U.S. patent application number 11/646919 was filed with the patent office on 2007-08-30 for processes for preparing darifenacin hydrobromide.
Invention is credited to Augusto Canavesi, Paola Daverio, Valeriano Merli.
Application Number | 20070203221 11/646919 |
Document ID | / |
Family ID | 38611049 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203221 |
Kind Code |
A1 |
Merli; Valeriano ; et
al. |
August 30, 2007 |
Processes for preparing darifenacin hydrobromide
Abstract
The invention encompasses processes for the preparation of
darifenacin hydrobromide.
Inventors: |
Merli; Valeriano; (Cremella
Lecco, IT) ; Canavesi; Augusto; (Locate Varesino
(CO), IT) ; Daverio; Paola; (Villasanta, IT) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
38611049 |
Appl. No.: |
11/646919 |
Filed: |
December 27, 2006 |
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Application
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Patent Number |
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60754395 |
Dec 27, 2005 |
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60772250 |
Feb 9, 2006 |
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60776311 |
Feb 23, 2006 |
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60809147 |
May 25, 2006 |
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60812579 |
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60836557 |
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60837407 |
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60850184 |
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60859332 |
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60873680 |
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Current U.S.
Class: |
514/422 ;
548/525 |
Current CPC
Class: |
C07D 307/79 20130101;
C07D 405/06 20130101; A61P 13/00 20180101; C07D 207/48 20130101;
C07D 207/09 20130101 |
Class at
Publication: |
514/422 ;
548/525 |
International
Class: |
A61K 31/4025 20060101
A61K031/4025; C07D 405/02 20060101 C07D405/02 |
Claims
1. A process for preparing darifenacin hydrobromide comprising: a)
combining 3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the
group consisting of a C.sub.6-9 aromatic hydrocarbon, a polar
aprotic organic solvent, and mixtures thereof, a sulfonyl halide,
and a base to obtain
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I,
##STR60## b) reacting the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I with
diphenylacetonitrile and an inorganic base in an organic solvent
selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar aprotic organic solvent, and mixtures thereof
to obtain
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of
formula II; ##STR61## c) reacting the
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile
intermediate of formula II with a bromine acceptor selected from
the group consisting of phenol and naphthol and an acid to obtain
(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula
III, ##STR62## wherein the bromine acceptor is phenol only when the
acid is HBr. d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)
acetonitrile salt of formula III and an inorganic base with a
solvent selected from the group consisting of water immiscible
organic solvent, a polar aprotic organic solvent, water, and
mixtures thereof to form a mixture; e) acidifying the mixture; f)
heating the mixture g) basifying the mixture; h) combining the
mixture with a C.sub.1-4 alcohol and L-tartaric acid to obtain
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI; ##STR63## i) reacting the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI with a compound of the formula V ##STR64## and a base in
a solvent selected from the group consisting of a C.sub.6-9
aromatic hydrocarbon, a polar organic solvent, water, and mixtures
thereof; and j) admixing HBr with the mixture to obtain darifenacin
bromide, wherein X is either C.sub.1-10 alkyl or C.sub.6-9 aryl, Y
is a leaving group selected from the group consisting of I, Cl,
mesyl, Br, tosyl, trifluoroacetyl, and trifluoromethansulfonyl, and
Z.sub.1 is an acid.
2. N-protected-3-(S)-pyrrolidinol of the formula, ##STR65## wherein
X is S, SO.sub.2, Si, or CO, and R is phenyl, tolyl, ortho, meta,
or para-xylyl, linear or branched C.sub.1-10 alkyl, H, or
CF.sub.3.
3. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is S
and R is phenyl.
4. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is S
and R is tolyl.
5. The N-protected-3-(S)-pyrrolidinol of claim 4, having a melting
temperature of about 108.degree. C., to about 112.degree. C.
6. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is S
and R is xylyl.
7. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is S
and R is linear or branched C.sub.1-10 alkyl.
8. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is
SO.sub.2 and R is phenyl.
9. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is
SO.sub.2 and R is tolyl.
10. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is
SO.sub.2 and R is xylyl.
11. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is
SO.sub.2 and R is linear or branched C.sub.1-10 alkyl.
12. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is Si
and R is linear or branched C.sub.1-10 alkyl.
13. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is CO
and R is H.
14. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is CO
and R is CF.sub.3.
15. The N-protected-3-(S)-pyrrolidinol of claim 2, wherein X is CO
and R is CH.sub.3.
16. A process for preparing darifenacin hydrobromide comprising
converting the N-protected-3-(S)-pyrrolidinol of claim 2 into
darifenacin hydrobromide.
17. A process for preparing
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I
##STR66## comprising combining 3-(S)-(+)-hydroxypyrrolidine, a
sulfonyl halide, a base, and a solvent selected from the group
consisting of a C.sub.6-9 aromatic hydrocarbon, a polar aprotic
organic solvent, and mixtures thereof to obtain
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine, wherein X is
either C.sub.1-10 alkyl or C.sub.6-9 aryl.
18. The process of claim 17, wherein X is C.sub.6-9 aryl.
19. The process of claim 17, wherein X is tolyl.
20. The process of claim 17, wherein the
3-(S)-(+)-hydroxypyrrolidine and the solvent are combined to form a
solution, followed by the addition of the sulfonyl halide and the
addition of the base.
21. The process of claim 20, wherein the combination is maintained
at a temperature of about 25.degree. C., to about reflux.
22. The process of claim 17, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene or o-, m-, or p-xylene.
23. The process of claim 17, wherein the polar aprotic organic
solvent is a C.sub.1-10 halogenated aliphatic hydrocarbon, amide,
or sulfoxide.
24. The process of claim 23, wherein the C.sub.1-10 halogenated
aliphatic hydrocarbon is dichloromethane, 1,2-dichloroethane, or
dichloropentane.
25. The process of claim 23, wherein the amide is a C.sub.1-2
amide.
26. The process of claim 25, wherein the C.sub.1-2 amide is
dimethylformamide, or dimethylacetamide.
27. The process of claim 23, wherein the sulfoxide is a C.sub.1-4
sulfoxide.
28. The process of claim 27, wherein the C.sub.1-4 sulfoxide is
dimethylsulfoxide.
29. The process of claim 17, wherein the solvent is toluene.
30. The process of claim 17, wherein the process further comprises
a phase transfer catalyst.
31. The process of claim 30, wherein the phase transfer catalyst is
selected from the group consisting of tetrabutylammonium bromide,
tributylmethylammonium chloride, tetrabutylammonium sulfate, and
dimethylsulfoxide.
32. The process of claim 31, wherein the phase transfer catalyst is
tetrabutylammonium bromide.
33. The process of claim 17, wherein the halide moiety of the
sulfonyl halide is selected from chloride, bromide, and iodide.
34. The process of claim 17, wherein the sulfonyl halide is
tosylchloride, mesylchloride, or brosylchloride.
35. The process of claim 34, wherein the sulfonyl halide is
tosylchloride.
36. The process of claim 17, wherein the base is an organic
base.
37. The process of claim 36, wherein the organic base is selected
from the group consisting of aliphatic and aromatic amines.
38. The process of claim 37, wherein the aliphatic amine is
triethylamine, methylmorpholine, N,N-diisopropylethyl amine.
39. The process of claim 37, wherein the aromatic amine is
pyridine.
40. The process of claim 17, wherein the base is an inorganic
base.
41. The process of claim 40, wherein the inorganic base is an
alkali base.
42. The process of claim 41, wherein the alkali base is sodium
hydroxide or potassium hydroxide.
43. The process of claim 17 further comprising recovering the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine.
44. A process for preparing darifenacin hydrobromide comprising: a)
preparing 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of the
following formula I ##STR67## by the process of claim 17; and b)
converting the 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine into
darifenacin hydrobromide, wherein X is either C.sub.1-10 alkyl or
C.sub.6-9 aryl.
45. A process for preparing
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil) acetonitrile of
formula II ##STR68## comprising combining
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I,
diphenylacetonitrile, and an inorganic base in an organic solvent
selected from the ##STR69## group consisting of a C.sub.6-9
aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures
thereof, and an inorganic base to obtain
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile,
wherein X is either C.sub.1-10alkyl or C.sub.6-9 aryl.
46. The process of claim 45, wherein X is C.sub.6-9 aryl.
47. The process of claim 46, wherein X is tolyl.
48. The process of claim 45, wherein the diphenylacetonitrile and
the organic solvent are combined, followed by the addition of the
inorganic base to form the mixture.
49. The process of claim 48, wherein the diphenylacetonitile and
the organic solvent are cooled to a temperature of about 25.degree.
C., to about 15.degree. C., prior to the addition of
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I.
50. The process of claim 48, wherein the combination is heated to a
temperature of about 50.degree. C., to about 100.degree. C.
51. The process of claim 45, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene.
52. The process of claim 45, wherein the polar aprotic organic
solvent is an amide or a sulfoxide.
53. The process of claim 52, wherein the amide is a C.sub.1-2
amide.
54. The process of claim 53, wherein the C.sub.1-2 amide is
dimethylformamide or dimethylacetamide.
55. The process of claim 52, wherein the sulfoxide is a C.sub.1-4
sulfoxide.
56. The process of claim 55, wherein the C.sub.1-4 sulfoxide is
dimethylsulfoxide.
57. The process of claim 45, wherein the solvent is
dimethylformamide.
58. The process of claim 45, wherein the inorganic base is a metal
alkoxide or an alkali hydroxide.
59. The process of claim 58, wherein the metal alkoxide is sodium
tert-butoxide, potassium tert-butoxide, or sodium methoxide.
60. The process of claim 58, wherein the alkali hydroxide is sodium
hydroxide, or potassium hydroxide.
61. The process of claim 45, wherein the inorganic base is sodium
tert-butoxide, or potassium tert-butoxide.
62. The process of claim 45, further comprising recovering the
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.
63. A process for preparing darifenacin hydrobromide comprising: a)
preparing
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of the
following formula II ##STR70## by the process of claim 45; and b)
converting the
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile into
darifenacin hydrobromide, wherein X is either C.sub.1-10 alkyl or
C.sub.6-9 aryl.
64. A process for preparing
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI ##STR71## comprising: a) combining
(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula
III, ##STR72## a solvent selected from the group consisting of a
water immiscible organic solvent, a polar aprotic organic solvent,
water, and mixtures thereof, and an inorganic base to form a
mixture; b) acidifying the mixture; c) heating the mixture; d)
basifying the mixture; and e) combining the mixture with a
C.sub.1-4 alcohol and L-tartaric acid to obtain
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate,
wherein Z.sub.1 is an acid.
65. The process of claim 64, wherein Z.sub.1 is HBr or HCl.
66. The process of claim 64, wherein the
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III
is converted into the free base of formula XI ##STR73## prior to
step b).
67. The process of claim 66, wherein the
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III
is converted into the free base of formula XI by combining the
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III
a solvent selected from the group consisting of water immiscible
organic solvent, a polar aprotic organic solvent, water, and
mixtures thereof, and an inorganic base.
68. The process of claim 64, wherein the water immiscible organic
solvent is a C.sub.6-9 aromatic hydrocarbon or a C.sub.10
halogenated aliphatic hydrocarbon.
69. The process of claim 68, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene, xylenes, isopropylbenzene, or styrene.
70. The process of claim 69, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene.
71. The process of claim 68, wherein the C.sub.1-10 halogenated
aliphatic hydrocarbon is dichloromethane, 2-dichloroethane,
1,1,-dichloroethane, or 1,5-dichloropentane.
72. The process of claim 71, wherein the C.sub.1-10 halogenated
aliphatic hydrocarbon is dichloromethane.
73. The process of claim 64, wherein the polar aprotic organic
solvent is an ester.
74. The process of claim 73, wherein the ester is ethyl
acetate.
75. The process of claim 64, wherein the solvent is a mixture of a
C.sub.1-10 halogenated aliphatic hydrocarbon and water.
76. The process of claim 75, wherein the C.sub.1-10 halogenated
aliphatic hydrocarbon is dichloromethane.
77. The process of claim 64, wherein the acidifying comprises
adding an acid to the mixture and heating the mixture.
