in Example
39(B)(b), 135 mg, 0.32 mmol) in methanol (10 mL) was treated with a
catalytic amount of sulfuric acid. The reaction mixture was
refluxed for 68 h. The reaction was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded
2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazole-4-carboxylic
acid methyl ester (71.4 mg, 54.8%) as a pale yellow solid: EI-HRMS
m/e calcd for C.sub.19H.sub.21N.sub.3O.sub.5S (M.sup.+) 403.1201,
found 403.1188.
EXAMPLE 27
2-12-(4-Amino-phenyl)-3-cyclopentyl-propionylaminol-thiazole-4-carboxylic
Acid Methyl Ester
[0242] 40
[0243] A solution of
2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-t-
hiazole-4-carboxylic acid methyl ester (prepared in Example 26,
60.0 mg, 0.14 mmol) in ethyl acetate (25 mL) was treated with 10%
palladium on activated carbon. The reaction mixture was stirred
under hydrogen gas at 60 psi at 25.degree. C. for 4.5 h. The
catalyst was then filtered off through a pad of celite (ethyl
acetate). The filtrate was concentrated in vacuo to give
2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-
e-4-carboxylic acid methyl ester (61.3 mg, 100%) as a pale yellow
oil: EI-HRMS m/e calcd for C.sub.19H.sub.23N.sub.3O.sub.3S
(M.sup.+) 373.1460, found 373.1454.
EXAMPLE 28
(A)
{2-12-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-ac-
etic Acid Ethyl Ester
[0244] 41
[0245] A solution of freshly prepared lithium diisopropylamide
(141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to
-78.degree. C. was treated with (3-chloro-phenyl)-acetic acid (3.41
g, 20.0 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(49.7 mL, 3:1). The resulting reaction solution was stirred at
-78.degree. C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol)
was then added in
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. The solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution (50 mL). The product was extracted into ethyl acetate
(1.times.150 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 85/15 hexanes/ethyl acetate) afforded
2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as
a yellow solid: mp 70-72.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17ClO.sub.2(M.sup.+) 252.0917, found 252.0915.
[0246] A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic
acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to
0.degree. C. and then treated with a 2.0M solution oxalyl chloride
in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 2 h. The reaction
mixture was then treated with (2-amino-thiazol-4-yl)-acetic acid
ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5
ML, 2.4 mmol). This solution was stirred at 25.degree. C. for 48 h.
At this time, the reaction was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
{2-[2-(3-chloro-phenyl)-3-cyclopentyl-pro-
pionylamino]-thiazol-4-yl}-acetic acid ethyl ester (254 mg, 60.3%)
as a white solid: mp 121-125.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.25ClN.sub.2O.sub.3S (M.sup.+) 420.1274, found
420.1268.
[0247] (B) In an analogous manner, there were obtained:
[0248] (a) From 2-amino-thiazole-4-carboxylic acid ethyl ester and
2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid:
2-[2-(3-Chloro-phenyl)--
3-cyclopentyl-propionylamino]thiazole-4-carboxylic acid ethyl ester
as a white solid: mp 167-168.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.23C1N.sub.2O.sub.3S (M.sup.+) 406.1117, found
406.1103.
[0249] (b) From 2-amino-pyridine and
2-(3-chloro-phenyl)-3-cyclopentyl-pro- pionic acid:
2-(3-Chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a
clear oil: EI-HRMS m/e calcd for C.sub.19H.sub.21CIN.sub.2O
(M.sup.+) 328.1342, found 328.1333.
[0250] (c) From 6-amino-nicotinic acid methyl ester and
2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid:
6-[2-(3-Chloro-phenyl)-- 3-cyclopentyl-propionylamino]-nicotinic
acid methyl ester as a colorless oil: EI-HRMS m/e calcd for
C.sub.21H.sub.23CIN.sub.2O.sub.3 (M.sup.+) 386.1397, found
386.1398.
EXAMPLE 29
{2-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic
Acid Methyl Ester
[0251] 42
[0252] A solution of
{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-
-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 28,
177.2 mg, 0.42 mmol) in methanol (15 mL) was treated with a
catalytic amount of sulfuiric acid. The reaction mixture was
refluxed for 40 h. The reaction was then concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30
hexanes/ethyl acetate) afforded
{2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-aceti-
c acid methyl ester (104.4 mg, 60.9%) as a clear oil: EI-HRMS m/e
calcd for C.sub.20H.sub.23ClN.sub.2O.sub.3S (M.sup.+) 406.1117,
found 406.1118.
EXAMPLE 30
2-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic
Acid Methyl Ester
[0253] 43
[0254] A solution of
2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]--
thiazole-4-carboxylic acid ethyl ester (prepared in Example
28(B)(a), 94.5 mg, 0.23 mmol) in methanol (15 mL) was treated with
a catalytic amount of sulfuric acid. The reaction mixture was
refluxed for 40 h. The reaction was then concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25
hexanes/ethyl acetate) afforded
2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxyli-
c acid methyl ester (36.8 mg, 40.3%) as a white solid: mp
95-98.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.21ClN.sub.2O.sub.3S (M.sup.+) 392.0961, found
392.0989.
EXAMPLE 31
(A)
{2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-ac-
etic Acid Ethyl Ester
[0255] 44
[0256] A solution of freshly prepared lithium diisopropylamide
(78.0 mL of a 0.91M stock solution, 70.98 mmol) cooled to
-78.degree. C. was treated with (4-chloro-phenyl)-acetic acid (5.76
g, 33.8 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(84 mL, 3:1). The resulting solution was stirred at -78.degree. C.
for 1 h. Iodomethylcyclopentane (7.45 g, 35.49 mmol) was then added
in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). This
solution was stirred at -78.degree. C. for 4 h. The reaction was
then warmed to 25.degree. C. and was stirred at 25.degree. C. for
16 h. The reaction mixture was then quenched by the dropwise
addition of a saturated aqueous ammonium chloride solution (20 mL).
The excess solvent was removed in vacuo. The residue was acidified
to pH=1 with a 1N aqueous hydrochloric acid solution. The mixture
was then poured into water (150 mL) and extracted with ethyl
acetate (3.times.50 mL). The organics were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (6.76 g,
79.1%) as a yellow solid: mp 82-84.degree. C.: EI-HRMS m/e calcd
for C.sub.14H.sub.17ClO.sub.2 (M.sup.+) 252.0917, found
252.0906.
[0257] A solution of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic
acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to
0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.55 mL, 1.1 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and then at 25.degree. C. for 1.5 h. The
reaction mixture was then treated with
(2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol)
and N,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was
stirred at 25.degree. C. for 24 h. At this time, the reaction was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 85/15 hexanes/ethyl acetate) afforded
{2-[2-(4-chloro-phenyl)-3-cyclopentyl-pro-
pionylamino]-thiazol-4-yl}-acetic acid ethyl ester (183.3 mg,
43.5%) as a pale yellow oil: EI-HRMS m/e calcd for
C.sub.21H.sub.25ClN.sub.2O.sub.3S (M.sup.+) 420.1274, found
420.1272.
[0258] (B) In an analogous manner, there were obtained:
[0259] (a) From 2-amino-thiazole-4-carboxylic acid ethyl ester and
2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid:
2-[2-(4-Chloro-phenyl)--
3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl
ester as a white solid: mp 114-116.degree. C.; EI-HRMS m/e calcd
for C.sub.20H.sub.23ClN.sub.2O.sub.3S (M.sup.+) 406.1117, found
406.1119.
[0260] (b) From 2-amino-pyridine and
2-(4-chloro-phenyl)-3-cyclopentyl-pro- pionic acid:
2-(4-Chloro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a
clear oil: EI-HRMS m/e calcd for C.sub.19H.sub.21ClN.sub.2O
(M.sup.+) 328.1342, found 328.1355.
[0261] (c) From 6-amino-nicotinic acid methyl ester and
2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid:
6-[2-(4-Chloro-phenyl)-- 3-cyclopentyl-propionylamino]-nicotinic
acid methyl ester as a white foam: EI-HRMS m/e calcd for
C.sub.21H.sub.23ClN.sub.2O.sub.3 (M.sup.+) 386.1397, found
386.1384.
EXAMPLE 32
2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic
Acid Methyl Ester:
[0262] 45
[0263] A solution of
2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]--
thiazole-4-carboxylic acid ethyl ester (prepared in Example
31(B)(a), 105 mg, 0.25 mmol) in methanol (10 mL) was treated with a
catalytic amount of sulfuric acid. The reaction mixture was
refluxed for 68 h. The reaction was concentrated in vacuo. High
pressure liquid chromatography (Chromegasphere SI-60, 10 .mu.m, 60
.ANG., 25 cm.times.23 cm ID, 75/25 heptane/ethyl acetate) afforded
2-[2-(4-chloro-phenyl)-3-cyclopentyl-prop-
ionylamino]-thiazole-4-carboxylic acid methyl ester (41.3 mg,
40.7%) as a white solid: mp 156-157.degree. C.; EI-HRMS m/e calcd
for C.sub.19H.sub.21ClN.sub.2O.sub.3S (M.sup.+) 392.0961, found
392.0956.
EXAMPLE 33
{2-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylaminol-thiazol-4-yl}-acetic
Acid Methyl Ester
[0264] 46
[0265] A solution of
{2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-
-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 31A,
76.1 mg, 0.18 mmol) in methanol (5 mL) was treated with a catalytic
amount of sulfuric acid. The reaction mixture was refluxed for 72
h. The reaction was concentrated in vacuo. High pressure liquid
chromatography (Chromegasphere SI-60, 10 .mu.M, 60 .ANG., 25
cm.times.23 cm ID, 75/25 heptane/ethyl acetate) afforded
{2-[3-cyclopentyl-2-(4-nitro-phenyl)-prop-
ionylamino]-thiazol-4-yl}-acetic acid methyl ester (21.5 mg, 29.2%)
as a colorless oil: EI-HRMS m/e calcd for
C.sub.20H.sub.23CIN.sub.2O.sub.3S (M.sup.+) 406.1117, found
406.1114.
EXAMPLE 34
2-(4-Chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propion-
amide
[0266] 47
[0267] A solution of
2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]--
thiazole-4-carboxylic acid methyl ester (prepared in Example 32,
127.7 mg, 0.31 mmol) in tetrahydrofuran (0.4 mL) was added to a
slurry of lithium aluminum hydride (15.0 mg, 0.39 mmol) in
tetrahydrofuran (2.24 mL) at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 2 h. The reaction was then quenched by
the dropwise addition of water. The reaction was then diluted with
more water (25 mL) and extracted with ethyl acetate (3.times.25
mL). The organics were dried over sodium sulfate, filtered and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 75/25 hexanes/ethyl acetate) afforded
2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propio-
namide (63.4 mg, 55.4%) as a white solid: mp 115-117.degree. C.;
EI-HRMS m/e calcd for C.sub.18H.sub.21ClN.sub.2O.sub.2S (M.sup.+)
364.1012, found 364.1004.
EXAMPLE 35
3-Cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-metanesulfonyl-phenyl)-
-propionamide
[0268] 48
[0269] A solution of
2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propion-
ylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in
Example 3(B)(b), 130 mg, 0.29 mmol) in diethyl ether (2 mL) was
cooled to 0.degree. C. and then slowly treated with lithium
aluminum hydride (17 mg, 0.44 mmol). The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 4 h.
After 4 h at 25.degree. C., thin layer chromatography indicated the
presence of starting material. An additional amount of lithium
aluminum hydride (11 mg, 0.29 mmol) was added to the reaction
mixture, and the reaction mixture was allowed to stir at 25.degree.
C. for 15 h. The reaction mixture was then slowly quenched by the
dropwise addition of water. The resulting mixture was partitioned
between water and ethyl acetate. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, ethyl acetate)
afforded
3-cyclopentyl-N-(4-hydroxymethyl-thiazol-2-yl)-2-(4-methanesulfo-
nyl-phenyl)-propionamide (55 mg, 46%) as a white solid: mp
124-126.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.24N.sub.2O.sub.4S.sub.2 (M.sup.+) 408.11-78, found
408.1164.
EXAMPLE 36
3-Cyclopentyl-N-14-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phe-
nyl)-propionamide
[0270] 49
[0271] A solution of
{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propio-
nylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in
Example 3(B)(d), 120 mg, 0.26 mmol) in diethyl ether (500 .mu.L)
was cooled to 0.degree. C. and then slowly treated with lithium
aluminum hydride (15 mg, 0.39 mmol). The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 1 h.
After 1 h at 25.degree. C., thin layer chromatography still
indicated the presence of the
{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4--
yl}-acetic acid ethyl ester. An additional amount of lithium
aluminum hydride (10 mg, 0.26 mmol) was added to the reaction
mixture, and the reaction mixture was allowed to stir at 25.degree.
C. for 1 h. The reaction mixture was then slowly quenched by the
dropwise addition of water (10 mL). The resulting mixture was
partitioned between water and ethyl acetate. The organic layer was
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3
hexanes/ethyl acetate) afforded
3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-ph-
enyl)-propionamide (20 mg, 18%) as a yellow foam: mp 84-87.degree.
C.; EI-HRMS m/e calcd for C.sub.20H.sub.26N.sub.2O.sub.4S.sub.2
(M.sup.+) 422.1334, found 422.1335.
EXAMPLE 37
(2R)-2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-c-
arboxylic Acid Methyl Ester
[0272] 50
[0273] A solution triphenylphosphine (164 mg, 0.63 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (112 mg, 0.63 mmol) in small
portions. The resulting orange reaction mixture was stirred at
0.degree. C. for 20 min and then treated with
(2R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared
in Example 54, 150 mg, 0.52 mmol). The reaction mixture was stirred
at 0.degree. C. for an additional 15 min and then allowed to warm
to 25.degree. C. The reaction mixture was then treated with
2-aminothiazole-4-carboxylic acid methyl ester (181 mg, 1.15 mmol).
The resulting reaction mixture was stirred at 25.degree. C. for 15
h. The crude reaction mixture was directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) to afford impure
(2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thia-
zole-4-carboxylic acid methyl ester. The impure product was diluted
with ethyl acetate and then washed with a saturated aqueous sodium
bicarbonate solution. The organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo to provide pure
(2R)-2-[3-cyclopentyl-2-(3,4-di-
chloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl
ester (92 mg, 41%) as a white solid: mp 143-144.degree. C.;
[.alpha.].sup.23.sub.58- 9=-10.20 (c=0.98, chloroform); EI-HRMS m/e
calcd for C.sub.19H.sub.20Cl.sub.2N.sub.2O.sub.3S (M.sup.+)
426.0572, found 426.0562.
EXAMPLE 38
(A)
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide:
[0274] 51
[0275] A solution of triphenylphosphine (28.80 g, 109.8 mmol) and
imidazole (14.9 g, 219.6 mmol) in methylene chloride (160 mL) was
cooled to 0.degree. C. and then slowly treated with iodine (27.87
g, 109.8 mmol). The reaction mixture was then treated dropwise with
a solution of cyclopentylmethanol (10.0 g, 99.8 mmol) in methylene
chloride (10 mL). The resulting reaction mixture was allowed to
warm to 25.degree. C., where it was stirred for 4 h. The reaction
mixture was then diluted with water (50 mL), and the reaction
mixture was further extracted with methylene chloride (3.times.20
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated in vacuo at 25.degree. C. The resulting
solid was washed with pentane (4.times.50 mL) and filtered through
a silica gel plug. The filtrate was concentrated in vacuo at
25.degree. C. to afford iodomethylcyclopentane (18.48 g, 88%) as a
clear colorless liquid: EI-HRMS m/e calcd for
C.sub.6H.sub.11I.sub.1 (M.sup.+) 209.9906, found 209.9911.
[0276] A solution of diisopropylamine (13.36 mL, 101.89 mmol) in
tetrahydrofuran (250 mL) was cooled to -78.degree. C. under a
nitrogen atmosphere and then treated with a 2.0M solution of
n-butyllithium in hexanes (51 mL, 101.89 mmol). The reaction
mixture was stirred at -78.degree. C. for 15 min, at which time, a
solution of 3,4-dichlorophenyl acetic acid (9.08 g, 44.3 mmol) in
tetrahydrofuran (60 mL) and hexamethylphosphoramide (20 mL) was
slowly added via a cannula. The bright yellow solution was allowed
to stir at -78.degree. C. for 1 h, at which time, a solution of
iodomethylcyclopentane (11.17 g, 53.2 mmol) in
hexamethylphosphoramide (10 mL) was added via a cannula. The
reaction mixture was stirred at -78.degree. C. for 1 h. The
reaction mixture was then allowed to warm to 25.degree. C., where
it was stirred for 14 h. The reaction mixture was then acidified to
pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid
solution and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, chloroform then 99/1 chloroform/methanol)
afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (10.28
g, 81%) as a white solid: mp 74.5-76.9.degree. C.; EI-HRMS m/e
calcd for C.sub.14H.sub.16Cl.sub.2O.sub.2 (M.sup.+) 286.0527, found
286.0534.
[0277] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (114 mg, 0.39 mmol) in methylene chloride (10 mL) was treated
with 1 drop of N,N-dimethylformamide and then cooled to 0.degree.
C. The reaction mixture was then treated with a 2.0M solution of
oxalyl chloride in methylene chloride (0.22 mL, 0.44 mmol). The
reaction mixture was stirred at 0.degree. C. for 30 min and then
treated with a solution of 2-aminopyridine (78 mg, 0.83 mmol) and
N,N-diisopropylethylamine (0.16 mL, 0.95 mmol) in tetrahydrofuran
(2 mL). The resulting reaction mixture was stirred at 25.degree. C.
for 14 h. The reaction mixture was then diluted with water (10 nmL)
and extracted with methylene chloride (2.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, hexanes then 19/1 to 4/1 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-pr-
opionamide (58 mg, 50%) as a white foam: EI-HRMS m/e calcd for
C.sub.19H.sub.20Cl.sub.2N.sub.2O (M.sup.+) 362.0953, found
362.0955.
[0278] (B) In an analogous manner, there were obtained:
[0279] (a) From 2-amino-5-nitropyridine and
3-cyclopentyl-2-(3,4-dichlorop- henyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-nitropyr-
idin)-2-yl-propionamide as a yellow-orange foam: EI-HRMS m/e calcd
for C.sub.19H.sub.19Cl.sub.2N.sub.3O.sub.3 (M.sup.+) 407.0803,
found 407.0799.
[0280] (b) From 2-amino-5-carboxymethylpyridine and
3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymethylpyridin)-2-yl-pro-
pionamide as a white foam: EI-HRMS m/e calcd for
C.sub.2H.sub.22Cl.sub.2N.- sub.2O.sub.3 (M.sup.+) 420.1007, found
420.0994.
[0281] (c) From 4-aminopyrimidine and
3-cyclopentyl-2-(3,4-dichlorophenyl)- -propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrimidine-6-yl-p-
ropionamide as a white foam: EI-HRMS m/e calcd for
C.sub.18H.sub.19Cl.sub.- 2N.sub.3O (M.sup.+) 363.0905, found
363.0910.
[0282] (d) From 2-amino-5-methylpyridine and
3-cyclopentyl-2-(3,4-dichloro- phenyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-methylp-
yridin)-2-yl-propionamide as a white solid: EI-HRMS m/e calcd for
C.sub.20H.sub.22Cl.sub.2N.sub.2O (M.sup.+) 376.1109, found
376.1119.
[0283] (e) From 2-amino-4-methylpyridine and
3-cyclopentyl-2-(3,4-dichloro- phenyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(4-methylp-
yridin)-2-yl-propionamide as a white solid: EI-HRMS m/e calcd for
C.sub.20H.sub.22Cl.sub.2N.sub.2O (M.sup.+) 376.1109, found
376.1106.
[0284] (f) From 2-amino-6-methylpyridine and
3-cyclopentyl-2-(3,4-dichloro- phenyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(6-methylp-
yridin)-2-yl-propionamide as a light yellow solid: EI-HRMS m/e
calcd for C.sub.20H.sub.22Cl.sub.2N.sub.2O (M.sup.+) 376.1109,
found 376.1107.
[0285] (g) From 2-amino-5-chloropyridine and
3-cyclopentyl-2-(3,4-dichloro- phenyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-chlorop-
yridin)-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for
C.sub.19H.sub.19Cl.sub.3N.sub.2O (M.sup.+) 396.0563, found
396.0564.
[0286] (h) From 2-amino-5-bromopyridine and
3-cyclopentyl-2-(3,4-dichlorop- henyl)-propionic acid:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-bromopyr-
idin)-2-yl-propionamide as a white solid: EI-HRMS m/e calcd for
C.sub.19H.sub.19BrCl.sub.2N.sub.2O (M.sup.+) 440.0058, found
440.0066.
EXAMPLE 39
(A)
3-Cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide
[0287] 52
[0288] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (prepared in Example 22, 263 mg, 1.0 mmol) in methylene
chloride (5 mL) was cooled to 0.degree. C. and then treated with a
2.0M solution of oxalyl chloride in methylene chloride (0.6 mL, 1.2
mmol) and a few drops of N,N-dimethylformamide. The reaction
mixture was stirred at 0.degree. C. for 15 min and then at
25.degree. C. for 1 h. The reaction mixture was then treated with a
solution of 2-aminopyridine (207 mg, 2.2 mmol) in tetrahydrofliran
(5 mL) and N,N-diisopropylethylamine (0.42 mL, 2.5 mmol). The
reaction mixture was stirred at 25.degree. C. for 24 h. At this
time, the reaction was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded
3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (110.2
mg, 32.5%) as a white solid: mp 152-154.degree. C.; EI-HRMS m/e
calcd for C.sub.19H.sub.21N.sub.3O.sub.3 (M.sup.+) 339.1582, found
339.1581.
[0289] (B) In an analogous manner, there were obtained:
[0290] (a) From 4-aminopyrimidine and
3-cyclopentyl-2-(4-nitro-phenyl)-pro- pionic acid:
3-Cyclopentyl-2-(4-nitro-phenyl)-N-pyrimidin-4-yl-propionamid- e as
a white solid: mp 152-153.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.20N.sub.4O.sub.3 (M.sup.+) 340.1535, found
340.1533.
[0291] (b) From 2-amino-thiazole-4-carboxylic acid ethyl ester and
3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid:
2-[3-Cyclopentyl-2-(4-ni-
tro-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester
as a pale yellow solid: mp 110-115.degree. C.; EI-HRMS m/e calcd
for C.sub.20H.sub.23N.sub.3O.sub.5S (M.sup.+) 417.1358, found
417.1346.
EXAMPLE 40
3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide
[0292] 53
[0293] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (2.55 g, 12.13
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was stirred at -78.degree. C. for 30 min and
then allowed to warn to 25.degree. C. where it was stirred for 24
h. The reaction mixture was quenched with water and then
concentrated in vacuo to remove tetrahydrofuran. The remaining
aqueous phase was acidified to pH 2 with a 10% aqueous hydrochloric
acid solution and then extracted with ethyl acetate (1.times.200
mL). The organic layer was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g,
35%) as a cream solid: mp 91-93.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.2S (M.sup.+) 264.1184, found 264.1177.
[0294] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg,
0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene
chloride (2 mL) was cooled to 0.degree. C. and then treated with
N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the
complete addition of N-bromosuccinimide, the reaction mixture was
allowed to warm to 25.degree. C. over 30 min. The orange reaction
mixture was then treated with 2-aminopyridine (151 mg, 1.60 numol),
and the resulting reaction mixture was stirred at 25.degree. C. for
15 h. The reaction mixture was then concentrated in vacuo to remove
methylene chloride. The remaining residue was partitioned between
water and ethyl acetate. The organic layer was washed with a 1N
aqueous hydrochloric acid solution, washed with a saturated aqueous
sodium bicarbonate solution, dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-y-
l-propionamide (83 mg, 32%) as a white solid: mp 127-128.degree.
C.; EI-HRMS m/e calcd for C.sub.20H.sub.24N.sub.2OS (M.sup.+)
340.1609, found 340.1611.
EXAMPLE 41
3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propiona-
mide
[0295] 54
[0296] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.300 mL). The organic layer was washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-trifluoromet-
hylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid:
mp 69-71.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0297] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(59.6 mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol)
in methylene chloride (468 .mu.L) was cooled to 0.degree. C. and
then treated with N-bromosuccinimide (36.7 mg, 0.206 mmol) in small
portions. After the complete addition of N-bromosuccinimide, the
reaction mixture was allowed to warm to 25.degree. C. over 30 min.
The orange reaction mixture was then treated with 2-aminopyridine
(35.2 mg, 0.374 mmol). The resulting reaction mixture was stirred
at 25.degree. C. for 16 h. The reaction mixture was then
concentrated in vacuo to remove methylene chloride. The remaining
residue was diluted with ethyl acetate (50 mL). The organic layer
was washed with a 10% aqueous hydrochloric acid solution
(1.times.50 mL), washed with a saturated aqueous sodium bicarbonate
solution (1.times.50 mL), washed with water (1.times.50 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfan-
yl-phenyl)-propionamide (25.0 mg, 34%) as a cream solid: mp
101-102.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.21F.sub.3N.sub.2O- S (M.sup.+) 394.1327, found
394.1321.
EXAMPLE 42
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide
[0298] 55
[0299] A solution of 2-aminopyridine (95 mg, 1.01 mmol) in
acetonitrile (2 mL) was treated with
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared
in Example 3(A), 250 mg, 0.84 mmol), triphenylphosphine (243 mg,
0.93 mmol), triethylamine (350 .mu.L, 2.53 mmol), and carbon
tetrachloride (1 mL). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The cloudy reaction mixture was diluted
with water and then extracted with methylene chloride. The organic
layer was dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/3 hexanes/ethyl acetate) afforded impure
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyr-
idin-2-yl-propionamide. Recrystallization from hexanes/methylene
chloride provided pure
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-pyridin-2-yl-p-
ropionamide (170 mg, 54%) as a white solid: mp 172-173.degree. C.;
EI-HRMS m/e calcd for C.sub.20H.sub.24N.sub.2O.sub.3S (M.sup.+)
372.1508, found 372.1498.
EXAMPLE 43
(A)
3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-pro-
pionamide
[0300] 56
[0301] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.300 mL). The organic layer was washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-trifluoromet-
hylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid:
mp 69-71.degree. C.; EI-HRMS mle calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0302] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 36 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (200 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 miL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 97/3
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trif-
luoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g,
99%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.2S (M.sup.+) 332.1058, found
332.1052.
[0303] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
methyl ester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was
treated with 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based
on 80%, 9.26 mmol). The reaction mixture was stirred at 25.degree.
C. for 17 h, at which time, thin layer chromatography showed the
presence of two new lower R.sub.f products. An additional 2.00 g of
3-chloroperoxybenzoic acid was added to the reaction mixture to
drive the conversion of the sulfoxide to the sulfone, and the
resulting reaction mixture was stirred at 25.degree. C. for 3 d.
The reaction mixture was concentrated in vacuo to remove methylene
chloride. The resulting residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
bicarbonate solution (3.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 19/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-trifluoromethanesulfon- yl-phenyl)propionic acid
methyl ester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956, found
364.0965.
[0304] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
methyl ester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (3.6 mL,
2.92 mmol). The reaction mixture was stirred at 25.degree. C. for
23 h and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo to afford
a cream solid. This solid was purified by triturating with diethyl
ether/petroleum ether to provide pure
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid
(527.0 mg, 77%) as a white solid: mp 143-145.degree. C.; EI-HRMS
m/e calcd for C.sub.15H.sub.17F.sub.3O.sub.4S (M.sup.+) 350.0800,
found 350.0816.
[0305] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
(118.9 mg, 0.34 mmol) and triphenylphosphine (133.5 mg, 0.51 mmol)
in methylene chloride (848 .mu.L) was cooled to 0.degree. C. and
then treated with N-bromosuccinimide (102.7 mg, 0.58 mmol) in small
portions. After the complete addition of N-bromosuccinimide, the
reaction mixture was allowed to warm to 25.degree. C. where it was
stirred for 45 min. The reaction mixture was then treated with
2-aminopyridine (95.8 mg, 1.02 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 22 h. The reaction mixture
was then concentrated in vacuo. Flash chromatography (Merck Silica
gel 60, 230-400 mesh, 5/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfo-
nyl-phenyl)-propionamide (37.1 mg, 26%) as a light yellow solid: mp
151-153.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.21F.sub.3N.sub.2O- .sub.3S (M.sup.+) 426.1225, found
426.1220.
[0306] (B) In an analogous manner, there were obtained:
[0307] (a) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and 2-amino-5-chloropyridine: N-(5-Chloro-pyridin-2-yl)-3-cyclopen-
tyl-2-(4-trifluoromethane-sulfonyl-phenyl)-propionamide as a cream
solid: mp 146-148.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.20ClF.sub.3N.s- ub.2O.sub.3S (M.sup.+) 460.0835,
found 460.0846.
[0308] (b) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and 2-amino-5-methyl pyridine: 3-Cyclopentyl-N-(5-methyl-pyridin-2-
-yl)-2-(4-trifluoro-methanesulfonyl-phenyl)-propionamide as a pale
yellow solid: mp 155-157.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.23F.sub.3N.sub.2O.sub.3S (M.sup.+) 440.1381, found
440.1376.
[0309] (c) From
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propion- ic acid
and 6-aminonicotinic acid methyl ester: 6-[3-Cyclopentyl-2-(4-trif-
luoromethanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl
ester as a yellow foam: mp 58-62.degree. C.; EI-HRMS m/e calcd for
C.sub.22H.sub.23F.sub.3N.sub.2O.sub.5S (M.sup.+) 484.1280, found
484.1274.
EXAMPLE 44
3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionam-
ide
[0310] 57
[0311] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenyla- cetic acid
methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found 229.0146.
[0312] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of 25 iodomethylcyclopentane (4.58 g, 21.8
mol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitrophenyl)-3-cy- clopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0313] A solution of
2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl
ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53
mmol) in dimethyl sulfoxide (3 mL) was heated at 130.degree. C. for
5 h. The black reaction mixture was then poured over ice (20 g),
resulting in the formation of a brown sticky substance. The
resulting mixture was then treated with ethyl acetate (50 mL) and
water (50 mL), and the layers were separated. The aqueous layer was
further extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propi- onic acid
methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.6S (M+H).sup.+ 356.1169, found 356.1175.
[0314] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-pro- pionic acid
methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL,
3.65 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting aqueous residue was diluted with
water (25 mL) and then treated with a 1N aqueous hydrochloric acid
solution (10 mL). The resulting aqueous layer was then extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/4
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfo-
nyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam.
Analytical data indicated the presence of a small impurity;
however, the
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
was used without further purification in subsequent reactions.
[0315] A solution of triphenylphosphine (138 mg, 0.53 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol) in small
portions. The reaction mixture was stirred at 0.degree. C. for 10
min and then treated with
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
(150 mg, 0.44 mmol). The resulting reaction mixture was stirred at
0.degree. C. for 5 min and then allowed to warm to 25.degree. C.,
where it was stirred for 25 min. The reaction mixture was then
treated with 2-aminopyridine (91 mg, 0.97 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 15 h. The crude
reaction mixture was directly purified by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to
afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nit-
rophenyl)-N-pyridin-2-yl-propionamide (106 mg, 58%) as a white
foam: mp 92-95.degree. C. (foam to gel); FAB-HRMS m/e calcd for
C.sub.20H.sub.23N.sub.3O.sub.5S (M+H)+418.1436, found 418.1430.
EXAMPLE 45
6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic
Acid Methyl Ester
[0316] 58
[0317] A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol),
methanol (75 mL), and concentrated hydrochloric acid (4 mL) was
heated under reflux for 16 h. The reaction mixture was allowed to
cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting solid was treated with water (20 mL) and
enough sodium bicarbonate to adjust the pH=8. The solution was then
extracted with ethyl acetate (3.times.25 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo to afford 6-aminonicotinic acid methyl ester (3.12 g, 71%)
as white foam: EI-HRMS m/e calcd for C.sub.7H.sub.8N.sub.2O.sub.2
(M.sup.+) 152.0586, found 152.0586.