78. The process of claim 77, wherein the acid is a strong acid.
79. The process of claim 77, wherein the acid is a strong mineral
acid.
80. The process of claim 79, wherein the strong mineral acid is
sulfuric acid or phosphoric acid.
81. The process of claim 79, wherein the strong mineral acid is
sulfuric acid.
82. The process of claim 77, wherein the mixture is heated to a
temperature of about 80.degree. C., to about 110.degree. C.
83. The process of claim 64, wherein the mixture is basified to a
pH of about 10 to about 13.
84. The process of claim 64, wherein the mixture is basified by
adding an inorganic base.
85. The process of claim 84, wherein the inorganic base is an
aqueous solution of an alkali base.
86. The process of claim 85, wherein the alkali base is an alkali
hydroxide, an alkali carbonate, or an alkali bicarbonate.
87. The process of claim 86, wherein the alkali hydroxide is sodium
hydroxide, potassium hydroxide.
88. The process of claim 86, wherein the alkali carbonate is sodium
carbonate, or potassium carbonate.
89. The process of claim 86, wherein the alkali bicarbonate is
sodium bicarbonate or potassium bicarbonate.
90. The process of claim 64, wherein the inorganic base is sodium
hydroxide.
91. The process of claim 64, wherein the C.sub.1-4 alcohol is
methanol, ethanol, isopropanol, or n-butanol.
92. The process of claim 64, wherein the C.sub.1-4 alcohol is
ethanol.
93. The process of claim 64, further comprising recovering the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI.
94. A process for preparing darifenacin hydrobromide comprising: a)
preparing the 3-(S)-(+)-(1-carbonyl-1,1-diphenylmethyl)pyrrolidine
tartrate by the process of claim, 64; and b) converting the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate into
darifenacin hydrobromide.
95. A compound of formula V ##STR74## wherein Y is a leaving group
selected from the group consisting of I, Cl, brosyl, Br, mesyl,
tosyl, trifluoroacetyl, and trifluoromethansulfonyl.
96. The compound of claim 95, wherein Y is Cl.
97. A process for preparing the compound of claim 95 comprising: a)
combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid, a C.sub.1-4
alcohol, and a catalyst to obtain
2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester; b) combining
the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a
reducing agent and a C.sub.4-6 alcohol to obtain
2(2,3-dihydrobenzofura-5-yl)-ethanol; and c) combining the
2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from
the group consisting of a C.sub.1-2 halogenated hydrocarbon,
C.sub.3-6 ester, and C.sub.6-9 aromatic hydrocarbon, and a
substance containing a leaving group selected from the group
consisting of Cl, Br, mesyl, brosyl, tosyl, trifluoroacetyl, and
trifluoromethansulfonyl to obtain the compound of formula V.
98. The process of claim 97, wherein Y is Cl.
99. The process of claim 97, wherein the C.sub.1-4 alcohol is
selected from the group consisting of methanol, ethanol, propanol,
and butanol.
100. The process of claim 97, wherein the C.sub.1-4 alcohol is
methanol.
101. The process of claim 97, wherein the C.sub.1-4 alcohol is
admixed with toluene.
102. The process of claim 97, wherein the catalyst is an acid.
103. The process of claim 102, wherein the acid is an organic
acid.
104. The process of claim 103, wherein the organic acid is selected
from the group consisting of sulfuric acid, p-toluenesulfonic acid
and methanesulfonic acid.
105. The process of claim 102, wherein the acid is an inorganic
acid.
106. The process of claim 105, wherein the inorganic acid is
selected from a group consisting of: HCl, HClO.sub.4, and
H.sub.3PO.sub.4.
107. The process of claim 102, wherein the acid is sulfuric
acid.
108. The process of claim 97, wherein step a) further comprises
heating.
109. The process of claim 108, wherein the heating is to a
temperature of about 60.degree. C., to about 70.degree. C.
110. The process of claim 108, wherein the heating is to a
temperature of about 65.degree. C., to about 70.degree. C.
111. The process of claim 97, wherein the C.sub.4-6 alcohol is
t-butanol.
112. The process of claim 97, wherein the C.sub.4-6 alcohol is
admixed with a C.sub.1-4 alcohol.
113. The process of claim 112, wherein the C.sub.4-6 alcohol is
t-butanol and the C.sub.1-4 alcohol is methanol.
114. The process of claim 97, wherein the reducing agent is a metal
hydride.
115. The process of claim 97, wherein the reducing agent is
selected from the group consisting of NaBH.sub.4, LiAlH.sub.4, and
sodium dihydro-bis-(2-methoxyethoxy) aluminate.
116. The process of claim 97, wherein the reducing agent is
NaBH.sub.4.
117. The process of claim 97, wherein step b) further comprises
heating.
118. The process of claim 117, wherein the heating is to a
temperature of about 65.degree. C., to about 75.degree. C.
119. The process of claim 97, wherein the heating is to a
temperature of about 70.degree. C. to 75.degree. C.
120. The process of claim 97, wherein the C.sub.1-2 halogenated
hydrocarbon is dichloromethane.
121. The process of claim 97, wherein the C.sub.3-6 ester is ethyl
acetate, isopropyl acetate, butyl acetate, or isobutylacetate.
122. The process of claim 97, wherein the C.sub.3-6 ester is ethyl
acetate.
123. The process of claim 97, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene, xylenes, isopropylbenzene, or styrene.
124. The process of claim 97, wherein the solvent is toluene.
125. The process of claim 97, wherein the substance containing a
leaving group is selected from the group consisting of SOCl.sub.2,
PC13, PCl.sub.5, POCl.sub.3, tosylchloride, mesylchloride,
brosylchloride, trifluoroacetyl chloride, and
trifluoromethansulfonyl chloride.
126. The process of claim 97, wherein the substance containing a
leaving group is selected from the group consisting of SOCl.sub.2,
PCl.sub.3, PC15, and POCl.sub.3
127. The process of claim 97, wherein the substance containing a
leaving group is selected from the group consisting of
SOCl.sub.2.
128. The process of claim 97, wherein the substance containing a
leaving group is selected from the group consisting of
tosylchloride, mesylchloride, brosylchloride, trifluoroacetyl
chloride, and trifluoromethansulfonyl chloride.
129. The process of claim 128, wherein the process further
comprises a base.
130. The process of claim 129, wherein the base is an organic
base.
131. The process of claim 130, wherein the organic base is an
aliphatic or aromatic amine.
132. The process of claim 131, wherein the aliphatic amine is
triethylamine, ethyldiisopropylamine, or N-methylmorpholine.
133. The process of claim 131, wherein the aromatic amine is
pyridine.
134. The process of claim 129, wherein the base is an inorganic
base.
135. The process of claim 134, wherein the inorganic base is an
alkali metal hydroxide or an alkali metal carbonate.
136. The process of claim 135, wherein the alkali metal hydroxide
is sodium hydroxide, potassium hydroxide, or cesium hydroxide.
137. The process of claim 135, wherein the alkali carbonate is
sodium carbonate, potassium carbonate, or cesium carbonate.
138. The process of claim 129, wherein the base is
triethylamine.
139. The process of claim 97, wherein step c) further comprises
heating.
140. The process of claim 139, wherein the heating is to a
temperature of about 60.degree. C., to about 80.degree. C.
141. The process of claim 139, wherein the heating is to a
temperature of about 60.degree. C., to about 70.degree. C.
142. The process of claim 97, further comprising recovering the
compound of formula V.
143. A process for preparing darifenacin hydrobromide comprising:
a) preparing a compound of the following formula V ##STR75## by the
process of claim 97; and b) converting the compound of formula V
into darifenacin hydrobromide, wherein Y is a leaving group
selected from the group consisting of I, Cl, brosyl, Br, mesyl,
tosyl, trifluoroacetyl, and trifluoromethansulfonyl.
144. A process for preparing the compound of claim 95, comprising:
a) combining a bisulfite complex of formula X, ##STR76## water,
NaOH, Na.sub.2CO.sub.3, a water immiscible hydrocarbon, and a
reducing agent to form a mixture; and b) combining the mixture with
a solvent selected from the group consisting of a C.sub.1-2
halogenated hydrocarbon, C.sub.3-6 ester, and C.sub.6-9 aromatic
hydrocarbon, a substance containing a leaving group selected from
the group consisting of Cl, Br, mesyl, brosyl, tosyl,
trifluoroacetyl, and trifluoromethansulfonyl to obtain the compound
of formula V.
145. The process of claim 144, wherein Y is Cl.
146. The process of claim 144, wherein the water immiscible
hydrocarbon is either a C.sub.6-9 aromatic hydrocarbon or a
saturated hydrocarbon.
147. The process of claim 146, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene, xylenes, isopropylbenzene, or styrene.
148. The process of claim 146, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene.
149. The process of claim 144, wherein the saturated hydrocarbon is
a C.sub.5-10 saturated hydrocarbon.
150. The process of claim 149, wherein the C.sub.5-10 saturated
hydrocarbon is a pentane, hexane, or heptane.
151. The process of claim 144, wherein the NaOH is added to a
suspension of the bisulfite complex of formula X in water to form a
basic mixture.
152. The process of claim 151, wherein the pH of the basic mixture
is about 9 to about 11.
153. The process of claim 151, wherein the basic mixture is cooled
to a temperature of about 20.degree. C., to about 0.degree. C.,
prior to the addition of the reducing agent.
154. The process of claim 144, wherein the reducing agent is
selected from the group consisting of NaBH.sub.4, LiAlH.sub.4, and
H.sub.2/Pd.
155. The process of claim 144, wherein the reducing agent is
NaBH.sub.4.
156. The process of claim 144, wherein a pH of about 9 to about 11
is maintained during the addition of the reducing agent.
157. The process of claim 144, wherein, step a) further comprises
heating the mixture to a temperature of about 10.degree. C. to
about 25.degree. C.
158. The process of claim 144, wherein, step a) leads to
2(2,3-dihydrobenzofura-5-yl)-ethanol.
159. The process of claim 144, further comprising recovering the
compound of formula V.
160. A process for preparing darifenacin hydrobromide comprising:
a) preparing a compound of the following formula V ##STR77## by the
process of claim 144, and b) converting the compound of formula V
into darifenacin hydrobromide, wherein Y is a leaving group
selected from the group consisting of I, Cl, brosyl, Br, mesyl,
tosyl, trifluoroacetyl, and trifluoromethansulfonyl.
161. A process for preparing darifenacin hydrobromide comprising:
a) combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
tartrate or the free base derivative of the following formula,
##STR78## a derivative of ethyl-dihydrobenzofuran of the following
formula V, a solvent selected from the group consisting of a
C.sub.6-9 aromatic hydrocarbon, a polar organic solvent, water, and
mixtures thereof, and a base to form a mixture; and b) admixing HBr
with the mixture to obtain darifenacin hydrobromide.
162. The process of claim 161, wherein the C.sub.6-9 aromatic
hydrocarbon is toluene.
163. The process of claim 161, wherein the polar aprotic organic
solvent is selected from the group consisting of an amide, a
C.sub.1-10 halogenated aliphatic hydrocarbon, a sulfoxide, an
ester, a nitrile, and a ketone.
164. The process of claim 163, wherein the C.sub.1-10 halogenated
hydrocarbon a C.sub.1-5 halogenated hydrocarbon.
165. The process of claim 164, wherein the C.sub.1-5 halogenated
hydrocarbon is dichloromethane.
166. The process of claim 163, wherein the sulfoxide is a C.sub.2-5
sulfoxide.
167. The process of claim 166, wherein the C.sub.2-5 sulfoxide is
dimethylsulfoxide.
168. The process of claim 163, wherein the ester is a C.sub.2-5
ester.
169. The process of claim 168, wherein the C.sub.2-5 ester is
ethylacetate.
170. The process of claim 163, wherein the nitrile is a C.sub.2-4
nitrile.
171. The process of claim 170, wherein the C.sub.2-4 nitrile is
acetonitrile.
172. The process of claim 163, wherein the ketone is a C.sub.3-6
ketone.
173. The process of claim 172, wherein the C.sub.3-6 ketone is
methylethyl ketone.
174. The process of claim 161, wherein the solvent is a mixture of
toluene and water or dichloromethane and water.