[0318] A solution of triphenylphosphine (1.23 g, 4.69 mmol) in
methylene chloride (15 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (947 mg, 5.32 mmol). The resulting
brown-purple solution was stirred at 0.degree. C. for 5 min and
then treated with
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared
in Example 54, 900 mg, 3.13 mmol). The reaction mixture was stirred
at 0.degree. C. and then allowed to warm to 25.degree. C. over 45
min. The reaction mixture was then treated with 6-aminonicotinic
acid methyl ester (620 mg, 4.07 mmol) and pyridine (0.38 mL, 4.7
mmol), and the reaction mixture was allowed to stir at 25.degree.
C. for 20 h. The resulting reaction mixture was diluted with water
(15 mL) and then extracted with methylene chloride (3.times.15 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 9/1 hexanes/ethyl acetate) afforded
6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylam-
ino]-nicotinic acid methyl ester (1.10 g, 84%) as a white foam:
[.alpha.].sup.23.sub.589=-68.0.degree. (c=0.128, chloroform);
FAB-HRMS m/e calcd for C.sub.21H.sub.22Cl.sub.2N.sub.2O.sub.3
(M+H).sup.+ 421.1086, found 421.1079.
EXAMPLE 46
6-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic
Acid
[0319] 59
[0320] A solution of
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymet-
hylpyridin)-2-yl-propionamide (prepared in Example 38(B)(b), 50 mg,
0.12 mmol) in ethanol (10 mL) at 25.degree. C. was treated with a
solution of potassium hydroxide (20 mg, 0.36 mmol) in water (2 mL).
The reaction was stirred at 25.degree. C. for 2 h. At this time,
the reaction was diluted with water (5 mL). The ethanol was removed
in vacuo. The aqueous layer was then acidified to pH=2 with a 1N
aqueous hydrochloric acid solution. This solution was extracted
with methylene chloride (3.times.10 mL). The organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate with acetic acid) afforded
6-[3-cyclopentyl-2-(3,4--
dichloro-phenyl)-propionylamino]-nicotinic acid (34 mg, 71%) as
white foam: EI-HRMS m/e calcd for
C.sub.20H.sub.20Cl.sub.2N.sub.2O.sub.3 (M.sup.+) 406.0851, found
406.0852.
EXAMPLE 47
6-[2-(4-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic
Acid
[0321] 60
[0322] A solution of
6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-- nicotinic
acid methyl ester (prepared in Example 31(B)(c), 62.6 mg, 0.16
mmol) in tetrahydrofaran/water/methanol (0.40 mL, 3:1:1) was
treated with a 2N aqueous sodium hydroxide solution (0.16 mL, 0.32
mmol). The reaction was stirred at 25.degree. C. for 24 h. The
reaction mixture was then poured into water and extracted with
chloroform (2.times.30 mL). The aqueous layer was then acidified to
pH=1 with a 1N aqueous hydrochloric acid solution. The product was
extracted into chloroform/methanol (9:1, 3.times.25 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 75/25
hexanes/ethyl acetate w/acetic acid) afforded
6-[2-(4-chloro-phenyl)-3-cy- clopentyl-propionylamino]-nicotinic
acid (17.0 mg, 31.5%) as a white solid: mp 206-208.degree. C.;
EI-HRMS m/e calcd for C.sub.20H.sub.21ClN.sub.2O.sub.2 (M.sup.+)
372.1240, found 372.1244.
EXAMPLE 48
6-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic
Acid
[0323] 61
[0324] A solution of
6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propion-
ylamino]-nicotinic acid methyl ester (prepared in Example 53(B)(a),
100 mg, 0.23 mmol) in tetrahydrofuran (500 .mu.L) was treated with
a 0.8M aqueous lithium hydroxide solution (300 .mu.L, 0.23 mmol).
The solution was stirred at 25.degree. C. for 4 h. The reaction
mixture was then directly purified by column chromatography. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/3
methanol/ethyl acetate) afforded
6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-nicotinic
acid (65 mg, 70%) as a white solid: mp 191-193.degree. C.; FAB-HRMS
m/e calcd for C.sub.21H.sub.24N.sub.2O.sub.5S (M+H).sup.+ 417.1484,
found 417.1484.
EXAMPLE 49
3-Cyclopentyl-2(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)-prop-
ionamide
[0325] 62
[0326] A solution of
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-carboxymet-
hylpyridin)-2-yl-propionamide (prepared in Example 38(B)(b), 398
mg, 0.95 mmol) in diethyl ether (30 mL) cooled to 0.degree. C. was
treated with lithium aluminum hydride (54 mg, 1.4 mmol). This
slurry was allowed to slowly warm to 25.degree. C. The reaction was
stirred at 25.degree. C. for 16 h. At this time, the reaction was
quenched with water (10 mL) and extracted with ethyl acetate
(3.times.15 mL). The organics were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxymethy-
l-pyridin-2-yl)-propionamide (131 mg, 35%) as a white foam: EI-HRMS
mn/e calcd for C.sub.20H.sub.22Cl.sub.2N.sub.2O.sub.2 (M.sup.+)
392.1058, found 392.1062.
EXAMPLE 50
2-(4-Chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-propion-
amide
[0327] 63
[0328] A solution of
6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-- nicotinic
acid methyl ester (prepared in Example 31(B)(c), 83.3 mg, 0.21
mmol) in tetrahydrofuran (2.1 mL) was added to a cooled (0.degree.
C.) slurry of lithium aluminum hydride (12.0 mg, 0.32 mmol) in
tetrahydrofuran (1.54 mL). The reaction mixture was stirred at
0.degree. C. for 2.5 h. The reaction was then quenched by the
dropwise addition of water (25 mL). The reaction was further
diluted with water and was then extracted with ethyl acetate
(3.times.35 mL). The organics were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-py-
ridin-2-yl)-propionamide (12.5 mg, 16.1%) as a white solid: mp
60-62.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.23ClN.sub.2O.sub.2(- M.sup.+) 358.1448, found
358.1443.
EXAMPLE 51
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionam-
ide
[0329] 64
[0330] A solution of
3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in
Example 38, 183 mg, 0.63 mmol) in methylene chloride (6.37 mL) was
cooled to 0.degree. C. and then treated with a 2.0M solution of
oxalyl chloride in methylene chloride (0.35 mL, 0.7 mmol) and a few
drops of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and then at 25.degree. C. for 30 min. The
reaction mixture was then treated with
5-benzyloxy-pyridin-2-ylamine (281 mg, 1.4 mmol) and
NA-diisopropylethylamine (0.26 mL, 1.5 mmol). The reaction mixture
was stirred at 25.degree. C. for 16 h. At this time, the reaction
was concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
N-(5-benzyloxy-pyridin-2-yl)--
3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (150 mg, 50.0%)
as a yellow solid: mp 47-49.degree. C.; EI-HRMS m/e calcd for
C.sub.26H.sub.26Cl.sub.2N.sub.2O.sub.2 (M.sup.+) 469.1449, found
469.1455.
[0331] A solution of
N-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dic-
hloro-phenyl)-propionamide (145.3 mg, 0.3 mmol) in methanol (5.1
mL) was treated with 10% palladium on activated carbon. The
reaction mixture was stirred under hydrogen gas at 25.degree. C.
for 16 h. The catalyst was then filtered off through a pad of
celite (ethyl acetate). The filtrate was concentrated in vacuo to
give 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-
-(5-hydroxy-pyridin-2-yl)-propionamide (92.2 mg, 78.5%) as a tan
solid: mp 79-81.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.20Cl.sub.2N.sub.2O.- sub.2 (M.sup.+) 378.0896, found
378.0890.
EXAMPLE 52
3-Cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl-
)-propionamide
[0332] 65
[0333] A solution of
6-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propion-
ylamino]-nicotinic acid methyl ester (prepared in example 53(B)(a),
110 mg, 0.26 mmol) in diethyl ether (500 .mu.L) was cooled to
0.degree. C. and then slowly treated with lithium aluminum hydride
(15 mg, 0.38 mmol). The reaction mixture was stirred at 0.degree.
C. for 30 min then allowed to warm to 25.degree. C. After 1 h at
25.degree. C., thin layer chromatography still indicated the
presence of the starting material. An additional amount of lithium
aluminum hydride (10 mg, 0.26 mmol) was added to the reaction
mixture, and the reaction mixture was allowed to stir at 25.degree.
C. for 1 h. The reaction mixture was then slowly quenched by the
dropwise addition of water (10 mL). The resulting mixture was
partitioned between water and ethyl acetate. The organic layer was
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3
hexanes/ethyl acetate) afforded the
3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-
-methanesulfonyl-phenyl)-propionamide (60 mg, 57%) as a yellow
foam: mp 74-77.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.26N.sub.2O.sub.4S (M.sup.+) 402.1613, found
402.1617.
EXAMPLE 53
(A)
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-p-
ropionamide
[0334] 66
[0335] A solution triphenylphosphine (177 mg, 0.68 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (132 mg, 0.74 mmol) in small
portions. The reaction mixture was allowed to warm to 25.degree. C.
over 30 min and then was treated with
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (prepared
in Example 3(A), 200 mg, 0.68 mmol). The reaction mixture was
stirred at 25.degree. C. for 30 min and then treated with
2-amino-5-methylpyridine (154 mg, 1.42 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 1 h. The crude
reaction mixture was directly purified by flash chromatography
(Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to
afford impure
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-prop-
ionamide as a red solid. The impure product was further purified by
precipitation from 1/1 hexanes/ethyl acetate to afford pure
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-prop-
ionamide (80 mg, 31%) as an off-white solid: mp 184-185.degree. C.;
EI-HRMS m/e calcd for C.sub.21H.sub.26N.sub.2O.sub.3S (M.sup.+)
386.1664, found 386.1664.
[0336] (B) In an analogous manner, there was obtained:
[0337] (a) From 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic
acid and 6-aminonicotinic acid methyl ester:
6-[3-Cyclopentyl-2-(4-methanesulf-
onyl-phenyl)-propionylamino]-nicotinic acid methyl ester as a
yellow foam: mp 82-85.degree. C.; EI-HRMS m/e calcd for
C.sub.22H.sub.26N.sub.2O.sub.5- S (M.sup.+) 430.1562, found
430.1571.
EXAMPLE 54
(A)
N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-pro-
pionamide
[0338] 67
[0339] A solution of
3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in
Example 38, 5.00 g, 17.4 mmol) in tetrahydrofuran (150 mL) cooled
to -78.degree. C. was treated with triethylamine (2.77 mL, 19.9
mmol) followed by trimethylacetyl chloride (2.24 mL, 18.2 mmol).
The resulting white slurry was stirred at -78.degree. C. for 15 min
and then at 0.degree. C. for 45 min. In a separate flask, a
solution of (S)-4-isopropyl-2-oxazolidinone (2.14 g, 16.57 mmol) in
tetrahydrofuran (80 mL) cooled to -78.degree. C. was treated with a
2.0M solution of n-butyllithium in hexanes (8.7 mL, 17.4 mmol). The
solution was stirred at -78.degree. C. for 10 min and then allowed
to warm to 25.degree. C. where it was stirred for an additional 10
min. At this time, the first reaction mixture was recooled to
-78.degree. C. The second reaction mixture was added to the first
reaction mixture over a period of 5 min via cannula. The combined
reaction was then stirred at -78.degree. C. for 15 min and then
allowed to warm to 25.degree. C. where it was stirred for an
additional 1.5 h. At this time, the reaction was quenched by the
addition of a saturated aqueous sodium bisulfite solution (50 mL)
and extracted with ethyl acetate (3.times.40 mL). The combined
organic layers were washed with a saturated aqueous sodium
bicarbonate solution (1.times.20 mL) and a saturated aqueous sodium
chloride solution (1.times.20 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded
(1) 3-[3-cyclopentyl-2(S)-(3,4-dichloro-p-
henyl)-propionyl]-4(S)-isopropyl-oxazolidin-2-one (2.15 g, 33%) as
a clear oil: [.alpha.].sup.23.sub.589=+87.50 (c=0.160, chloroform);
EL-HRMS m/e calcd for C.sub.20H.sub.25Cl.sub.2NO.sub.3 (M.sup.+)
397.1211, found 397.1215 and (2)
3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-4-
(S)-isopropyl-oxazolidin-2-one (1.88 g, 28%) as a white solid: mp
71.9-74.6.degree. C.; [.alpha.].sup.23.sub.589=-27.6.degree.
(c=0.188, chloroform); EI-HRMS m/e calcd for
C.sub.20H.sub.25Cl.sub.2NO.sub.3 (M.sup.+) 397.1211, found
397.1212.
[0340] A solution of
3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl-
]-4(S)-isopropyl-oxazolidin-2-one (1.88 g, 4.72 mmol) in
tetrahydrofuran (73 mL) and water (22 mL) cooled to 0.degree. C.
was treated with a 30% aqueous hydrogen peroxide solution (2.1 mL)
and lithium hydroxide (394 mg, 9.4 mmol). The reaction was stirred
at 0.degree. C. for 1 h. At this time, the reaction was quenched
with a saturated aqueous sodium sulfite solution (16 mL) followed
by the addition of a 0.5N aqueous sodium bicarbonate solution (50
mL). The tetrahydrofuran was then removed in vacuo. The residue was
diluted with water (40 mL) and extracted with methylene chloride
(3.times.20 mL). The aqueous layer was then acidified to pH=2 with
5N aqueous hydrochloric acid solution and extracted with ethyl
acetate (4.times.25 mL). The combined organic layers were then
dried over sodium sulfate, filtered, and concentrated in vacuo to
afforded of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid
(928 mg, 70%) as a white solid: mp 75.1-78.3.degree. C.;
[.alpha.].sup.23.sub.589=-50.3.degree. (c=0.100, chloroform);
EI-HRMS m/e calcd for C.sub.14H.sub.16Cl.sub.2O.sub.2 (M.sup.+)
286.0527, found 286.0535.
[0341] A solution of triphenylphosphine (344 mg, 1.31 mmol) in
methylene chloride (10 mL) cooled to 0.degree. C. was treated with
N-bromosuccinimide (263 mg, 1.48 mmol). The reaction solution was
stirred at 0.degree. C. for 5 min. At this time,
3-cyclopentyl-2-(R)-(3,4-dichlor- o-phenyl) propionic acid (250 mg,
0.87 mmol) was added. The reaction was allowed to slowly warm to
25.degree. C. over 45 min. At this time, 5-chloro-2-aminopyridine
(145 mg, 1.13 mmol) and pyridine (0.11 mL, 1.31 mmol) were added to
the reaction mixture. The reaction was stirred at 25.degree. C. for
20 h. At this time, the reaction was diluted with water (10 mL) and
extracted with methylene chloride (3.times.10 mL). The organics
were dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
90/10 hexanes/ethyl acetate) afforded
N-(5-chloro-pyridin-2-yl)3-cyclopentyl-2--
(R)-(3,4-dichloro-phenyl)-propionamide (289 mg, 84%) as a white
solid: mp 125-128.degree. C.;
[.alpha.].sup.23.sub.589=-65.6.degree. (c=0.16, chloroform);
EI-HRMS m/e calcd for C.sub.19H.sub.19Cl.sub.3N.sub.2O (M.sup.+)
396.0563, found 396.0565.
[0342] (B) In an analogous manner, there were obtained:
[0343] (a) From 2-amnino pyridine and
3-cyclopentyl-2-(R)-(3,4-dichloro-ph- enyl) propionic acid:
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-
-yl-propionamide as a white foam:
[.alpha.].sup.23.sub.589=-56.2.degree. (c=0.153, chloroform);
EI-HRMS m/e calcd for C.sub.19H.sub.20Cl.sub.2N.su- b.2O (M.sup.+)
362.0953, found 362.0952.
[0344] (b) From 2-aminothiazole and
3-cyclopentyl-2-(R)-(3,4-dichloro-phen- yl) propionic acid:
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-thiazol-2-y-
l-propionamide as a white solid: mp 133.4-136.5.degree. C.;
[.alpha.].sup.23.sub.589=-66.0.degree. (c=0.106, chloroform);
EI-HRMS m/e calcd for C.sub.17H.sub.18Cl.sub.2N.sub.2OS (M.sup.+)
368.0517, found 368.0519.
[0345] (c) From 2-(amino-thiazol-5-yl)-oxo-acetic acid ethyl ester
and
3-cyclopentyl-2-(R)-3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid:
(2R)-{2-[3-Cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-5-y-
l}-oxo-acetic acid ethyl ester as a light yellow foam: mp
117-120.degree. C.; FAB-HRMS m/e calcd for
C.sub.21H.sub.22Cl.sub.2N.sub.2O.sub.4S (M+H).sup.+ 469.0755, found
469.0753.
[0346] (d) From ethyl 2-amino-4-thiazole glyoxylate and
3-cyclopentyl-2-(R)-3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid:
(2R)-{2-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazol-4--
yl}-oxo-acetic acid ethyl ester as a white solid: EI-HRMS m/e calcd
for C.sub.21H.sub.22Cl.sub.2N.sub.2O.sub.4S (M.sup.+) 468.0677,
found 468.0677.
EXAMPLE 55
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide
[0347] 68
[0348] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 200 mg, 0.70 mmol),
benzotriazol-1-yloxy-tris(di- methylamino)phosphonium
hexafluorophosphate (310 mg, 0.70 mmol), N,N-diisopropylethylamine
(244 .mu.L, 1.40 mmol), and 2-aminoimidazole sulfate (140 mg, 1.05
mmol) in dry N,N-dimethylformamide (5 mL) was stirred at 25.degree.
C. under nitrogen for 15 h. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was washed with
a 1N aqueous hydrochloric acid solution, washed with water, and
washed with a saturated aqueous sodium chloride solution. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/3 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1-
H-imidazol-2-yl)-propionamide (81.4 mg, 33%) as a white solid: mp
58-60.degree. C.; EI-HRMS m/e calcd for
C.sub.17H.sub.19Cl.sub.2N.sub.3O (NV) 351.0905, found 351.0901.
EXAMPLE 56
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionami-
de
[0349] 69
[0350] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 70.7 mg, 0.25 mmol) in oxalyl
chloride (215 .mu.L, 2.46 mmol) was cooled to 0.degree. C. and then
treated with 1 drop of dry N,N-dimethylformamide. The reaction
mixture was stirred at 0.degree. C. for 30 min and then stirred at
25.degree. C. for 3 h. The reaction mixture was concentrated in
vacuo to afford a yellow oil. This yellow oil was dissolved in a
small amount of methylene chloride and then slowly added to a
solution of 3-amino-5-methylisoxazole (48.3 mg, 0.49 mmol) and
triethylamine (68 mL, 0.49 mmol) in methylene chloride (1.2 mL).
The resulting reaction mixture was stirred at 25.degree. C. for 14
h. The reaction mixture was concentrated in vacuo to remove
methylene chloride. The resulting residue was diluted with ethyl
acetate (100 mL) and then washed with a 10% aqueous hydrochloric
acid solution. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-
-methyl-isoxazol-3-yl)-propionamide (78.3 mg, 87%) as a yellow
glass: mp 84-86.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.20Cl.sub.2N.sub.2O- .sub.2 (M+H).sup.+ 367.0981,
found 367.0982.
EXAMPLE 57
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-oxazol-2-yl-propionamide
[0351] 70
[0352] A solution of
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (102 mg, 0.23 mmol),
3-cyclopentyl-2-(3,4-dichlorophe- nyl)-propionic acid (prepared in
Example 38, 60 mg, 0.21 mmol), N,N-diisopropylethylamine (73 .mu.L,
0.42 mmol), and 2-aminooxazole (27 mg, 0.31 mmol) in dry
N,N-dimethylformamide (1 mL) was stirred at 25.degree. C. under
nitrogen for 15 h. The reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with a 1N
aqueous hydrochloric acid solution, washed with water, and washed
with a saturated aqueous sodium chloride solution. The organic
layer was dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-ox- azol-2-yl-propionamide
(34.9 mg, 47%) as a white solid: mp 134-136.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.18Cl.sub.2N.sub.2O.sub.2(M.sup.+) 352.0745,
found 352.0750.
EXAMPLE 58
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide
[0353] 71
[0354] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 625.2 mg, 2.18 mmol),
O-benzotriazol-1-yl-N,N,N'- ,N'-tetramethyluronium
hexafluorophosphate (908.3 mg, 2.39 mmol),
N,N-diisopropylethylamine (1.1 mL, 6.53 mmol), and
3-aminopyridazine (310.6 mg, 3.27 mmol) in dry
N,N-dimethylformamide (11 mL) was stirred at 25.degree. C. under
nitrogen for 72 h. The reaction mixture was concentrated in vacuo
to remove N,N-dimethylformamide. The resulting residue was diluted
with ethyl acetate (200 mL). The organic layer was washed with a
10% aqueous hydrochloric acid solution and washed with a saturated
aqueous sodium chloride solution. The organic layer was dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-p-
ropionamide (493.8 mg, 62%) as a white foam: mp 70-71.degree. C.;
EI-HRMS m/e calcd for C.sub.18H.sub.19Cl.sub.2N.sub.3O (M.sup.+)
363.0905, found 363.0908.
EXAMPLE 59
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide
[0355] 72
[0356] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 100 mg, 0.35 mmol) in methylene
chloride (1 mL) was treated with 2 drops of dry
N,N-dimethylformamide. The reaction mixture was cooled to 0.degree.
C. and then treated dropwise with oxalyl chloride (34 mL, 0.39
mmol). The reaction mixture was stirred at 0.degree. C. for 10 min
and then stirred at 25.degree. C. for 2 h. The reaction mixture was
concentrated in vacuo. The resulting residue was dissolved in a
small amount of methylene chloride and was slowly added to a cooled
(0.degree. C.) solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in
methylene chloride (1 mL). The resulting reaction mixture was
stirred at 0.degree. C. for 30 min and then stirred at 25.degree.
C. for 2 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
water and extracted with ethyl acetate (3.times.50 mL). The
combined organic extracts were washed with a saturated aqueous
sodium chloride solution. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-p-
ropionamide (85.4 mg, 67%) as a white solid: mp 103-105.degree. C.;
EI-HRMS m/e calcd for C.sub.18H.sub.19Cl.sub.2N.sub.3O (M.sup.+)
363.0905, found 363.0915.
EXAMPLE 60
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrimidine-6-yl-propionamide
[0357] 73
[0358] A solution of
3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (prepared in
Example 54(A), 200 mg, 0.69 mmol) in methylene chloride (5 mL) was
treated with 1 drop of N,N-dimethylformamide and then cooled to
0.degree. C. The reaction mixture was then treated with a 2.0M
solution of oxalyl chloride in methylene chloride (0.52 mL, 1.04
rmmol). The reaction mixture was stirred at 0.degree. C. for 30 min
and then treated with a solution of 4-aminopyrimidine (131 mg, 1.38
mmol) in tetrahydrofuran (10 mL) and pyridine (0.28 mL, 3.45 mmol).
The resulting reaction mixture was stirred at 23.degree. C. for 14
h. The reaction mixture was then diluted with water (10 mL) and
extracted with methylene chloride (3.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 3/2 hexanes/ethyl acetate) afforded
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyrimidin-4-yl-propionamide
(147 mg, 60%) as a white solid: mp 166.5-169.3.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.19Cl.sub.2N.sub.3O (M.sup.+) 363.0905,
found 363.0909.
EXAMPLE 61
3-Cyclopentyl-2-(4-methanesulfinyl-phenyl)-N-thiazol-2-yl-propionamide
[0359] 74
[0360] A solution of diisopropylamine (3.2 mL, 23.16 mmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (2.3 mL, 23.16 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
4-(methylthio)phenylacetic acid (2.01 g, 11.03 mmol) in dry
tetrahydrofuran (10.3 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim- idinone (3.4 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (2.55 g, 12.13
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was stirred at -78.degree. C. for 30 min and
then allowed to warm to 25.degree. C. where it was stirred for 24
h. The reaction mixture was quenched with water and then
concentrated in vacuo to remove tetrahydrofuran. The remaining
aqueous phase was acidified to pH=2 with a 10% aqueous hydrochloric
acid solution and then extracted with ethyl acetate (1.times.200
mL). The organic layer was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (1.01 g,
35%) as a cream solid: mp 91-93.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.2S (M.sup.+) 264.1184, found 264.1177.
[0361] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg,
0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene
chloride (2 mL) was cooled to 0.degree. C. and then slowly treated
with N-bromosuccinimide (150 mg, 0.84 mmol). After the complete
addition of N-bromosuccinimide, the reaction mixture was allowed to
warm to 25.degree. C. over 30 min. The reaction mixture was then
treated with 2-aminothiazole (160 mg, 1.60 mmol), and the resulting
reaction mixture was stirred at 25.degree. C. for 15 h. The
reaction mixture was then concentrated in vacuo to remove methylene
chloride. The remaining residue was diluted with water and ethyl
acetate. The organic layer was washed with a 1N aqueous
hydrochloric acid solution, washed with a saturated aqueous sodium
bicarbonate solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 2/1 hexanes/ethyl acetate) afforded crude
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide
as a yellow solid. Recrystallization from 3/1 hexanes/ethyl acetate
afforded pure
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamid-
e (114 mg, 44%) as a white solid: mp 195-196.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.22N.sub.2OS.sub.2 (M.sup.+) 346.1174,
found 346.1171.
[0362] A solution
3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-
-propionamide (75 mg, 0.216 mmol) in methylene chloride (1 mL) was
treated with 3-chloroperoxybenzoic acid (75% grade, 50 mg, 0.216
mmol). The reaction mixture was immediately monitored by thin layer
chromatography and the results indicated the immediate absence of
starting material. The reaction mixture was partitioned between
water and methylene chloride and then washed with a saturated
aqueous sodium bicarbonate solution. The organic layer was further
washed with water and then dried over magnesium sulfate, filtered,
and concentrated in vacuo. Recrystallization from 1/1 hexanes/ethyl
acetate afforded 3-cyclopentyl-2-(4-methanesulfinyl-phenyl)-
-N-thiazol-2-yl-propionamide (25 mg, 32%) as a white solid: mp
170-173.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.22N.sub.2O.sub.2S- .sub.2 (M.sup.+) 362.1123, found
362.1121.
EXAMPLE 62
{2-p-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylaminol-thi-
azol-4-yl}-acetic Acid Ethyl Ester
[0363] 75
[0364] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.300 mL). The organic layer was washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-trifluoromet-
hylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid:
mp 69-71.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0365] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 36 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (200 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 97/3
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trif-
luoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g,
99%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.2S (M.sup.+) 332.1058, found
332.1052.
[0366] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
methyl ester (1.14 g, 3.43 numol) in methylene chloride (8.6 mL)
was treated with 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g
based on 80%, 9.26 mmol). The reaction mixture was stirred at
25.degree. C. for 17 h, at which time, thin layer chromatography
showed the presence of two new lower R.sub.f products. An
additional 2.00 g of 3-chloroperoxybenzoic acid was added to the
reaction mixture to drive the conversion of the sulfoxide to the
sulfone, and the resulting reaction mixture was stirred at
25.degree. C. for 3 d. The reaction mixture was concentrated in
vacuo to remove methylene chloride. The resulting residue was
diluted with ethyl acetate (300 mL). The organic phase was washed
with a saturated aqueous sodium bicarbonate solution (3.times.100
mL), washed with a saturated aqueous sodium chloride solution
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-trifluoromethanesulfon- yl-phenyl)propionic acid
methyl ester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956, found
364.0965.
[0367] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
methyl ester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (3.6 mL,
2.92 mmol). The reaction mixture was stirred at 25.degree. C. for
23 h and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo to afford
a cream solid. This solid was purified by triturating with diethyl
ether/petroleum ether to provide pure
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid
(527.0 mg, 77%) as a white solid: mp 143-145.degree. C.; EI-HRMS
m/e calcd for C.sub.15H.sub.17F.sub.3O.sub.4S (M.sup.+) 350.0800,
found 350.0816.
[0368] A solution of triphenylphosphine (97 mg, 0.371 mmol) in
methylene chloride (1.5 ML) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (66 mg, 0.371 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-trifl-
uoromethanesulfonyl-phenyl)propionic acid (100 mg, 0.285 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 10 min,
allowed to warm to 25.degree. C., and then treated with ethyl
.sup.2-amino-4-thiazoleacetate (123 mg, 0.657 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 3 d. The reaction
mixture was then concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded
{2-[.sup.3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl-am-
ino]-thiazol-4-yl}-acetic acid ethyl ester (107 mg, 72%) as a
yellow foam: mp 48-51.degree. C.; EI-HRMS m/e calcd for
C.sub.22H.sub.25F.sub.3N.sub.2- O.sub.5S.sub.2 (M.sup.+) 518.1157,
found 518.1157.
EXAMPLE 63
N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-pheny-
l)-propionamide
[0369] 76
[0370] A solution of diisopropylamine (2.4 mL, 16.80 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (6.7 mL, 16.80 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
4-(trifluoromethylthio)phenylacetic acid (1.89 g, 8.00 mmol) in dry
tetrahydrofuran (7.5 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (2.5 mL). The
reaction mixture was allowed to stir at -78.degree. C. for 55 min,
at which time, a solution of iodomethylcyclopentane (1.85 g, 8.80
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 41 h. The reaction mixture was quenched with water
and then concentrated in vacuo to remove tetrahydrofiran. The
remaining aqueous phase was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.300 mL). The organic layer was washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-trifluoromet-
hylsulfanyl-phenyl)propionic acid (1.47 g, 58%) as a cream solid:
mp 69-71.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.2S (M.sup.+) 318.0901, found
318.0912.
[0371] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
(1.33 g, 4.18 mmol) in methanol (10 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 36 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (200 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 97/3
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trif-
luoromethylsulfanyl-phenyl)propionic acid methyl ester (1.37 g,
99%) as a light yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.2S (M.sup.+) 332.1058, found
332.1052.
[0372] A solution of
3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)pro- pionic acid
methyl ester (1.14 g, 3.43 mmol) in methylene chloride (8.6 mL) was
treated with 3-chloroperoxybenzoic acid (80-85% grade, 2.00 g based
on 80%, 9.26 mmol). The reaction mixture was stirred at 25.degree.
C. for 17 h, at which time, thin layer chromatography showed the
presence of two new lower R.sub.f products. An additional 2.00 g of
3-chloroperoxybenzoic acid was added to the reaction mixture to
drive the conversion of the sulfoxide to the sulfone, and the
resulting reaction mixture was stirred at 25.degree. C. for 3 d.
The reaction mixture was concentrated in vacuo to remove methylene
chloride. The resulting residue was diluted with ethyl acetate (300
mL). The organic phase was washed with a saturated aqueous sodium
bicarbonate solution (3.times.100 mL), washed with a saturated
aqueous sodium chloride solution (1.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 19/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-trifluoromethanesulfon- yl-phenyl)propionic acid
methyl ester (1.19 g, 95%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956, found
364.0965.
[0373] A solution of
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)pr- opionic acid
methyl ester (708.2 mg, 1.94 mmol) in tetrahydrofuran (2.4 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (3.6 mL,
2.92 mmol). The reaction mixture was stirred at 25.degree. C. for
23 h and then concentrated in vacuo to remove tetrahydrofuran. The
remaining aqueous layer was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were washed with a
saturated aqueous sodium chloride solution (1.times.100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo to afford
a cream solid. This solid was purified by triturating with diethyl
ether/petroleum ether to provide pure
3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid
(527.0 mg, 77%) as a white solid: mp 143-145.degree. C.; EI-HRMS
m/e calcd for C.sub.15H.sub.17F.sub.3O.sub.4S (M.sup.+) 350.0800,
found 350.0816.
[0374] A solution of triphenylphosphine (206 mg, 0.785 mmol) in
methylene chloride (4 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (140 mg, 0.785 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 3-cyclopentyl-2-(4-trifl-
uoromethanesulfonyl-phenyl)propionic acid (250 mg, 0.710 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 10 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with
2-amino-5-bromopyridine (271 mg, 1.57 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 15 h. The reaction mixture
was then concentrated in vacuo. Flash chromatography (Merck Silica
gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded the pure
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-tr-
ifluoromethanesulfonyl-phenyl)-propionamide (226 mg, 63%) as a
yellow foam: mp 130-132.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.20BrF.sub.3N.sub.2O.sub.3S (M.sup.+) 504.0330, found
504.0325.
EXAMPLE 64
2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0375] 77
[0376] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitro-phenyl- acetic
acid methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd
for C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found
229.0146.
[0377] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitro-phenyl)-3-c- yclopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0378] A solution of
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl
ester (260 mg, 0.834 mmol) in tetrahydrofuran (3 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (1.25 mL, 1.00
mmol). The reaction mixture was stirred at 25.degree. C. for 15 h.
The resulting reaction mixture was partitioned between water (50
mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous
hydrochloric acid solution (10 mL). The layers were shaken and
separated. The aqueous layer was further extracted with ethyl
acetate (50 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl- -propionic acid (243 mg,
98%) as a yellow solid which was used without further purification:
mp 112-115.degree. C.; FAB-HRMS m/e calcd for
C.sub.14H.sub.16C1NO.sub.4 (M+H).sup.+ 298.0847, found
298.0851.
[0379] A solution of triphenylphosphine (105 mg, 0.403 mnol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 2-(4-chloro-3-nitro-phen- yl)-3-cyclopentyl-propionic
acid (100 mg, 0.336 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then allowed to warm to
25.degree. C., where it was stirred for 20 min. The reaction
mixture was then treated with 2-aminothiazole (74 mg, 0.739 mmol).
The resulting reaction mixture was stirred at 25.degree. C. for 15
h. The crude reaction mixture was treated with a solution of
hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by
flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate). The pure
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
(93 mg, 73%) was obtained as a pale yellow foam: mp 68-72.degree.
C. (foam to gel); EI-HRMS m/e calcd for
C.sub.17H.sub.18ClN.sub.3O.sub.3S (M.sup.+) 379.0757, found
379.0760.
EXAMPLE 65
2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
[0380] 78
[0381] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitro-phenyl- acetic
acid methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd
for C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found
229.0146.
[0382] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitro-phenyl)-3-c- yclopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0383] A solution of
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl
ester (260 mg, 0.834 mmol) in tetrahydrofuran (3 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (1.25 mL, 1.00
mmol). The reaction mixture was stirred at 25.degree. C. for 15 h.
The resulting reaction mixture was partitioned between water (50
mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous
hydrochloric acid solution (10 mL). The layers were shaken and
separated. The aqueous layer was further extracted with ethyl
acetate (50 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl- -propionic acid (243 mg,
98%) as a yellow solid which was used without further purification:
mp 112-115.degree. C.; FAB-HRMS m/e calcd for
C.sub.14H.sub.16C1NO.sub.4 (M+H).sup.+ 298.0847, found
298.0851.
[0384] A solution of triphenylphosphine (105 mg, 0.403 mmol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 2-(4-chloro-3-nitro-phen- yl)-3-cyclopentyl-propionic
acid (100 mg, 0.336 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then allowed to warm to
25.degree. C., where it was stirred for 20 min. The reaction
mixture was then treated with 2-aminopyridine (70 mg, 0.739 mmol).
The resulting reaction mixture was stirred at 25.degree. C. for 15
h. The crude reaction mixture was treated with a solution of
hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by
flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate). The pure
2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
(60 mg, 48%) was obtained as a pale yellow foam: mp 48-52.degree.
C. (foam to gel); EI-HRMS m/e calcd for
C.sub.19H.sub.20CIN.sub.3O.sub.3 (M.sup.+) 373.1193, found
373.1185.
EXAMPLE 66
N-(5-Bromo-pyridin-2-yl)-3-cyclopenty1-2-(4-methanesulfonyl-3-nitro-phenyl-
)-propionamide
[0385] 79
[0386] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenyla- cetic acid
methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found 229.0146.
[0387] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitrophenyl)-3-cy- clopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0388] A solution of
2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl
ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53
mmol) in dimethyl sulfoxide (3 mL) was heated at 130.degree. C. for
5 h. The black reaction mixture was then poured over ice (20 g),
resulting in the formation of a brown sticky substance. The
resulting mixture was then treated with ethyl acetate (50 mL) and
water (50 mL), and the layers were separated. The aqueous layer was
further extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propi- onic acid
methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.6S (M+H).sup.+ 356.1169, found 356.1175.
[0389] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-pro- pionic acid
methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL,
3.65 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting aqueous residue was diluted with
water (25 mL) and then treated with a 1N aqueous hydrochloric acid
solution (10 mL). The resulting aqueous layer was then extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/4
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfo-
nyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam.
Analytical data indicated the presence of a small impurity;
however, the
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
was used without further purification in subsequent reactions.
[0390] A solution of triphenylphosphine (212 mg, 0.81 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (144 mg, 0.81 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 3-cyclopentyl-2-(4-metha-
nesulfonyl-3-nitrophenyl)-propionic acid (250 mg, 0.73 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C., where it was stirred for
30 min. The reaction mixture was then treated with
2-amino-5-bromopyridine (279 mg, 1.61 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 15 h. The crude reaction
mixture was directly purified by flash chromatography, (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate), to afford
N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesu-
lfonyl-3-nitro-phenyl)-propionamide (121 mg, 33%) as a white foam:
mp 80-83.degree. C. (foam to gel); FAB-HRMS m/e calcd for
C.sub.20H.sub.22BrN.sub.3O.sub.5S (M+H).sup.+ 496.0542, found
496.0543.
EXAMPLE 67
3-Cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-p-
ropionamide
[0391] 80
[0392] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25IC and then filtered to remove the Amberlyst.RTM. 15 ion exchange
resin. The filtrate was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate)
afforded 4-chloro-3-nitrophenylacetic acid methyl ester (1.91 g,
89%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found 229.0146.
[0393] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitrophenyl)-3-cy- clopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.8ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0394] A solution of
2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl
ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53
mmol) in dimethyl sulfoxide (3 mL) was heated at 130.degree. C. for
5 h. The black reaction mixture was then poured over ice (20 g),
resulting in the formation of a brown sticky substance. The
resulting mixture was then treated with ethyl acetate (50 mL) and
water (50 mL), and the layers were separated. The aqueous layer was
further extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propi- onic acid
methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.6S (M+H).sup.+ 356.1169, found 356.1175.
[0395] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-pro- pionic acid
methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL,
3.65 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting aqueous residue was diluted with
water (25 mL) and then treated with a 1N aqueous hydrochloric acid
solution (10 mL). The resulting aqueous layer was then extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/4
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfo-
nyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam.
Analytical data indicated the presence of a small impurity;
however, the
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
was used without further purification in subsequent reactions.
[0396] A solution of triphenylphosphine (138 mg, 0.53 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 3-cyclopentyl-2-(4-metha-
nesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C., where it was stirred for
25 min. The reaction mixture was then treated with 2-aminothiazole
(97 mg, 0.97 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was directly
purified by flash chromatography, (Merck Silica gel 60, 230-400
mesh, 1/1 hexanes/ethyl acetate), to afford
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-t-
hiazol-2-yl-propionamide (96 mg, 52%) as a pale yellow solid: mp
121-124.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.21N.sub.3O.sub.5- S.sub.2 (M+H).sup.+ 424.1001, found
424.1000.
[0397] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-t-
hiazol-2-yl-propionamide (150 mg, 0.354 mmol) in methanol (3 mL)
was treated with 10% palladium on activated carbon (50 mg). The
reaction mixture was stirred under a positive pressure of hydrogen
gas (balloon) at 25.degree. C. and atmospheric pressure for 3 h.
The catalyst was then filtered off through a pad of celite, and the
celite pad was washed well with ethyl acetate. The filtrate was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 20/1 methylene chloride/methanol) afforded
3-cyclopentyl-2-(3-hydroxyamino-4-methanesulf-
onyl-phenyl)-N-thiazol-2-yl-propionamide (85 mg, 59%) as a white
solid: mp 124-126.degree. C.; EI-HRMS m/e calcd for
Cl.sub.8H.sub.23N.sub.3O.sub.4S- .sub.2 (M) 409.1130, found
409.1131.
EXAMPLE 68
2-(3-Amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona-
mide
[0398] 81
[0399] A solution of 4-chloro-3-nitrophenylacetamide (2.00 g, 9.32
mmol) in methanol (40 mL) was treated with Amberlyst.RTM. 15 ion
exchange resin (15.00 g). The resulting reaction mixture was heated
under reflux for 64 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered to remove the Amberlyst.RTM. 15 ion
exchange resin. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded 4-chloro-3-nitrophenyla- cetic acid
methyl ester (1.91 g, 89%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.9H.sub.8ClNO.sub.4 (M.sup.+) 229.0142, found 229.0146.
[0400] A solution of diisopropylamine (3.35 mL, 23.9 mmol) in dry
tetrahydrofuran (45 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (15 mL) was
cooled to -78.degree. C. and then treated dropwise with a 2.5M
solution of n-butyllithium in hexanes (9.56 mL, 23.9 mmol) over a
10 min period. The pale yellow reaction mixture was stirred at
-78.degree. C. for 20 min and then slowly treated with a solution
of 4-chloro-3-nitrophenylacetic acid methyl ester (5.00 g, 21.8
mmol) in a small amount of tetrahydrofuran over a 15 min period.
The reaction mixture turned deep purple (almost black) in color.
The reaction mixture was then stirred at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (4.58 g, 21.8 mol)
in a small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was then stirred at -78.degree. C. and then
allowed to warm to 25.degree. C., where it was stirred for 48 h.
The reaction mixture was quenched with a saturated aqueous ammonium
chloride solution (50 mL), and the resulting reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The remaining
residue was diluted with ethyl acetate (150 mL) and water (50 mL).
The organic phase was washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 4/1 hexanes/ethyl acetate) afforded
2-(4-chloro-3-nitrophenyl)-3-cy- clopentyl-propionic acid methyl
ester (2.17 g, 32%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.18ClNO.sub.4 (M.sup.+) 311.0924, found 311.0927.
[0401] A solution of
2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl
ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53
mmol) in dimethyl sulfoxide (3 mL) was heated at 130.degree. C. for
5 h. The black reaction mixture was then poured over ice (20 g),
resulting in the formation of a brown sticky substance. The
resulting mixture was then treated with ethyl acetate (50 mL) and
water (50 mL), and the layers were separated. The aqueous layer was
flurther extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propi- onic acid
methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.6S (M+H).sup.+ 356.1169, found 356.1175.
[0402] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-pro- pionic acid
methyl ester (865 mg, 2.43 mmol) in tetrahydrofuran (6 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (4.6 mL,
3.65 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The reaction mixture was concentrated in vacuo to remove
tetrahydrofuran. The resulting aqueous residue was diluted with
water (25 mL) and then treated with a 1N aqueous hydrochloric acid
solution (10 mL). The resulting aqueous layer was then extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/4
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfo-
nyl-3-nitrophenyl)-propionic acid (723 mg, 87%) as a white foam.
Analytical data indicated the presence of a small impurity;
however, the
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid
was used without further purification in subsequent reactions.
[0403] A solution of triphenylphosphine (138 mg, 0.53 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (94 mg, 0.53 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 3-cyclopentyl-2-(4-metha-
nesulfonyl-3-nitrophenyl)-propionic acid (150 mg, 0.44 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C., where it was stirred for
25 min. The reaction mixture was then treated with 2-aminothiazole
(97 mg, 0.97 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was directly
purified by flash chromatography, (Merck Silica gel 60, 230-400
mesh, 1/1 hexanes/ethyl acetate), to afford
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-t-
hiazol-2-yl-propionamide (96 mg, 52%) as a pale yellow solid: mp
121-124.degree. C.; FAB-HRMS m/e calcd for
C.sub.18H.sub.21N.sub.3O.sub.5- S.sub.2 (M+H).sup.+ 424.1001, found
424.1000.
[0404] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-t-
hiazol-2-yl-propionamide (100 mg, 0.236 mmol) in methanol (2 mL)
was treated with a solution of ammonium chloride (27 mg, 0.500
mmol) in water (200 .mu.L). The reaction mixture was then treated
with zinc dust (151 mg, 2.31 mmol). The reaction mixture was heated
under reflux for 2 h. The reaction mixture was allowed to cool to
25.degree. C. and then filtered through a pad of celite. The celite
pad was washed well with methanol. The filtrate was concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded
2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propion-
amide (40 mg, 43%) as a white solid: mp 207-209.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.23N.sub.3O.sub.3S.sub.2 (M.sup.+)
393.1181, found 393.1180.
EXAMPLE 69
3-Cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-propion-
amide
[0405] 82
[0406] A solution of 3-(trifluoromethylthio)phenylacetic acid (5.00
g, 21.17 mmol) in methanol (50 mL) was treated slowly with 10 drops
of concentrated sulfuric acid. The resulting reaction mixture was
heated under reflux for 18 h. The reaction mixture was allowed to
cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The residue was diluted with ethyl acetate (100 mL). The
organic phase was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL), dried over magnesium
sulfate, and filtered. The filtrate was concentrated in vacuo to
afford (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester
(5.28 g, 99%) as a pale yellow oil which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.9F.sub.3O.sub.2S
(M.sup.+) 250.0275, found 250.0274.
[0407] A solution of diisopropylamine (1.5 mL, 10.5 mmol) in dry
tetrahydrofuran (27 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (8 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (4.2 mL, 10.5 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
(3-trifluoromethylsulfanyl-p- henyl)-acetic acid methyl ester (2.50
g, 10.0 mmol) in a small amount of tetrahydrofuran. The reaction
mixture was 25 allowed to stir at -78.degree. C. for 1 h, at which
time, a solution of iodomethylcyclopentane (2.10 g, 10.0 mmol) in a
small amount of dry tetrahydrofuran was added dropwise. The
reaction mixture was allowed to warm to 25.degree. C. where it was
stirred for 15 h. The reaction mixture was quenched with water (50
mL) and then partitioned between water (75 mL) and ethyl acetate
(75 mL). The layers were shaken and separated. The organic layer
was dried over magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 8/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromet-
hylsulfanyl-phenyl)-propionic acid methyl ester (2.95 g, 89%) as a
colorless oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.2S (M) 332.1058, found 332.1047.
[0408] A solution of
3-cyclopentyl-2-(3-trifluoromethylsulfanyl-phenyl)-pr- opionic acid
methyl ester (2.75 g, 8.27 mmol) in methylene chloride (30 mL) was
treated with 3-chloroperoxybenzoic acid (80-85% grade, 4.28 g based
on 80%, 20.67 mmol). The reaction mixture was stirred at 25.degree.
C. for 6 h, at which time, thin layer chromatography showed the
presence of two new lower R.sub.f products. An additional 4.00 g of
3-chloroperoxybenzoic acid was added to the reaction mixture to
drive the conversion of the sulfoxide to the sulfone, and the
resulting reaction mixture was stirred at 40.degree. C. for 3 d.
The reaction mixture was allowed to cool to 25.degree. C. and then
partitioned between water (100 mL) and methylene chloride (100 mL).
The layers were shaken and separated. The organic phase was washed
twice with a saturated aqueous sodium bicarbonate solution, washed
with water, dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/methylene chloride) afforded
3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid
methyl ester (2.07 g, 69%) as a colorless oil: EI-HRMS m/e calcd
for C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956, found
364.0947.
[0409] A solution of
3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-p- ropionic
acid methyl ester (1.28 g, 3.52 mmol) in tetrahydrofuran (12 mL)
was treated with a 0.8M aqueous lithium hydroxide solution (4.9 mL,
3.88 mmol). The reaction mixture was stirred at 25.degree. C. for
24 h and then concentrated in vacuo to remove tetrahydrofaran. The
resulting yellow oil was partitioned between water (50 mL) and
ethyl acetate (50 mL) and then treated with a 1N aqueous
hydrochloric acid solution. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromet-
hanesulfonyl-phenyl)-propionic acid (1.09 g, 99%) as a viscous
yellow oil that solidified upon sitting to a white solid: mp
86-88.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17F.sub.3O.sub.4S (M.sup.+) 350.0800, found
350.0792.
[0410] A solution of triphenylphosphine (194 mg, 0.74 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (132 mg, 0.74 mmol). The
reaction mixture was stirred at 0.degree. C. for 15 min and then
treated with 3-cyclopentyl-2-(3-trifl-
uoromethanesulfonyl-phenyl)-propionic acid (200 mg, 0.57 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. over 30 min. The reaction
mixture was then treated with 2-aminothiazole (143 mg, 1.43 mmol).
The resulting reaction mixture was stirred at 25.degree. C. for 15
h. The crude reaction mixture was then directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) to afford pure
3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethanesulfonyl-phenyl)-p-
ropionamide (178 mg, 72%) as a light yellow foam: mp 61-64.degree.
C. (foam to gel); EI-HRMS m/e calcd for
C.sub.18H.sub.19F.sub.3N.sub.2O.sub.- 3S.sub.2 (M.sup.+) 432.0789,
found 432.0790.
EXAMPLE 70
3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-thiazol-2-yl-propion-
amide
[0411] 83
[0412] A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid
(2.50 g, 11.25 mmol) in methanol (25 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 15 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
(3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.58
g, 97%) as a colorless oil: EI-HRMS mle calcd for
C.sub.10H.sub.8F.sub.4O.sub.2 (M.sup.+) 236.0460, found
236.0457.
[0413] A solution of diisopropylamine (1.5 mL, 10.67 mmol) in dry
tetrahydrofuran (24 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (8 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (4.3 mL, 10.67 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 45
min and then treated dropwise with a solution of
(3-fluoro-4-trifluoromethyl-- phenyl)-acetic acid methyl ester
(2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. The
reaction mixture was allowed to stir at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (2.24 g, 10.67
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 15 h. The reaction mixture was quenched with a
saturated aqueous ammonium chloride solution (10 mL) and then
partitioned between water (75 mL) and ethyl acetate (75 mL). The
layers were shaken and separated. The aqueous layer was further
extracted with ethyl acetate (1.times.75 mL). The combined organic
layers were washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
5/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluo-
ro-4-trifluoromethyl-phenyl)-propionic acid methyl ester (2.69 g,
83%) as a colorless oil: EI-HRMS m/e calcd for
C.sub.16H.sub.18F.sub.4O.sub.2 (M.sup.+) 318.1243, found
318.1250.
[0414] A solution of
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-p- ropionic
acid methyl ester (1.80 g, 5.69 mmol) in tetrahydrofuran (15 mL)
was treated with a 0.8M aqueous lithium hydroxide solution (7.1 mL,
5.69 mmol). The reaction mixture was stirred at 25.degree. C. for
15 h. The reaction mixture was concentrated in vacuo. The resulting
residue was diluted with ethyl acetate (100 mL) and then washed
with a 5% aqueous hydrochloric acid solution and a saturated
aqueous sodium chloride solution. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluo-
ro-4-trifluoromethyl-phenyl)-propionic acid (1.11 g, 64%) as a
white solid: mp 93-95.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.16F.sub.4O.sub.2 (M+H).sup.+ 305.1165, found
305.1175.
[0415] A solution of triphenylphosphine (312 mg, 1.19 mmol) in
methylene chloride (5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The
reaction mixture was stirred at 0.degree. C. for 30 min and then
treated with 3-cyclopentyl-2-(3-fluor-
o-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 15 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminothiazole
(218 mg, 2.18 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 3 d. The crude reaction mixture was then directly
purified by flash chromatography (Merck Silica gel 60, 230-400
mesh, 2/1 hexanes/ethyl acetate) to afford
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N--
thiazol-2-yl-propionamide (243 mg, 64%) as a white solid: mp
194-195.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.18F.sub.4N.sub.2O- S (M.sup.+) 386.1076, found
386.1076.
EXAMPLE 71
3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propion-
amide
[0416] 84
[0417] A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid
(2.50 g, 11.25 mmol) in methanol (25 mL) was treated slowly with 4
drops of concentrated sulfuric acid. The resulting reaction mixture
was heated under reflux for 15 h. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
1/1 hexanes/ethyl acetate) afforded
(3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.58
g, 97%) as a colorless oil: EI-HRMS m/e calcd for
C.sub.10H.sub.8F.sub.4O.sub.2 (M.sup.+) 236.0460, found
236.0457.
[0418] A solution of diisopropylamine (1.5 mL, 10.67 mmol) in dry
tetrahydrofuran (24 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (8 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (4.3 mL, 10.67 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 45
min and then treated dropwise with a solution of
(3-fluoro-4-trifluoromethyl-- phenyl)-acetic acid methyl ester
(2.40 g, 10.16 mmol) in a small amount of tetrahydrofuran. The
reaction mixture was allowed to stir at -78.degree. C. for 1 h, at
which time, a solution of iodomethylcyclopentane (2.24 g, 10.67
mmol) in a small amount of dry tetrahydrofuran was added dropwise.
The reaction mixture was allowed to warm to 25.degree. C. where it
was stirred for 15 h. The reaction mixture was quenched with a
saturated aqueous ammonium chloride solution (10 mL) and then
partitioned between water (75 mL) and ethyl acetate (75 mL). The
layers were shaken and separated. The aqueous layer was further
extracted with ethyl acetate (75 mL). The combined organic layers
were washed with a saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 5/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-tri-
fluoromethyl-phenyl)-propionic acid methyl ester (2.69 g, 83%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.18F.sub.4O.sub.2
(M.sup.+) 318.1243, found 318.1250.
[0419] A solution of
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-p- ropionic
acid methyl ester (1.80 g, 5.69 mmol) in tetrahydrofuran (15 mL)
was treated with a 0.8M aqueous lithium hydroxide solution (7.1 mL,
5.69 mmol). The reaction mixture was stirred at 25.degree. C. for
15 h. The reaction mixture was concentrated in vacuo. The resulting
residue was diluted with ethyl acetate (100 mL) and then washed
with a 5% aqueous hydrochloric acid solution and a saturated
aqueous sodium chloride solution. The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 2/1
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluo-
ro-4-trifluoromethyl-phenyl)-propionic acid (1.11 g, 64%) as a
white solid: mp 93-95.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.16F.sub.4O.sub.2 (M+H).sup.+ 305.1165, found
305.1175.
[0420] A solution of triphenylphosphine (312 mg, 1.19 mmol) in
methylene chloride (5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The
reaction mixture was stirred at 0.degree. C. for 30 min and then
treated with 3-cyclopentyl-2-(3-fluor-
o-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 15 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminopyridine
(205 mg, 2.18 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 3 d. The crude reaction mixture was then directly
purified by flash chromatography (Merck Silica gel 60, 230-400
mesh, 2/1 hexanes/ethyl acetate) to afford
3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N--
pyridin-2-yl-propionamide (171 mg, 45%) as a pale yellow foam: mp
40-44.degree. C. (foam to gel); EI-HRMS m/e calcd for
C.sub.20H.sub.20F.sub.4N.sub.2O (M.sup.+) 380.1512, found
380.1519.
EXAMPLE 72
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona-
mide
[0421] 85
[0422] A solution of 4-(methylthio)phenylacetic acid (21.21 g,
116.38 mmol) in methanol (291 mL) was treated slowly with
concentrated sulfuric acid (3 mL). The resulting reaction mixture
was heated under reflux for 3 d. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting residue was diluted with diethyl ether (600
mL). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (3.times.300 mL) and a saturated aqueous
sodium chloride solution (1.times.300 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g,
92%) as a yellow liquid which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.2S
(M.sup.+) 196.0558, found 196.0559.
[0423] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl
ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was
slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction
mixture was stirred at 25.degree. C. for 4 h, at which time, thin
layer chromatography still indicated the presence of a substantial
amount of starting material. The reaction mixture was treated with
more bromine (1.74 mL, 33.84 mmol). The reaction mixture was
stirred an additional 4 h at 25.degree. C. and then quenched with a
10% aqueous sodium bisulfite solution (150 mL). The reaction
mixture was concentrated in vacuo to remove carbon tetrachloride.
The resulting aqueous layer was extracted with ethyl acetate
(3.times.150 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid
methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.10H.sub.11BrO.sub.2S (M.sup.+) 273.9663, found
273.9661.
[0424] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry
tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (7 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
(3-bromo-4-methylsulfanyl-ph- enyl)-acetic acid methyl ester (6.10
g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (5.59
g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 15 h. The reaction mixture was quenched
with water (300 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining aqueous phase was extracted with
ethyl acetate (3.times.150 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
2-(3-bromo-4-methylsulf- anyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.21BrO.sub.2S (M.sup.+) 356.0446, found
356.0435.
[0425] A solution of
2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was
treated with 3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based
on 57%, 5.99 mmol). The reaction mixture was stirred at 25.degree.
C. for 3 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
diethyl ether (300 mL). The organic phase was washed with a
saturated aqueous sodium bicarbonate solution (3.times.200 mL) and
a saturated aqueous sodium chloride solution (1.times.100 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1
hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-ph-
enyl)-3-cyclopentyl-propionic acid methyl ester (1.09 g, 94%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.19BrO.sub.4S
(M.sup.+) 388.0344, found 388.0343.
[0426] A solution of
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic acid
methyl ester (1.62 g, 4.16 mol) in methanol (10 mL) was treated
with a 1N aqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The
reaction mixture was stirred at 25.degree. C. for 27 h. The
reaction mixture was concentrated in vacuo to remove methanol. The
resulting aqueous residue was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.400 mL). The organic layer was washed with water
(1.times.300 mL) and a saturated aqueous sodium chloride solution
(1.times.300 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated in vacuo to afford
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(1.39 g, 89%) as a white solid which was used without further
purification: mp 149-150.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.19BrO.sub.4S (M+H).sup.+ 375.0266, found
375.0274.
[0427] A solution of triphenylphosphine (168 mg, 0.64 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 2-(3-bromo-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
25 min. The reaction mixture was then treated with 2-aminothiazole
(117 mg, 1.17 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-t-
hiazol-2-yl-propionamide (214 mg, 88%) as a yellow solid: mp
106-107.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.21BrN.sub.2O.sub.- 3S.sub.2 (M.sup.+) 456.0177, found
456.0175.
EXAMPLE 73
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propiona-
mide
[0428] 86
[0429] A solution of 4-(methylthio)phenylacetic acid (21.21 g,
116.38 mmol) in methanol (291 mL) was treated slowly with
concentrated sulfuric acid (3 mL). The resulting reaction mixture
was heated under reflux for 3 d. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting residue was diluted with diethyl ether (600
mL). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (3.times.300 mL) and a saturated aqueous
sodium chloride solution (1.times.300 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g,
92%) as a yellow liquid which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.2S
(M.sup.+) 196.0558, found 196.0559.
[0430] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl
ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was
slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction
mixture was stirred at 25.degree. C. for 4 h, at which time, thin
layer chromatography still indicated the presence of a substantial
amount of starting material. The reaction mixture was treated with
more bromine (1.74 mL, 33.84 mmol). The reaction mixture was
stirred an additional 4 h at 25.degree. C. and then quenched with a
10% aqueous sodium bisulfite solution (150 mL). The reaction
mixture was concentrated in vacuo to remove carbon tetrachloride.
The resulting aqueous layer was extracted with ethyl acetate
(3.times.150 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid
methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.10H.sub.11BrO.sub.2S (M.sup.+) 273.9663, found
273.9661.
[0431] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry
tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (7 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
(3-bromo-4-methylsulfanyl-ph- enyl)-acetic acid methyl ester (6.10
g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (5.59
g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 15 h. The reaction mixture was quenched
with water (300 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining aqueous phase was extracted with
ethyl acetate (3.times.150 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
2-(3-bromo-4-methylsulf- anyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.21BrO.sub.2S (M.sup.+) 356.0446, found
356.0435.
[0432] A solution of
2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was
treated with 3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based
on 57%, 5.99 mmol). The reaction mixture was stirred at 25.degree.
C. for 3 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
diethyl ether (300 mL). The organic phase was washed with a
saturated aqueous sodium bicarbonate solution (3.times.200 mL) and
a saturated aqueous sodium chloride solution (1.times.100 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1
hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-ph-
enyl)-3-cyclopentyl-propionic acid methyl ester (1.09 g, 94%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.19BrO.sub.4S
(M.sup.+) 388.0344, found 388.0343.
[0433] A solution of
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic acid
methyl ester (1.62 g, 4.16 mol) in methanol (10 mL) was treated
with a 1N aqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The
reaction mixture was stirred at 25.degree. C. for 27 h. The
reaction mixture was concentrated in vacuo to remove methanol. The
resulting aqueous residue was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.400 mL). The organic layer was washed with water
(1.times.300 mL) and a saturated aqueous sodium chloride solution
(1.times.300 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated in vacuo to afford
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(1.39 g, 89%) as a white solid which was used without further
purification: mp 149-150.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.19BrO.sub.4S (M+H).sup.+ 375.0266, found
375.0274.
[0434] A solution of triphenylphosphine (168 mg, 0.64 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (114 mg, 0.64 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 2-(3-bromo-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
25 min. The reaction mixture was then treated with 2-aminopyridine
(110 mg, 1.17 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-p-
yridin-2-yl-propionamide (175 mg, 73%) as a white foam: mp
99-101.degree. C.; FAB-HRMS m/e calcd for
C.sub.20H.sub.23BrN.sub.2O.sub.3S (M+H).sup.+ 451.0692, found
451.0689.
EXAMPLE 74
2-(3-Bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-pyridin-2-yl)-3-cyclopenty-
l-propionamide
[0435] 87
[0436] A solution of 4-(methylthio)phenylacetic acid (21.21 g,
116.38 mmol) in methanol (291 mL) was treated slowly with
concentrated sulfuric acid (3 mL). The resulting reaction mixture
was heated under reflux for 3 d. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting residue was diluted with diethyl ether (600
mL). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (3.times.300 mL) and a saturated aqueous
sodium chloride solution (1.times.300 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g,
92%) as a yellow liquid which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.2S
(M.sup.+) 196.0558, found 196.0559.
[0437] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl
ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was
slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction
mixture was stirred at 25.degree. C. for 4 h, at which time, thin
layer chromatography still indicated the presence of a substantial
amount of starting material. The reaction mixture was treated with
more bromine (1.74 mL, 33.84 mmol). The reaction mixture was
stirred an additional 4 h at 25.degree. C. and then quenched with a
10% aqueous sodium bisulfite solution (150 mL). The reaction
mixture was concentrated in vacuo to remove carbon tetrachloride.
The resulting aqueous layer was extracted with ethyl acetate
(3.times.150 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid
methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.10H.sub.11BrO.sub.2S (M.sup.+) 273.9663, found
273.9661.
[0438] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry
tetrahydrofuiran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (7 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
(3-bromo-4-methylsulfanyl-ph- enyl)-acetic acid methyl ester (6.10
g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (5.59
g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 15 h. The reaction mixture was quenched
with water (300 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining aqueous phase was extracted with
ethyl acetate (3.times.150 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
2-(3-bromo-4-methylsulf- anyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.21BrO.sub.2S (M.sup.+) 356.0446, found
356.0435.
[0439] A solution of
2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was
treated with 3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based
on 57%, 5.99 mmol). The reaction mixture was stirred at 25.degree.
C. for 3 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
diethyl ether (300 mL). The organic phase was washed with a
saturated aqueous sodium bicarbonate solution (3.times.200 mL) and
a saturated aqueous sodium chloride solution (1.times.100 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1
hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-ph-
enyl)-3-cyclopentyl-propionic acid methyl ester (1.09 g, 94%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.19BrO.sub.4S
(M.sup.+) 388.0344, found 388.0343.
[0440] A solution of
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic acid
methyl ester (1.62 g, 4.16 mol) in methanol (10 mL) was treated
with a 1N aqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The
reaction mixture was stirred at 25.degree. C. for 27 h. The
reaction mixture was concentrated in vacuo to remove methanol. The
resulting aqueous residue was acidified to pH=2 with a 10% aqueous
hydrochloric acid solution and then extracted with ethyl acetate
(1.times.400 mL). The organic layer was washed with water
(1.times.300 mL) and a saturated aqueous sodium chloride solution
(1.times.300 mL). The organic layer was then dried over sodium
sulfate, filtered, and concentrated in vacuo to afford
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(1.39 g, 89%) as a white solid which was used without further
purification: mp 149-150.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.19BrO.sub.4S (M+H).sup.+ 375.0266, found
375.0274.