175. The process of claim 161, wherein the base is an aliphatic or
aromatic amine, alkali carbonate, or alkali bicarbonate.
176. The process of claim 161, wherein the base is triethylamine,
tributylamine, methylmorpholine, N,N-diisopropylethyl amine,
pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate
or potassium bicarbonate.
177. The process of claim 161, wherein the mixture is heated prior
to adding HBr.
178. The process of claim 177, wherein the mixture is heated to a
temperature of about 50.degree. C., to about reflux.
179. The process of claim 161, further comprising recovering the
darifenacin hydrobromide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
provisional application Ser. Nos. 60/754,395, filed Dec. 27, 2005;
60/772,250, filed Feb. 9, 2006; 60/776,311, filed Feb. 23, 2006;
60/809,147, filed May 25, 2006; 60/813,579, filed Jun. 8, 2006;
60/836,557, filed Aug. 8, 2006; 60/837,407, filed Aug. 10, 2006;
60/850,184, filed Oct. 5, 2006; 60/859,332, filed Nov. 15, 2006;
and 60/873,680, filed Dec. 7, 2006, hereby incorporated by
reference. This application is also related to U.S. application
Ser. No. ______, filed Dec. 27, 2006 and entitled "Processes for
Preparing Darifenacin Hydrobromide" [Attorney docket no.
12670/82309A]; and Ser. No. ______, filed Dec. 27, 2006 and
entitled "Pure Darifenacin Hydrobromide Substantially Free of
Oxidized Darifenacin and Salts Thereof and Process for the
Preparation Thereof" [Attorney docket no. 12670/A400US1], hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses processes for the preparation of
darifenacin hydrobromide.
BACKGROUND OF THE INVENTION
[0003] Darifenacin,
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphen-
ylacetamide, a compound having the chemical structure, ##STR1## is
a selective M3 receptor antagonist. Blockade of destructor muscle
activity manifests in an increase in urine volume that the bladder
can retain, reduction of urination frequency, and decrease in
pressure and urgency associated with the urge to urinate, and
thereby episodes of incontinence are reduced.
[0004] Darifenacin is administered as the hydrobromide salt,
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphen-
ylacetamide hydrobromide, of the structure ##STR2## and is marketed
under the trade name ENABLEX.RTM. by Novartis.
[0005] U.S. Pat. No. 5,096,890, hereby incorporated by reference,
discloses three routes for the synthesis of darifenacin
hydrobromide; all of which comprise the cumbersome and hazardous
Mitsunobu reaction, described in the following Scheme. ##STR3##
[0006] Accordingly, 1-tosyl-3-(R)-pyrrolidinol is reacted with
methyl tosylate, and with diethylazodicarboxylate (DEAD), a very
dangerous reagent. Typically, the product is contaminated with
triphenylphosphine oxide, which is very difficult to separate from
the desired product. Moreover, other toxic and hazardous reagents,
such as pyridine and NaH, are used in other steps of the
synthesis.
[0007] The process disclosed in U.S. publication No. 20003/0191176
for the preparation of Darifenacin hydrobromide requires the use of
BF.sub.3, which is also a toxic reagent.
[0008] Therefore, there is a need in the art for a process for the
preparation of darifenacin hydrobromide that does not use toxic and
dangereous reagents and that can be performed on an industrial
scale. The present invention provides such processes.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the invention encompasses an
N-protected-3-(S)-pyrrolidinol of the formula, ##STR4## wherein X
is S, SO.sub.2, Si, or CO, and R is phenyl, tolyl, ortho, meta, or
para-xylyl, linear or branched C.sub.1-10 alkyl, H, or
CF.sub.3.
[0010] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising converting the
N-protected-3-(S)-pyrrolidinol into darifenacin hydrobromide.
[0011] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising: a) combining
3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group
consisting of a C.sub.6-9 aromatic hydrocarbon, a polar aprotic
organic solvent, and mixtures thereof, a sulfonyl halide, and a
base to obtain 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of
formula I, ##STR5## b) reacting the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I with
diphenylacetonitrile and an inorganic base in an organic solvent
selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar aprotic organic solvent, and mixtures thereof
to obtain
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of
formula II; ##STR6## c) reacting the
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile
intermediate of formula II with a bromine acceptor selected from
the group consisting of phenol and naphthol and an acid to obtain
(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula
III, ##STR7## wherein the bromine acceptor is phenol only when the
acid is HBr; d) combining the (S)-2,2-diphenyl-2-(3-pyrrolidinil)
acetonitrile salt of formula III and an inorganic base with a
solvent selected from the group consisting of water immiscible
organic solvent, a polar aprotic organic solvent, water, and
mixtures thereof to form a mixture; e) acidifying the mixture; f)
heating the mixture; g) basifying the mixture; h) combining the
mixture with a C.sub.1-4 alcohol and L-tartaric acid to obtain
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI; ##STR8## i) reacting the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI with a compound of the formula V ##STR9## and a base in
a solvent selected from the group consisting of a C.sub.6-9
aromatic hydrocarbon, a polar organic solvent, water, and mixtures
thereof; and j) admixing HBr with the mixture to obtain darifenacin
bromide, wherein X is either C.sub.1-10 alkyl or C.sub.6-9 aryl Y
is a leaving group selected from the group consisting of I, Cl,
mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy, and Z.sub.1 is an acid.
[0012] In another embodiment, the invention encompasses a process
for preparing 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of
formula I ##STR10## comprising combining
3-(S)-(+)-hydroxypyrrolidine, a sulfonyl halide, and a base in a
solvent selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar aprotic organic solvent, and mixtures thereof
to obtain 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine, wherein
X is either C.sub.1-10 alkyl or C.sub.6-9 aryl.
[0013] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising preparing
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine and converting the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine into darifenacin
hydrobromide.
[0014] In another embodiment, the invention encompasses a process
for preparing (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)
acetonitrile of formula II ##STR11## comprising combining
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I,
diphenylacetonitrile, and an inorganic base in an organic solvent
selected from the ##STR12## group consisting of a C.sub.6-9
aromatic hydrocarbon, a polar aprotic organic solvent, and mixtures
thereof, and an inorganic base to obtain
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile,
wherein X is either C.sub.1-10 alkyl or C.sub.6-9 aryl.
[0015] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising preparing
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile and
converting the
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile into
darifenacin hydrobromide.
[0016] In another embodiment, the invention encompasses a process
for preparing 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
tartrate comprising: a) combining
(S)-2,2-diphenyl-2-(3-pyrrolidinil) acetonitrile salt of formula
III, ##STR13## a solvent selected from the group consisting of a
water immiscible organic solvent, a polar aprotic organic solvent,
water, and mixtures thereof, and an inorganic base to form a
mixture; b) acidifying the mixture; c) heating the mixture; d)
basifying the mixture; and e) combining the mixture with a
C.sub.1-4 alcohol and L-tartaric acid to obtain
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate,
wherein Z.sub.1 is an acid.
[0017] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising preparing
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate and
converting the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate into
darifenacin hydrobromide.
[0018] In another embodiment, the invention encompasses a compound
of formula V ##STR14## wherein Y is a leaving group selected from
the group consisting of I, Cl, mesyloxy, Br, tosyloxy,
trifluoroacetyloxy, and trifluoromethansulfonyloxy,
[0019] In another embodiment, the invention encompasses a process
for preparing the compound of formula V; ##STR15## comprising: a)
combining 2(2,3-dihydrobenzofura-5-yl)-acetic acid, a C.sub.1-4
alcohol, and a catalyst to obtain
2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester; b) combining
the 2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester with a
reducing agent and a C.sub.4-6 alcohol to obtain
2(2,3-dihydrobenzofura-5-yl)-ethanol; and c) combining the
2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from
the group consisting of a C.sub.1-2 halogenated hydrocarbon,
C.sub.3-6 ester, and C.sub.6-9 aromatic hydrocarbon, and a
substance containing a leaving group selected from the group
consisting of Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy, to obtain the compound of formula V,
wherein Y is a leaving group selected from the group consisting of
I, Cl, mesyloxy, Br, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy.
[0020] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising preparing the
compound of formula V ##STR16## and converting the compound of
formula V into darifenacin hydrobromide, wherein Y is a leaving
group selected from the group consisting of I, Cl, brosyloxy, Br,
mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy.
[0021] In another embodiment, the invention encompasses a process
for preparing a compound of the formula V, ##STR17## comprising: a)
combining the bisulfite complex of formula X, ##STR18## water,
NaOH, Na.sub.2CO.sub.3, a water immiscible hydrocarbon, and a
reducing agent to form a mixture; and b) combining the mixture with
a solvent selected from the group consisting of a C.sub.1-2
halogenated hydrocarbon, C.sub.3-6 ester, and C.sub.6-9 aromatic
hydrocarbon, a substance containing a leaving group selected from
the group consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy,
trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the
compound of formula V, wherein Y is a leaving group selected from
the group consisting of I, Cl, brosyloxy, Br, mesyloxy, tosyloxy,
trifluoroacetyloxy, and trifluoromethansulfonyloxy.
[0022] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising preparing the
compound of formula V ##STR19## and converting the compound of
formula V into darifenacin hydrobromide, wherein Y is a leaving
group selected from the group consisting of I, Cl, brosyloxy, Br,
mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy.
[0023] In another embodiment, the invention encompasses a process
for preparing darifenacin hydrobromide comprising: a) combining
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate or
the free base derivative of the following formula, ##STR20## a
derivative of ethyl-dihydrobenzofuran of the following formula V,
##STR21## a solvent selected from the group consisting of a
C.sub.6-9 aromatic hydrocarbon, a polar organic solvent, water, and
mixtures thereof, and a base to form a mixture; and b) admixing HBr
with the mixture to obtain darifenacin hydrobromide.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The invention encompasses an N-protected-3-(S)-pyrrolidinol
of the formula, ##STR22## wherein X is S, SO.sub.2, Si, or CO, and
R is phenyl, tolyl, ortho, meta, or para-xylyl, linear or branched
C.sub.1-10 alkyl, H, or CF.sub.3. Preferably, X is SO.sub.2.
Preferably, R is tolyl.
[0025] In one preferred embodiment, X is S, and R is phenyl, such
that the N-protected-3-(S)-pyrrolidinol corresponds to
N-phenylthio-3-(S)-pyrrolidinol of the structure ##STR23## In
another preferred embodiment, X is S, and R is tolyl, such that the
N-protected-3-(S)-pyrrolidinol corresponds to
N-Tolylthio-3-(S)-pryrrolidinol of the structure ##STR24## The
N-tolylthio-3-(S)-Pyrrolidinol may be characterized by a melting
temperature of about 108.degree. C. to about 112.degree. C. When X
is S, and R is xylyl, the N-protected-3-(S)-pyrrolidinol
corresponds to N-Xylylthio-3-(S)-pyrrolidinol of the structure
##STR25## In another preferred embodiment, X is S, and R is linear
or branched C.sub.1-10 alkyl, such that the
N-protected-3-(S)-pyrrolidinol corresponds to
N-Alkylthio-3-(S)-Pyrrolidinol of the structure ##STR26## In
another preferred embodiment, X is SO.sub.2, and R is phenyl, such
that the N-protected-3-(S)-pyrrolidinol corresponds to
N-Benzensulfonyl-3-(S)-Pyrrolidinol of the structure ##STR27## In
another preferred embodiment, X is SO.sub.2, and R is tolyl, such
that the N-protected-3-(S)-pyrrolidinol corresponds to
N-Tosyl-3-(S)-Pyrrolidinol of the structure ##STR28## In another
preferred embodiment, X is SO.sub.2, and R is xylyl, such that the
N-protected-3-(S)-pyrrolidinol corresponds to
N-Xylylsulfonyl-3-(S)-Pyrrolidinol of the structure ##STR29##
[0026] In another preferred embodiment, X is SO.sub.2, and R is
linear or branched C.sub.1-10 alkyl, such that the
N-protected-3-(S)-pyrrolidinol corresponds to
N-Alkylsulfonyl-3-(S)-pyrrolidinol of the structure ##STR30## In
another preferred embodiment, X is Si, and R is linear or branched
C.sub.1-10 alkyl, such that the N-protected-3-(S)-pyrrolidinol
corresponds to N-Alkylsilyl-3-(S)-pyrrolidinol of the structure
##STR31## In another preferred embodiment, X is CO, and R is H,
such that the N-protected-3-(S)-pyrrolidinol corresponds to
N-Formyl-3-(S)-pyrrolidinol of the structure ##STR32## In another
preferred embodiment, X is CO, and R is CF.sub.3, such that the
3-(S)-(+)-hydroxypyrrolidine corresponds to
N-protected-3-(S)-pyrrolidinol of the structure ##STR33## In
another preferred embodiment, X is CO, and R is CH.sub.3, such that
the N-protected-3-(S)-pyrrolidinol corresponds to
N-Acetyl-3-(S)-pyrrolidinol of the structure ##STR34##
[0027] The N-protected-3-(S)-pyrrolidinol may be converted into
darifenacin hydrobromide. ##STR35##
[0028] The invention also encompasses a process for the preparation
of darifenacin hydrobromide according to the following general
scheme: ##STR36## wherein X is either C.sub.1-10 alkyl or C.sub.6-9
aryl Y is a leaving group selected from the group consisting of I,
Cl, mesyl, Br, tosyl, trifluoroacetyl, and trifluoromethansulfonyl,
and Z is an acid. Preferably, X is a C.sub.6-9 aryl, and more
preferably tolyl. Preferably, Y is Cl. Preferably, Z is HBr or HCl.