[0441] A solution of triphenylphosphine (154 mg, 0.59 mmol) in
methylene chloride (3 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (104 mg, 0.59 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 2-(3-bromo-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with
2-amino-5-bromopyridine (203 mg, 1.17 mmol). The resulting reaction
mixture was stirred at 25.degree. C. for 15 h. The crude reaction
mixture was then directly purified by flash chromatography (Merck
Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford
the 2-(3-bromo-4-methanesulfonyl-phenyl)-N-(5-bromo-py-
ridin-2-yl)-3-cyclopentyl-propionamide (164 mg, 58%) as a white
foam: mp 83-86.degree. C. (foam to gel); FAB-HRMS m/e calcd for
C.sub.20H.sub.22Br.sub.2N.sub.2O.sub.3S (M+H).sup.+ 528.9796, found
528.9783.
EXAMPLE 75
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propiona-
mide
[0442] 88
[0443] A solution of 4-(methylthio)phenylacetic acid (21.21 g,
116.38 numol) in methanol (291 mL) was treated slowly with
concentrated sulfuric acid (3 mL). The resulting reaction mixture
was heated under reflux for 3 d. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting residue was diluted with diethyl ether (600
mL). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (3.times.300 mL) and a saturated aqueous
sodium chloride solution (1.times.300 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g,
92%) as a yellow liquid which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.2S
(M.sup.+) 196.0558, found 196.0559.
[0444] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl
ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was
slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction
mixture was stirred at 25.degree. C. for 4 h, at which time, thin
layer chromatography still indicated the presence of a substantial
amount of starting material. The reaction mixture was treated with
more bromine (1.74 mL, 33.84 mmol). The reaction mixture was
stirred an additional 4 h at 25.degree. C. and then quenched with a
10% aqueous sodium bisulfite solution (150 mL). The reaction
mixture was concentrated in vacuo to remove carbon tetrachloride.
The resulting aqueous layer was extracted with ethyl acetate
(3.times.150 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid
methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.10H.sub.11BrO.sub.2S (M.sup.+) 273.9663, found
273.9661.
[0445] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry
tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (7 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol).
The resulting reaction mixture was stirred at -78.degree. C. for 30
min and then treated dropwise with a solution of
(3-bromo-4-methylsulfanyl-ph- enyl)-acetic acid methyl ester (6.10
g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (5.59
g, 26.60 mmol) in a small amount of dry tetrahydrofliran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 15 h. The reaction mixture was quenched
with water (300 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining aqueous phase was extracted with
ethyl acetate (3.times.150 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
2-(3-bromo-4-methylsulf- anyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.21BrO.sub.2S (M.sup.+) 356.0446, found
356.0435.
[0446] A solution of
2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was
treated with 3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based
on 57%, 5.99 mmol). The reaction mixture was stirred at 25.degree.
C. for 3 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
diethyl ether (300 mL). The organic phase was washed with a
saturated aqueous sodium bicarbonate solution (3.times.200 mL) and
a saturated aqueous sodium chloride solution (1.times.100 nmL),
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1
hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-ph-
enyl)-3-cyclopentyl-propionic acid methyl ester (1.09 g, 94%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.19BrO.sub.4S
(M.sup.+) 388.0344, found 388.0343.
[0447] A mixture of
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (990.0 mg, 2.54 mmol) and copper(I) cyanide (273.3 mg,
3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) was heated under
reflux for 4 h. The reaction was allowed to cool to 25.degree. C.,
and the crude reaction mixture was directly purified without
further chemical work-up. Flash chromatography (Merck Silica gel
60, 70-230 mesh, 100% hexanes then 3/1 hexanes/ethyl acetate)
afforded
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (646.5 mg, 76%) as a very light yellow oil: EI-HRMS
m/e calcd for C.sub.17H.sub.21NO.sub.4S (M.sup.+) 335.1191, found
335.1185.
[0448] A solution of
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic acid
methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6
mmol). The reaction mixture was stirred at 25.degree. C. for 2.5 h.
The reaction mixture was partitioned between water and ethyl
acetate and then acidified to pH=2 with a 10% aqueous hydrochloric
acid solution. The layers were shaken and separated. The resulting
organic layer was washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo to afford crude
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow
solid. An analytical sample was obtained by recrystallization from
ethyl acetate to afford
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
as a white solid: mp 180-181.degree. C.; EI-HRMS m/e calcd for
C.sub.16H.sub.19NO.sub.4S (M.sup.+) 321.1034, found 321.1039.
[0449] A solution of triphenylphosphine (98 mg, 0.37 mmol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The
reaction mixture was stirred at 0.degree. C. for 15 min and then
treated with 2-(3-cyano-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.31 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminothiazole
(68 mg, 0.68 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-t-
hiazol-2-yl-propionamide (117 mg, 93%) as a white solid: mp
145-148.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.21N.sub.3O.sub.3S- .sub.2 (M.sup.+) 403.1024, found
403.1023.
EXAMPLE 76
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propiona-
mide
[0450] 89
[0451] A solution of 4-(methylthio)phenylacetic acid (21.21 g,
116.38 mmol) in methanol (291 mL) was treated slowly with
concentrated sulfuric acid (3 mL). The resulting reaction mixture
was heated under reflux for 3 d. The reaction mixture was allowed
to cool to 25.degree. C. and then concentrated in vacuo to remove
methanol. The resulting residue was diluted with diethyl ether (600
mL). The organic layer was washed with a saturated aqueous sodium
bicarbonate solution (3.times.300 mL) and a saturated aqueous
sodium chloride solution (1.times.300 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo to
afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g,
92%) as a yellow liquid which was used without further
purification: EI-HRMS m/e calcd for C.sub.10H.sub.12O.sub.2S
(M.sup.+) 196.0558, found 196.0559.
[0452] A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl
ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was
slowly treated with bromine (1.74 mL, 33.84 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 4 h, at which
time, thin layer chromatography still indicated the presence of a
substantial amount of starting material. The reaction mixture was
treated with more bromine (1.74 mL, 33.84 mmol). The reaction
mixture was stirred an additional 4 h at 25.degree. C. and then
quenched with a 10% aqueous sodium bisulfite solution (150 mL). The
reaction mixture was concentrated in vacuo to remove carbon
tetrachloride. The resulting aqueous layer was extracted with ethyl
acetate (3.times.150 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl
acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid
methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.10H.sub.11BrO.sub.2S (M.sup.+) 273.9663, found
273.9661.
[0453] A solution of diisopropylamine (3.4 mL, 24.38 mmol) in dry
tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (7 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (9.8 mL, 24.38 mmol).
The reaction mixture was stirred at -78.degree. C. for 30 min and
then treated dropwise with a solution of
(3-bromo-4-methylsulfanyl-phenyl)-ace- tic acid methyl ester (6.10
g, 22.17 mmol) in dry tetrahydrofuran (21 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (5.59
g, 26.60 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 15 h. The reaction mixture was quenched
with water (300 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining aqueous phase was extracted with
ethyl acetate (3.times.150 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded
2-(3-bromo-4-methylsulfanyl-ph- enyl)-3-cyclopentyl-propionic acid
methyl ester (4.52 g, 57%) as a light yellow oil: EI-HRMS m/e calcd
for C.sub.16H.sub.21BrO.sub.2S (M.sup.+) 356.0446, found
356.0435.
[0454] A solution of
2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (1.07 g, 2.99 mmol) in methylene chloride (15 mL) was
treated with 3-chloroperoxybenzoic acid (57-86% grade, 1.81 g based
on 57%, 5.99 mmol). The reaction mixture was stirred at 25.degree.
C. for 3 h. The reaction mixture was concentrated in vacuo to
remove methylene chloride. The resulting residue was diluted with
diethyl ether (300 mL). The organic phase was washed with a
saturated aqueous sodium bicarbonate solution (3.times.200 mL) and
a saturated aqueous sodium chloride solution (1.times.100 mL),
dried over sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1
hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-ph-
enyl)-3-cyclopentyl-propionic acid methyl ester (1.09 g, 94%) as a
colorless oil: EI-HRMS m/e calcd for C.sub.16H.sub.19BrO.sub.4S
(M.sup.+) 388.0344, found 388.0343.
[0455] A mixture of
2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-pro- pionic acid
methyl ester (990.0 mg, 2.54 mmol) and copper(I) cyanide (273.3 mg,
3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) was heated under
reflux for 4 h. The reaction was allowed to cool to 25.degree. C.,
and the crude reaction mixture was directly purified without
further chemical work-up. Flash chromatography (Merck Silica gel
60, 70-230 mesh, 100% hexanes then 3/1 hexanes/ethyl acetate)
afforded
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester (646.5 mg, 76%) as a very light yellow oil: EI-HRMS
m/e calcd for C.sub.17H.sub.21NO.sub.4S (M.sup.+) 335.1191, found
335.1185.
[0456] A solution of
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic acid
methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6
mmol). The reaction mixture was stirred at 25.degree. C. for 2.5 h.
The reaction mixture was partitioned between water and ethyl
acetate and then acidified to pH=2 with a 10% aqueous hydrochloric
acid solution. The layers were shaken and separated. The resulting
organic layer was washed with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered, and concentrated
in vacuo to afford crude
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow
solid. An analytical sample was obtained by recrystallization from
ethyl acetate to afford
2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
as a white solid: mp 180-181.degree. C.; EI-HRMS m/e calcd for
C.sub.16H.sub.19NO.sub.4S (M.sup.+) 321.1034, found 321.1039.
[0457] A solution of triphenylphosphine (98 mg, 0.37 mmol) in
methylene chloride (1 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (67 mg, 0.37 mmol). The
reaction mixture was stirred at 0.degree. C. for 15 min and then
treated with 2-(3-cyano-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.31 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminopyridine
(64 mg, 0.68 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3-cyano-4-nmethanesulfonyl-phenyl)-3-cyclopentyl-N--
pyridin-2-yl-propionamide (94.5 mg, 76%) as a yellow foam: mp
87-90.degree. C. (foam to gel); EI-HRMS m/e calcd for
C.sub.21H.sub.23N.sub.3O.sub.3S (M.sup.+) 397.1460, found
397.1460.
EXAMPLE 77
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
[0458] 90
[0459] A mixture of aluminum chloride (72.35 g, 0.54 mol) in
chloroform (181 mL) was cooled to 0.degree. C. and stirred until
the solid material dissolved. The reaction mixture was then slowly
treated with ethyl oxalyl chloride (61 mL, 0.54 mol), and the
resulting reaction mixture was stirred at 0.degree. C. for 30 min.
The reaction mixture was then slowly treated with ethyl phenyl
sulfide (25.00 g, 0.18 mol). The solution turned to a wine color
and slowly became gum-like. The resulting reaction mixture was then
stirred at 0.degree. C. for 2 h. The reaction mixture was slowly
poured into a large amount of ice/water. The resulting aqueous
layer was extracted with chloroform (3.times.200 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 9/1 hexanes/ethyl acetate) afforded
(4-ethylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (23.64 g, 55%)
as a yellow oil. The material was used without further purification
and characterization in subsequent reactions.
[0460] A solution of iodomethylcyclopentane (4.60 g, 21.89 mmol)
and triphenylphosphine (5.74 g, 21.89 mmol) in acetonitrile (22 mL)
was heated under reflux for 2 weeks. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
provide an orange solid. The orange solid was triturated with
diethyl ether and then filtered. The solid was washed well with
diethyl ether until the washings showed the absence of
iodomethylcyclopentane and triphenylphosphine by thin layer
chromatography. The solid was allowed to air dry to afford
cyclopentylmethyl triphenylphosphonium iodide (8.92 g, 86%) as a
light orange solid: mp 195-198.degree. C.; FAB-HRMS m/e calcd for
C.sub.24H.sub.26P (M+H).sup.+ 345.1772, found 345.1784.
[0461] A suspension of cyclopentylmethyl triphenylphosphonium
iodide (24.48 g, 51.82 mmol) in dry tetrahydrofuran (100 mL) was
cooled to 0.degree. C. and then treated dropwise with a 1.0M
solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (52
mL, 51.82 mmol). The bright orange reaction mixture was stirred at
0.degree. C. for 1 h. The reaction mixture was then treated with
(4-ethylsulfanyl-phenyl)-oxo-aceti- c acid ethyl ester (9.50 g,
39.87 mmol). The resulting reaction mixture was allowed to warm to
25.degree. C. where it was stirred for 20 h. The reaction mixture
was concentrated in vacuo to remove tetrahydrofuran and then
diluted with water (300 mL). The aqueous layer was extracted with
ethyl acetate (3.times.200 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded the
3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester
(6.08 g, 50%) as a yellow oil containing a 1.82:1 mixture of
(E):(Z) isomers: FAB-LRMS m/e calcd for C.sub.18H.sub.24O.sub.2S
(M+H).sup.+ integer mass 304, found 305. The isomeric mixture was
used without further separation in subsequent reactions.
[0462] A solution of
3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester
[5.76 g, 18.92 mmol, (E):(Z) =1.82:1] in methylene chloride (47 mL)
was slowly treated with 3-chloroperoxybenzoic acid (57-86% grade,
11.45 g based on 57%, 37.83 mmol). The reaction mixture was stirred
at 25.degree. C. for 1 h. The reaction mixture was concentrated in
vacuo to remove methylene chloride. The resulting residue was
diluted with diethyl ether (300 mL). The organic phase was washed
with a saturated aqueous sodium bicarbonate solution (3.times.200
mL) and a saturated aqueous sodium chloride solution (1.times.200
mL), dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester
(4.89 g, 77%) as a colorless oil. The product was a 3:1 mixture of
(E):(Z) isomers that was used without further purification and
characterization.
[0463] A solution of
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester
[4.89 g, 14.53 mmol, (E):(Z) =3:1] in ethanol (36 mL) was slowly
treated with 10% palladium on activated carbon (244.5 mg). The
reaction mixture was stirred under a positive pressure of hydrogen
gas (balloon) at 25.degree. C. and atmospheric pressure for 44 h.
The catalyst was then filtered off through a pad of celite, and the
celite pad was washed well with ethyl acetate. The filtrate was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)- -propionic acid ethyl
ester (3.50 g, 71%) as a colorless viscous oil: FAB-LRMS m/e calcd
for C.sub.18H.sub.26O.sub.4S (M+H).sup.+ integer mass 338, found
339.
[0464] A solution of
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl
ester (2.50 g, 7.39 mmol) in tetrahydrofuran (30 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86
mmol). The reaction mixture was stirred at 25.degree. C. for 23 h.
The resulting reaction mixture was partitioned between water (75
mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous
hydrochloric acid solution (15 mL). The layers were shaken and
separated. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (2.20 g,
96%) as a white solid which was used without further purification:
mp 137-138.degree. C.; FAB-HRMS m/e calcd for
C.sub.16H.sub.22O.sub.4S (M+H).sup.+ 311.1317, found 311.1321.
[0465] A solution of triphenylphosphine (279 mg, 1.06 mmol) in
methylene chloride (5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-ethan- esulfonyl-phenyl)-propionic
acid (300 mg, 0.97 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then allowed to warm to
25.degree. C. where it was stirred for 30 min. The reaction mixture
was then treated with 2-aminothiazole (213 mg, 2.13 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The crude reaction mixture was then directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) to afford
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
(330 mg, 87%) as a pale yellow solid: mp 178-179.degree. C.;
EI-HRMS m/e calcd for C.sub.19H.sub.24N.sub.2O.sub.3S.sub.2
(M.sup.+) 392.1228, found 392.1230.
EXAMPLE 78
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide
[0466] 91
[0467] A mixture of aluminum chloride (72.35 g, 0.54 mol) in
chloroform (181 mL) was cooled to 0.degree. C. and stirred until
the solid material dissolved. The reaction mixture was then slowly
treated with ethyl oxalyl chloride (61 mL, 0.54 mol), and the
resulting reaction mixture was stirred at 0.degree. C. for 30 min.
The reaction mixture was then slowly treated with ethyl phenyl
sulfide (25.00 g, 0.18 mol). The solution turned to a wine color
and slowly became gum-like. The resulting reaction mixture was then
stirred at 0.degree. C. for 2 h. The reaction mixture was slowly
poured into a large amount of ice/water. The resulting aqueous
layer was extracted with chloroform (3.times.200 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 9/1 hexanes/ethyl acetate) afforded
(4-ethylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (23.64 g, 55%)
as a yellow oil. The material was used without further purification
and characterization in subsequent reactions.
[0468] A solution of iodomethylcyclopentane (4.60 g, 21.89 mmol)
and triphenylphosphine (5.74 g, 21.89 mmol) in acetonitrile (22 mL)
was heated under reflux for 2 weeks. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo to
provide an orange solid. The orange solid was triturated with
diethyl ether and then filtered. The solid was washed well with
diethyl ether until the washings showed the absence of
iodomethylcyclopentane and triphenylphosphine by thin layer
chromatography. The solid was allowed to air dry to afford
cyclopentylmethyl triphenylphosphonium iodide (8.92 g, 86%) as a
light orange solid: mp 195-198.degree. C.; FAB-HRMS m/e calcd for
C.sub.24H.sub.26P (M+H).sup.+ 345.1772, found 345.1784.
[0469] A suspension of cyclopentylmethyl triphenylphosphonium
iodide (24.48 g, 51.82 mmol) in dry tetrahydrofuran (100 mL) was
cooled to 0.degree. C. and then treated dropwise with a 1.0M
solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (52
mL, 51.82 mmol). The bright orange reaction mixture was stirred at
0.degree. C. for 1 h. The reaction mixture was then treated with
(4-ethylsulfanyl-phenyl)-oxo-aceti- c acid ethyl ester (9.50 g,
39.87 mmol). The resulting reaction mixture was allowed to warm to
25.degree. C. where it was stirred for 20 h. The reaction mixture
was concentrated in vacuo to remove tetrahydrofuran and then
diluted with water (300 mL). The aqueous layer was extracted with
ethyl acetate (3.times.200 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 19/1 hexanes/ethyl acetate) afforded the
3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester
(6.08 g, 50%) as a yellow oil containing a 1.82:1 mixture of
(E):(Z) isomers: FAB-LRMS m/e calcd for C.sub.18H.sub.24O.sub.2S
(M+H).sup.+ integer mass 304, found 305.
[0470] A solution of
3-cyclopentyl-2-(4-ethylsulfanyl-phenyl)-acrylic acid ethyl ester
[5.76 g, 18.92 mmol, (E):(Z)=1.82:1] in methylene chloride (47 mL)
was slowly treated with 3-chloroperoxybenzoic acid (57-86% grade,
11.45 g based on 57%, 37.83 mmol). The reaction mixture was stirred
at 25.degree. C. for 1 h. The reaction mixture was concentrated in
vacuo to remove methylene chloride. The resulting residue was
diluted with diethyl ether (300 mL). The organic phase was washed
with a saturated aqueous sodium bicarbonate solution (3.times.200
mL) and a saturated aqueous sodium chloride solution (1.times.200
mL), dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester
(4.89 g, 77%) as a colorless oil. The product was a 3:1 mixture of
(E):(Z) isomers that was used without further purification and
characterization.
[0471] A solution of
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-acrylic acid ethyl ester
[4.89 g, 14.53 mmol, (E):(Z)=3:1] in ethanol (36 mL) was slowly
treated with 10% palladium on activated carbon (244.5 mg). The
reaction mixture was stirred under a positive pressure of hydrogen
gas (balloon) at 25.degree. C. and atmospheric pressure for 44 h.
The catalyst was then filtered off through a pad of celite, and the
celite pad was washed well with ethyl acetate. The filtrate was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)- -propionic acid ethyl
ester (3.50 g, 71%) as a colorless viscous oil: FAB-LRMS m/e calcd
for C.sub.18H.sub.26O.sub.4S (M+H).sup.+ integer mass 338, found
339.
[0472] A solution of
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl
ester (2.50 g, 7.39 mmol) in tetrahydrofuran (30 mL) was treated
with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86
mmol). The reaction mixture was stirred at 25.degree. C. for 23 h.
The resulting reaction mixture was partitioned between water (75
mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous
hydrochloric acid solution (15 mL). The layers were shaken and
separated. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (2.20 g,
96%) as a white solid which was used without further purification:
mp 137-138.degree. C.; FAB-HRMS m/e calcd for
C.sub.16H.sub.22O.sub.4S (M+H).sup.+ 311.1317, found 311.1321.
[0473] A solution of triphenylphosphine (279 mg, 1.06 mmol) in
methylene chloride (5 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The
reaction mixture was stirred at 0.degree. C. for 20 min and then
treated with 3-cyclopentyl-2-(4-ethan- esulfonyl-phenyl)-propionic
acid (300 mg, 0.97 mmol). The resulting reaction mixture was
stirred at 0.degree. C. for 10 min and then allowed to warm to
25.degree. C. where it was stirred for 30 min. The reaction mixture
was then treated with 2-aminopyridine (200 mg, 2.13 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 15 h.
The crude reaction mixture was then directly purified by flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/1
hexanes/ethyl acetate) to afford
3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-pyridin-2-yl-propionamide
(185 mg, 50%) as a pale orange solid: mp 144-145.degree. C.;
EI-HRMS m/e calcd for C.sub.21H.sub.26N.sub.2O.sub.3S (M.sup.+)
386.1664, found 386.1660.
EXAMPLE 79
2-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionami-
de
[0474] 92
[0475] A solution of 3,4-difluorophenylacetic acid (5.00 g, 29.05
mmol) in methanol (73 mL) was slowly treated with concentrated
sulfuric acid (4 mL). The resulting reaction mixture was heated
under reflux for 65 h. The reaction mixture was allowed to cool to
25.degree. C. and then concentrated in vacuo to remove methanol.
The resulting residue was slowly diluted with a saturated aqueous
sodium bicarbonate solution (300 mL) and then extracted with ethyl
acetate (1.times.300 mL). The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford
(3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 99%) as a
yellow oil which was used without further purification.
[0476] A solution of sodium thiomethoxide (6.39 g, 86.69 mmol) in
dimethyl sulfoxide (72 mL) was treated with
(3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 28.89
mmol). The reaction mixture was stirred at 25.degree. C. for 2 h
then heated at 70.degree. C. for 15 min, at which time, thin layer
chromatography indicated the absence of starting material and the
presence of a very polar new product. The reaction indicated that
the ester hydrolyzed to the acid upon heating. The resulting
reaction mixture was allowed to cool to 25.degree. C. The reaction
mixture was then treated with a 10% aqueous hydrochloric acid
solution (200 mL) and then extracted with chloroform (3.times.200
mL). The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford a yellow oil. This
yellow oil was dissolved in methanol (100 mL) and then slowly
treated with concentrated sulfuric acid (5 mL). The resulting
reaction mixture was heated under reflux for 3 h. The reaction
mixture was allowed to cool to 25.degree. C. and then concentrated
in vacuo to remove methanol. The resulting residue was slowly
diluted with a saturated aqueous sodium bicarbonate solution (300
mL) and then extracted with ethyl acetate (1.times.300 mL). The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford an inseparable, isomeric mixture of
(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester as a
yellow oil (4.65 g, 75%) which was used without further
purification and characterization.
[0477] A solution of the inseparable, isomeric mixture of
(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester (4.44
g, 20.72 mmol) in methylene chloride (103 mL) was slowly treated
with 3-chloroperoxybenzoic acid (57-86% grade, 13.80 g based on
57%, 45.59 mmol). The reaction mixture was stirred at 25.degree. C.
for 4 h. The reaction mixture was concentrated in vacuo to remove
methylene chloride. The resulting residue was diluted with ethyl
acetate (300 mL). The organic phase was washed with a saturated
aqueous sodium bicarbonate solution (1.times.200 mL) and a
saturated aqueous sodium chloride solution (1.times.200 mL), dried
over magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 20/1 methylene
chloride/ethyl acetate) afforded an inseparable, isomeric mixture
of (3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester as a
colorless liquid (3.31 g, 65%) which was used without further
purification and characterization.
[0478] A solution of the inseparable, isomeric mixture of
(3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester (2.28
g, 9.26 mmol) in dimethyl sulfoxide (23 mL) was treated with sodium
thiomethoxide (1.37 g, 18.52 mmol). The reaction mixture was
stirred at 25.degree. C. for 4 h and then quenched with a 10%
aqueous hydrochloric acid solution. The aqueous layer was extracted
with chloroform (1.times.400 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded an
inseparable, isomeric mixture of
(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl
ester and (4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid
methyl ester as a yellow liquid (2.19 g, 86%) which was used
without further purification and characterization.
[0479] A solution of the inseparable, isomeric mixture of
(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl
ester and (4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid
methyl ester (2.19 g, 7.98 mmol) in methylene chloride (20 mL) was
slowly treated with 3-chloroperoxybenzoic acid (57-86% grade, 6.41
g based on 57%, 31.93 mmol). The reaction mixture was stirred at
25.degree. C. for 5 h and then slowly quenched with a 1.5N aqueous
sodium sulfite solution. The resulting reaction mixture was
extracted with methylene chloride (300 mL). The organic phase was
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 10/1
methylene chloride/ethyl acetate) afforded
(3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g,
77%) as a white solid: mp 157-158.degree. C.; EJ-HRMS m/e calcd for
C.sub.11H.sub.14O.sub.6S.sub.2 (M.sup.+) 306.0232, found
306.0234.
[0480] A solution of diisopropylamine (951 .mu.L, 6.79 mmol) in dry
tetrahydrofuran (6 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi- none (2 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
(3,4-bis-methanesulfonyl-phe- nyl)-acetic acid methyl ester (1.89
g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (1.56
g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 64 h. The reaction mixture was quenched
with water (150 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining residue was further diluted with
water (100 mL) and then extracted with ethyl acetate (1.times.250
mL). The organic layer was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propio- nic acid
methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.17H.sub.24O.sub.6S.sub.2 (M.sup.+) 388.1014, found
388.1014.
[0481] A solution of
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-prop- ionic acid
methyl ester (1.17 g, 3.01 mmol) in tetrahydrofuran (12 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (5.6 mL,
4.52 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The resulting reaction mixture was partitioned between water (75
mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous
hydrochloric acid solution (10 mL). The layers were shaken and
separated. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propioni- c acid
(1.10 g, 98%) as a white foam which was used without further
purification: mp 64-68.degree. C. (foam to gel); FAB-HRMS m/e calcd
for C.sub.16H.sub.22O.sub.6S.sub.2 (M+H).sup.+ 375.0936, found
375.0932.
[0482] A solution of triphenylphosphine (154 mg, 0.59 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 2-(3,4-bis-methanesulfon-
yl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminothiazole
(118 mg, 1.18 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionam-
ide (150 mg, 61%) as a pale yellow foam: mp 104-107.degree. C.;
EI-HRMS m/e calcd for C.sub.19H.sub.24N.sub.2O.sub.5S.sub.3
(M.sup.+) 456.0847, found 456.0846.
EXAMPLE 80
2-(3,4-Bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionami-
de
[0483] 93
[0484] A solution of 3,4-difluorophenylacetic acid (5.00 g, 29.05
mmol) in methanol (73 mL) was slowly treated with concentrated
sulfuric acid (4 mL). The resulting reaction mixture was heated
under reflux for 65 h. The reaction mixture was allowed to cool to
25.degree. C. and then concentrated in vacuo to remove methanol.
The resulting residue was slowly diluted with a saturated aqueous
sodium bicarbonate solution (300 mL) and then extracted with ethyl
acetate (1.times.300 mL). The organic layer was dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford
(3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 99%) as a
yellow oil which was used without further purification.
[0485] A solution of sodium thiomethoxide (6.39 g, 86.69 mmol) in
dimethyl sulfoxide (72 mL) was treated with
(3,4-difluoro-phenyl)-acetic acid methyl ester (5.38 g, 28.89
mmol). The reaction mixture was stirred at 25.degree. C. for 2 h
then heated at 70.degree. C. for 15 min, at which time, thin layer
chromatography indicated the absence of starting material and the
presence of a very polar new product. The reaction indicated that
the ester hydrolyzed to the acid upon heating. The resulting
reaction mixture was allowed to cool to 25.degree. C. The reaction
mixture was then treated with a 10% aqueous hydrochloric acid
solution (200 mL) and then extracted with chloroform (3.times.200
mL). The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford a yellow oil. This
yellow oil was dissolved in methanol (100 mL) and then slowly
treated with concentrated sulfuric acid (5 mL). The resulting
reaction mixture was heated under reflux for 3 h. The reaction
mixture was allowed to cool to 25.degree. C. and then concentrated
in vacuo to remove methanol. The resulting residue was slowly
diluted with a saturated aqueous sodium bicarbonate solution (300
mL) and then extracted with ethyl acetate (1.times.300 mL). The
organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford an inseparable, isomeric mixture of
(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester as a
yellow oil (4.65 g, 75%) which was used without further
purification and characterization.
[0486] A solution of the inseparable, isomeric mixture of
(3-fluoro-4-methylsulfanyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methylsulfanyl-phenyl)-acetic acid methyl ester (4.44
g, 20.72 mmol) in methylene chloride (103 mL) was slowly treated
with 3-chloroperoxybenzoic acid (57-86% grade, 13.80 g based on
57%, 45.59 mmol). The reaction mixture was stirred at 25.degree. C.
for 4 h. The reaction mixture was concentrated in vacuo to remove
methylene chloride. The resulting residue was diluted with ethyl
acetate (300 mL). The organic phase was washed with a saturated
aqueous sodium bicarbonate solution (1.times.200 mL) and a
saturated aqueous sodium chloride solution (1.times.200 mL), dried
over magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 70-230 mesh, 20/1 methylene
chloride/ethyl acetate) afforded an inseparable, isomeric mixture
of (3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester as a
colorless liquid (3.31 g, 65%) which was used without further
purification and characterization.
[0487] A solution of the inseparable, isomeric mixture of
(3-fluoro-4-methanesulfonyl-phenyl)-acetic acid methyl ester and
(4-fluoro-3-methanesulfonyl-phenyl)-acetic acid methyl ester (2.28
g, 9.26 mmol) in dimethyl sulfoxide (23 mL) was treated with sodium
thiomethoxide (1.37 g, 18.52 mmol). The resulting reaction mixture
was stirred at 25.degree. C. for 4 h and then quenched with a 10%
aqueous hydrochloric acid solution. The aqueous layer was extracted
with chloroform (1.times.400 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate) afforded an
inseparable, isomeric mixture of
(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl
ester and (4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid
methyl ester as a yellow liquid (2.19 g, 86%) which was used
without further purification and characterization.
[0488] A solution of the inseparable, isomeric mixture of
(3-methanesulfonyl-4-methylsulfanyl-phenyl)-acetic acid methyl
ester and (4-methanesulfonyl-3-methylsulfanyl-phenyl)-acetic acid
methyl ester (2.19 g, 7.98 mmol) in methylene chloride (20 mL) was
slowly treated with 3-chloroperoxybenzoic acid (57-86% grade, 6.41
g based on 57%, 31.93 mmol). The reaction mixture was stirred at
25.degree. C. for 5 h and then slowly quenched with a 1.5N aqueous
sodium sulfite solution. The resulting reaction mixture was
extracted with methylene chloride (300 mL). The organic phase was
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 70-230 mesh, 10/1
methylene chloride/ethyl acetate) afforded
(3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g,
77%) as a white solid: mp 157-158.degree. C.; EI-HRMS m/e calcd for
C.sub.11H.sub.14O.sub.6S.sub.2 (M.sup.+) 306.0232, found
306.0234.