The process of the invention allows one to prepare darifenacin
hydrobromide without the need to employ the cumbersome Mitsunobu
reaction. In addition, the process can be practiced on an
industrial scale with minimum production hazards.
[0029] The process comprises: combining
3-(S)-(+)-hydroxypyrrolidine, a solvent selected from the group
consisting of a C.sub.6-9 aromatic hydrocarbon, a polar aprotic
organic solvent, and mixtures thereof, a sulfonyl halide, and a
base to obtain the intermediate of formula I; reacting the
intermediate of formula I with diphenylacetonitrile, and an
inorganic base in an organic solvent selected from the group
consisting of a C.sub.6-9 aromatic hydrocarbon, a polar aprotic
organic solvent, and mixtures thereof to obtain the intermediate of
formula II; reacting the intermediate of formula II with a bromine
acceptor selected from the group consisting of phenol and naphthol
and an acid to obtain the intermediate of formula III, wherein the
bromine acceptor is phenol only when the acid is HBr; combining the
intermediate of formula III with an inorganic base in a solvent
selected from the group consisting of water immiscible organic
solvent, a polar aprotic organic solvent, water, and mixtures
thereof, acidifying, heating, basifying, combining with a C.sub.1-4
alcohol and L-tartaric acid to obtain the intermediate of formula
VI; and reacting the intermediate of formula VI with a derivative
of ethyl-dihydrobenzofuran of the formula V and a base in a solvent
selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar organic solvent, water, and mixtures thereof,
and adding HBr to obtain darifenacin bromide.
[0030] The N--O-sulfonation reaction of the present invention is
performed using solvents that are not hazardous and toxic, as
compared to the pyridine that is used in U.S. Pat. No. 5,096,890.
Also, the reaction leads to a much higher yield (the process of the
invention provides darifenacin hydrobromide in 96% yield, while
U.S. Pat. No. 5,096,890 reports the preparation of darifenacin
hydrobromide in 75% yield). Moreover, the product is isolated very
easily from a mixture of toluene and water, as compared to the
difficult isolation performed in U.S. Pat. No. 5,096,890, which
includes recovering the product by time consuming steps, such as
distillation of pyridine, extractions with dichloromethane, and
crystallization from n-propanol. Hence, the sulfonation reaction
limits the process from being scaled up.
[0031] The intermediate of formula I,
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine ##STR37## is
prepared by a process comprising combining
3-(S)-(+)-hydroxypyrrolidine of the following formula, ##STR38## a
solvent selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar aprotic organic solvent, and mixtures thereof,
a sulfonyl halide, and a base; wherein X is either C.sub.1-10 alkyl
or C.sub.6-9 aryl. Preferably, X is C.sub.6-9 aryl, and more
preferably tolyl.
[0032] When X is tolyl, the compound of formula I refers to
1-tosyl-3-(S)-(-)-tosyloxypyrrolidine of the following formula.
##STR39##
[0033] Typically, the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I is
obtained by the above process in a purity of about 95% to about 99%
area by HPLC. The starting material, 3-(S)-(+)-hydroxypyrrolidine
is commercially available.
[0034] Typically, combining the 3-(S)-(+)-hydroxypyrrolidine and
the solvent provides a solution. The sulfonyl halide is then added
to the solution to form a mixture. The addition of the sulfonyl
halide to the solution leads to a rise in the temperature of the
solution, typically to about 35.degree. C. to about 40.degree. C.
Preferably, the base is then added to the mixture to form a
reaction mixture, which leads to a second rise in temperature,
typically to about 50.degree. C. to about 60.degree. C. Preferably,
after the base is added, the reaction mixture is maintained at a
temperature of about 25.degree. C. to about reflux, more
preferably, at about 50.degree. C. to about 55.degree. C.
Preferably, after addition of the base, the reaction mixture is
maintained for about 2 to about 10 hours, more preferably, for
about 4 to about 6 hours.
[0035] Preferably, the C.sub.6-9 aromatic hydrocarbon is toluene or
o-, m-, or p-xylene. Preferably, the polar aprotic organic solvent
is a C.sub.1-10 halogenated aliphatic hydrocarbon, amide, or
sulfoxide. A preferred C.sub.1-10 halogenated aliphatic hydrocarbon
is C.sub.1-5 halogenated hydrocarbon, more preferably,
dichloromethane (referred to as DCM), 1,2,dichloroethane or
dichloropentane. Preferably, the amide is C.sub.1-2 amide, more
preferably, either dimethylformamide (referred to as DMF) or
dimethylacetamide (referred to as DMA). Preferably, the sulfoxide
is C.sub.1-4sulfoxide, more preferably, dimethylsulfoxide (referred
to as DMSO). The more preferred solvent is toluene.
[0036] Optionally, a phase transfer catalyst (referred to as PTC)
may be used to increase the reaction rate. When the solvent is a
C.sub.6-9 aromatic hydrocarbon, preferably, a phase transfer
catalyst is used. Preferably, the PTC is added to the solution of
3-(S)-(+)-hydroxypyrrolidine prior to the addition of the sulfonyl
halide. Preferably, the PTC is selected from the group consisting
of tetrabutylammonium bromide, ALIQUAT.RTM. tributylmethylammonium
chloride, tetrabutylammonium sulfate, and DMSO, and more preferably
tetrabutylammonium bromide.
[0037] Preferably, the halide moiety of the sulfonyl halide is
selected from chloride, bromide, and iodide, and more preferably
chloride. Preferably, the sulfonyl halide is tosylchloride,
mesylchloride, or brosylchloride, and more preferably
tosylchloride. Preferably, the sulfonyl halide is added
portion-wise.
[0038] Preferably, the base is either an inorganic base or an
organic base. A preferred organic base is selected from the group
consisting of aliphatic and aromatic amines. Preferably, the
aliphatic amine is triethylamine, methylmorpholine, or
N,N-diisopropylethyl amine. A preferred aromatic amine is pyridine.
The inorganic base is added, preferably, in a form of an aqueous
solution. The aqueous solution contains, preferably, an alkali
base, and more preferably either sodium hydroxide or potassium
hydroxide. Preferably, the base is added slowly, more preferably
over about a half an hour to about two hours, and even more
preferably over about one hour.
[0039] The process for preparing
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I may
further comprise a recovery step. The
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine may be recovered by
any method known to one of ordinary skill in the art. Such methods
include, but are not limited to, adding water to the reaction
mixture; cooling the reaction mixture to obtain a precipitate of
the 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine, and filtering
the precipitate from the reaction mixture. Preferably, the addition
of water provides a suspension. Preferably, the suspension is
cooled to a temperature of about 20.degree. C. to about -5.degree.
C., and more preferably to about 5.degree. C. to about 0.degree.
C., to induce precipitation of the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine. Preferably, the
cooled suspension is maintained for at least about one hour,
preferably, for about 1 to about 2 hours, to give a precipitate of
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine. The precipitate is
then filtered and dried.
[0040] The 1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of
formula I thus obtained may then be converted to darifenacin
bromide.
[0041] The intermediate of formula II,
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile
##STR40## is prepared by a process comprising combining
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I,
diphenylacetonitrile, an organic solvent selected from the group
consisting of a C.sub.6-9 aromatic hydrocarbon, a polar aprotic
organic solvent, and mixtures thereof, and an inorganic base;
wherein X is either C.sub.1-10 alkyl or C.sub.6-9 aryl. Preferably,
X is C.sub.6-9 aryl, and more preferably tolyl.
[0042] When X is tolyl, the compound of formula II refers to
(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile of the
following formula. ##STR41##
[0043] (S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile
of the formula II is obtained by the above process in a purity of
about 95% to about 99% area by HPLC, and more preferably about 99%
to about 100% area by HPLC.
[0044] Typically, combining the diphenylacetonitrile and the
organic solvent provides a first mixture. The addition of the
inorganic base to the first mixture typically causes the
temperature of the first mixture to rise to about 20.degree. C. to
about 40.degree. C., and preferably to about 25.degree. C. to about
35.degree. C. Preferably, the first mixture is cooled to a
temperature of about 30.degree. C. to about 15.degree. C., and more
preferably to a temperature of about 25.degree. C. to about
15.degree. C., prior to the addition of the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I.
Typically, the addition of the
1-X-sulfonyl-3-(S)-(-)-X-sulfonyloxypyrrolidine of formula I
provides a second mixture. Preferably, the second mixture is heated
to a temperature of about 50.degree. C. to about 100.degree. C.,
and more preferably to a temperature of about 70.degree. C. to
about 75.degree. C. The heated second mixture is maintained,
preferably, for about 3 to about 6 hours, and more preferably, for
about 4 to about 5 hours.
[0045] Preferably, the C.sub.6-9 aromatic hydrocarbon is toluene.
Preferably, the polar aprotic organic solvent is either amide or
sulfoxide. A preferred amide is C.sub.1-2 amide, more preferably,
either DMF or DMA. A preferred sulfoxide is C.sub.1-4 sulfoxide,
more preferably, DMSO. The more preferred organic solvent is
DMF.
[0046] Preferably, the inorganic base is either a metal alkoxide or
an alkali hydroxide. A preferred metal alkoxide is either sodium
tert-butoxide or sodium methoxide. A preferred alkali hydroxide is
either sodium or potassium hydroxide. The more preferred inorganic
base is a metal alkoxide, most preferably either sodium or
potassium tert-butoxide.
[0047] The process for preparing
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of
formula II may further comprise a recovery step. The
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of
formula II may be recovered by adding to the second mixture to a
mixture of water and a solvent selected from the group consisting
of toluene, DCM, ethyl acetate (referred to as EtOAc), butyl
acetate (referred to as BuOAc), and n-butanol to form a mixture
having an aqueous and an organic phase; separating the aqueous and
organic phases; washing the organic phase with water; and
concentrating the organic phase under reduced pressure to obtain a
concentrated residue. The residue is then cooled to a temperature
of about 10.degree. C. to about -10.degree. C., and preferably to
about 3.degree. C. to about -3.degree. C., to give a precipitate of
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile.
[0048] The
(S)-2,2-diphenyl-2-(1-X-sulfonyl-3-pyrrolidinil)acetonitrile of
formula II thus obtained may then be converted to darifenacin
bromide, for example, by the process disclosed in Example 1 of U.S.
Pat. No. 5,096,890 (reproduced below as Comparative Example
23).
[0049] The intermediate of formula III,
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt, is prepared
by a process comprising heating a mixture comprising the compound
of formula II, a bromine acceptor selected from phenol and naphthol
and an acid, wherein the bromine acceptor is phenol only when the
acid is HBr. Preferably, the mixture is heated to a temperature of
about 80.degree. C. to about 120.degree. C., more preferably, to
about 117.degree. C. to about 120.degree. C. Preferably, the heated
mixture is maintained for about 1 hour to about 2 hours, more
preferably, for about 1 hour to about 1.5 hours. Preferably, the
acid is selected from a group consisting of: phosphoric acid,
perchloric acid, tribromomethanesulfonic acid, and HBr, more
preferably, HBr. When using HBr as the acid, it is added in a form
of an aqueous solution, having a concentration of about 30% to
about 60%, more preferably, of about 48% to about 60%.