[0489] A solution of diisopropylamine (951 .mu.L, 6.79 mmol) in dry
tetrahydrofuran (6 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi- none (2 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a
2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The
resulting reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
(3,4-bis-methanesulfonyl-phe- nyl)-acetic acid methyl ester (1.89
g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The
resulting reaction mixture was allowed to stir at -78.degree. C.
for 1 h, at which time, a solution of iodomethylcyclopentane (1.56
g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added
dropwise. The reaction mixture was allowed to warm to 25.degree. C.
where it was stirred for 64 h. The reaction mixture was quenched
with water (150 mL) and then concentrated in vacuo to remove
tetrahydrofuran. The remaining residue was further diluted with
water (100 mL) and then extracted with ethyl acetate (1.times.250
mL). The organic layer was washed with a saturated aqueous sodium
chloride solution (1.times.100 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propio- nic acid
methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS mle calcd for
C.sub.17H.sub.24O.sub.6S.sub.2 (M) 388.1014, found 388.1014.
[0490] A solution of
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-prop- ionic acid
methyl ester (1.17 g, 3.01 mmol) in tetrahydrofuran (12 mL) was
treated with a 0.8M aqueous lithium hydroxide solution (5.6 mL,
4.52 mmol). The reaction mixture was stirred at 25.degree. C. for 3
h. The resulting reaction mixture was partitioned between water (75
mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous
hydrochloric acid solution (10 mL). The layers were shaken and
separated. The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propioni- c acid
(1.10 g, 98%) as a white foam which was used without further
purification: mp 64-68.degree. C. (foam to gel); FAB-HRMS m/e calcd
for C.sub.16H.sub.22O.sub.6S.sub.2 (M+H).sup.+ 375.0936, found
375.0932.
[0491] A solution of triphenylphosphine (154 mg, 0.59 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
slowly treated with N-bromosuccinimide (105 mg, 0.59 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and then
treated with 2-(3,4-bis-methanesulfon-
yl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol). The
resulting reaction mixture was stirred at 0.degree. C. for 5 min
and then allowed to warm to 25.degree. C. where it was stirred for
30 min. The reaction mixture was then treated with 2-aminopyridine
(110 mg, 1.18 mmol). The resulting reaction mixture was stirred at
25.degree. C. for 15 h. The crude reaction mixture was then
directly purified by flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 hexanes/ethyl acetate) to afford
2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionam-
ide (117 mg, 49%) as a pale yellow foam: mp 107-110.degree. C.;
EI-HRMS m/e calcd for C.sub.21H.sub.26N.sub.2O.sub.5S.sub.2
(M.sup.+) 450.1283, found 450.1282.
EXAMPLE 81
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]
triazin-3-yl-propionamide
[0492] 94
[0493] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared in Example 38, 400 mg, 1.40 mmol) in dry pyridine (5
mL) was treated with 1,3-dicyclohexylcarbodiimide (316 mg, 1.53
mmol). The reaction mixture was stirred at 25.degree. C. for 3.5 h
and then treated with 3-amino-1,2,4-triazine (296 mg, 3.08 mmol)
and an additional amount of pyridine (1 mL). The reaction mixture
was warmed at 100.degree. C. for 20 h. The reaction mixture was
concentrated in vacuo to remove pyridine. The resulting residue was
diluted with ethyl acetate then filtered. The filtrate was washed
with a 1N aqueous hydrochloric acid solution and washed with water.
The organic layer was dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 1/1 ethyl acetateihexanes) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,2,4]triazin-3-yl-propionamide
(40.9 mg, 8%) as a yellow-orange solid: mp 81-83.degree. C.;
EI-HRMS m/e calcd for C.sub.17H.sub.18Cl.sub.2N.sub.4O (M.sup.+)
364.0858, found 364.0857.
EXAMPLE 82
3-Cyclopentyl-2-(4-sulfamoyl-phenyl)-N-thiazol-2-yl-propionamide
[0494] 95
[0495] A solution of diisopropylamine (3.3 mL, 23.5 mmol) in dry
tetrahydrofuran (50 mL) and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid- inone (10 mL) was
cooled to -78.degree. C. under nitrogen and then treated with a 10M
solution of n-butyllithium in hexanes (2.35 mL, 23.5 mmol). The
yellow reaction mixture was stirred at -78.degree. C. for 30 min
and then treated dropwise with a solution of
4-methylsulfonylphenylacetic acid (2.40 g, 11.2 mmol) in a small
amount of dry tetrahydrofaran. After approximately one-half of the
4-methylsulfonylphenylacetic acid in dry tetrahydrofuran was added,
a precipitate formed. Upon further addition of the remaining
4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the
reaction mixture became thick in nature. After complete addition of
the 4-methylsulfonylphenylacetic acid in dry tetrahydrofuran, the
reaction mixture was very thick and became difficult to stir. An
additional amount of dry tetrahydrofuran (20 mL) was added to the
thick reaction mixture, and the reaction mixture was stirred at
-78.degree. C. for 45 min, at which time, a solution of
iodomethylcyclopentane (2.35 g, 11.2 mmol) in a small amount of dry
tetrahydrofuran was added dropwise. The reaction mixture was
allowed to warm to 25.degree. C. where it was stirred for 15 h. The
reaction mixture was quenched with water (100 mL), and the
resulting yellow reaction mixture was concentrated in vacuo to
remove tetrahydrofuran. The aqueous residue was acidified to pH=2
using concentrated hydrochloric acid. The aqueous layer was
extracted with ethyl acetate. The organic phase was dried over
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 1/3
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (1.80 g,
52%) as a white solid: mp 152-154.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.4S (M.sup.+) 296.1082, found 296.1080.
[0496] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g,
16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in
methylene chloride (41 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small
portions. The reaction mixture color changed from light yellow to a
darker yellow then to brown. After the complete addition of
N-bromosuccinimide, the reaction mixture was allowed to warm to
25.degree. C. over 30 min. The brown reaction mixture was then
treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting
reaction mixture was stirred at 25.degree. C. for 19 h. The
reaction mixture was then concentrated in vacuo to remove methylene
chloride. The remaining black residue was diluted with a 10%
aqueous hydrochloric acid solution (400 mL) and then extracted with
ethyl acetate (3.times.200 mL). The combined organic layers were
washed with a saturated aqueous sodium chloride solution
(1.times.200 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
70-230 mesh, 1/3 hexanes/ethyl acetate then 1/1 hexanes/ethyl
acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl-
)-N-thiazol-2-yl-propionamide (4.49 g, 72%) as a white solid: mp
216-217.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.22N.sub.2O.sub.3S- .sub.2 (M.sup.+) 378.1072, found
378.1071.
[0497] A solution of diisopropylamine (559 .mu.L, 3.99 mmol) in dry
tetrahydrofuran (1.2 mL) was cooled to -78.degree. C. under
nitrogen and then treated with a 2.5M solution of n-butyllithium in
hexanes (1.6 mL, 3.99 mmol). The resulting reaction mixture was
allowed to warm to 0.degree. C. and then was treated with
3-cyclopentyl-2-(4-methanesulfonyl-
-phenyl)-N-thiazol-2-yl-propionamide (463.1 mg, 1.22 mmol) in small
portions. The reaction mixture turned orange in color. The reaction
mixture was then allowed to warm to 25.degree. C. where it was
stirred for 30 min. After 30 min at 25.degree. C., the reaction
mixture was cooled back down to 0.degree. C. and then treated with
a 1M solution of tributylborane in tetrahydrofuran (1.8 mL, 1.84
mmol). The resulting reaction mixture was stirred at 0.degree. C.
for 10 min then allowed to warm to 25.degree. C. The reaction
mixture was stirred at 25.degree. C. for 30 min then heated under
reflux for 20 h. The reaction mixture was cooled to 0.degree. C.
and then treated with water (3 mL) followed by sodium acetate
(702.5 mg, 8.56 mmol) and then finally hydroxyamine-O-sulfonic acid
(484.2 mg, 4.28 mmol). The resulting reaction mixture was stirred
at 0.degree. C. for 30 min then allowed to warm to 25.degree. C.
where it was stirred for 44 h. The reaction mixture was
concentrated in vacuo to remove tetrahydrofuran. The resulting
aqueous residue was diluted with ethyl acetate (150 mL). The
organic layer was washed with a saturated aqueous sodium
bicarbonate solution (1.times.100 mL) and a saturated aqueous
sodium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 70-230 mesh, 3/2 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-sulfamoyl-phenyl)-N-th-
iazol-2-yl-propionamide (191.8 mg, 72%) as a white solid: mp
179-181.degree. C.; EI-HRMS m/e calcd for
C.sub.17H.sub.21N.sub.3O.sub.2S- .sub.2 (M.sup.+) 379.1024, found
379.1029.
EXAMPLE 83
3-Cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamide
[0498] 96
[0499] A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic
acid (prepared from Example 38, 200.0 mg, 0.70 mmol),
O-benzotriazol-1-yl-N,N,- N',N'-tetramethyluronium
hexafluorophosphate (316.9 mg, 0.84 mmol),
N,N-diisopropylethylamine (365 mL, 2.09 mmol), and
2-amino-1,3,4-thiadiazole (140.8 mg, 1.39 mmol) in dry
N,N-dimethylformamide (2 mL) was stirred at 25.degree. C. under
nitrogen for 20 h. The reaction mixture was concentrated in vacuo
to remove N,N-dimethylformamide. The resulting residue was diluted
with ethyl acetate (100 mL). The organic layer was washed with a
saturated aqueous sodium bicarbonate solution (1.times.50 mL), a
10% aqueous hydrochloric acid solution (1.times.100 mL), and a
saturated aqueous sodium chloride solution (1.times.100 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 2/1 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[1,3,4]thiadiazol-2-yl-propionamid-
e (197.3 mg, 77%) as a white foam: mp 90-91.degree. C.; EI-HRMS m/e
calcd for C.sub.16H.sub.17Cl.sub.2N.sub.3OS (M.sup.+) 369.0469,
found 369.0476.
EXAMPLE 84
(A)
2-(4-Cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
[0500] 97
[0501] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.32M stock solution, 7.13 mmol) cooled to -78.degree. C.
was treated with (4-bromo-phenyl)-acetic acid methyl ester (1.48 g,
6.48 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(16.2 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 45 min. Iodomethylcyclopentane (1.49 g, 7.13 mmol) was then
added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL).
The reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 18 h. The reaction mixture was then quenched by
the dropwise addition of a saturated aqueous ammonium chloride
solution (10 mL). This mixture was poured into water (100 mL) and
extracted with ethyl acetate (3.times.50 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(1.times.50 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 95/5 hexanes/ethyl acetate) afforded
2-(4-bromo-phenyl)-3-cyclopent- yl-propionic acid methyl ester
(1.60 g, 79.3%) as a clear oil: EI-HRMS m/e calcd for
C.sub.15H.sub.19O.sub.2Br (M.sup.+) 310.0568 found 310.0564.
[0502] A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic
acid methyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide
(4.01 mL) was treated with copper(I) cyanide (144 mg, 1.60 mmol).
The mixture was heated at 170.degree. C. for 1 h. At this time, the
reaction was cooled to 25.degree. C. and poured into aqueous
ammonium hydroxide (5 mL). The solution was diluted with water (25
mL) and extracted with ethyl acetate (3.times.35 mL). The organics
were dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
90/10 hexanes/ethyl acetate) afforded
2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6
g, 15.8%) as a clear oil: EI-HRMS m/e calcd for
C.sub.16H.sub.19NO.sub.2 (M.sup.+) 257.1415 found 257.1406.
[0503] A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic
acid methyl ester (65.0 mg, 0.25 mmol) in
tetrahydrofuran/water/methanol (2.5 mL, 3:1:1) was treated with a
1N aqueous lithium hydroxide solution (0.27 mL, 0.27 mmol). The
reaction was stirred at 25.degree. C. for 6 h. At this time, the
reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid
solution and extracted with chloroform/methanol (9:1, 3.times.25
mL). The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid (36.0 mg, 58.6%) as
a white solid: mp 126-128.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.17NO.sub.2(M.sup.+) 243.1259 found 243.1268.
[0504] A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic
acid (33.0 mg, 0.13 mmol) in methylene chloride (1.36 mL) was
cooled to 0.degree. C. and then treated with a 2.0M solution of
oxalyl chloride in methylene chloride (0.07 mL, 0.14 mmol) and a
few drops of N,N-dimethylformamide. The reaction mixture was
stirred at 0.degree. C. for 10 min and at 25.degree. C. for 30 min.
The reaction mixture was then treated with a solution of
2-aminothiazole (30.0 mg, 0.29 mmol) and N,N-diisopropylethylamine
(0.05 mL, 0.32 mmol) in tetrahydrofuran (0.67 mL). This solution
was stirred at 25.degree. C. for 3 h. At this time, the reaction
was concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (44.1
mg, 100%) as a white solid: mp 64-66.degree. C.; EI-HRMS m/e calcd
for C.sub.18H.sub.19N.sub.3OS (M.sup.+) 325.1248 found
325.1247.
[0505] (B) In an analogous manner, there was obtained:
[0506] (a) From 2-aminopyridine and
2-(4-cyano-phenyl)-3-cyclopentyl-propi- onic acid:
2-(4-Cyano-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide as a
white solid: mp 61-63.degree. C.; EI-HRMS m/e calcd for
C.sub.20H.sub.21N.sub.3O (M.sup.+) 319.1684, found 319.1697.
[0507] (b) From 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid and
6-amino-nicotinic acid methyl ester:
6-[2-(4-Cyano-phenyl)-3-cyclopentyl-- propionylamino]-nicotinic
acid methyl ester as a white solid: mp 62-64.degree. C.; EI-HRMS
m/e calcd for C.sub.22H.sub.23N.sub.3O.sub.3 (M.sup.+) 377.1739,
found 377.1736.
EXAMPLE 85
(A)
3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide
[0508] 98
[0509] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.31M stock solution, 7.13 mmol) cooled to -78.degree. C.
was treated with (4-trifluoromethyl)phenylacetic acid (693 mg, 3.4
mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 30 min.
Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in
hexamethylphosphoramide (1 mL). The reaction mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of saturated aqueous
ammonium chloride solution (10 mL). The excess solvent was removed
in vacuo. The residue was acidified to pH=1 with a 1N aqueous
hydrochloric acid solution. The mixture was poured into water (150
mL) and extracted with ethyl acetate (3.times.100 mL). The organics
were dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
95/5 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9
mg, 65%) as a white solid: mp 94-95.degree. C.; FAB-HRMS m/e calcd
for C.sub.15H.sub.17F.sub.3O.sub.2(M+Na)+309.1079, found
309.1072.
[0510] A solution of
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (170 mg, 0.38 mmol),
3-cyclopentyl-2-(4-trifluorometh- yl-phenyl)-propionic acid (100
mg, 0.34 mmol), and 2-aminopyridine (36 mg, 0.38 mmol) in
N,N-dimethylformamide (1.75 mL) was treated with
N,N-diisopropylethylamine (0.12 mL, 0.73 mmol). The reaction
mixture was stirred at 25.degree. C. for 18 h. At this time, the
reaction was poured into water (50 mL) and extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were washed
with a 1N aqueous hydrochloric acid solution (1.times.50 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 90/10
hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl--
2-(4-trifluoromethyl-phenyl)-propionamide (127 mg, 53.3%) as a
white gum: EI-HRMS m/e calcd for C.sub.20H.sub.21F.sub.3N.sub.2O
(M.sup.+) 362.1605, found 362.1592.
[0511] (B) In an analogous manner, there was obtained:
[0512] (a) From 6-amino-nicotinic acid methyl ester and
3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic:
6-[3-Cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionylamino]-nicotinic
acid methyl ester as a white gum: EI-HRMS m/e calcd for
C.sub.22H.sub.23F.sub.3N.sub.2O.sub.3 (M.sup.+) 420.1660, found
420.1661.
EXAMPLE 86
(A)
2-[4-(Butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propiona-
mide
[0513] 99
[0514] A solution of freshly prepared lithium diisopropylamide
(430.55 mL of a 0.3M stock solution, 129.16 mmol) cooled to
-78.degree. C. was treated with (4-nitro-phenyl)-acetic acid ethyl
ester (prepared in Example 22, 26.32 g, 125.83 mmol) in
tetrahydrofuran/hexamethylphosphoram- ide (312.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 45 min.
Iodomethylcyclopentane (27.75 g, 132.1 mmol) was then added in
hexamethylphosphoramide (27.75 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (250 mL). This mixture was concentrated
in vacuo. The residue was diluted with water (250 mL) and extracted
with ethyl acetate (3.times.300 mL). The organics were washed with
a saturated aqueous lithium chloride solution (2.times.250 mL),
dried over magnesium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30
g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.4 (M.sup.+) 291.1470, found 291.1470.
[0515] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was
treated with 10% palladium on activated carbon. The reaction
mixture was stirred under hydrogen gas at 60 psi at 25.degree. C.
for 18 h. The catalyst was then filtered off through a pad of
celite (ethyl acetate). The filtrate was concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded 2-(4-amino-phenyl)-3-cyclopen-
tyl-propionic acid ethyl ester (3.52 mg, 53.3%) as a yellow oil:
EI-HRMS m/e calcd for C.sub.16H.sub.23NO.sub.2 (M.sup.+) 261.1729
found 261.1727.
[0516] A mixture of concentrated hydrochloric acid (0.38 mL) and
ice (380 mg) cooled to 0.degree. C. was treated with
2-(4-amino-phenyl)-3-cyclopen- tyl-propionic acid ethyl ester (497
mg, 1.90 mmol). After 5 min, a solution of sodium nitrite (139 mg,
2.01 mmol) in water (0.31 mL) was added to the reaction mixture.
The resulting solution was stirred at 0.degree. C. for 5 min. At
this time, the solution was added to a solution of n-butyl
mercaptan (0.23 mL, 2.20 mmol) in water (0.41 mL) warmed to
45.degree. C. The reaction was stirred at 45.degree. C. for 3 h. At
this time, the reaction was diluted with water (50 mL) and
extracted with chloroform (3.times.50 mL). The organics were dried
over sodium sulfate, filtered, and concentrated in vacuo. The crude
brown oil (588 mg) in methylene chloride (8.8 mL) was cooled to
0.degree. C. and treated with 3-chloroperoxybenzoic acid (80-85%
grade, 1.5 g, 8.78 mmol). The reaction mixture was stirred at
25.degree. C. for 18 h. At this time, the reaction was diluted with
water (75 mL) and extracted with chloroform (2.times.30 mL). The
organics were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
80/20 hexanes/ethyl acetate) afforded
2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propionic acid ethyl
ester (144.3 mg, 20.7%) as a yellow oil: EI-HRMS m/e calcd for
C.sub.20H.sub.30O.sub.4S (M.sup.+) 366.1865 found 366.1858.
[0517] A solution of
2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-propio- nic acid
ethyl ester (140 mg, 0.38 mmol in tetrahydrofuran/water/methanol
(0.95 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide
solution (0.76 mL, 0.76 mmol). The reaction was stirred at
25.degree. C. for 8 h. At this time, the reaction was acidified to
pH=1 with a 1N aqueous hydrochloric acid solution and extracted
with chloroform (3.times.50 mL). The organics were dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 90/10
chloroform/methanol) afforded
2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopen- tyl-propionic acid
(88.3 mg, 68.4%) as a clear oil: FAB-HRMS m/e calcd for
C.sub.18H.sub.26O.sub.4S (M+H).sup.+ 339.1631 found 339.1638.
[0518] A solution of triphenylphosphine (99 mg, 0.37 mmol) and
N-bromosuccinimide (76 mg, 0.42 mmol) in methylene chloride (1.26
mL) cooled to 0.degree. C. was treated with
2-[4-(butane-1-sulfonyl)-phenyl]-- 3-cyclopentyl-propionic acid (85
mg, 0.25 mmol) in methylene chloride. The reaction mixture was
stirred at 25.degree. C. for 45 min. At this time, the reaction was
treated with 2-aminothiazole (33 mg, 0.32 mmol) and pyridine (0.03
mL, 0.37 mmol). The reaction was stirred at 25.degree. C. for 18 h.
The reaction mixture was then concentrated in vacuo to remove
methylene chloride. At this time, the reaction was diluted with
water (50 mL) and extracted with chloroform (3.times.50 mL). The
organics were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh,
50/50 hexanes/ethyl acetate) afforded
2-[4-(butane-1-sulfonyl)-phenyl]-3-cyclopentyl-N-thiazo-
l-2-yl-propionamide (69.3 mg, 65.6%) as an off-white solid: mp
163-165.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.28N.sub.2O.sub.3S- .sub.2 (M.sup.+) 420.1541 found
420.1535.
[0519] (B) In an analogous manner, there was obtained:
[0520] (a) From 2-aminothiazole and
3-cyclopentyl-2-[4-(propane-1-sulfonyl- )-phenyl]-propionic acid:
3-Cyclopentyl-2-[4-(propane-1-sulfonyl)-phenyl]--
N-thiazol-2-yl-propionamide as a yellow oil: EI-HRMS m/e calcd for
C.sub.20H.sub.26N.sub.2O.sub.3S.sub.2 (M.sup.+) 406.1385 found
406.1389.
EXAMPLE 87
(A)
3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-pro-
pionamide
[0521] 100
[0522] A solution of freshly prepared lithium diisopropylamide
(35.32 mL of a 0.31M stock solution, 10.95 mmol) cooled to
-78.degree. C. was treated with
(.sup.4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0
mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyr-
imidinone (12.42 mL, 3:1). The resulting solution was stirred at
-78.degree. C. for 1 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol)
was then added in
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 24 h. This solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution (50 mL). The product was extracted into ethyl acetate
(1.times.300 mL) and diethyl ether (1.times.50 mL). The organics
were dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid
(1.28 g, 84.3%) as a white solid: mp 65-68.degree. C.; EI-HRMS m/e
calcd for C.sub.15H.sub.16F.sub.4O.sub.2(M.sup.+) 305.1165, found
305.1174.
[0523] A solution of
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-p- ropionic
acid (304 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to
0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 24 h. The reaction
mixture was then treated with 2-amino-thiazole (175 mg, 1.75 mmol)
and N,N-diisopropylethylamine (0.4 mL, 2.41 mmol). This solution
was stirred at 25.degree. C. for 48 h. At this time, the reaction
was concentrated in vacuo. High pressure liquid chromatography
(Chromegasphere SI-60, 10 .mu.M, 60 .ANG., 25 cm.times.23 cm ID,
60/40 heptane/ethyl acetate) afforded
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-thiazol-2--
yl-propionamide (326 mg, 84.5%) as a light yellow solid: mp
125-127.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.18F.sub.4N.sub.2O- S (M.sup.+) 386.1076, found
386.1086.
[0524] (B) In an analogous manner, there was obtained:
[0525] (a) From ethyl 2-amino-4-thiazole glyoxylate and
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid:
{2-[3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-t-
hiazol-4-yl}-oxo-acetic acid ethyl ester as a light yellow solid:
mp 155-158.degree. C.; FAB-HRMS m/e calcd for
C.sub.22H.sub.22F.sub.4N.sub.2- O.sub.4S (M+H).sup.+ 487.1314,
found 487.1319.
[0526] (b) From 5-methyl-2-aminopyridine and
3-cyclopentyl-2-(4-fluoro-3-t- rifluoromethyl-phenyl)-propionic
acid: 3-Cyclopentyl-2-(4-fluoro-3-trifluo-
romethyl-phenyl)-N-(5-methyl-pyridin-2-yl)-propionamide as a white
solid: mp 132-133.degree. C.; EI-HRMS m/e calcd for
C.sub.21H.sub.22F.sub.4N.sub- .2O (M.sup.+) 392.1668, found
392.1669.
[0527] (c) From 2-aminopyridine and
3-cyclopentyl-2-(4-fluoro-3-trifluorom- ethyl-phenyl)-propionic
acid: 3-Cyclopentyl-2-(4-fluoro-3-trifluoromethyl--
phenyl)-N-pyridin-2-yl-propionamide as a light yellow oil: EI-HRMS
m/e calcd for C.sub.20H.sub.20F.sub.4N.sub.2O (M.sup.+) 380.1511,
found 380.1521.
EXAMPLE 88
3-Cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide
[0528] 101
[0529] A solution of freshly prepared lithium diisopropylamide
(35.32 mL of a 0.31M stock solution, 10.9 mmol) cooled to
-78.degree. C. was treated with (3-trifluoromethyl-phenyl)-acetic
acid (1.02 g, 5.0 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(12.4 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 3 h. Iodomethylcyclopentane (1.16 g, 5.52 mmol) was then
added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16
mL). The reaction mixture was stirred at -78.degree. C. for 4 h.
The reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. This solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution (50 mL). The product was extracted into ethyl acetate
(3.times.100 mL) and diethyl ether (1.times.50 mL). The organics
were washed with a saturated aqueous lithium chloride solution
(2.times.100 mL) and a saturated aqueous sodium chloride solution
(1.times.150 mL), dried over magnesium sulfate and sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with
acetic acid) afforded
3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propioni- c acid (1.16
g, 80.5%) as an off-white solid: mp 64-65.degree. C.; EI-HRMS m/e
calcd for C.sub.15H.sub.17F.sub.3O.sub.2 (M+Na.sup.+) 309.1079,
found 309.1084.
[0530] A solution of
3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (286 mg,
1.0 mmol) in methylene chloride (10 mL) was cooled to 0.degree. C.
and then treated with a 2.0M solution of oxalyl chloride in
methylene chloride (0.6 mL, 1.2 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 1.25 h. The
reaction mixture was then treated with a solution of
2-aminothiazole (175 mg, 1.75 mmol) and N,N-diisopropylethylamine
(0.42 mL, 2.41 mmol) in tetrahydrofuran (10 mL). This solution was
stirred at 25.degree. C. for 24 h. At this time, the reaction was
concentrated in vacuo. High pressure liquid chromatography
(Chromegasphere SI-60, 10 .mu.M, 60 .ANG., 25 cm.times.23 cm ID,
60/40 heptane/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-
-2-(3-trifluoromethyl-phenyl)-propionamide (299.2 mg, 81.4%) as a
light yellow solid: mp 134-136.degree. C.; EI-HRMS m/e calcd for
C.sub.18H.sub.19F.sub.3N.sub.2OS (M.sup.+) 368.1170, found
368.1165.
EXAMPLE 89
(A)
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-
-2-yl-propionamide
[0531] 102
[0532] A solution of freshly prepared lithium duisopropylamide
(35.3 mL of a 0.31M stock solution, 10.9 mmol) cooled to
-78.degree. C. was treated with
(4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol)
in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(12.4 miL, 3:1). The resulting solution was stirred at -78.degree.
C. for 1 h. At this time, the reaction was treated with a solution
of iodomethylcyclopentane (1.16 g, 5.52 nunol) in
1,3-dimethyl-3,4,5,6-tetra- hydro-2(1H)-pyrimidinone (1.2 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. This solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution (50 mL). The product was extracted into ethyl acetate
(3.times.1 00 mL) and diethyl ether (1.times.50 mL). The organics
were dried over magnesium sulfate and sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid)
afforded
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid
(1.28 g, 84.3%) as a white solid: mp 66-68.degree. C.; EI-HRMS m/e
calcd for C.sub.15H.sub.16F.sub.4O.sub.2(M.sup.+) 305.1165, found
305.1174.
[0533] A solution of
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-p- ropionic
acid (7.77 g, 25.3 mmol) in methanol (50 mL) was treated slowly
with concentrated sulfuric acid (0.01 mL). The resulting reaction
mixture was heated under reflux for 24 h. The reaction mixture was
allowed to cool to 25.degree. C. and then concentrated in vacuo.
The residue was dissolved in ethyl acetate (75 mL) and washed with
a saturated aqueous sodium bicarbonate solution (1.times.50 mL),
water (1.times.50 mL), and a saturated aqueous sodium chloride
solution (4.times.50 mL). The organics were dried over magnesium
sulfate and sodium sulfate, filtered, and concentrated in vacuo to
afford 3-cyclopentyl-2-(4-fluoro-3-trifluorometh-
yl-phenyl)-propionic acid methyl ester (8.48 g, 87.5%) as yellow
oil: EI-HRMS m/e calcd for C.sub.16H.sub.18F.sub.4O.sub.2 (M.sup.+)
318.1243, found 318.1240.
[0534] A solution of
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-p- ropionic
acid methyl ester (7.0 g, 21.9 mmol) in N,N-dimethylformamide (50
mL) was treated with sodium methanethiolate (2.61 g, 33.0 mmol).
The reaction mixture was then heated at 100-110.degree. C. for 24
h. At this time, the reaction was poured onto a mixture of ice and
a 2N aqueous hydrochloric acid solution (100 mL). This mixture was
extracted into ethyl acetate (3.times.75 mL) and diethyl ether
(1.times.50 mL). The organics were then washed with water
(1.times.75 mL) and a saturated aqueous sodium chloride solution
(3.times.100 mL). The organics were dried over magnesium sulfate
and sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 85/15
hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulf-
anyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (2.48 g,
35.5%) as a pale yellow oil: EI-HRMS m/e calcd for
C.sub.17H.sub.21F.sub.3O.sub.- 2S (M.sup.+) 346.1214, found
346.1212.
[0535] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-p-
henyl)-propionic acid methyl ester (2.36 g, 6.81 mmol) in methylene
chloride (75 mL) at 25.degree. C. was treated with
3-chloroperoxybenzoic acid (80-85% grade, 9.69 g, 40.1 mmol). The
reaction mixture was stirred at 25.degree. C. for 16 h. At this
time, the reaction was diluted with methylene chloride (75 mL). The
solution was washed with a saturated aqueous sodium l0 bisulfite
solution (2.times.50 mL), water (1.times.50 mL), a saturated
aqueous sodium chloride solution (3.times.75 mL), a saturated
aqueous sodium bicarbonate solution (1.times.75 mL), and a
saturated aqueous sodium chloride solution (3.times.75 mL). The
organics were dried over magnesium sulfate and sodium sulfate,
filtered, and concentrated in vacuo to afford
3-cyclopentyl-2-(4-methanesulfonyl-3-trif-
luoromethyl-phenyl)-propionic acid methyl ester (2.88 g) as a clear
oil: EI-HRMS m/e calcd for C.sub.17H.sub.21F.sub.3O.sub.4S
(M.sup.+) 378.1112 found 3-78.1116.
[0536] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl--
phenyl)-propionic acid methyl ester (395 mg, 1.04 mmol) and
2-aminothiazole (209 mg, 1.38 mmol) in a solution of magnesium
methoxide in methanol (7.4 wt %, 2.09 mL, 1.38 mmol) was heated at
110.degree. C. for 24 h. The reaction mixture was then concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
50/50 hexanes/ethyl acetate) afforded the
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethy-
l-phenyl)-N-thiazol-2-yl-propionamide (256.7 mg, 55.1%) as a white
solid: mp 95-100.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.21F.sub.3N.sub.- 2O.sub.3S.sub.2 (M.sup.+)446.0946,
found 446.0944.
[0537] (B) In an analogous manner, there was obtained:
[0538] (a) From (2-amino-thiazol-4-yl)-acetic acid methyl ester and
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic
acid: {
2-[3-Cyclopentyl-2-(4-methanesulfonyl-3-tkifluoromethyl-phenyl)-p-
ropionylamino]-thiazol-4-yl}-acetic acid methyl ester as a white
solid: mp 81-86.degree. C.; FAB-HRMS m/e calcd for
C.sub.22H.sub.25F.sub.3N.sub.2O.- sub.5S.sub.2 (M+H).sup.+
518.1157, found 518.1161.
[0539] (b) From 2-amino-thiazole-4-carboxylic acid methyl ester and
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic
acid:
2-[3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-pro-
pionylamino]-thiazole-4-carboxylic acid methyl ester as a white
solid: mp 117-121.degree. C.; FAB-HRMS m/e calcd for
C.sub.21H.sub.23F.sub.3N.sub.2- O.sub.5S.sub.2 (M+H).sup.+
504.1000, found 504.1000.
EXAMPLE 90
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-y-
l-propionamide
[0540] 103
[0541] A solution of freshly prepared lithium diisopropylamide
(141.28 mL of a 0.31M stock solution, 43.8 mmol) cooled to
-78.degree. C. was treated with
(4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (4.44 g, 20.0 mmol)
in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrim-
idinone (49.68 mL, 3:1). The resulting solution was stirred at
-78.degree. C. for 1 h. At this time, the reaction was treated with
a solution of iodomethylcyclopentane (4.64 g, 22.09 mmol) in
1,3-dimethyl-3,4,5,6-tetra- hydro-2(1H)-pyrimidinone (4.6 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. This solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution. The product was extracted into ethyl acetate (3.times.400
mL) and diethyl ether (1.times.200 mL). The organics were dried
over magnesium sulfate and sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid)
afforded 3-cyclopentyl-2-(4-fluor-
o-3-trifluoromethyl-phenyl)-propionic acid (3.37 g, 55.4%) as a
white solid: mp 66-68.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.16F.sub.4- O.sub.2 (M.sup.+) 305.1165, found
305.1174.
[0542] A solution of
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-p- ropionic
acid (1.52 g, 5.0 mmol) in N,N-dimethylformamide (10 mL) was
treated with sodium methanethiolate (0.59 g, 7.5 mmol). The
reaction mixture was then heated to 100-110.degree. C. for 14 h. At
this time, the reaction was poured onto a mixture of ice and a 2N
aqueous hydrochloric acid solution (25 mL). This mixture was
extracted into ethyl acetate (3.times.35 mL) and diethyl ether
(1.times.25 mL). The organics were then washed with water
(1.times.50 mL) and a saturated aqueous sodium chloride solution
(3.times.75 mL). The organics were dried over magnesium sulfate and
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate w/acetic acid) afforded
3-cyclopentyl-2-(4-methylsulfanyl-3-trifl-
uoromethyl-phenyl)-propionic acid (1.36 g, 83.4%) as a pale yellow
oil: EI-HRMS m/e calcd for C.sub.16H.sub.19F.sub.3O.sub.2S
(M.sup.+) 332.1058, found 332.1057.
[0543] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-p-
henyl)-propionic acid (1.29 g, 3.89 mmol) in ethanol (25 mL) was
treated slowly with concentrated sulfuric acid (0.01 mL). The
resulting reaction mixture was heated under reflux for 48 h. zzz
The reaction mixture was allowed to cool to 25.degree. C. and then
concentrated in vacuo. The residue was dissolved in ethyl acetate
(35 mL) and washed with a saturated aqueous sodium bicarbonate
solution (1.times.15 mL), water (1.times.15 mL), and a saturated
aqueous sodium chloride solution (3.times.20 mL). The organics were
dried over magnesium sulfate and sodium sulfate, filtered, and
concentrated in vacuo to afford
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic
acid ethyl ester (1.39 g, 94.8%) as yellow oil: EI-HRMS m/e calcd
for C.sub.18H.sub.23F.sub.3O.sub.2S (M.sup.+) 360.1370, found
360.1370.
[0544] A solution of
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-p-
henyl)-propionic acid ethyl ester (1.32 g, 3.69 mmol) in methylene
chloride (50 mL) at 25.degree. C. was treated with
3-chloroperoxybenzoic acid (80-85% grade, 4.8 g, 19.8 mmol). The
reaction mixture was stirred at 25.degree. C. for 4 d. At this
time, the reaction was diluted with methylene chloride (25 mL).
This solution was washed with a saturated aqueous sodium bisulfite
solution (1.times.50 mL), water (1.times.50 mL), a saturated
aqueous sodium bicarbonate solution (1.times.50 mL), water
(1.times.50 mL), and a saturated aqueous sodium chloride solution
(3.times.50 mL). The organics were dried over magnesium sulfate and
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 70/30
hexanes/ethyl acetate with acetic acid) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethy-
l-phenyl)-propionic acid ethyl ester (1.28 g, 89.0%) as a clear
oil: EI-HRMS m/e calcd for C.sub.18H.sub.23F.sub.3O.sub.4S (NC)
392.1269 found 392.1268.
[0545] A solution of
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl--
phenyl)-propionic acid ethyl ester (707 mg, 1.80 mmol in
tetrahydrofliran/water (24 mL, 3:1) was treated with lithium
hydroxide (166 mg, 3.97 mmol). The reaction was stirred at
25.degree. C. for 24 h. At this time, the reaction concentrated in
vacuo. The residue was diluted with water (25 mL) and extracted
with diethyl ether (1.times.15 mL). The aqueous layer was acidified
to pH=1 with a 2N aqueous hydrochloric acid solution, and extracted
with chloroform (3.times.25 mL). The organics were washed with
water (1.times.25 mL), a saturated aqueous sodium chloride solution
(3.times.25 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanes-
ulfonyl-3-trifluoromethyl-phenyl)-propionic acid (426.7 mg, 65%) as
a white solid: mp 122-123.degree. C.; EI-HRMS m/e calcd for
C.sub.16H.sub.19F.sub.3O.sub.4S (M.sup.+) 364.0956 found
364.0956.
[0546] A solution of and
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromet-
hyl-phenyl)-propionic acid (73 mg, 0.2 mmol) and triphenylphosphlne
(79 mg, 0.3 mmol) in methylene chloride (5.0 mL) was cooled to
0.degree. C. and then treated with N-bromosuccinimide (60.5 mg,
0.34 mmol). After the complete addition of N-bromosuccinimide, the
reaction mixture was allowed to warmn to 25.degree. C. over 30 min.
The reaction mixture was then treated with 2-aminopyridine (28.2
mg, 0.3 mmol) and pyridine (1 drop). The resulting reaction mixture
was stirred at 25.degree. C. for 48 h. The reaction mixture was
then diluted with methylene chloride (50 mL). The organic layer was
washed with water (1.times.50 mL) and a saturated aqueous sodium
chloride solution (2.times.25 mL), dried over magnesium sulfate and
sodium sulfate, filtered, and concentrated in vacuo. High pressure
liquid chromatography (Chromegasphere SI-60, 10 .mu.M, 60 .ANG., 25
cm.times.23 cm ID, 50/50 heptane/ethyl acetate) afforded
3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2--
yl-propionamide (54.2 mg, 61.5%) as a white solid: mp 86-89.degree.
C.; EI-HRMS m/e calcd for C.sub.21H.sub.23F.sub.3N.sub.2O.sub.3S
(M.sup.+) 440.1383, found 440.1381.
EXAMPLE 91
3-Cyclopentyl-2-(4-methylsulfanyl-3-trfluoromethyl-phenyl)-N-thiazo1-2-yl--
propionamide
[0547] 104
[0548] A solution of
3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-p- ropionic
acid (prepared in Example 87, 1.52 g, 5.0 mmol) in
N,N-dimethylformamide (10 mL) was treated with sodium
methanethiolate (593 mg, 7.5 mmol). The reaction mixture was then
heated to 100-110.degree. C. for 14 h. At this time, the reaction
was cooled to 25.degree. C. and poured onto a 1N aqueous
hydrochloric acid solution (25 mL) and extracted into ethyl acetate
(3.times.25 mL) and diethyl ether (1.times.25 mL). The organics
were then washed with water (1.times.50 mL) and a saturated aqueous
sodium chloride solution (3.times.75 mL), dried over magnesium
sulfate and sodium sulfate, filtered, and concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-3-trifl-
uoromethyl-phenyl)-propionic acid (1.37 g, 82.4%) as a pale yellow
oil: EI-HRMS m/e calcd for C.sub.16H.sub.19F.sub.3O.sub.2S
(M.sup.+) 332.1058, found 332.1057.
[0549] A solution of
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (188 mg, 0.42 mmol) and
3-cyclopentyl-2-(4-methylsulf-
anyl-3-trifluoromethyl-phenyl)-propionic acid (94 mg, 0.28 mmol) in
N,N-dimethylformamide (5 mL) was treated with
N,N-diisopropylethylamine (150 .mu.L, 0.85 mmol) and
2-aminothiazole (42.5 mg, 0.42 mmol). The mixture was stirred at
25.degree. C. for 48 h. At this time, the reaction mixture was
poured into cold water (25 mL) containing a 1N aqueous hydrochloric
acid solution (50 mL) and extracted into ethyl acetate (2.times.75
mL) and diethyl ether (1.times.25 mL). The organics were then
washed with water (2.times.75 mL) and a saturated aqueous sodium
chloride solution (3.times.75 mL), dried over magnesium sulfate and
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-y-
l-propionamide (50.5 mg, 43.1%) as a clear oil: FAB-HRMS m/e calcd
for C.sub.19H.sub.21F.sub.3N.sub.2OS.sub.2 (M+H).sup.+ 415.1125,
found 415.1123.
EXAMPLE 92
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propion-
amide
[0550] 105
[0551] A solution of aluminum trichloride (34.8 g, 261.4 mmol) in
chloroform (120 mL) under argon and cooled to 0.degree. C. and was
then treated dropwise with a solution of ethyl chlorooxoacetate
(18.7 mL, 167.5 mmol) in chloroform (120 mL). The mixture was then
stirred at 0.degree. C. for 30 min. After this time a solution of
2-chlorothioanisole (25.0 g, 156.5 mmol) in chloroform (120 mL) was
added dropwise to the above mixture at 0.degree. C. and it turned
red in color. It was allowed to warm to 25.degree. C. and stirred
for an additional 3.5 h. The reaction was quenched by slowly adding
water (500 mL). The solution turned yellow in color and was then
transferred to a separatory funnel and extracted with chloroform
(3.times.50 mL). The organic phase was dried over sodium sulfate,
filtered and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester
(31.37 g, 77%) as a yellow oil.
[0552] A solution of cylcopenytlmethyl triphenylphosphine iodide
(725 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was cooled to
0.degree. C. To this cooled solution was added sodium
bis(trimethylsilyl)amide (1.0 M in THF, 2.14 mL, 2.14 mmol) and the
reaction turned red in color. It was stirred at 0.degree. C. for 45
minutes and then a solution of
(3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (355
mg, 1.37 mmol) in tetrahydrofuran (5 mL) was added slowly. The
reaction was warmed to 25.degree. C. and stirred for 20 h. The
reaction was diluted with water (50 mL) and transferred to a
separatory funnel and extracted with diethyl ether (3.times.25 mL).
The organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. Chromatography (Biotage Flash 12M column,
80/20 hexanes/ethyl acetate) afforded
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-acrylic acid
ethyl ester (267 mg, 60%, mixture of E and Z isomers (2:1)) as a
yellow oil and taken on without characterization.
[0553] A solution of E and Z
2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclop- entyl-acrylic acid
ethyl ester (100 mg, 0.31 mmol) dissolved in methylene chloride (5
mL) cooled to 0.degree. C. was treated with 3-chloroperoxybenzoic
acid (80%, 157 mg, 0.729 mmol) and stirred for 3.5 h. The reaction
mixture was diluted with methylene chloride (25 mL), transferred to
a separatory finnel and washed with saturated aqueous sodium
carbonate solution (2.times.10 mL) and brine (2.times.10 mL). The
organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo. Chromatography (Biotage Flash 12M column,
80/20 hexanes/ethyl acetate) afforded
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-acr- ylic acid
ethyl ester (95 mg, 86%, mixture of E and Z isomers (2:1)) as a
colorless oil and taken on without characterization.
[0554] The mixture of E and Z isomers of
2-(3-chloro-4-methanesulfonyl-phe- nyl)-3-cyclopentyl-acrylic acid
ethyl ester (1.04 g, 2.91 mmol), nickel chloride hexahydrate (69
mg, 0.29 mmol) and methanol (25 mL) were placed in a flask under
argon. To this green solution was then added sodium borohydride
(221 mg, 5.83 mmol) slowly in small portions using an ice bath if
necessary to keep the temperature at 20.degree. C. The solution
turned black and a fine precipitate formed after addition of the
sodium borohydride. This was then stirred at 25.degree. C. for 1.5
h. After such time the reaction was filtered through celite and
washed with methanol. The filtrate and washings were combined and
concentrated in vacuo to reduce the volume. The residual solution
was then diluted with water (15 mL) and extracted with ethyl
acetate (3.times.15 mL) dried over sodium sulfate, filtered and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 75/25 hexanes/ethyl acetate) afforded a mixture of
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
methyl ester and
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl- -propionic
acid ethyl ester (transesterification occurred under the reaction
conditions) (937 mg) as a clear colorless oil. (It was carried on
without characterization because it was a mixture of esters).
[0555] The mixture of
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-- propionic
acid methyl ester and 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cy-
clopentyl-propionic acid ethyl ester, from above, (937 mg) was
dissolved in ethanol (30 mL) and allowed to dissolve. To this
solution was then added a solution of potassium hydroxide (733 mg,
13.1 mmol) in water (7 mL). The yellow solution was then stirred
for 3 h at 25.degree. C. It was concentrated in vacuo to remove the
ethanol and then 1N hydrochloric acid was added until the pH=2.
This was then extracted with methylene chloride (3.times.15 mL).
The organic layers were then dried over sodium sulfate, filtered
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 75/25 hexanes/ethyl acetate plus 1% acetic acid)
afforded
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(787 mg, 82% over two steps) as a white solid: mp:
123.9-126.2.degree. C.; FAB-HRMS m/e calcd for
C.sub.15H.sub.19O.sub.4SCl (M+H).sup.+ 331.0771, found
331.0776.
[0556] Triphenylphosphine (238 mg, 0.91 mmol) was dissolved in
methylene chloride (10 mL) and cooled to 0.degree. C. To this
solution was added N-bromosuccinimide (183 mg, 1.03 mmol) and was
stirred at 0.degree. C. until it was completely dissolved and
became light purple in color. The
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(200 mg, 0.61 mmol) was then added and it was stirred at 0.degree.
C. for 20 min and then warmed to 25.degree. C. and stirred for 30
min. After such time 2-aminopyridine (85 mg, 0.91 mmol) and
pyridine (0.088 mL, 1.09 mmol) were added and it was stirred at
25.degree. C. for 16 h. The reaction was then diluted with water
(10 mL) and then extracted with methylene chloride (3.times.15 mL).
The organic layers were then combined and dried over sodium
sulfate, filtered and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate)
afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-p-
yridin-2-yl-propionamide (210 mg, 85%) as a colorless oil: EI-HRMS
m/e calcd for C.sub.20H.sub.23N.sub.2O.sub.3SCl (M.sup.+) 406.1118,
found 406.1120.
EXAMPLE 93
N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclo
pentyl-propionamide
[0557] 106
[0558] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(prepared in Example 92, 200 mg, 0.61 mmol) and stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
was stirred for 30 min. After such time, the reaction mixture was
treated with 2-amino-5-bromopyridine (157 mg, 0.91 mmol) and
pyridine (0.088 mL, 1.09 mmol), and reaction mixture was stirred at
25.degree. C. for 16 h. The reaction was then diluted with water
(10 mL) and then extracted with methylene chloride (3.times.15 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(-
5-bromo-pyridin-2-yl)-propionamide (245 mg, 83%) as a white foam:
EI-HRMS m/e calcd for C.sub.20H.sub.22Br ClN.sub.2O.sub.3S
(M.sup.+) 484.0223, found 484.0222.
EXAMPLE 94
N-(5-Chloro-pyridin-2-yl)-2-(3-chloro-4-metanesulfonyl-phenyl)-3-cyclopent-
yl-propionamide
[0559] 107
[0560] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(prepared in Example 92, 200 mg, 0.61 mmol) and stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
was stirred for 30 min. After such time, the reaction mixture was
treated with 2-amino-5-chloropyridine (117 mg, 0.91 mmol) and
pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was
stirred at 25.degree. C. for 16 h. The reaction was then diluted
with water (10 mL) and then extracted with methylene chloride
(3.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(-
5-chloro-pyridin-2-yl)-propionamide (110 mg, 41%) as a yellow foam:
EI-HRMS m/e calcd for C.sub.20H.sub.22 Cl.sub.2N.sub.2O.sub.3S
(M.sup.+) 440.0728, found 440.0728.
EXAMPLE 95
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-trifluoromethyl-p-
yridin-2-yl)-propionamide
[0561] 108
[0562] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(prepared in Example 92, 200 mg, 0.61 mmol) and stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
was stirred for 30 min. After such time, the reaction mixture was
treated with 2-amino-5-trifluoromethyl-pyridine (147 mg, 0.91 mmol)
and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture was
stirred at 25.degree. C. for 16 h. The reaction was then diluted
with water (10 mL) and then extracted with methylene chloride
(3.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate)
afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-c-
yclopentyl-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide (122 mg,
43%) as a white foam: EI-HRMS m/e calcd for C.sub.20H.sub.22
ClF.sub.3N.sub.2O.sub.3S (M.sup.+) 474.0992, found 474.0990.
EXAMPLE 96
{2-[2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-th-
iazol-4-yl}-oxo-acetic Acid Ethyl Ester
[0563] 109
[0564] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid
(prepared in Example 92, 200 mg, 0.61 mmol) and stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
was stirred for 30 min. After such time, the reaction mixture was
treated with 2-(amino-thiazol-4-yl)-oxo-acetic acid ethyl ester
(182 mg, 0.91 mmol) and pyridine (0.088 mL, 1.09 mmol), and the
reaction mixture was stirred at 25.degree. C. for 16 h. The
reaction was then diluted with water (10 mL) and then extracted
with methylene chloride (3.times.15 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
75/25 hexanes/ethyl acetate) afforded
{2-[2-(3-chloro-4-methanesulf-
onyl-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-oxo-acetic
acid ethyl ester (208 mg, 67%) as a clear colorless oil: EI-HRMS
m/e calcd for C.sub.22H.sub.25ClN.sub.2O.sub.6S.sub.2 (M.sup.+)
513.0921, found 513.0919.
EXAMPLE 97
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-prop-
ionamide
[0565] 110
[0566] A mixture of
2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-pr- opionic
acid (prepared in Example 92, 6.07 g, 18.35 mmol),
(R)-(+)-4-benzyl-2-oxazolidinone (2.83 g, 15.96 mmol), and
triethylamine (6.68 mL, 47.71 mmol) in toluene (50 mL) was heated
at 80.degree. C. under argon until a homogeneous solution was
obtained. The reaction mixture was then treated with
trimethylacetyl chloride (3.55 mL, 28.81 mmol) in toluene (10 mL),
and the reaction became yellow in color and a precipitate formed.
The reaction mixture was then heated at 80.degree. C. for 36 h. The
reaction was cooled to 25.degree. C. and then the toluene was
removed in vacuo. The residue was diluted with ethyl acetate (150
mL). The organic layer was washed with a 1N aqueous hydrochloric
solution (1.times.100 mL), a 10% aqueous sodium carbonate solution
(1.times.100 mL), and a saturated aqueous sodium chloride solution
(1.times.100 mL). The organic layer was then dried over magnesium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 90/5/5 methylene
chloride/hexanes/ethyl acetate) afforded (1)
4(R)-benzyl-3-[2(S)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-pro-
pionyl]-oxazolidin-2-one (2.08 g, 23%) as a white foam:
[.alpha.].sup.23.sub.589=+10.4.degree. (c=0.144, chloroform);
FAB-HRMS mn/e calcd for C.sub.25H.sub.28ClNO.sub.5S (M+H).sup.+
490.1455, found 490.1457 and (2)
4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)--
3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 25%) as a white
foam: [.alpha.].sup.23.sub.589=-93.90 (c=0.165, chloroform);
FAB-HRMS m/e calcd for C.sub.25H.sub.28ClNO.sub.5S (M+H).sup.+
490.1455, found 490.1443.
[0567] A solution of lithium hydroxide (215 mg, 9.0 mmol) in water
(2.8 mL) was treated with a 30% aqueous hydrogen peroxide solution
(2.0 mL, 18 mmol). This freshly prepared lithium hydroperoxide
solution was then cooled to 0.degree. C. and then slowly added to a
cooled (0.degree. C.) solution of
4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyc-
lopentyl-propionyl]-oxazolidin-2-one (2.20 g, 4.5 mmol) in
tetrahydrofaran (18 mL) and water (5.8 mL). After 1.5 h at
0.degree. C., the reaction was quenched with a 1.5N aqueous sodium
sulfite solution (25 mL) and was diluted with water (150 mL). The
aqueous layer was extracted with diethyl ether (3.times.50 mL). The
aqueous layer was then acidified with a 1N aqueous hydrochloric
acid solution to pH=2 and extracted with ethyl acetate (3.times.50
mL). The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate with 1%
acetic acid) afforded
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopen- tyl-propionic
acid (1.26 g, 85%) as a white solid: mp 106.1-108.8.degree. C.;
[.alpha.].sup.23.sub.589=-43.0.degree. (c=0.172, chloroform);
EI-HRMS m/e calcd for C.sub.15H.sub.19ClO.sub.4S (M.sup.+)
330.0692, found 330.0690.
[0568] A solution of triphenylphosphine (248 mg, 0.94 mmol) in
methylene chloride (9 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (190 mg, 1.07 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic
acid (208 mg, 0.63 mmol). The reaction mixture was stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
was stirred for 30 min. After such time, the reaction mixture was
treated with 2-aminothiazole (95 mg, 0.94 mmol) and pyridine (0.092
mL, 1.13 mmol), and the reaction mixture was stirred at 25.degree.
C. for 16 h. The reaction was then diluted with water (10 mL) and
then extracted with methylene chloride (3.times.15 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Biotage chromatography (FLASH 40S,
Silica, 65/35 hexanes/ethyl acetate) afforded
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-pro-
pionamide (210 mg, 81%) as a white foam:
[.alpha.].sup.23.sub.589=-54.3.de- gree. (c=0.081, chloroform);
EI-HRMS m/e calcd for C.sub.18H.sub.21ClN.sub- .2O.sub.3S.sub.2
(M.sup.+) 412.0682, found 412.0679.
EXAMPLE 98
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-prop-
ionamide
[0569] 111
[0570] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic
acid (prepared in Example 97, 200 mg, 0.61 mmol). The reaction
mixture was stirred at 0.degree. C. for 20 min and then warmed to
25.degree. C. where it was stirred for 30 min. After such time, the
reaction mixture was treated with 2-aminopyridine (85 mg, 0.91
mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture
was stirred at 25.degree. C. for 16 h. The reaction was then
diluted with water (10 mL) and then extracted with methylene
chloride (3.times.15 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo. Biotage
chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate)
afforded
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-pro-
pionamide (202 mg, 81.5%) as a white foam:
[.alpha.].sup.23.sub.589=-41.8.- degree. (c=0.098, chloroform);
EI-HRMS m/e calcd for C.sub.20H.sub.23ClN.sub.2O.sub.3S (M.sup.+)
406.1118, found 406.1119.
EXAMPLE 99
N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclop-
entyl-propionamide
[0571] 112
[0572] A solution of triphenylphosphine (238 mg, 0.91 mmol) in
methylene chloride (10 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic
acid (prepared in Example 97, 200 mg, 0.61 mmol). The reaction
mixture was stirred at 0.degree. C. for 20 min and then warmed to
25.degree. C. where it was stirred for 30 min. After such time, the
reaction mixture was treated with 2-aminopyridine (85 mg, 0.91
mmol) and pyridine (0.088 mL, 1.09 mmol), and the reaction mixture
was stirred at 25.degree. C. for 16 h. The reaction was then
diluted with water (10 mL) and then extracted with methylene
chloride (3.times.15 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo. Biotage
chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate)
afforded
N-(5-bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclo-
pentyl-propionamide (222 mg, 76%) as an off-white foam:
[.alpha.].sup.23.sub.589=-48.6.degree. (c=0.105, chloroform);
EI-HRMS m/e calcd for C.sub.20H.sub.22BrCIN.sub.2O.sub.3S (M.sup.+)
484.0223, found 484.0223.
EXAMPLE 100
N-(5-Cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamid-
e
[0573] 113
[0574] A solution of nickel(II) bromide (253 mg, 1.16 mmol),
triphenylphosphine (1.15 g, 4.39 mmol), and zinc powder (113 mg,
1.73 mmol) in acetonitrile (11 mL) was stirred under argon at
60.degree. C. for 1 h. The reaction turned dark brown in color.
After such time, the reaction mixture was treated with sodium
cyanide (578 mg, 11.8 mmol) and 2-amino-5-bromopyridine (2.00 g,
11.6 mmol), and the reaction mixture was stirred at 60.degree. C.
for 16 h. The reaction mixture was then cooled to 25.degree. C.,
diluted with ethyl acetate (50 mL), and then filtered through
celite. The filtrate was concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl
acetate) afforded 6-amino-nicotinonitrile (577 mg, 42%) as a white
solid: mp 156.8-158.5.degree. C.; EI-HRMS m/e calcd for
C.sub.6H.sub.5N.sub.3 (M.sup.+) 119.0483, found 119.0480.
[0575] A solution of triphenylphosphine (1.23 g, 4.70 mmol) in
methylene chloride (26 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (948 mg, 5.33 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in
Example 38, 900 mg, 3.13 mmol). The reaction mixture was stirred at
0.degree. C. for 20 min and then warmed to 25.degree. C. where it
stirred for 30 min. After such time, the reaction mixture was
treated with 6-amino-nicotinonitrile (560 mg, 4.70 mmol) and
pyridine (0.46 mL, 5.64 mmol), and the reaction mixture was stirred
at 25.degree. C. for 16 h. The reaction was then diluted with water
(25 mL) and then extracted with methylene chloride (3.times.25 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded
N-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro--
phenyl)-propionamide (882 mg, 73%) as a pink foam: EI-HRMS m/e
calcd for C.sub.20H.sub.19Cl.sub.2N.sub.3O (M.sup.+) 387.0905,
found 387.0905.
EXAMPLE 101
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl-
)-propionamide
[0576] 114
[0577] A solution of
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared
in Example 54, 200 mg, 0.69 mmol) in methylene chloride (10 mL) and
one drop of N,N-dimethylformamide was cooled to 0.degree. C. and
then treated with a 2.0M solution of oxalyl chloride in methylene
chloride (0.42 mL, 0.84 mmol). Gas evolution began immediately. The
reaction mixture was allowed to warm slowly to 25.degree. C. where
it was stirred for 30 min. After this time, the reaction mixture
was treated with a solution of N,N-diisopropylethylamine (0.24 mL,
1.39 mmol) and 5-trifluoromethyl-2-aminopyridine (150 mg, 0.905
mmol) in tetrahydrofuran (4 mL) in one portion. The resulting
reaction mixture was stirred for 16 h at 25.degree. C. After such
time, the reaction was diluted with water (15 mL) and was extracted
with methylene chloride (3.times.15 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
90/10 hexanes/ethyl acetate) afforded the
3-cyclopentyl-2(R)-(3,4-d-
ichloro-phenyl)-N-(5-trifluoromethyl-pyridin-2-yl)-propionamide (77
mg, 26%) as a white solid: mp 113.8-117.5.degree. C.; EI-HRMS m/e
calcd for C.sub.20H.sub.19Cl.sub.2F.sub.3N.sub.2O (M.sup.+)
430.0826, found 430.0835.
EXAMPLE 102
6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic
Acid
[0578] 115
[0579] A solution of
6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl-
amino]-nicotinic acid methyl ester (prepared in Example 45, 188 mg,
0.45 mmol) in tetrahydrofuran (3 mL) was treated with a 3N aqueous
hydrochloric acid solution (3 mL). The resulting reaction mixture
was heated under reflux at 60.degree. C. for 4 h. After such time,
the reaction was cooled to 25.degree. C., diluted with water (5
mL), and then extracted with ethyl acetate (3.times.20 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 90/10 hexanes/ethyl acetate with 1% acetic acid)
afforded
6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic
acid (8 mg, 4%) as a white solid:
[.alpha.].sup.23.sub.589=-41.4.degree. (c=0.099, chloroform);
FAB-HRMS m/e calcd for C.sub.20H.sub.20Cl.sub.2N.s- ub.2O.sub.3
(M+H).sup.+ 407.0930, found 407.0928.
EXAMPLE 103
6-[3-Cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotina-
mide
[0580] 116
[0581] A solution of
6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylami-
no]-nicotinic acid (prepared in Example 46, 125 mg, 0.31 mmol),
N,N-diisopropylethylamine (0.10 mL, 0.61 mmol), and
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide
(15 mL) at 25.degree. C. was treated dropwise with a 2.0M solution
of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The
resulting reaction mixture was stirred at 25.degree. C. for 16 h.
The reaction mixture was then diluted with water (10 mL) and
extracted with ethyl acetate (3.times.10 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
50/50 hexanes/ethyl acetate) afforded
6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)--
propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid:
mp 229.1-231.7.degree. C.; FAB-HRMS m/e calcd for
C.sub.21H.sub.23Cl.sub.2N.- sub.3O.sub.2 (M+H).sup.+ 420.1245,
found 420.1247.
EXAMPLE 104
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide
[0582] 117
[0583] A solution of
3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared in
Example 38, 100 mig, 0.35 mmol) in methylene chloride (5 mL) and
one drop of N,N-dimethylformamide was cooled to 0.degree. C. and
then treated with a 2.0M solution of oxalyl chloride in niethylene
chloride (0.20 mL, 0.39 mmol). Gas evolution began immediately. The
reaction mixture was stirred for 30 min at 0.degree. C. After this
time, the reaction mixture was treated with a solution of
NFN-diisopropylethylamine (0.15 mL, 0.84 mmol) and amninopyrazine
(69 mig, 0.73 nimol) in tetrahydrofliran (4 mL) in one portion. The
resulting reaction mixture was stirred for 16 h at 25.degree. C.
The reaction mixture was then diluted with water (10 mL) and
extracted with methylene chloride (3.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 90/10 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide
(38 mg, 30%) as a yellow solid: mp 46.5-51.3.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.19Cl.sub.2N.sub.3O (M.sup.+) 363.0905,
found 363.0907.
EXAMPLE 105
N-(5-Bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propiona-
mide
[0584] 118
[0585] A solution of triphenylphosphine (411 mg, 1.57 mmol) in
methylene chloride (15 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (316 mg, 1.78 mmol). The reaction
mixture was stirred at 0.degree. C. until it was completely
dissolved and became light purple in color. The reaction mixture
was then treated with
3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared
in Example 54, 300 mg, 1.05 mmol). The reaction mixture was stirred
at 0.degree. C. for 20 min and then warmed to 25.degree. C. where
it was stirred for 30 min. After such time, the reaction mixture
was treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol) and
pyridine (0.15 mL, 1.88 mmol). The resulting reaction mixture was
stirred at 25.degree. C. for 16 h. The reaction was then diluted
with water (10 mL) and extracted with methylene chloride
(3.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate)
afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichlo-
ro-phenyl)-propionamide (448 mg, 97%) as a white solid: mp
107.3-109.9.degree. C.; [.alpha.].sup.23.sub.589=-66.7.degree.
(c=0.084, chloroform); EI-HRMS m/e calcd for
C.sub.19H.sub.19BrCl.sub.2N.sub.2O (M.sup.+) 440.0058, found
440.0056.
EXAMPLE 106
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)
Propionamide
[0586] 119
[0587] A solution of
6-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl-
amino]-nicotinic acid methyl ester (prepared in Example 45, 398 mg,
0.95 mmol) in diethyl ether (30 mL) was cooled to 0.degree. C. and
then treated with lithium aluminum hydride (54 mg, 1.4 mmol) in one
portion. There was immediate gas evolution. The reaction mixture
was allowed to slowly warm to 25.degree. C. and was stirred at
25.degree. C. 16 h. After such time, the reaction mixture was
diluted with water (10 mL) and then extracted with ethyl acetate
(3.times.15 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(-
5-hydroxymethyl-pyridin-2-yl) propionamide (131 mg, 35%) as a white
foam: FAB-HRMS m/e calcd for C.sub.20H.sub.22Cl.sub.2N.sub.2O.sub.2
(M+H).sup.+ 392.1058, found 392.1062.
EXAMPLE 107
3-Cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
[0588] 120
[0589] A mixture of magnesium metal (4.81 g, 200 mmol) and dry
tetrahydrofuran (10 mL) under argon was treated with a solution of
1,2-dibromoethane (0.94 g, 5 mmol) in dry tetrahydrofuran (5 mL).