[0050] The (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of
formula III may be recovered by a process comprising cooling the
mixture to a temperature of about 30.degree. C. to about 15.degree.
C., more preferably, to a temperature of about 30.degree. C. to
about 25.degree. C., followed by extracting with a C.sub.1-10
halogenated aliphatic hydrocarbon, and washing with brine. The
organic phase is then concentrated under reduce pressure to give a
residue containing the compound of formula III and the solvent.
Preferably, the C.sub.1-10 halogenated aliphatic hydrocarbon is
C.sub.1-5 halogenated hydrocarbon, more preferably, C.sub.1-3
halogenated hydrocarbon. Most preferably, the C.sub.1-3 halogenated
hydrocarbon is selected from the group consisting of DCM,
chloroform, dichloroethane, 1,1-dichloroethane, and
1,5-dichloropentane.
[0051] The residue is then combined with a second solvent selected
from the group consisting of BuOAc, toluene, acetone, 2-butanone,
and diisopropylether, followed by a complete removal of the
C.sub.1-10 halogenated aliphatic hydrocarbon, preferably, by
distillation, to give a second residue.
[0052] The second residue, containing the compound of formula III
and a solvent selected form the group consisting of BuOAc, toluene,
acetone, 2-butanone, and diisopropylether can be purified by a
crystallization process from a solvent selected from the group
consisting of C.sub.1-10 ester, C.sub.1-10 ketone, C.sub.1-10
ether, C.sub.1-10 aliphatic hydrocarbon, C.sub.6-9 aromatic
hydrocarbon, and mixtures thereof.
[0053] Preferably, the C.sub.1-10 ester is ethylacetate,
n-butylacetate, i-butylacetate, or n-propylacetate, more
preferably, ethylacetate. Preferably, the C.sub.1-10 ketone is
acetone, 2-butanone, methyl-isobutylketone, or cyclohexanone. A
preferred C.sub.1-10 ether is diethylether, diisopropylether,
dibutylether, or methyl isobutylether. Preferably, the C.sub.1-10
aliphatic hydrocarbon is pentane, hexanes, heptanes, or petroleum
ether. Preferably, the C.sub.6-9 aromatic hydrocarbon is toluene or
xylenes. Preferably, a mixture of ethyl acetate (EtOAc) and hexane
is used.
[0054] The intermediate
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine pyrrolidine
tartrate of the formula VI, ##STR42## is prepared by a process
comprising combining (S)-2,2-diphenyl-2-(3-pyrrolidinil)
acetonitrile salt of formula III, ##STR43## a solvent selected from
the group consisting of water immiscible organic solvent, a polar
aprotic organic solvent, water, and mixtures thereof, and an
inorganic base to obtain a mixture; acidifying the mixture; heating
the mixture; basifying the mixture; and combining the mixture with
a C.sub.1-4 alcohol and L-tartaric acid; wherein Z.sub.1 is an
acid. Preferably Z.sub.1 is either HBr or HCl.
[0055] Optionally, the free base of the following formula ##STR44##
may be used as a starting material. The free base of formula XI may
be obtained by combining
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile salt of formula III
a solvent selected from the group consisting of water immiscible
organic solvent, a polar aprotic organic solvent, water, and
mixtures thereof, and an inorganic base.
[0056] Preferably, the water immiscible organic solvent is either a
C.sub.6-9 aromatic hydrocarbon or a C.sub.1-10 halogenated
aliphatic hydrocarbon. Preferably, the C.sub.6-9 aromatic
hydrocarbon is toluene, xylenes, i-propylbenzene or styrene, more
preferably, toluene. A preferred C.sub.1-10 halogenated aliphatic
hydrocarbon is DCM, 2-dichloroethane, 1,1-dichloroethane, or
1,5-dichloropentane.
[0057] Preferably, the polar aprotic organic solvent is an ester,
more preferably, EtOAc. The more preferred solvent is a mixture of
C.sub.1-10 halogenated aliphatic hydrocarbon and water, and most
preferably, of DCM and water.
[0058] Preferably, the inorganic base is an aqueous solution of an
alkali base. A preferred alkali base is an alkali hydroxide, an
alkali carbonate, or an alkali bicarbonate. Preferably, the alkali
hydroxide is either sodium hydroxide or potassium hydroxide.
Preferably, the alkali carbonate is either sodium carbonate or
potassium carbonate. A preferred alkali bicarbonate is either
sodium bicarbonate or potassium bicarbonate. The more preferred
base is alkali hydroxide, most preferably, sodium hydroxide.
[0059] Typically, the acidifying comprises adding an acid to the
mixture and heating. Preferably, the mixture is heated to a
temperature of about 80.degree. C. to about 110.degree. C., and
more preferably to a temperature of about 90.degree. C. to about
100.degree. C. The mixture is maintained, preferably, for about 15
to about 20 hours, and more preferably, for about 16 to about 18
hours.
[0060] After maintaining, the mixture is basified, preferably, to a
pH of about 10 to about 13 and more preferably, to a pH of about 11
to about 12. Preferably, the mixture is basified by adding an
inorganic base. The addition of the base creates a foam, which is
then dissolved in the C.sub.1-4 alcohol and mixed with the
L-tartaric acid to provide
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
the formula VII.
[0061] Preferably, the acid is a strong acid, more preferably a
strong mineral acid, and even more preferably either sulfuric acid
or phosphoric acid. Most preferably, the acid is sulfuric acid.
Preferably, the concentration of the acid is of about 75% to about
90%, more preferably, about 80% to about 85%.
[0062] The foam may be recovered by cooling the reaction mixture to
a temperature of about 30.degree. C. to about 15.degree. C., more
preferably, to about 25.degree. C. to about 20.degree. C., followed
by increasing the pH to obtain a mixture having an aqueous phase
and an organic phase. The phases are separated and the aqueous
phase is then extracted with a solvent selected from the group
consisting of DCM, EtOAc, and toluene, followed by washing the
resulting combined organic phases with water, and evaporating the
solvent.
[0063] Preferably, the C.sub.1-4 alcohol is methanol, ethanol,
isopropanol, or n-butanol, more preferably ethanol, and most
preferably 96% ethanol.
[0064] The process for preparing
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI may further comprise a recovery step. The
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI may be recovered by cooling the solution to a
temperature of about 5.degree. C. to about -5.degree. C.,
preferably, to about 3.degree. C. to about -3.degree. C., to induce
precipitation of the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate,
followed by filtering the precipitated
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate from
the solution.
[0065] The 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
tartrate of formula VI thus obtained may then be converted to
darifenacin bromide.
[0066] According to the process of the invention,
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI is reacted with derivatives of ethyl-dihydrobenzofuran
of the formula V to obtain darifenacin hydrobromide.
[0067] The invention encompasses a compound of formula V; ##STR45##
wherein Y is a leaving group selected from the group consisting of
I, Cl, brosyloxy, Br, mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy. Preferably, Y is Cl. When Y is Cl, the
compound of formula V corresponds to
5-(2-chloroethyl)-2,3-dihydrobenzo[2,3-b]furan of the following
formula. ##STR46##
[0068] The derivatives of ethyl-dihydrobenzofuran of the formula V;
##STR47## are prepared by a process comprising reacting
2(2,3-dihydrobenzofura-5-yl)-acetic acid of the formula, ##STR48##
a C.sub.1-4 alcohol, and a catalyst to obtain
2(2,3-dihydrobenzofura-5-yl)-acetic acid methyl ester of the
formula ##STR49## combining the 2(2,3-dihydrobenzofura-5-yl)-acetic
acid methyl ester with a reducing agent, in a C.sub.4-6 alcohol to
obtain 2(2,3-dihydrobenzofura-5-yl)-ethanol of the formula
##STR50## and combining the 2(2,3-dihydrobenzofura-5-yl)-ethanol, a
solvent selected from the group consisting of a C.sub.1-2
halogenated hydrocarbon, C.sub.3-6 ester, and C.sub.6-9 aromatic
hydrocarbon, and a substance containing a leaving group selected
from the group consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy,
trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the
compound of formula V; wherein Y is a leaving group selected from
the group consisting of I, Cl, brosyl, Br, mesyl, tosyl,
trifluoroacetyl, and trifluoromethansulfonyl. Preferably Y is
Cl.
[0069] The starting 2(2,3-dihydrobenzofura-5-yl)-acetic acid is
commercially available.
[0070] Preferably, the C.sub.1-4 alcohol is selected from the group
consisting of methanol, ethanol, propanol, and butanol, and more
preferably methanol. Optionally, a mixture of solvents may be used.
Preferably, the mixture is that of C.sub.1-4 alcohol and toluene,
and more preferably of methanol and toluene.
[0071] Preferably, the catalyst is an acid. Preferably, the acid is
either an organic or an inorganic acid selected from the group
consisting of sulfuric acid, p-toluenesulfonic acid,
methanesulfonic acid, HCl, HClO.sub.4, and H.sub.3PO.sub.4. More
preferably, the acid is an inorganic acid, and even more preferably
a mineral acid, and most preferably sulfuric acid.
[0072] The reaction between the 2(2,3-dihydrobenzofura-5-yl)-acetic
acid, the C.sub.1-4 alcohol and the catalyst may be performed,
preferably, with heating. Preferably, the heating is done to a
temperature of about 60.degree. C. to about 70.degree. C., and more
preferably about 65.degree. C. to about 70.degree. C. Preferably,
heating is done for about 1 to about 5 hours, and more preferably
for about 2 to about 3 hours.
[0073] The process for preparing the
2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester may further
comprise a recovery step. The 2(2,3-dihydrobenzofura-5-yl)-acetic
acid methylester may be recovered by a method known to one of
ordinary skill in the art. Preferably, the
2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester is recovered
by adding a base to the reaction mixture comprising
2(2,3-dihydrobenzofura-5-yl)-acetic acid methylester; removing the
solvent; adding a C.sub.6-9 aromatic hydrocarbon; washing with a
basic solution; and removing the solvent. Preferably, the base is
sodium bicarbonate. Preferably, removing the solvent from the
reaction mixture provides a residue. Preferably, the addition of a
C.sub.6-9 aromatic hydrocarbon to the residue provides a solution.
Preferably, the C.sub.6-9 aromatic hydrocarbon is toluene.
Preferably, the basic solution is sodium bicarbonate. Preferably,
the C.sub.4-6 alcohol is t-butanol. Preferably, a mixture of
C.sub.1-4 alcohol and C.sub.4-6 alcohol is used, instead of the
C.sub.4-6 alcohol alone. More preferably, the mixture is that of
methanol and t-butanol.
[0074] Preferably, the reducing agent is a metal hydride.
Preferably, the metal hydride is selected from the group consisting
of NaBH.sub.4, LiAlH.sub.4, and VITRIDE.RTM. sodium
dihydro-bis-(2-methoxyethoxy) aluminate. More preferably, the
reducing agent is NaBH.sub.4
[0075] Combining the 2(2,3-dihydrobenzofura-5-yl)-acetic acid
methylester, the reducing agent, and the C.sub.4-6 alcohol provides
a suspension. Preferably, the suspension is heated to a temperature
of about 65.degree. C. to about 75.degree. C., more preferably, of
about 70.degree. C. to about 75.degree. C. Preferably, the
C.sub.1-4 alcohol is added drop-wise. Preferably, the drop-wise
addition is done over a period of about 2 to about 6 hours, and
more preferably over a period of about 5 to about 6 hours.
Typically, adding the C.sub.1-4 alcohol provides a mixture.
Preferably, the mixture is maintained for a total time of about 5
to about 10 hours, and more preferably for about 5 to about 7
hours. If the reaction is not completed after 5 to about 10 hours,
a second amount of a reducing agent can be added. Preferably, the
reducing agent is added with a C.sub.1-4 alcohol. After the
addition of the reducing agent and a C.sub.1-4 alcohol, the
reaction is further maintained, preferably, for about 1 to about 14
hours, more preferably, for about 2 to about 3 hours.
[0076] The process for preparing the
2(2,3-dihydrobenzofura-5-yl)-ethanol may further comprise a
recovery step. The 2(2,3-dihydrobenzofura-5-yl)-ethanol may be
recovered by any method known to one of ordinary skill in the art.
Preferably, the 2(2,3-dihydrobenzofura-5-yl)-ethanol is recovered
by removing the solvent; adding water and a solvent selected from
the group consisting of toluene, dichloromethane, and ethyl acetate
to obtain a mixture having an aqueous phase and an organic phase;
separating the aqueous and organic phases; extracting the organic
phase with water and a solvent selected from the group consisting
of toluene, dichloromethane, and ethyl acetate; extracting the
organic phase with water; and removing the solvent. Preferably, the
C.sub.1-2 halogenated hydrocarbon is dichloromethane. A preferred
C.sub.3-6 ester is ethyl acetate, isopropylacetate, butylacetate,
or isobutylacetate. Preferably, the C.sub.6-9 aromatic hydrocarbon
is toluene, xylenes, i-propylbenzene, or styrene. The preferred
solvent is toluene.
[0077] Preferably, the substance containing a leaving group is
selected from the group consisting of SOCl.sub.2, PCl.sub.3,
PCl.sub.5, POCl.sub.3, tosylchloride, mesylchloride,
brosylchloride, trifluoroacetyl chloride, and
trifluoromethansulfonyl chloride. Preferably, the substance
containing a leaving group is SOCl.sub.2, PCl.sub.3, PCl.sub.5, or
POCl.sub.3, more preferably, SOCl.sub.2. Preferably, the substance
containing a leaving group is added drop-wise. When the substance
containing a leaving group is one of tosylchloride, mesylchloride,
brosylchloride, trifluoroacetyl chloride, and
trifluoromethansulfonyl chloride, a base may also be used.
Preferably, the base is either an organic or an inorganic base. The
organic base may be, preferably, an aliphatic or aromatic amine.
Preferably, the aliphatic amine is triethylamine,
ethyldiisopropylamine, or N-methylmorpholine. A preferred aromatic
amine is pyridine. The inorganic base is preferably either an
alkali metal hydroxide or an alkali metal carbonate. Preferably,
the alkali metal hydroxide is sodium hydroxide, potassium
hydroxide, or cesium hydroxide. A preferred alkali metal carbonate
is sodium, potassium, or cesium carbonate. The more preferred base
is an organic base, preferably, triethylamine.
[0078] Preferably, combining the
2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from
the group consisting of a C.sub.1-2 halogenated hydrocarbon,
C.sub.3-6 ester, and C.sub.6-9 aromatic hydrocarbon, a substance
containing a leaving group provides a mixture. Preferably, the
mixture is heated to a temperature of about 60.degree. C. to about
80.degree. C., more preferably, of about 60.degree. C. to about
70.degree. C. The mixture is, preferably, maintained, for about 12
to about 20 hours, more preferably, for about 15 to about 18
hours.
[0079] The process for preparing the derivative of
ethyl-dihydrobenzofuran of the formula V may further comprise a
recovery step. The derivative of ethyl-dihydrobenzofuran of the
formula V may be recovered by any method known to one of ordinary
skill in the art. Preferably, the derivative of
ethyl-dihydrobenzofuran of the formula V is recovered by cooling
the reaction mixture to a temperature of about 30.degree. C. to
about 15.degree. C., preferably, to about 25.degree. C. to about
20.degree. C., followed by adding the reaction mixture to a basic
solution to form a mixture having an aqueous phase and an organic
phase; separating the aqueous and organic phases; extracting the
aqueous phase with toluene; washing the organic phase with water;
removing the solvent; and decolorizing the obtained residue.
Preferably, the basic solution is of sodium bicarbonate.
Decolorization may be done by any method known to one of ordinary
skill in the art, such as using activated charcoal.
[0080] The recovered derivative of ethyl-dihydrobenzofuran of
formula V may be purified by crystallization from methanol/water or
methanol/water/acetone. The process comprises dissolving the
derivative of ethyl-dihydrobenzofuran of formula V in methanol, and
adding water or a mixture of water and acetone, followed by
maintaining for about an hour to about 3 hours to promote
crystallization of the derivative of ethyl-dihydrobenzofuran of
formula V. The crystallized derivative of ethyl-dihydrobenzofuran
of formula V is then filtered, washed and dried.
[0081] Preferably, when the starting commercially available acid
analogue 2,3-dihydrobenzofuran-5-acetic acid ##STR51## has less
than 0.4% area by HPLC of 5-benzofuranacetic acid, the obtained
##STR52## 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran of formula III
##STR53## has less than 0.5% of 2-(benzofuran-5-yl)ethanol of
following formula. ##STR54## Preferably, the use of the compound of
formula III having less than 0.5% area by HPLC of
2-(benzofuran-5-yl)ethanol in a combination with an aromatic
hydrocarbon, more preferably, C.sub.6-9 aromatic hydrocarbon, most
preferably toluene, as a solvent, provides ethyl-dihydrobenzofuran
of formula V having less than 0.25% ethyl-benzofuran of the
following formula, ##STR55## as exemplified in Examples 21 and 22
below.
[0082] Alternatively, the derivatives of ethyl-dihydrobenzofuran of
the formula V, ##STR56## are prepared by a process comprising
combining a bisulfite complex of formula X, ##STR57## water, NaOH,
Na.sub.2CO.sub.3, a water immiscible hydrocarbon, and a reducing
agent to form a mixture comprising of
2(2,3-dihydrobenzofura-5-yl)-ethanol; and combining the mixture
comprising of 2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent
selected from the group consisting of C.sub.1-2 halogenated
hydrocarbons, C.sub.3-6 esters, and C.sub.6-9 aromatic hydrocarbons
and a substance containing a leaving group selected from the group
consisting of Cl, Br, mesyloxy, brosyloxy, tosyloxy,
trifluoroacetyloxy, and trifluoromethansulfonyloxy to obtain the
compound of formula V, wherein Y is a leaving group selected from
the group consisting of I, Cl, brosyl, Br, mesyl, tosyl,
trifluoroacetyl, and trifluoromethansulfonyl. Preferably, Y is
Cl.
[0083] The starting compound of formula X may be prepared by
combining 2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde, a water
immiscible hydrocarbon, and Na.sub.2S.sub.2O.sub.5 to form a
mixture of the compound of formula X. Preferably, the water
immiscible hydrocarbon is either a C.sub.6-9 aromatic hydrocarbon
or a saturated hydrocarbon. Preferably, the saturated hydrocarbons
are C.sub.5-10 saturated hydrocarbons, more preferably, pentane,
hexanes or heptanes. Peferably, the C.sub.6-9 aromatic hydrocarbon
is toluene, xylenes, i-propylbenzene, or styrene. The more
preferred solvent is toluene. Na.sub.2S.sub.2O.sub.5 may be used in
a solid form or in a form of an aqueous solution. Preferably,
Na.sub.2S.sub.2O.sub.5 is used in a form of an aqueous solution.
Preferably, after the addition of Na.sub.2S.sub.2O.sub.5 the
mixture obtained is maintained at a temperature of about 15.degree.
C. to about 35.degree. C., more preferably, at about 20.degree. C.
to about 25.degree. C. Preferably, the mixture is maintained for
about 2 hours to about 4 hours to obtain the compound of formula X.
Preferably, NaOH is added to a suspension of the compound of
formula X in water to obtain a basic mixture comprising
2-(2,3-dihydrobenzofuran-5-yl)acetaldehyde. Preferably, the pH of
the basic mixture is about 9 to about 11, more preferably about 9.5
to about 10.5, and even more preferably about 10 to about 10.2.
[0084] Preferably, after adjusting the pH, Na.sub.2CO.sub.3 and a
water immiscible hydrocarbon are added to obtain a mixture.
Preferably, the water immiscible hydrocarbon is either a C.sub.6-9
aromatic hydrocarbon or a saturated hydrocarbon. Preferably, the
C.sub.6-9 aromatic hydrocarbon is toluene. Preferably, the
saturated hydrocarbons are C.sub.5-10 saturated hydrocarbons. A
preferred saturated hydrocarbon is either heptane or cyclohexane.
The more preferred solvent is toluene, xylenes, i-propylbenzene, or
styrene.
[0085] Preferably, the mixture is cooled to a temperature of about
20.degree. C. to about 0.degree. C., more preferably to about
10.degree. C. to about 5.degree. C., prior to the addition of the
reducing agent. Preferably, adding a reducing agent provides a
reaction mixture. Preferably, the reducing agent is selected from
the group consisting of NaBH.sub.4, LiAlH.sub.4, and H.sub.2/Pd. A
solution or solid NaBH.sub.4 may be used. Preferably, a solution of
NaBH.sub.4 is used. Preferably, the NaBH.sub.4 is in solution in
water or an alcohol. Preferably, the alcohol is a C.sub.3-6
alcohol, propanol, i-propanol, butanol, i-butanol, amylalcohol, or
cyclohexanol. The more preferred solvent is water.
[0086] Preferably, the solution of the reducing agent is added
drop-wise. Preferably, the drop-wise addition is done over a period
of about 0.5 hour to about 1.5 hours, and more preferably over
about 45 to about 60 minutes.
[0087] Preferably, a pH of about 9 to about 11, more preferably,
about 9.8 to about 10.2 is maintained during the addition.
[0088] Preferably, after the addition of the reducing agent, the
temperature is raised to about 10.degree. C. to about 25.degree.
C., more preferably, to about 15.degree. C. to about 25.degree. C.
Preferably, after raising the temperature, the reaction mixture is
maintained for about 0.5 hour to about 1.5 hours, more preferably,
for about 1 hour, to obtain the
2(2,3-dihydrobenzofura-5-yl)-ethanol.
[0089] Preferably, combining the
2(2,3-dihydrobenzofura-5-yl)-ethanol with a solvent selected from
the group consisting of a C.sub.1-2 halogenated hydrocarbon,
C.sub.3-6 ester, and C.sub.6-9 aromatic hydrocarbon, and a
substance containing a leaving group provides a mixture.
Preferably, the mixture is heated to a temperature of about
60.degree. C. to about 80.degree. C., more preferably, of about
60.degree. C. to about 70.degree. C. The mixture is, preferably,
maintained, for about 12 to about 20 hours, more preferably, for
about 15 to about 18 hours. Preferably, the heated mixture provides
ethyl-dihydrobenzofuran of the formula V.
[0090] The derivative of ethyl-dihydrobenzofuran of formula V may
then be converted to darifenacin bromide.
[0091] Darifenacin hydrobromide is prepared from the
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI by a process comprising combining
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate of
formula VI or the free base derivative of the formula XI, ##STR58##
a derivative of ethyl-dihydrobenzofuran of the formula V, a solvent
selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar organic solvent, water, and mixtures thereof,
and a base to form a mixture; and admixing HBr with the mixture to
obtain darifenacin hydrobromide, wherein Y is a leaving group
selected from the group consisting of I, Cl, brosyl, Br, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.
[0092] The free base derivative of
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate may
be obtained by the process described above for the preparation of
compound of formula VI, excluding the last step, wherein C.sub.1-4
alcohol and L-tartaric acid are added.
[0093] Preferably, the polar aprotic organic solvent is selected
from the group consisting of an amide, a C.sub.1-10 halogenated
aliphatic hydrocarbon, a sulfoxide, an ester, a nitrile, and a
ketone. A preferred amide is DMF. A preferred C.sub.1-10
halogenated aliphatic hydrocarbon is C.sub.1-5 halogenated
aliphatic hydrocarbon, more preferably, DCM. Preferably, the
sulfoxide is C.sub.2-5 sulfoxide, more preferably, DMSO.
Preferably, the ester is C.sub.2-5 ester, more preferably, EtOAc. A
preferred ketone is C.sub.3-6 ketone, more preferably, MEK
Preferably, the nitrile is C.sub.2-4 nitrile, more preferably, ACN.
Preferably, the C.sub.6-9 aromatic hydrocarbon is C.sub.6-9
aromatic hydrocarbon, more preferably, toluene. Preferred mixtures
are either that of toluene and water or that of DCM and water. The
more preferred solvent is water.