The resulting reaction mixture was stirred for 10 min to activate
the magnesium metal. The reaction mixture was then treated dropwise
with a solution of cycloheptyl bromide (17.7 g, 100 mmol) in dry
tetrahydrofuran (30 mL), one-fifth portion over a period of 5 min.
The resulting reaction mixture was stirred for 5-10 min to initiate
the exothermic reaction. The remaining portion of the cycloheptyl
bromide solution was then added dropwise while controlling the
inside temperature below 50.degree. C. After complete addition, the
solution was stirred for 1 h and then diluted with dry
tetrahydroftiran (80 mL). In a separate reaction flask, a mixture
of lithium chloride (8.48 g, 200 mmol, predried at 130.degree. C.
under high vacuum for 3 h) and copper(I) cyanide (8.96 g, 100 mmol)
in dry tetrahydrofuran (110 mL) was stirred at 25.degree. C. under
argon for 10 min to obtain a clear solution. The reaction mixture
was cooled to -70.degree. C. and then slowly treated with the
freshly prepared cycloheptylmagnesium bromide. After the addition,
the reaction mixture was allowed to warm to -10.degree. C. where it
was stirred for 5 min. The resulting reaction mixture was again
cooled back to -70.degree. C. and then treated with methyl
propiolate (7.57 g, 90 mmol). The reaction mixture was stirred for
15 h at -70.degree. C. to -50.degree. C. and then slowly treated
with a solution of iodine (34.3 g, 135 mmol) in dry tetrahydrofuran
(30 mL), with the temperature kept at -70.degree. C. to -60.degree.
C. After addition of the iodine solution, the cooling bath was
removed, and the reaction mixture was allowed to warm to 25.degree.
C. where it was stirred for 2 h. The reaction mixture was then
poured into a solution consisting of a saturated aqueous ammonium
chloride solution (400 mL) and ammonium hydroxide (100 mL), and the
organic compound was extracted into ethyl acetate (3.times.200 mL).
The combined organic extracts were successively washed with a
saturated aqueous sodium thiosulfate solution (1.times.400 mL) and
a saturated aqueous sodium chloride solution (1.times.400 mL). The
organic layer was then dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 20/1 to 10/1 hexanes/diethyl ether)
afforded (E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (17.86
g, 64%) as a colorless oil: EI-HRMS m/e calcd for
C.sub.11H.sub.17IO.sub.2 (M.sup.+) 308.0273, found 308.0273.
[0590] A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh)
and dry tetrahydrofuran (3 mL) under argon was treated with
1,2-dibromoethane (0.38 g, 2 mmol). The zinc suspension was then
heated with a heat gun to ebullition, allowed to cool, and heated
again. This process was repeated three times to make sure the zinc
dust was activated. The activated zinc dust suspension was then
treated with trimethylsilyl chloride (220 mg, 2 mmol), and the
suspension was stirred for 15 min at 25.degree. C. The reaction
mixture was then treated dropwise with a solution of
(E)-3-cycloheptyl-2-iodo-acrylic acid methyl ester (6.16 g, 20
mmol) in dry tetrahydrofuran (5 mL) over 10 min. The reaction
mixture was then stirred at 40-45.degree. C. for 1 h and then
stirred overnight at 25.degree. C. The reaction mixture was then
diluted with dry tetrahydrofuran (10 mL), and the stirring was
stopped to allow the excess zinc dust to settle down (.about.2 h).
In a separate reaction flask, bis(dibenzylideneacetone)palladium(0)
(270 mg, 0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry
tetrahydrofuran (25 mL) was stirred at 25.degree. C. under argon
for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23
g, 18 mmol) and the freshly prepared zinc compound in
tetrahydrofuran. The resulting brick red solution was heated at
50.degree. C. for 24 h. The reaction mixture was cooled to
25.degree. C. and then poured into a saturated aqueous ammonium
chloride solution (150 mL), and the organic compound was extracted
into ethyl acetate (3.times.150 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.300 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded
(E)-3-cycloheptyl-2-(4-methanesulfonyl-ph- enyl)-acrylic acid
methyl ester (6.01 g, 99%) as a viscous yellow oil: EI-HRMS m/e
calcd for C.sub.18H.sub.24O.sub.4S (M.sup.+) 336.1395, found
336.1395.
[0591] A solution of nickel(II) chloride hexahydrate (7.8 mg, 0.033
mmol) and (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylic
acid methyl ester (111 mg, 0.33 nimol) in methanol (3 mL) was
cooled to 0.degree. C. and then treated with sodium borohydride (25
mg, 0.66 mmol) in two portions. After the addition, the black
reaction mixture was stirred for 15 min at 0.degree. C. and then
allowed to warm to 25.degree. C. where it was stirred for 15 h. The
black solid was filtered using filter paper and washed with
methanol. The combined solvents were concentrated in vacuo, and the
residue was diluted with water (25 mL) and ethyl acetate (25 mL).
The two layers were separated, and the aqueous layer was extracted
with ethyl acetate (1.times.15 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.50 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo to afford racemic
3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl
ester (101 mg, 91%) as a colorless oil: EI-HRMS m/e calcd for
C.sub.18H.sub.26O.sub.4S (M.sup.+) 338.1552, found 338.1555.
[0592] A solution of
3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl
ester (95 mg, 0.28 mmol) in ethanol (2 mL) was treated with a 1N
aqueous sodium hydroxide solution (1.5 mL). The solution was heated
at 45-50.degree. C. for 15 h, at which time, thin layer
chromatography analysis of the reaction mixture indicated the
absence of starting material. The reaction mixture was concentrated
in vacuo to remove ethanol. The residue was diluted with water (10
mL) and extracted with diethyl ether (1.times.20 mL) to remove any
neutral impurities. The aqueous layer was then acidified with a 1N
aqueous hydrochloric acid solution, and the resulting acid was
extracted into ethyl acetate (2.times.15 mL). The combined organic
layers were washed with a saturated aqueous sodium chloride
solution (1.times.50 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to afford
3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (78 mg,
86%) as a white solid: EI-HRMS m/e calcd for
C.sub.17H.sub.24O.sub.4S (M+H).sup.+ 325.1474, found 325.1478.
[0593] A solution of triphenylphosphine (116 mg, 0.44 mmol) in
methylene chloride (2 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (78 mg, 0.44 mmol). The reaction
mixture was stirred at 0.degree. C. for 30 mm and then treated with
a solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic
acid (72 mg, 0.22 mmol) in methylene chloride (2 mL). The clear
solution was stirred for 10 min at 0.degree. C. and then allowed to
warm to 25.degree. C. where it was stirred for 1.5 h. The reaction
mixture was then treated with 2-aminothiazole (66 mg, 0.66 mmol),
and the resulting suspension was stirred for 20 h at 25.degree. C.
The reaction mixture was then concentrated in vacuo to remove
methylene chloride, and the residue was diluted with ethyl acetate
(30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The
two layers were separated, and the aqueous layer was extracted with
ethyl acetate (1.times.10 mL). The combined organic extracts were
successively washed with a saturated aqueous sodium bicarbonate
solution (1.times.20 mL) and a saturated aqueous sodium chloride
solution (1.times.30 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. Biotage chromatography (FLASH
40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded
3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
(68 mg, 76%) as an amorphous solid: EI-HRMS m/e calcd for
C.sub.20H.sub.26N.sub.2O.sub.3S.sub.2 (M.sup.+) 406.1426, found
406.1424.
EXAMPLE 108
3-Cyclohexyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
[0594] 121
[0595] A mixture of zinc dust (16.34 g, 250 mmol, Aldrich, -325
mesh) and dry tetrahydrofuran (6 mL) under argon was treated with
1,2-dibromoethane (0.94 g, 5 mmol). The zinc suspension was then
heated with a heat gun to ebullition, allowed to cool, and heated
again. This process was repeated three times to make sure the zinc
dust was activated. The activated zinc dust suspension was then
treated with trimethylsilyl chloride (0.54 g, 5 mmol), and the
suspension was stirred for 15 min at 25.degree. C. The reaction
mixture was then treated dropwise with a solution of cyclohexyl
iodide (21 g, 100 mmol) in dry tetrahydrofuran (30 mL) over 15 min.
During the addition, the temperature rose to 60.degree. C. The
reaction mixture was then stirred for 3 h at 40-45.degree. C. The
reaction mixture was then cooled to 25.degree. C. and diluted with
dry tetrahydrofuran (60 mL). The stirring was stopped to allow the
excess zinc dust to settle down (.about.3 h). In a separate
reaction flask, a mixture of lithium chloride (8.48 g, 200 mmol,
predried at 130.degree. C. under high vacuum for 3 h) and copper(I)
cyanide (8.95 g, 100 mmol) in dry tetrahydrofiran (110 mL) was
stirred for 10 min at 25.degree. C. to obtain a clear solution. The
reaction mixture was cooled to -70.degree. C. and then slowly
treated with the freshly prepared zinc solution using a syringe.
After the addition, the reaction mixture was allowed to warm to
0.degree. C. where it was stirred for 5 min. The reaction mixture
was again cooled back to -70.degree. C. and then slowly treated
with methyl propiolate (7.56 g, 90 mmol). The resulting reaction
mixture was stirred for 15 h at -70.degree. C. to -50.degree. C.
and then slowly treated with a solution of iodine (34.26 g, 135
mmol) in dry tetrahydrofiran (30 mL), with the temperature kept at
-70.degree. C. to -60.degree. C. After addition of the iodine
solution, the cooling bath was removed, and the reaction mixture
was allowed to warm to 25.degree. C. where it was stirred for 2 h.
The reaction mixture was then poured into a solution consisting of
a saturated aqueous ammonium chloride solution (400 mL) and
ammonium hydroxide (100 mL), and the organic compound was extracted
into ethyl acetate (3.times.250 mL). The combined organic extracts
were successively washed with a saturated aqueous sodium
thiosulfate solution (1.times.500 mL) and a saturated aqueous
sodium chloride solution (1.times.500 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 9/1
hexanes/diethyl ether) afforded (E)-3-cyclohexyl-2-iodo-acrylic
acid methyl ester (26.3 g, 99%) as a light pink oil: EI-HRMS m/e
calcd for C.sub.10H.sub.15IO.sub.2 (M.sup.+) 294.0117, found
294.0114.
[0596] A mixture of zinc dust (2.6 g, 40 mmol, Aldrich, -325 mesh)
and dry tetrahydrofuran (3 mL) under argon was treated with
1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then
heated with a heat gun to ebullition, allowed to cool, and heated
again. This process was repeated three times to make sure the zinc
dust was activated. The activated zinc dust suspension was then
treated with trimethylsilyl chloride (217 mg, 2 mmol), and the
suspension was stirred for 15 min at 25.degree. C. The reaction
mixture was then treated dropwise with a solution of
(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (5.88 g, 20 mmol)
in dry tetrahydrofuran (5 mL) over 5 min. During the addition, the
temperature rose to 50.degree. C. The reaction mixture was then
stirred at 40-45.degree. C. for 1 h and then stirred overnight at
25.degree. C. The reaction mixture was then diluted with dry
tetrahydrofuran (10 mL), and the stirring was stopped to allow the
excess zinc dust to settle down (.about.2 h). In a separate
reaction flask, bis(dibenzylideneacetone)pall- adium(0) (270 mg,
0.5 mmol) and triphenylphosphine (520 mg, 2 mmol) in dry
tetrahydrofuran (25 mL) was stirred at 25.degree. C. under argon
for 10 min and then treated with 4-bromophenyl methyl sulfone (4.23
g, 18 mmol) and the freshly prepared zinc compound in
tetrahydrofuran. The resulting brick red solution was heated at
50.degree. C. for 24 h, at which time, thin layer chromatography
analysis of the reaction mixture indicated the absence of starting
material. The reaction mixture was cooled to 25.degree. C. and then
poured into a saturated aqueous ammonium chloride solution (150
mL), and the organic compound was extracted into ethyl acetate
(3.times.100 mL). The combined organic extracts were washed with a
saturated aqueous sodium chloride solution (1.times.200 mL), dried
over anhydrous magnesium sulfate, filtered, and concentrated in
vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/2
hexanes/ethyl acetate) afforded
(E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic acid methyl
ester (5.79 g, 99%) as a low melting white solid: EI-HRMS m/e calcd
for C.sub.17H.sub.22O.sub.4S (M.sup.+) 322.1238, found
322.1236.
[0597] A solution of nickel(II) chloride hexahydrate (157 mg, 0.66
mmol) and (E)-3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-acrylic
acid methyl ester (1.07 g, 3.31 mmol) in methanol (30 mL) was
cooled to 0.degree. C. and then treated with sodium borohydride
(380 mg, 10 mmol) in four portions. After the addition, the black
reaction mixture was stirred for 15 min at 0.degree. C. and then
allowed to warm to 25.degree. C. where it was stirred for 15 h. The
black solid was filtered using filter paper and washed with
methanol. The combined solvents were concentrated in vacuo, and the
residue was diluted with water (50 mL) and ethyl acetate (50 mL).
The two layers were separated, and the aqueous layer was extracted
with ethyl acetate (1.times.25 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.50 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo to afford racemic
3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl
ester (1.04 g, 97%) as an amorphous white solid: EI-HRMS m/e calcd
for C.sub.17H.sub.24O.sub.4S (M.sup.+) 324.1395, found
324.1395.
[0598] A solution of
3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl
ester (1.00 g, 3.08 mmol) in ethanol (15 mL) was treated with a 1N
aqueous sodium hydroxide solution (6 mL). The solution was heated
at 45-50.degree. C. for 15 h, at which time, thin layer
chromatography analysis of the mixture indicated the absence of
starting material. The reaction mixture was then concentrated in
vacuo to remove ethanol, and the residue was diluted with water (20
mL) and extracted with diethyl ether (1.times.40 mL) to remove any
neutral impurities. The aqueous layer was acidified with a 1N
aqueous hydrochloric acid solution. The resulting acid was
extracted into ethyl acetate (2.times.50 mL). The combined organic
layers were washed with a saturated aqueous sodium chloride
solution (1.times.50 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to afford
3-cyclohexyl-2-(4-methanesu- lfonyl-phenyl)-propionic acid (570 mg,
60%) as a white solid: mp 139-143.degree. C.; EI-HRMS m/e calcd for
C.sub.16H.sub.22O.sub.4S (M.sup.+) 310.1239, found 310.1241.
[0599] A solution of triphenylphosphine (416 mg, 1.58 mmol) in
methylene chloride (8 mL) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (281 mg, 1.58 mmol). The reaction
mixture was stirred at 0.degree. C. for 30 min and then treated
with a solution of
3-cyclohexyl-2-(4-methanesulfonyl-phenyl)-propionic acid (290 mg,
0.93 mmol) in methylene chloride (5 mL). The clear solution was
stirred for 15 min at 0.degree. C. and then allowed to warm to
25.degree. C. where it was stirred for 1.5 h. The reaction mixture
was then treated with 2-aminothiazole (233 mg, 2.32 mmol), and the
resulting suspension was stirred for 20 h at 25.degree. C. The
reaction mixture was concentrated in vacuo to remove methylene
chloride, and the residue was diluted with ethyl acetate (50 mL)
and a 1N aqueous hydrochloric acid solution (50 mL). The two layers
were separated, and the aqueous layer was extracted with ethyl
acetate (1.times.30 mL). The combined organic extracts were
successively washed with a saturated aqueous sodium bicarbonate
solution (1.times.50 mL) and a saturated aqueous sodium chloride
solution (1.times.50 mL), dried over anhydrous magnesium sulfate,
filtered, and, concentrated in vacuo. Biotage chromatography (FLASH
40S, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded
3-cyclohexyl-2-(4-methanesulfonyl-phe-
nyl)-N-thiazol-2-yl-propionamide (337 mg, 92%) as an amorphous
solid: EI-HRMS m/e calcd for C.sub.19H.sub.24N.sub.2O.sub.3S.sub.2
(M.sup.+) 392.1228, found 392.1230.
EXAMPLE 109
3-Cyclopentyl-2-(3-nitrophenyl)-N-thiazol-2-yl-propionamide
[0600] 122
[0601] A solution of (3-nitro-phenyl)-acetic acid (5.0 g, 27.6
mmol) in methanol (50 mL) was treated with a catalytic amount of
sulfuiric acid. The reaction mixture was refluxed for 48 h. The
reaction was then concentrated in vacuo. The residue was dissolved
in methylene chloride (50 mL) and washed with a saturated aqueous
sodium bicarbonate solution (2.times.25 mL), water (1.times.50 mL)
and a saturated aqueous sodium chloride solution (1.times.50 mL).
The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo to give (4-nitro-phenyl)-acetic
acid methyl ester (5.27 g, 97.9%) as a pale yellow solid: mp
29-30.degree. C.; EI-HRMS mle calcd for C.sub.9H.sub.9NO.sub.4
(M.sup.+) 195.053 1, found 195.0532.
[0602] A solution of freshly prepared lithium diisopropylamide
(43.3 mL of a 0.3M stock solution, 12.99 mmol) cooled to
-78.degree. C. was treated with (3-nitro-phenyl)-acetic acid methyl
ester (2.45 g, 12.56 mmol) in
tetrahydrofuranl/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(32 mL, 3:1). The resulting solution was stirred at -78.degree. C.
for 45 min. At this time, the reaction was treated with a solution
of iodomethylcyclopentane (2.78 g, 13.23 mmol) in
1,3-dimethyl-3,4,5,6-tetra- hydro-2(1H)-pyrimidinone (2.78 mL) and
the mixture was stirred at -78.degree. C. for 3 h. The reaction was
warmed to 25.degree. C. and was stirred at 25.degree. C. for 16 h.
The reaction mixture was then quenched by the dropwise addition of
a saturated aqueous ammonium chloride solution (25 mL) and was
concentrated in vacuo. The residue was diluted with water (50 mL)
and extracted with ethyl acetate (3.times.50 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(2.times.25 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-nitro-phenyl)-propioni- c acid methyl ester
(1.63 g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for
C.sub.15H.sub.19NO.sub.4 (M.sup.+) 277.1314, found 277.1317.
[0603] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic
acid methyl ester (0.55 g, 2.0 immol) in tetrahydrofuran/water (12
mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol).
The reaction was stirred at 25.degree. C. for 48 h. The
tetrahydrofuran was then removed in vacuo. The residue was diluted
with water (25 mL) and extracted with ether (1.times.20 mL). The
aqueous layer was acidified to pH=2 with a 3N aqueous hydrochloric
acid solution. The solution was extracted with methylene chloride
(3.times.25 mL). The organics were washed with a saturated aqueous
sodium chloride solution (2.times.25 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo to give
3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as
a tan solid: mp 95-99.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17NO.sub.- 4 (M.sup.+) 263.1157, found 263.1156.
[0604] A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic
acid (432 mg, 1.64 mmol) in methylene chloride (16 mL) was cooled
to 0.degree. C. and then treated with a 2.0M solution of oxalyl
chloride in methylene chloride (0.90 mL, 1.80 mmol) and a few drops
of N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 1.2 h. The
reaction mixture was then treated with a solution of
2-aminothiazole (361.4 mg, 3.61 mmol) and N,N-diisopropylethylamine
(0.70 mL, 3.93 mmol) in tetrahydrofuran (16 mL). The reaction
mixture was stirred at 25.degree. C. for 6 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(nitrophenyl)-N-thiazol-2-yl-propionamide (409.3
mg, 72.2%) as a tan solid: mp 171-174.degree. C.; EI-HRMS m/e calcd
for C.sub.17H.sub.19N.sub.3O.sub.3S (M.sup.+) 345.1147, found
345.1153.
EXAMPLE 110
3-Cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide
[0605] 123
[0606] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.31M stock solution, 7.13 mmol) cooled to -78.degree. C.
was treated with (.sup.3-methoxy-phenyl)-acetic acid methyl ester
(1.07 g, 5.94 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(14.8 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 45 min. At this time, the reaction was treated with a
solution of iodomethylcyclopentane (1.37 g, 6.53 mmol) in
1,3-dimethyl-3,4,5,6-tetrah- ydro-2(1H)-pyrimidinone (1.16 mL). The
reaction mixture was stirred at -78.degree. C. for 3 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 16 h. At this time, the reaction was quenched by
the dropwise addition of a saturated aqueous ammonium chloride
solution. This solution was diluted with water (100 mL) and
extracted into ethyl acetate (3.times.50 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(1.times.75 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 95/5 hexanes/ethyl acetate) afforded
.sup.3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester
(1.39 g, 89.1%) as a clear oil: EI-HRMS m/e calcd for
C.sub.16H.sub.22O.sub.3 (M.sup.+) 262.1568, found 262.1561.
[0607] A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic
acid methyl ester (1.39 g, 5.29 mmol) in
tetrahydrofuran/water/methanol (13.2 mL, 3:1:1) at 25.degree. C.
was treated with a 2N aqueous sodium hydroxide solution (3.97 mL,
7.94 mmol). The reaction was stirred at 25.degree. C. for 48 h. At
this time, the reaction mixture was poured into water (50 mL) and
extracted with chloroform (3.times.25 mL). The aqueous layer was
acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The
aqueous layer was extracted with a solution of chloroform/methanol
(9:1). The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 70/30 hexanes/ethyl acetate with glacial acetic acid)
afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid (1.05 g,
79.8%) as a clear wax: EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.3 (M.sup.+) 248.1412, found 248.1409.
[0608] A solution of 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic
acid (500 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to
0.degree. C. was treated with a 2.0M solution of oxalyl chloride in
methylene chloride (1.1 mL, 2.20 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min then at 25.degree. C. for 30 min. The
reaction mixture was then treated with 2-aminothiazole (444 mg,
4.42 rmmol) and N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) in
tetrahydrofuran (10.1 mL). This solution was stirred at 25.degree.
C. for 18 h. At this time, the reaction was concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-methoxy-phenyl)-N-thia- zol-2-yl-propionamide
(549 mg, 82.6%) as a white solid: mp 44-45.degree. C.; EI-HRMS m/e
calcd for C.sub.18H.sub.22N.sub.2O.sub.2S(M.sup.+) 330.1402 found
330.1398.
EXAMPLE 111
3-Cyclopentyl-2-(3-hydroxy-phenyl)-N-thiazol-2-yl-propionamide
[0609] 124
[0610] A 1.0M solution of boron tribromide in methylene chloride
(3.53 mL, 3.53 mmol) at 25.degree. C. was treated with a solution
of 3-cyclopentyl-2-(3-methoxy-phenyl)-N-thiazol-2-yl-propionamide
(prepared in Example 110, 0.11 g, 0.35 mmol) in methylene chloride
(3.5 mL). This solution was stirred at 25.degree. C. for 1 h. At
this time, the reaction was cooled to 0.degree. C. and treated with
a dilute aqueous ammonium hydroxide solution. This mixture was
stirred at 0.degree. C. for 15 min. At this time, the aqueous layer
was separated from the organic layer. The aqueous layer was
extracted with chloroform (3.times.50 mL). The organics were dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-hydroxy-phenyl)-N-thia- zol-2-yl-propionamide
(50 mg, 44.7%) as a white solid: mp 177-179.degree. C.; EI-HRMS m/e
calcd for C.sub.17H.sub.20N.sub.2O.sub.2S (M.sup.+) 316.1245 found
316.1244.
EXAMPLE 112
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide
[0611] 125
[0612] A solution of freshly prepared lithium diisopropylamide (23
mL of a 0.31M stock solution, 7.13 mmol) cooled to -78.degree. C.
was treated with (4-trifluoromethoxy-phenyl)-acetic acid (0.74 g,
3.39 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(8.5 mL, 3:1). The resulting solution was stirred at -78.degree. C.
for 45 min. At this time, the reaction was treated with a solution
of iodomethylcyclopentane (0.78 g, 3.73 mmol) in
1,3-dimethyl-3,4,5,6-tetrah- ydro-2(1H)-pyrimidinone (1 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 18 h. The reaction mixture was then quenched by
the dropwise addition of saturated aqueous ammonium chloride
solution (10 mL). The resulting mixture was concentrated in vacuo
to remove the excess solvent. The residue was diluted with water
(100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid
solution. This solution was extracted with ethyl acetate
(3.times.50 mL). The organics were washed with a saturated aqueous
lithium chloride solution (1.times.100 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)
afforded 3-cyclopentyl-2-(4-trifluoromethoxy-pheny- l)-propionic
acid (0.31 g, 30.6%) as a tan solid: mp 62-64.degree. C.; EI-HRMS
m/e calcd for C.sub.15H.sub.17F.sub.3O.sub.3(M.sup.+) 302.1129
found 302.1131.
[0613] A solution of
3-cyclopentyl-2-(4-rifluoromethoxy-phenyl)-propionic acid (0.16 g,
0.52 mmol) in methylene chloride (5.3 mL) cooled to 0.degree. C.
was treated with a 2.0M solution of oxalyl chloride in methylene
chloride (0.29 mL, 0.58 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (0.11 g, 1.16 mmol) and N,N-diisopropylethylamine
(0.22 mL, 1.27 mmol) in tetrahydrofuran (2.65 mL). The reaction
mixture was stirred at 25.degree. C. for 18 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide
(203.8 mg, 100%) as a white solid: mp 168-170.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.19F.sub.3N.sub.2O.sub.2S (M.sup.+)
384.1119, found 384.1118.
EXAMPLE 113
3-Cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide
[0614] 126
[0615] A solution of freshly prepared lithium diisopropylamide
(58.5 mL of a 0.91M stock solution, 53.2 mmol) cooled to
-78.degree. C. was treated with (3,4-dimethoxy-phenyl)-acetic acid
(4.97 g, 25.3 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(25.3 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 45 min and at 25.degree. C. for 15 min. At this time, the
reaction was cooled to 0.degree. C. and was treated with a solution
of iodomethylcyclopentane (5.87 g, 27.8 mmol) in
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The
reaction mixture was stirred at 0.degree. C. for 30 min. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 18 h. The reaction mixture was then quenched by
the dropwise addition of saturated aqueous ammonium chloride
solution (10 mL). The resulting mixture was concentrated in vacuo.
The residue was diluted with water (100 mL) and acidified to pH=1
with a 1N aqueous hydrochloric acid solution. This solution was
extracted with ethyl acetate (3.times.50 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dimethox- y-phenyl)-propionic acid (4.5 g,
63.8%) as a yellow solid: mp 111-112.degree. C.; EI-HRMS m/e calcd
for C.sub.16H.sub.22O.sub.4 (M.sup.+) 278.1518 found 278.1517.
[0616] A solution of
3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-propionic acid (0.50 g, 1.79
mmol) in methylene chloride (17.9 mL) cooled to 0.degree. C. was
treated with a 2.0M solution of oxalyl chloride in methylene
chloride (1.0 mL, 1.97 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (0.39 g, 3.95 mmol) and N,N-diisopropylethylamine
(0.76 mL, 4.3 mmol) in tetrahydrofuran (8.98 mL). The reaction
mixture was stirred at 25.degree. C. for 18 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide
(665 mg, 100%) as a pale yellow solid: mp 50-52.degree. C.; EJ-HRMS
m/e calcd for C.sub.19H.sub.24N.sub.2O.sub.3S (M.sup.+) 360.1507,
found 360.1516.
EXAMPLE 114
3-Cyclopenty1-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide
[0617] 127
[0618] A 1.0M solution of boron tribromide in methylene chloride
(7.43 mL, 7.43 mmol) at 25.degree. C. was treated with a solution
of
3-cyclopentyl-2-(3,4-dimethoxy-phenyl)-N-thiazol-2-yl-propionamide
(prepared in Example 113, 0.27 g, 0.74 mmol) in methylene chloride
(7.43 mL). This solution was stirred at 25.degree. C. for 1 h. At
this time, the reaction was cooled to 0.degree. C. and treated with
a dilute aqueous ammonium hydroxide solution. This mixture was
stirred at 0.degree. C. for 20 min. At this time, the reaction was
poured into water and was extracted with chloroform (3.times.50
mL). The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3,4-dihydroxy-phenyl)-N-thiazol-2-yl-propionamide
(38.8 mg, 15.7%) as a white solid: mp 170-173.degree. C.; EI-HRMS
m/e calcd for C.sub.17H.sub.20N.sub.2O.sub.3S (M.sup.+) 332.1194
found 332.1192.
EXAMPLE 115
3-Cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide
[0619] 128
[0620] A solution of freshly prepared lithium diisopropylamide
(58.5 mL of a 0.93M stock solution, 53.2 mmol) cooled to
-78.degree. C. was treated with (4-methoxy-phenyl)-acetic acid
(4.21 g, 25.35 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(25.3 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 45 min. At this time, the reaction was treated with a
solution of iodomethylcyclopentane (5.85 g, 27.8 mmol) in
1,3-dimethyl-3,4,5,6-tetrah- ydro-2(1H)-pyrimidinone (1 mL). The
reaction mixture was stirred at -78.degree. C. for 45 min and at
0.degree. C. for 1 h. The reaction was then warmed to 25.degree. C.
and was stirred at 25.degree. C. for 16 h. The reaction mixture was
then quenched by the dropwise addition of saturated aqueous
ammonium chloride solution (10 mL). The excess solvent was removed
in vacuo. The residue was acidified to pH=1 with a 1N aqueous
hydrochloric acid solution. This mixture was poured into water (50
mL) and extracted with ethyl acetate (3.times.50 mL). The organics
were washed with a saturated aqueous lithium chloride solution
(1.times.100 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methoxy-phenyl)-propio- nic acid (2.76 g, 43.8%)
as a yellow solid: mp 119-121.degree. C.; EI-HRMS m/e calcd for
C.sub.15H.sub.20O.sub.3 (M.sup.+) 248.1412 found 248.1415.
[0621] A solution of 3-cyclopentyl-2-(4-methoxy-phenyl)-propionic
acid (500 mg, 2.0 mmol) in methylene chloride (20.1 mL) cooled to
0.degree. C. was treated with a 2.0M solution of oxalyl chloride in
methylene chloride (1.1 mL, 2.21 mrol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min then at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (444 mg, 4.42 mmol) and N,N-diisopropylethylamine
(0.84 mL, 4.83 mmol) in tetrahydrofuran (10.1 mL). This solution
was stirred at 25.degree. C. for 18 h. At this time, the reaction
was concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propionamide (638
mg, 95.8%) as a pale yellow solid: mp 166-167.degree. C.; EI-HRMS
m/e calcd for C.sub.18H.sub.22N.sub.2O.sub.2S (M.sup.+) 330.1402
found 330.1398.
EXAMPLE 116
3-Cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide
[0622] 129
[0623] A solution
3-cyclopentyl-2-(4-methoxy-phenyl)-N-thiazol-2-yl-propio- namide
(1.03 g, 3.12 mmol) in methylene chloride (31.26 mL) at 25.degree.
C. was treated with a 1.0M solution of boron tribromide in
methylene chloride (31.26 mL, 31.26 mmol). This solution was
stirred at 25.degree. C. for 4 h. At this time, the reaction was
cooled to 0.degree. C. and was then quenched by the dropwise
addition of a dilute aqueous ammonium hydroxide solution. The
resulting solution was stirred at 0.degree. C. for 15 min. This
mixture was then poured into water (50 mL) and extracted with ethyl
acetate (3.times.30 mL). The organics were dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate)
afforded
3-cyclopentyl-2-(4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide
(626.8 mg, 63.4%) as a off-white solid: mp 198-200.degree. C.;
EI-HRMS m/e calcd for C.sub.17H.sub.20N.sub.2O.sub.2S (M.sup.+)
316.1245 found 316.1256.
EXAMPLE 117
4-[2-Cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic Acid
Methyl Ester
[0624] 130
[0625] A solution of 4-methyl-benzoic acid (10 g, 73.4 mmol) in
benzene (133 mL) was treated with benzoyl peroxide (72 mg, 0.29
mmol). This mixture was heated to reflux until it became
homogeneous. At this time, the reaction was treated with
N-bromosuccinimide (13 g, 73.4 mmol) and additional benzoyl
peroxide (72 mg, 0.29 mmol). This mixture was heated at reflux for
2.5 h. At this time, the reaction was cooled to 25.degree. C. The
resulting precipitate was collected by filtration and washed with
hot water (50 mL). The solid was taken up in water (150 mL). This
slurry was heated at 80.degree. C. and then filtered while hot. The
solid that was collected was dried in vacuo to afford
4-bromomethyl-benzoic acid (12.3, 77.9%) as a white solid: mp
224-226.degree. C.; EI-HRMS m/e calcd for C.sub.8H.sub.7BrO.sub.2
(M.sup.+) 213.9629, found 213.9628.