[0094] The base may be an inorganic base or an organic base. A
preferred organic base is selected from the group consisting of
aliphatic and aromatic amines. Preferably, the aliphatic amine is
triethylamine, tribytulamine, methylmorpholine, or
N,N-diisopropylethyl amine. Preferably, the aromatic amine is
pyridine. A preferred inorganic base is either alkali carbonate or
alkali bicarbonate. Preferably, the alkali carbonate is sodium
carbonate or potassium carbonate. Preferably, the alkali
bicarbonate is either sodium bicarbonate or potassium bicarbonate.
The most preferred base is an alkali carbonate, even most
preferably, potassium carbonate.
[0095] Preferably, the mixture is heated to a temperature of about
50.degree. C. to about reflux, and more preferably to a temperature
of about 60.degree. C. to about reflux, prior to admixing with HBr.
Preferably, the mixture is maintained, under heating, for about 1
to about 5 hours, and more preferably for about 2 to about 3 hours.
After maintaining the mixture, the mixture is cooled to a
temperature of 35.degree. C. to about 15.degree. C., and preferably
to about 25.degree. C. to about 15.degree. C. Preferably, after
cooling, an organic solvent selected from the group consisting of
DCM, EtOAc, and butyl acetate is added to the mixture, to give a
mixture having an aqueous phase and an organic phase. The phases
are then separated, and HBr is admixed with the organic phase.
Preferably, HBr is added to the organic phase.
[0096] Preferably, a small amount of an anhydride may be added to
the organic phase, after separating the phases, followed by
maintaining for about 1 to about 3 hours. After maintaining, the
organic solvent is removed, and a C.sub.2-5 alcohol and hydrobromic
acid are added, to obtain darifenacin hydrobromide. Preferably, the
C.sub.2-5 alcohol is n-butanol, sec-butanol, ethanol,
2-methyl-2-butanol, or isopropanol, more preferably, n-butanol.
[0097] Darifenacin hydrobromide may be recovered by removing the
residual water and the organic solvent from the acidic mixture
obtained after the addition of HBr, preferably, by distillation
under vacuum, to induce precipitation of the darifenacin
hydrobromide. The mixture is then cooled to room temperature and
the resulting precipitate of darifenacin hydrobromide is separated
from the mixture by filtration.
[0098] Darifenacin hydrobromide may be further purified by
crystallizing the recovered precipitate from a C.sub.2-5 alcohol.
The process comprises suspending the precipitate in a C.sub.2-5
alcohol, heating the suspension to a temperature sufficient to
induce dissolution of the darifenacin hydrobromide, and cooling the
resulting solution to induce crystallization of the darifenacin
hydrobromide. Prior to cooling, the solution may be purified with
active charcoal. The crystallized product may be isolated by
filtration, washing and drying. Preferably, the C.sub.2-5 alcohol
is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, or
isopropanol, and more preferably n-butanol.
[0099] The obtained darifenacin hydrobromide may have a purity of
about 99% to about 100% area by HPLC, preferably about 99.6%-99.85%
area by HPLC, and more preferably about 99.7% to about 99.8% area
by HPLC.
[0100] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one of ordinary skill in the art from consideration of the
specification. The invention is further defined by reference to the
following examples. It will be apparent to those of ordinary skill
in the art that many modifications, both to materials and methods,
may be practiced without departing from the scope of the
invention.
EXAMPLES
[0101] TABLE-US-00001 HPLC Column & Packing: GEMINI C18 110A
250 mm .times. 4.6 mm .times. 5.0 .mu.m (cat. No. 00G-4435-E0) from
Phenomenex (or equivalent) Buffer: K.sub.2HPO.sub.4 0.02 M pH 7.0:
3.48 g of K.sub.2HPO.sub.4 in 1000 ml of deionized water, adjust pH
at 7.0 .+-. 0.2 with H.sub.3PO.sub.4 15% (w/v). Filter on a 0.45
.mu.m filter. Eluent A: Acetonitrile Gradient: Time (min) % Buffer
% Eluent A 0 50 50 20 30 70 30 30 70 Equilibrium time: 8 minutes
Sample volume: 5.0 .mu.l Flow Rate: 1.0 ml/min Detector: UV at 215
nm Column temperature: 35.degree. C. Diluent: H.sub.2O:Acetonitrile
(50:50)
Example 1
Preparation of 1-tosyl-3-(S)-(-)tosyloxypyrrolidine (Formula I)
[0102] (S)-3-pyrrolidinol (30 g, 0.344 moles) was dissolved in
toluene (150 ml) and tetrabutylammonium bromide (3.39 g, 0.0105
moles) was added to the solution. p-Toluensulfonylchloride (140.94
g, 0.7393 moles) was then added portion-wise to the solution,
causing the temperature of the solution to rise to 35 to 40.degree.
C. Then, 30% NaOH (112.1 g, 0.8407 moles) was slowly added to the
solution over about 1 hour, causing the temperature of the solution
to rise to 55 to 60.degree. C. After maintaining the solution for 5
hours at 55-60.degree. C., the reaction was complete. Water (30 ml)
was then added, and the resulting suspension was cooled to
0.degree. C. over 1 hour to give a solid. The solid was filtered
and washed with cold toluene and water to give the title compound.
(Dry weight 127.95 g, yield 94%, HPLC purity 99.2% area). The main
impurity is 1-tosyl-3-(S)-pyrrolidinol (reaction intermediate) in
an amount of 0.05% area by HPLC.
Example 2
Preparation of
(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (Formula
II)
[0103] Diphenylacetonitrile (63.7 g, 0.3296 moles) was dissolved in
DMF (395 ml), followed by adding sodium tert-butylate (31.75 g,
0.33 moles), which caused the temperature of the solution to rise
to 35.degree. C. After cooling the solution to 20.degree. C.,
1-tosyl-3-(S)-(-)tosyloxypyrrolidine (126.5 g, 0.3198 moles) was
added. The solution was warmed to 70 to 75.degree. C., and, after
maintaining the solution at 70 to 75.degree. C. for 4 hours, the
reaction was complete. Water (250 ml) and toluene (500 ml) were
then added to the solution to form a two phase mixture having an
aqueous and an organic phase. The phases were stirred at 70.degree.
C. and separated. The aqueous phase was extracted with toluene (50
ml), followed by washing the combined organic phases three times
with water (100 ml each), and concentrating under vacuum to give a
250 ml residual volume. The residual volume was cooled to 0.degree.
C. to obtain a precipitate. The precipitate was filtered and washed
with toluene and water to give the title compound. (Dry weight 116
g, yield 86.5%, and HPLC purity 99.3% area). The main impurities
present are residual starting materials: diphenylacetonitrile and
N--O-ditosyl-3-(S)-pyrrolidinol in amounts of 0.1% area by HPLC
each.
Example 3
Preparation of (S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile
hydrobromide(S-DIPACP.HBr) (Formula III)
[0104] In a 2 1 reactor equipped with mechanical stirrer,
thermometer and condenser HBr 48% (1.100 ml), Phenol (44,08 g), and
S-DIPACP-N-Tosyl
[(S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile] (220 g)
were loaded under nitrogen. The suspension was warmed to reflux
(118-120.degree. C.) to obtain a biphasic system. After 1 hr, the
reaction was complete (residual starting material 0.33%). The
reaction mixture was then cooled to 25-30.degree. C. and
dichloromethane (478 ml) was added. After stirring (5 min) the
phases were separated (organic phase is upper layer) and the
aqueous phase was extracted with dichloromethane (100 ml) and the
phases again separated (organic phase is upper layer). The
collected organic phases were concentrated to 280-290 ml by solvent
distillation at atmospheric pressure to obtain an oily residue
(T.sub.int64.degree. C.). Maintaining internal temperature at
65-70.degree. C. ethylacetate (287 ml) was slowly added to the
residue. (It is necessary to maintain temperature and to add ethyl
acetate slowly to avoid sudden product crystallization).
Distillation was continued at atmospheric pressure to reach a
volume of 380-390 ml (T.sub.int 80.degree. C., T.sub.head
70.degree. C.). Ethyl acetate (191 ml) was added to the obtained
suspension and distillation was continued at atmospheric pressure
to reach a volume of 380-390 ml (T.sub.int 84.degree. C.,
T.sub.head 72.degree. C.). Repeated distillations are necessary to
eliminate as much dichloromethane as possible in such a way as to
increase yield. The suspension was cooled at 50-55.degree. C. and
ethyl acetate (300 ml) was added. The suspension was cooled to
20-25.degree. C. and after 1 hr, was cooled to -7-8.degree. C.
After 2 hrs, the suspension was filtered and washed three times
with cold ethyl acetate (95 ml) each. After washings, the product
became white (initially it was pink). The wet product was dried
under vacuum at 50-55.degree. C. for 6-7 hrs to obtain the title
compound. (Dry weight 166.3 g, yield 87.4%, HPLC purity 99.93%
area).
Example 4
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide using
(3-Naphtol as bromine acceptor (Formula III)
[0105] (S)-2,2-diphenyl-2-(1-tosyl-3-pyrrolidinil)acetonitrile (5
g, 0.0120 moles) was added to 48% HBr (25 ml) together with
.beta.-naphtol (1.73 g, 0.0120 moles), to give a suspension. The
suspension was warmed to reflux (117-120.degree. C.), and, after 1
hour the reaction was complete. After cooling to 30.degree. C.,
dichloromethane (10 ml) was added, and the mixture was stirred for
5 minutes. The phases were separated, and the aqueous phase was
extracted with dichloromethane (5 ml). The combined organic phases
were washed with saturated solution of NaCl, and then concentrated
under vacuum to give a residual volume of 10 ml.
[0106] Ethyl acetate (10 ml) was added to the residual volume, and
the distillation was continued at atmospheric pressure until a
residual volume of 8 ml was obtained. Ethyl acetate was added, and
the distillation continued until the dichloromethane was eliminated
(residual volume 8 ml). Ethyl acetate (15 ml) and hexane (10 ml)
were added to give a suspension. The suspension was cooled to
0.degree. C. for 2 hours to give a precipitate that was filtered
and washed with ethyl acetate to give the title compound. (Dry
weight 3.0 g; yield 72.4%).
Example 5
Preparation of (S)-2-
{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-acetonitrile
hydrobromide (Formula III)
[0107] Potassium carbonate (14.94 g, 0.1081 moles) was dissolved in
water (45 ml), followed by adding
(S)-2,2-diphenyl-2-(3-pyrrolidinil)acetonitrile hydrobromide (18.55
g, 0.0540 moles) and 5-(2-bromoethyl)-2,3-dihydrobenzo[2,3-b]furan
(13.5 g, 0.05945 moles) to give a suspension. The suspension was
warmed to 75.degree. C., and, after 4 hours, the reaction was
considered to be complete (unreacted starting material 1.5% area by
HPLC). The heterogeneous mixture was cooled to 25.degree. C. and
ethyl acetate (100 ml) was added. After stirring, the phases were
separated, the organic layer was washed with water, and the phases
separated. 48% hydrobromic acid (9.6 g, 0.05668 moles) was added,
and
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-aceton-
itrile hydrobromide was crystallized from the suspension. The
suspension was cooled to 15-18.degree. C. for one hour, and the
precipitate was filtered and washed with ethyl acetate to give the
title compound. (Dry weight 23.8 g; yield 89.93%).
Example 6
Preparation of
3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5--
yl)ethyl]pyrrolidine hydrobromide (Formula III)
[0108] KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol
(7 ml), to obtain a suspension. The suspension was warmed to
60.degree. C. for 1 hour, followed by adding
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-aceton-
itrile hydrobromide (1 g, 0.00204 moles), and warming the reaction
mixture (suspension) to reflux for 21-22 hours. After cooling,
water (5 ml) was added to the reaction mixture to form a two-phase
mixture, and the phases were separated. The solvent was distilled
from the organic phase under vacuum, and a residue (0.900 g) was
obtained and dissolved in methylethylketone (3 ml). The solution
was filtered to eliminate undissolved solid, and 48% HBr (0.344 g,
0.00204 moles) was added. The solvent was distilled under vacuum,
and a solid foam was obtained. The foam was slurried in
diisopropylether, filtered, and washed to give the title compound.