[0626] A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol)
in acetonitrile (186 mL) was treated with a solution of sodium
cyanide (1.0 g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol)
in water (24 mL). The reaction mixture was heated at reflux for 2
h. At this time, the reaction was cooled to 25.degree. C. and
concentrated in vacuo. The resulting solution was washed with
chloroform (1.times.50 mL). The aqueous layer was acidified to pH=3
with a 1N aqueous hydrochloric acid solution. The aqueous layer was
extracted with a solution of chloroform/methanol (9:1, 3.times.100
mL). The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo to afford 4-cyanomethyl-benzoic acid (0.79 g,
26.3%) as a white solid: mp 193-195.degree. C.; EI-HRMS m/e calcd
for C.sub.9H.sub.7NO.sub.2 (M.sup.+) 161.0476, found 161.0483.
[0627] A solution of 4-cyanomethyl-benzoic acid (0.53 g, 3.31 mmol)
in a 50% aqueous hydrochloric acid solution (42.8 mL) was heated at
80.degree. C. for 16 h. At this time, the reaction was cooled to
25.degree. C. and brought to pH=3 by the dropwise addition of a 50%
aqueous sodium hydroxide solution. The resulting mixture was
diluted with water and extracted with butanol (2.times.50 mL). The
organics were then extracted with water (5.times.50 mL, pH=6-7).
The aqueous extracts were brought to pH=3 with a 3M aqueous
hydrochloric acid solution and concentrated in vacuo to afford
4-carboxymethyl-benzoic acid (70 mg, 11.7%) as a white solid: mp
235-237.degree. C.; EI-HRMS m/e calcd for C.sub.9H.sub.8O.sub.4
(M.sup.+) 180.0422, found 180.
[0628] A mixture of 4-carboxymethyl-benzoic acid (0.20 g, 1.11
mmol) and nickel(II) chloride hexahydrate (27 mg, 0.11 mol) in
methanol (1.11 mL) was heated at 120.degree. C. for 24 h. At this
time, the reaction mixture was cooled to 25.degree. C. and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 70/30 hexanes/ethyl acetate) afforded
4-methoxycarbonylmethyl-benzoic acid methyl ester (66.7 mg, 28.8%)
as a clear oil: EI-HRMS m/e calcd for C.sub.11H.sub.12O.sub.4
(M.sup.+) 208.0735, found 208.0733.
[0629] A solution of freshly prepared lithium diisopropylamide (2.3
mL of a 0.31M stock solution, 0.71 mmol) cooled to -78.degree. C.
was treated with a solution of 4-methoxycarbonylmethyl-benzoic acid
methyl ester (66 mg, 0.31 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-p-
yrimidinone (0.85 mL, 3:1). The resulting solution was stirred at
-78.degree. C. for 45 min. At this time, the reaction was treated
with a solution of iodomethylcyclopentane (86 mg, 0.40 mmol) in
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and stirred at 25.degree.
C. for 18 h. At this time, the reaction mixture was quenched by the
slow addition of a saturated aqueous ammonium chloride solution (10
nmL). The reaction mixture was then poured into water (50 mL). This
solution was extracted into ethyl acetate (3.times.25 mL). The
organics were dried over sodium sulfate, filtered, and concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
80/20 hexanes/ethyl acetate) afforded
4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester
(60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for
C.sub.17H.sub.22O.sub.4(- M.sup.+) 290.1518, found 290.1518.
[0630] A solution of
4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester
(0.40 g, 1.37 mmol) in tetrahydrofuran/water/methanol (13.7 mL,
3:1:1) was treated with a 1N aqueous lithium hydroxide solution.
The reaction mixture was stirred at 25.degree. C. for 1 h. At this
time, the reaction was poured into water. The aqueous layer was
acidified to pH=1 with a 1N aqueous hydrochloric acid solution and
extracted with a solution of chloroform/methanol (9:1, 4.times.25
mL). The organics were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 50/50 hexanes/ethyl acetate) afforded a mixture of
4-(1-carboxy-2-cyclopentyl-e- thyl)-benzoic acid methyl ester and
4-(1-carboxy-2-cyclopentyl-ethyl)-benz- oic acid methyl ester
(161.8 mg, 42.5%) as a clear oil: EI-HRMS m/e calcd for
C.sub.16H.sub.20O.sub.4 (M.sup.+) 276.1361, found 276.1364.
[0631] A solution of the mixture of
4-(1-carboxy-2-cyclopentyl-ethyl)-benz- oic acid methyl ester and
4-(1-carboxy-2-cyclopentyl-ethyl)-benzoic acid methyl ester (24.2
mg, 0.08 mmol) in methylene chloride (0.87 mL) cooled to 0.degree.
C. was treated with a 2.0M solution of oxalyl chloride in methylene
chloride (0.05 mL, 0.10 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (19.3 mg, 0.19 mmol) and N,N-diisopropylethylamine
(0.04 mL, 0.21 mmol) in tetrahydrofuran (0.44 mL). The reaction
mixture was stirred at 25.degree. C. for 4 h. At this time, the
reaction was concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid
methyl ester (18.1 mg, 57.6%) as an off-white solid: mp
54-56.degree. C.; EI-HRMS m/e calcd for
C.sub.19H.sub.22N.sub.2O.sub.3S (M.sup.+) 358.1351, found
358.1346.
EXAMPLE 118
3-Cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide
[0632] 131
[0633] A solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.0
g, 5.87 mmol) in methanol (20 mL) was treated with a catalytic
amount of sulfuric acid. The reaction was heated at 120.degree. C.
for 6 h. At this time, the reaction was concentrated in vacuo.
Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded (3-fluoro-4-hydroxy-phenyl)-acetic
acid methyl ester (1.05 g, 97.6%) as a white solid: mp
34-36.degree. C.: EI-HRMS m/e calcd for C.sub.9H.sub.9FO.sub.3
(M.sup.+) 184.0535, found 184.0533.
[0634] A mixture of 3-fluoro-4-hydroxy-phenyl)-acetic acid methyl
ester (1.0 g, 5.43 mmol), potassium carbonate (1.87 g, 13.57 mmol),
and methyl iodide (1.12 g, 8.14 mmol) in acetone (27.1 mL) was
heated at 90.degree. C. for 4 h. At this time, the potassium
carbonate was removed by filtration. The filtrate was concentrated
in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh,
80/20 hexanes/ethyl acetate) afforded
(3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.01 g,
94.3%) as a clear oil: EI-HRMS m/e calcd for
C.sub.10H.sub.11FO.sub.3(M.sup.+) 198.0692, found 198.0693.
[0635] A solution of freshly prepared lithium diisopropylamide
(21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to -78.degree.
C. was treated with a solution of
(3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38
mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(-
1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred
at -78.degree. C. for 45 min. At this time, the reaction was
treated with a solution of iodomethylcyclopentane (1.47 g, 7.02
mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL).
The reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was warmed to 25.degree. C. and stirred at 25.degree. C.
for 48 h. The reaction mixture was then quenched by the slow
addition of a saturated aqueous ammonium chloride solution (10 mL).
The reaction mixture was then poured into water (100 mL) and
extracted with ethyl acetate (3.times.50 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(1.times.50 mL), dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 90/10 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-fluoro-4-methoxy-pheny- l)-propionic acid methyl
ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21FO.sub.3(M.sup.+) 280.1477 found 280.1474.
[0636] A solution of
3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl
ester (1.04 g, 3.73 mmol) in tetrahydrofuran/water/methanol (9.3
mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution
(3.73 mL, 3.73 mmol). The reaction was stirred at 25.degree. C. for
18 h. At this time, the reaction was acidified to pH=1 with a 1N
aqueous hydrochloric acid solution and extracted with ethyl acetate
(3.times.50 mL). The organics were dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-fluoro-4-m- ethoxy-phenyl)-propionic acid (707.8
mg, 71.3%) as a white solid: mp 149-151.degree. C.; EI-HRMS m/e
calcd for C.sub.15H.sub.19F O.sub.3 (M.sup.+) 266.1318 found
266.1317.
[0637] A solution of
3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid (400.0
mg, 1.50 mmol) in methylene chloride (5.0 mL) cooled to 0.degree.
C. was treated with a 2.0M solution of oxalyl chloride in methylene
chloride (0.82 mL, 1.65 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 10 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
2-aminothiazole (331 mg, 3.30 mmol) and N,N-diisopropylethylamine
(0.62 mL, 3.60 mmol) in tetrahydrofuran (7.5 mL). This solution was
stirred at 25.degree. C. for 18 h. At this time, the reaction was
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-2-yl-propionamide
(538.4 mg, 100%) as a white solid: mp 51-53.degree. C.: EI-HRMS m/e
calcd for C.sub.18H.sub.21FN.sub.2O.sub.2S (M.sup.+) 348.1307 found
348.1312.
EXAMPLE 119
3-Cyclopentyl-2-(3-fluoro-4-hydroxy-phenyl)-N-thiazol-2-yl-propionamide
[0638] 132
[0639] A solution of
3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-N-thiazol-
-2-yl-propionamide (prepared in Example 118, 305.4 mg, 0.87 mmol)
in methylene chloride (8.7 mL) at 25.degree. C. was treated with a
1.0M solution of boron tribromide in methylene chloride (8.75 mL,
8.75 mmol). This solution was stirred at 25.degree. C. for 5 h. At
this time, the reaction was cooled to 0.degree. C. and quenched by
the dropwise addition of a dilute aqueous ammonium hydroxide
solution. The resulting solution was stirred at 0.degree. C. for 15
min. This mixture was then poured into water (50 mL) and extracted
with ethyl acetate (3.times.30 mL). The organics were dried over
sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (Merck Silica gel 60, 230-400 mesh, 50/50
hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(3-fluoro-4-hydroxy-pheny-
l)-N-thiazol-2-yl-propionamide (212.7 mg, 72.5%) as a white solid:
mp 199-201.degree. C.: EI-HRMS m/e calcd for
C.sub.17H.sub.19FN.sub.2O.sub.2- S (M.sup.+) 334.1151 found
334.1152.
EXAMPLE 120
6-[2-(3-Chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic
Acid
[0640] 133
[0641] A solution of freshly prepared lithium diisopropylamide
(141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to
-78.degree. C. was treated with (3-chloro-phenyl)-acetic acid (3.41
g, 20.0 mmol) in
tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
(49.7 mL, 3:1). The resulting solution was stirred at -78.degree.
C. for 1 h. At this time, the reaction was treated with a solution
of iodomethylcyclopentane (4.64 g, 22.08 mmol) in
1,3-dimethyl-3,4,5,6-tetra- hydro-2(1H)-pyrimidinone (4.64 mL). The
reaction mixture was stirred at -78.degree. C. for 4 h. The
reaction was then warmed to 25.degree. C. and was stirred at
25.degree. C. for 48 h. This solution was then quenched by the slow
addition of the reaction mixture to a 2N aqueous hydrochloric acid
solution (50 mL). The product was extracted into ethyl acetate
(1.times.150 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography (Merck
Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded
2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as
a yellow solid: mp 70-72.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17ClO.sub.2(M.sup.+) 252.0917, found 252.0915.
[0642] A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic
acid (504 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to
0.degree. C. was treated with a 2.0M solution of oxalyl chloride in
methylene chloride (1.1 mL, 2.2 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 2 h. The reaction
mixture was then treated with 6-amino-nicotinic acid methyl ester
(532 mg, 3.5 mmol) and N,N-diisopropylethylamine (0.84 mL, 4.8
mmol). This solution was stirred at 25.degree. C. for 18 h. At this
time, the reaction was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate)
afforded
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid
methyl ester (151.9 mg, 19.7%) as a colorless oil: EI-HRMS m/e
calcd for C.sub.21H.sub.23ClN.sub.2O.sub.3 (M.sup.+) 386.1397,
found 386.1398.
[0643] A solution of
6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-- nicotinic
acid methyl ester (146.9 mg, 0.38 mmol) in
tetrahydrofuran/water/methanol (10 mL, 3:1:1) at 25.degree. C. was
treated with a 2N aqueous sodium hydroxide solution (0.4 mL, 0.80
mmol). The reaction mixture was stirred at 25.degree. C. for 4 d.
At this time, the reaction was concentrated in vacuo. The residue
was diluted with water (50 mL) and extracted with diethyl ether
(1.times.50 mL). The aqueous layer was acidified to pH=1 by the
dropwise addition of a 3N aqueous hydrochloric acid solution. This
solution was extracted with a solution of methylene
chloride/methanol (3:1, 3.times.75 mL). The organics were dried
over magnesium sulfate, filtered, and concentrated in vacuo. The
resulting solid was triturated with diethyl ether/hexanes (2:1) to
afford 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nico-
tinic acid (63.6 mg, 44.4%) as a white solid: mp 251-255.degree.
C.; EI-HRMS m/e calcd for C.sub.20H.sub.21ClN.sub.2O.sub.3
(M.sup.+) 372.1240, found 372.1250.
EXAMPLE 121
6-[3-Cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic Acid
Methyl Ester
[0644] 134
[0645] A solution of freshly prepared lithium diisopropylamide
(430.55 mL of a 0.3M stock solution, 129.16 mmol) cooled to
-78.degree. C. was treated with (4-nitro-phenyl)-acetic acid ethyl
ester (26.32 g, 125.83 mmol) in
tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The
resulting solution was stirred at -78.degree. C. for 45 min. At
this time, the reaction was treated with a solution of
iodomethylcyclopentane (27.75 g, 132.1 mmol) in
hexamethylphosphoramide (27.75 mL). The mixture was stirred at
-78.degree. C. for 4 h. The reaction was then warmed to 25.degree.
C. and was stirred at 25.degree. C. for 16 h. The reaction mixture
was then quenched by the dropwise addition of a saturated aqueous
ammonium chloride solution (250 mL). This mixture was concentrated
in vacuo. The resulting residue was diluted with water (250 mL) and
extracted with ethyl acetate (3.times.300 mL). The organics were
washed with a saturated aqueous lithium chloride solution
(2.times.250 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (Merck Silica gel 60,
230-400 mesh, 98/2 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30
g, 77.2%) as an yellow oil: EI-HRMS m/e calcd for
C.sub.16H.sub.21NO.sub.4 (M.sup.+) 291.1470, found 291.1470.
[0646] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid ethyl ester (14.1 g, 48.06 mmol) in tetrahydrofuran/water (300
mL, 3:1) was treated with lithium hydroxide (4.35 g, 103.67 mmol).
The reaction was stirred at 25.degree. C. for 21 h. The
tetrahydrofuran was then removed in vacuo. The residue was diluted
with water (75 mL) and extracted with ether (3.times.75 mL). The
aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric
acid solution and extracted into methylene chloride (3.times.75
mL). The organics were washed with a saturated aqueous sodium
chloride solution (2.times.100 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford
3-cyclopentyl-2-(4-nitro-ph- enyl)-propionic acid (11.97 g, 93.6%)
as a yellow solid: mp 119-125.degree. C.; EI-HRMS m/e calcd for
C.sub.14H.sub.17NO.sub.4 (M.sup.+) 263.1157, found 263.1162.
[0647] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (526 mg, 2.0 mmol) in methylene chloride (20 mL) cooled to
0.degree. C. was treated with a 2.0M solution of oxalyl chloride in
methylene chloride (1.2 mL, 2.4 mmol) and a few drops of
N,N-dimethylformamide. The reaction mixture was stirred at
0.degree. C. for 15 min and at 25.degree. C. for 30 min. The
reaction mixture was then treated with a solution of
6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) in
tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8
mmol). This solution was stirred at 25.degree. C. for 48 h. At this
time, the reaction was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded 6-[3-cyclopentyl-2-(4-nitro-p-
henyl)-propionylamino]-nicotinic acid methyl ester (353.9 mg,
44.6%) as a pale orange glass: EI-HRMS m/e calcd for
C.sub.21H.sub.23N.sub.3O.sub.5 (M.sup.+) 397.1637, found
397.1631.
EXAMPLE 122
2-(4-Amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
[0648] 135
[0649] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (prepared in Example 22, 263 mg, 1.0 mmol) in methylene
chloride (10 mL) cooled to 0.degree. C. was treated with a 2.0M
solution of oxalyl chloride in methylene chloride (0.6 mL, 1.2
mmol) and a few drops of N,N-dimethylformamide. The reaction
mixture was stirred at 0.degree. C. for 15 min and at 25.degree. C.
for 30 min. The reaction mixture was then treated with a solution
of 2-aminopyridine (200.6 mg, 2.14 mmol) in tetrahydrofuran (5 mL)
and N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). This solution
was stirred at 25.degree. C. for 48 h. At this time, the reaction
was concentrated in vacuo. Flash chromatography (Merck Silica gel
60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded
3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (138.6
mg, 40.9%) as a pale yellow glass: EI-HRMS m/e calcd for
C.sub.19H.sub.21N.sub.3O.sub.3 (M.sup.+) 339.1581, found
339.1582.
[0650] A mixture of
3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propio- namide (130
mg, 0.38 mmol) in ethyl acetate (50 mL) and methanol (5 mL) was
treated with a catalytic amount of 10% palladium on activated
carbon (50 mg). The resulting mixture was shaken at 25.degree. C.
under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this
time, the catalyst was removed by filtration through a plug of
celite. The filtrate was concentrated in vacuo to afford
2-(4-amino-phenyl)-3-cyclopentyl-N-pyridi- n-2-yl-propionamide
(99.9 mg, 84.3%) as a tan oil: EI-HRMS m/e calcd for
C.sub.19H.sub.23N.sub.3O (M.sup.+) 309.1834, found 309.1849.
EXAMPLE 123
6-[2-(4-Amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic Acid
Methyl Ester
[0651] 136
[0652] A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic
acid (prepared in Example 22, 526 mg, 2.0 nimol) in methylene
chloride (20 mL) cooled to 0.degree. C. was treated with a 2.0M
solution of oxalyl chloride in methylene chloride (1.2 mL, 2.4
mmol) and a few drops of N,N-dimethylformamide. The reaction
mixture was stirred at 0.degree. C. for 15 min and at 25.degree. C.
for 30 min. The reaction mixture was then treated with a solution
of 6-amino-nicotinic acid methyl ester (532 mg, 3.5 mmol) in
tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.84 mL, 4.8
mmol). This solution was stirred at 25.degree. C. for 48 h. At this
time, the reaction was concentrated in vacuo. Flash chromatography
(Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate)
afforded
6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid
methyl ester (353.9 mg, 44.6%) as a pale orange glass: EI-HRMS m/e
calcd for C.sub.21H.sub.23N.sub.3O.sub.5 (M.sup.+) 397.1637, found
397.1631.
[0653] A mixture of
6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-ni- cotinic
acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) was
treated with a catalytic amount of 10% palladium on activated
carbon (30 mg). The resulting mixture was shaken at 25.degree. C.
under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this
time, the catalyst was removed by filtration through a plug of
celite. The filtrate was concentrated in vacuo to afford
6-[2-(4-amino-phenyl)-3-cyclopentyl-propi- onylamino]-nicotinic
acid methyl ester (262.8 mg, 94.7%) as a pale yellow glass: EI-HRMS
m/e calcd for C.sub.21H.sub.25N.sub.3O.sub.3 (M.sup.+) 367.1895,
found 367.1899.
EXAMPLE 124
3-Cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-
-propionamide
[0654] 137
[0655] A solution of isoamyl nitrite (4.02 mL, 30 mmol) in dimethyl
disulfide (19.8 mL, 220 mmol) at 25.degree. C. was slowly treated
with 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The
reaction was exothermic with gas evolution. The resulting brown
reaction mixture was heated to 80-90.degree. C. for 2 h, at which
time, thin layer chromatography analysis of the reaction mixture
indicated the absence of starting material. The reaction mixture
was cooled to 25.degree. C. and then concentrated in vacuo. The
resulting residue was dissolved in ethyl acetate (200 mL). The
organic layer was washed successively with a 1N aqueous
hydrochloric acid solution (1.times.200 mL) and a saturated aqueous
sodium chloride solution (1.times.200 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. Biotage
chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate)
afforded 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.73
g, 87%) as a brown oil: EI-HRMS m/e calcd for
C.sub.8H.sub.6BrF.sub.3S (M.sup.+) 269.9326, found 269.9327.
[0656] A solution of
4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.71 g, 17.4
mmol) in methylene chloride (100 mL) was cooled to -10.degree. C.
and then treated with 3-chloroperoxybenzoic acid (86% grade, 9.0 g,
52.2 mmol). The reaction mixture was stirred at -10.degree. C. for
10 min and then allowed to warm to 25.degree. C. where it was
stirred overnight. At this time, thin layer chromatography analysis
of the reaction mixture indicated the absence of starting material.
The reaction mixture was then filtered, and the solids were washed
with methylene chloride (1.times.50 mL). The filtrate was
concentrated in vacuo. The resulting residue was dissolved in ethyl
acetate (100 mL). The organic layer was washed successively with a
saturated aqueous sodium bicarbonate solution (2.times.100 mL) and
a saturated aqueous sodium chloride solution (1.times.100 mL),
dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo to afford a yellow solid. Recrystallization from methylene
chloride (20 mL), diethyl ether (10 mL), and hexanes afforded
4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene (3.46 g, 57%)
as a white solid: mp 110-112.degree. C.; EI-HRMS m/e calcd for
C.sub.8H.sub.6BrF.sub.3O.sub.2S (M.sup.+) 301.9224, found
301.9223.
[0657] A mixture of zinc dust (1.3 g, 20 mmol, Aldrich, -325 mesh)
and dry tetrahydrofuran (2 mL) under argon was treated with
1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then
heated with a heat gun to ebullition, allowed to cool, and heated
again. This process was repeated three times to make sure the zinc
dust was activated. The activated zinc dust suspension was then
treated with trimethylsilyl chloride (110 mg, 1 mmol), and the
suspension was stirred for 15 min at 25.degree. C. The reaction
mixture was then treated dropwise with a solution of
(E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared in
Example 108, 2.5 g, 8.5 mmol) in dry tetrahydrofuran (3 mL) over 5
min. After the addition, the reaction mixture was stirred for 1 h
at 40-45.degree. C. and then stirred overnight at 25.degree. C. The
reaction mixture was then diluted with dry tetrahydrofuran (4 mL),
and the stirring was stopped to allow the excess zinc dust to
settle down (.about.2 h). In a separate reaction flask,
bis(dibenzylideneacetone)palladium(0) (108 mg, 0.2 mmol) and
triphenylphosphine (209 mg, 0.8 nmmol) in dry tetrahydrofuran (10
mL) was stirred at 25.degree. C. under argon for 10 min and then
treated with 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene
(2.12 g, 7 mmol) and the freshly prepared zinc compound in
tetrahydrofuran. The resulting brick red solution was heated at
40-45.degree. C. for 2 d. The reaction mixture was cooled to
25.degree. C. and then poured into a saturated aqueous ammonium
chloride solution (100 mL), and the organic compound was extracted
into ethyl acetate (3.times.75 mL). The combined organic extracts
were washed with a saturated aqueous sodium chloride solution
(1.times.100 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. Biotage chromatography (FLASH 40M,
Silica, 9/1 to 3/1 hexanes/ethyl acetate) afforded
(E)-3-cyclohexyl-2-(4-methanesulfonyl-
-3-trifluoromethyl-phenyl)-acrylic acid methyl ester (2.7 g, 99%)
as a viscous oil: EI-HRMS m/e calcd for
C.sub.18H.sub.21F.sub.3O.sub.4S (M.sup.+) 391.1191, found
391.1200.
[0658] A solution of nickel(II) chloride hexahydrate (36.6 mg,
0.154 mmol) and
(E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acryl-
ic acid methyl ester (302 mg, 0.77 mmol) in methanol (8 mL) was
cooled to 0.degree. C. and then treated with sodium borohydride (87
mg, 2.29 mmol) in four portions. After the addition, the black
reaction mixture was stirred for 15 min at 0.degree. C. and then
allowed to warm to 25.degree. C. where it was stirred for 15 h. The
black solid was filtered using filter paper and washed with
methanol. The combined solvents were concentrated in vacuo, and the
residue was diluted with ethyl acetate (50 mL). The organic layer
was washed successively with a 3N -aqueous hydrochloric acid
solution (1.times.50 mL), a saturated aqueous sodium bicarbonate
solution (1.times.50 mL) and a saturated aqueous sodium chloride
solution (1.times.50 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to afford racemic
3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic
acid methyl ester (280 mg, 93%) as a viscous oil: EI-HRMS m/e calcd
for C.sub.18H.sub.23F.sub.3O.sub.4S (M.sup.+) 392.1269, found
392.1276.
[0659] A solution of
3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-p-
henyl)-propionic acid methyl ester (265 mg, 0.67 mmol) in ethanol
(5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5
mL). The solution was heated at 45-50.degree. C. for 5 h, at which
time, thin layer chromatography analysis of the mixture indicated
the absence of starting material. The reaction mixture was then
concentrated in vacuo to remove ethanol, and the residue was
diluted with water (20 mL) and extracted with diethyl ether
(1.times.40 mL) to remove any neutral impurities. The aqueous layer
was acidified with a 1N aqueous hydrochloric acid solution. The
resulting acid was extracted into ethyl acetate (2.times.50 mL).
The combined organic layers were washed with a saturated aqueous
sodium chloride solution (1.times.50 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to afford
3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propio-
nic acid (249 mg, 97%) as a viscous oil: EI-HRMS m/e calcd for
C.sub.17H.sub.21F.sub.3O.sub.4S (M.sup.+) 378.1113, found
378.1121.
[0660] A solution of triphenylphosphine (279 mg, 1.06 mmol) in
methylene chloride (5 ML) was cooled to 0.degree. C. and then
treated with N-bromosuccinimide (188.7 mg, 1.06 mmol). The reaction
mixture was stirred at 0.degree. C. for 30 min and then treated
with a solution of
3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic
acid (237 mg, 0.626 mmol) in methylene chloride (4 mL). The clear
solution was stirred for 15 min at 0.degree. C. and then allowed to
warm to 25.degree. C. where it was stirred for 2 h. The reaction
mixture was then treated with 2-aminothiazole (188 mg, 1.88 mmol),
and the resulting suspension was stirred for 15 h at 25.degree. C.
The reaction mixture was concentrated in vacuo to remove methylene
chloride, and the residue was diluted with ethyl acetate (50 mL)
and a 1N aqueous hydrochloric acid solution (50 mL). The two layers
were separated, and the aqueous layer was extracted with ethyl
acetate (1.times.30 mL). The combined organic extracts were
successively washed with a saturated aqueous sodium bicarbonate
solution (1.times.50 mL) and a saturated aqueous sodium chloride
solution (1.times.50 mL), dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. Biotage chromatography (FLASH
40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded
3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-y-
l-propionamide (83 mg, 29%) as an amorphous solid: EI-HRMS m/e
calcd for C.sub.20H.sub.23F.sub.3N.sub.2O.sub.3S.sub.2 (M.sup.+)
460.1102, found 460.1100.
BIOLOGICAL ACTIVITY EXAMPLES
Example A
In Vitro Glucokinase Activity
[0661] Glucokinase Assay:
[0662] Glucokinase (GK) was assayed by coupling the production of
glucose-6-phosphate to the generation of NADH with
glucose-6-phosphate dehydrogenase (G6PDH, 0.75-1 kunits/mg;
Boehringer Mannheim, Indianapolis, Ind.) from Leuconostoc
mesenteroides as the coupling enzyme (Scheme 2). Recombinant
138
[0663] Human liver GK1 was expressed in E. coli as a glutathione
S-transferase fusion protein (GST-GK) [Liang et al, 1995] and was
purified by chromatography over a glutathione-Sepharose 4B affinity
column using the procedure provided by the manufacturer (Amersham
Pharmacia Biotech, Piscataway, N.J.). Previous studies have
demonstrated that the enzymatic properties of native GK and GST-GK
are essentially identical (Liang et al, 1995; Neet et al.,
1990).
[0664] The assay was conducted at 25.degree. C. in a flat bottom
96-well tissue culture plate from Costar (Cambridge, Mass.) with a
final incubation volume of 120 .mu.l. The incubation mixture
contained: 25 mM Hepes buffer (pH, 7.1), 25 mM KCl, 5 mM D-glucose,
1 mM ATP, 1.8 mM NAD, 2 mM MgCl.sub.2, 1 .mu.M
sorbitol-6-phosphate, 1 mM dithiothreitol, test drug or 10% DMSO,
1.8 unit/ml G6PDH, and GK (see below). All organic reagents were
>98% pure and were from Boehringer Mannheim with the exceptions
of D-glucose and Hepes that were from Sigma Chemical Co, St Louis,
Mo. Test compounds were dissolved in DMSO and were added to the
incubation mixture minus GST-GK in a volume of 12 .mu.l to yield a
fmal DMSO concentration of 10%. This mix was preincubated in the
temperature controlled chamber of a SPECTRAmax 250 microplate
spectrophotometer (Molecular Devices Corporation, Sunnyvale,
Calif.) for 10 minutes to allow temperature equilibrium and then
the reaction was started by the addition of 20 .mu.l GST-GK.
[0665] After addition of enzyme, the increase in optical density
(OD) at 340 nm was monitored over a 10 minute incubation period as
a measure of GK activity. Sufficient GST-GK was added to produce an
increase in OD.sub.340 of 0.08 to 0.1 units over the 10 minute
incubation period in wells containing 10% DMSO, but no test
compound. Preliminary experiments established that the GK reaction
was linear over this period of time even in the presence of
activators that produced a 5-fold increase in GK activity. The GK
activity in control wells was compared with the activity in wells
containing test GK activators, and the concentration of activator
that produced a 50% increase in the activity of GK, i.e., the
SC.sub.1.5, was calculated. All of the compounds of formula I
described in the Synthesis Examples had an SC.sub.1.5 less than or
equal to 30 .mu.M.
[0666] Liang, Y., Kesavan, P., Wang, L., Niswender, K., Tanizawa,
Y., Permut, M. A., Magnuson, M., and Matschinsky, F. M. Variable
effects of maturity-onset-diabetes-of-youth (MODY)-associated
glucokinase mutations on the substrate interactions and stability
of the enzyme. Biochem. J. 309: 167-173, 1995.
[0667] Neet, K., Keenan, R. P., and Tippett, P. S. Observation of a
kinetic slow transition in monomeric glucokinase. Biochemistry
29;770-777, 1990.
Example B
In Vivo Activity
[0668] Glucokinase Activator in vivo Screen Protocol
[0669] C57BL/6J mice are orally dosed via gavage with Glucokinase
(GK) activator at 50 mg/kg body weight following a two hour fasting
period. Blood glucose determinations are made five times during the
six hour post-dose study period.
[0670] Mice (n=6) are weighed and fasted for a two hour period
prior to oral treatment. GK activators are formulated at 6.76 mg/ml
in Gelucire vehicle (Ethanol:Gelucire44/14:PEG400q.s. 4:66:30
v/w/v. Mice are dosed orally with 7.5 .mu.l formulation per gram of
body weight to equal a 50 mg/kg dose. Immediately prior to dosing,
a pre dose (time zero) blood glucose reading is acquired by
snipping off a small portion of the animals tail (.about.1 mm) and
collecting 15 .mu.l blood into a heparinized capillary tube for
analysis. Following GK activator administration, additional blood
glucose readings are taken at 1, 2, 4 and 6 hours post dose from
the same tail wound. Results are interpreted by comparing the mean
blood glucose values of six vehicle treated mice with six GK
activator treated mice over the six hour study duration. Compounds
are considered active when they exhibit a statistically significant
(p .ltoreq.0.05) decrease in blood glucose compared to vehicle for
two consecutive assay time points.
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