(Dry weight 0.750 g; yield 72%).
Example 7
Preparation of
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate
(Formula VI)
[0109] 3-(S)-(+)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine
hydrobromide (80 g 0.2330 moles) was converted into its
corresponding free base by treating with dichloromethane (400 ml),
water (150 ml) and 30% NaOH (35 g). After phase separation and
evaporation of the solvent from the organic phase, an oil residue
was obtained. The oil residue was added to 90% H.sub.2SO.sub.4 (130
ml), and the mixture was heated to 100.degree. C. for 17 hours.
After cooling, the mixture was neutralized with sulfuric acid until
a pH of 12 was obtained. The product was extracted with
dichloromethane (250 ml). After washings with water, the solvent
was evaporated by distillation, and the product was obtained as a
foam (45.7 g). The foam was dissolved in 96% ethanol (460 ml), and
L-Tartaric acid (26.9 g) was added, followed by cooling to
0.degree. C., to induce crystallization of the tartrate salt. The
salt was filtered after 1 hour, and washed with 96% ethanol to give
the title compound. (Dry weight 64.5 g; yield 64.5%).
Example 8
Preparation of 3-(S)-(+)-(1-carbamoyl-1,diphenylmethyl)pyrrolidine
Tartrate (Formula VI)
A) Free Base Preparation
[0110] A four necked round bottomed flask equipped with a
thermometer, mechanical stirrer and condenser was charged, under
N.sub.2, with 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
hydrobromide (96 g), Dichloromethane (280 ml), and water (20 ml).
The temperature was maintained at 25-30.degree. C. during the
loading of NaOH 30% (41.2 g). The obtained heterogeneous system was
stirred for 5 min. and the phases were separated. The organic phase
was washed with water (41.2 ml), and the phases were separated. The
organic phase was concentrated under vacuum until a final volume of
120 ml was obtained.
b) Hydrolysis Reaction
[0111] A four necked round bottomed flask equipped with
thermometer, mechanical stirrer and condenser to eliminate
dichloromethane by distillation, was charged under N.sub.2 with
H.sub.2SO.sub.490% (180 ml).
[0112] The sulfuric acid solution was warmed to 50-55.degree. C.,
and the organic solution obtained above (120 ml) was added slowly
allowing dichloromethane elimination by distillation. During the
addition the mixture was warmed continuously to maintain an
internal temperature of 60-65.degree. C. When dichloromethane
distillation stopped, the internal temperature was raised to
98-102.degree. C. allowing residual dichloromethane elimination by
distillation. Then, the temperature was maintained at
98-102.degree. C. for 14-14.5 hrs.
[0113] The reaction mixture was cooled to 25-30.degree. C. and
added slowly to a mixture of NaOH 30% (958.3 g), water (720 g), and
toluene (480 ml), allowing the internal temperature to reach
55-60.degree. C. After stirring at 55-60.degree. C. the phases were
separated at 55-60.degree. C. The aqueous phase was been extracted
at 55-60.degree. C. with toluene (160 ml).
[0114] The collected organic phases, maintained at 60-65.degree.
C., were washed at 60-65.degree. C. with water 240 ml, and then
n-butanol (200 ml), water (20 ml) and L-tartaric acid (42.05 g)
were added to the separated organic phase at 45-65.degree. C. The
mixture was stirred at 45-65.degree. C. until the L-tartaric acid
was almost completely dissolved. At the same time a formation of a
salt was detected, at the beginning as a white oil, and then as
white solid. The suspension was cooled to 15-25.degree. C. and
filtered after two hours. When the suspension was too sticky it was
found useful to warm to 60-65.degree. C. and after 10-15 min to
cool to 15-25.degree. C. and filter. The cake was washed three
times with n-butanol (50 ml each), and after 15 hrs of drying at
50-55.degree. C. under vacuum 107 g of the title compound was
obtained. (Yield: 88.9%. HPLC purity: 99.88% area).
Example 9
Preparation of 2(2,3-Dihydrobenzofura-5-v)acetic acid, methyl
ester
[0115] 98% H.sub.2SO.sub.4 (2 g) was added to a solution of
2(2,3-Dihydrobenzofura-5-y)acetic acid (200 g) in MeOH (500 ml),
and the mixture was refluxed for 3 hrs (TLC: SiO.sub.2,
toluene/AcOEt 8:2; starting material not detected). After cooling
to room temperature, NaHCO.sub.3 (6.7 g) was added to the reaction
mixture, and the solvent was distilled off at atmospheric pressure
(about 440 ml), to give a light pink oily residue.
[0116] The oily residue was dissolved in toluene (250 ml), and
washed with NaHCO.sub.3 6% (50 ml). After the phases were
separated, the solvent was eliminated under vacuum distillation to
obtain a light pink oily residue (227 g).
Example 10
Preparation of 2(2,3-Dihydrobenzofura-5-y) ethanol
[0117] 2(2,3-Dihydrobenzofura-5-y)acetic acid, methyl ester (227 g
residue) was dissolved in t-BuOH (600 ml), and then NaBH.sub.4
(46.8 g) was added. The suspension was warmed to reflux and
methanol (100 ml) was added very slowly in about 6 hrs maintaining
reaction mixture at reflux. After the methanol addition, the
reaction was maintained at reflux for half an hour (In process
control revealed complete ester transformation. 400 ml of the
t-BuOH-MeOH mixture was distilled off at atmospheric pressure.
Water (400 ml) was added to residue and the distillation continued
until T.sub.int=93.degree. C. and T.sub.head=83.degree. C. Water
(400 ml) was added, and the distillation continued until
T.sub.int.96.degree. C. and T.sub.head=96.degree. C. The reaction
mixture was cooled to 70-75.degree. C. and toluene (300 ml) was
added. The separated organic phase was washed with water (100 ml)
and NaCl 15% (100 ml). After the solvent was eliminated under
vacuum distillation, an oily residue (176.8 g) of the title
compound was obtained. The residue solidified upon cooling.
Example 11
2(2,3-Dihydrobenzofuran-5-y) ethylchloride
[0118] SOCl.sub.2 (74.7 g) was added to a solution of
2(2,3-Dihydrobenzofura-5-y) ethanol 80 g in toluene (400 ml) while
maintaining the temperature below 25.degree. C. The reaction
mixture was stirred at 60.degree. C. for 14 h and then cooled to
room temperature. A reaction sample was quenched into 10%
Na.sub.2CO.sub.3 (Residual 2(2,3-Dihydrobenzofura-5-y) ethanol 0.6%
area by HPLC), and the pH was adjusted to 10-11 (measured on
aqueous phase) by addition of 10% NaOH (about 480 ml) while
maintaining the temperature below 30.degree. C. The organic phase
was separated. The aqueous phase was extracted with toluene (50
ml). The collected organic phases were washed twice with H.sub.2O
(100 ml each) and anhydrified under vacuum distillation (residual
pressure 40-50 mm Hg, T.sub.int50-55.degree. C.). To the organic
phase, 20 g of TONSIL.RTM. silicate decolorizing agent and 4.2 g of
ANTICHROMOS charcoal were added, stirred for 30 min at room
temperature, filtered off and washed with toluene (2.times.30 ml),
the decolorized solution was concentrated under vacuum (residual
pressure 40-50 mm Hg, T.sub.int50-55.degree. C.) to eliminate
toluene. Water (25 ml) was added to obtain a residue, and the
residual toluene was eliminated by azeotropic distillation under
vacuum (residual pressure 40-50 mm Hg, T.sub.int50-55.degree. C.).
This residue was dissolved in methanol (373 ml) and charcoal (2 g)
was added. After 20 minutes at 50-55.degree. C. charcoal was
filtered off and washed with hot methanol (2.times.10 ml). The
obtained decolorized solution was cooled at 20.degree.-30.degree.
C., and 2(2,3-Dihydrobenzofuran-5-y) ethylchloride crystallized in
the suspension. Water (280 ml) was added to the suspension at
25.degree.-30.degree. C. over about 60 min to obtain a sticky, but
stirrable, suspension. After 1 hr at 20-25.degree. C. the solid was
filtered, and washed three times with MeOH-Water 1:1 (20 ml each).
The wet solid was dried at 35-40.degree. C. max for 15 hrs to give
the title compound. (Dry weight 81.8 g.
[0119] Yield 92%. HPLC purity 99.2% area).
Example 12
Preparation of (S)-Darifenacin Hydrobromide
[0120] A 50 ml reactor was loaded with
--(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (4
g, 9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95
g, 10.68 mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and
water (12.5 ml), to obtain a heterogeneous mixture. The
heterogeneous mixture was heated to reflux (103.degree. C.) for 2.5
hours. After cooling, dichloromethane, EtOAc or BuOAc (15 ml) were
added, and, after stirring, the phases were separated. Acetic
anhydride (0.5 ml) was added to the organic phase, and, after 1
hour at room temperature, the residual
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was
transformed into N-Acetyl derivative. The solvent was removed by
distillation, and n-butanol (25 ml) was added to the residue. 48%
hydrobromic acid (1.72 g) was also added, and the residual DCM was
removed under vacuum distillation. In the case of EtOAc or BuOAc,
distillation under vacuum is useful to eliminate water. Darifenacin
hydrobromide crystallized, and, after cooling to room temperature,
the darifenacin hydrobromide was filtered and washed. (Wet solid
4.17 g).
Example 13
Preparation of (S)-Darifenacin Hydrobromide
[0121] A 50 ml reactor was loaded with
(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine free base (2.6
g, 9.29 mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95
g, 10.68 mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and
water (12.5 ml) to obtain a heterogeneous mixture. The
heterogeneous mixture was heated to reflux (103.degree. C.) for 2
to 5 hours. After cooling, dichloromethane, Ethyl acetate, or
Butylacetate (15 ml) was added, and, after stirring, the phases
were separated. Acetic anhydride (0.5 ml) was added to the organic
phase, and, after 1 hour at room temperature, the residual
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was
transformed into N-Acetyl derivative (as described in example 11).
Half of the solvent was removed by distillation, and n-butanol (25
ml) was added to the residue. 48% hydrobromic acid (1.72 g) was
also added, and the residual DCM was removed under vacuum
distillation. In the case of EtOAC or BuOAc, distillation under
vacuum is useful to eliminate water. Darifenacin hydrobromide
crystallized, and, after cooling to room temperature, the
darifenacin hydrobromide was filtered and washed. (Dry solid 2.5
g).
Example 14
Preparation of (S)-Darifenacin Hydrobromide
[0122] A 150 ml reactor was loaded with water (37.5 ml), potassium
carbonate (12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride
(DBF-EtCl) (5.48 g). The mixture was warmed to 60-65.degree. C. and
DBF-EtCl melted. Then,
(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate (12 g)
was loaded and the heterogeneous mixture was warmed to reflux
(101-102.degree. C.) for 5 hrs.
[0123] The reaction mixture was cooled to 80-85.degree. C. and
n-butanol (60 ml) was added. The internal temperature was
maintained at 75-80.degree. C., and the mixture was stirred until
complete dissolution was obtained. Then, the mixture was cooled to
25-30.degree. C. and the phases were separated. The organic phase
was washed twice with water (30 ml) and the phases were
separated.
[0124] Water was removed by vacuum distillation until a residual
volume of 60 ml was obtained, and then n-butanol (30 ml) was added.
Then, acetic anhydride (0.6 ml) was loaded and the mixture was
stirred at 20-30.degree. C. for 1 hr, followed by loading HBr 48%
(4.7 g) at 25-27.degree. C. The water and 20 ml of butanol were
removed by vacuum distillation to obtain a suspension of
darifenacin hydrobromide. The suspension was stirred at
25-30.degree. C. for 2 hrs, and then cooled to 0-5.degree. C., and
filtered after 1 hr. The cake was washed with cold n-Butanol
(3.times.3 ml), and dried under vacuum at 50-55.degree. C. for 6-7
hrs. (Dry weight 11.2-11.5. Yield 79-81%).
Example 15
Crystallization of (S)-darifenacin hydrobromide
[0125] A 100 ml reactor was loaded with crude darifenacin
hydrobromide (10 g), n-butanol (70 ml), and charcoal (0.3 g). The
mixture was warmed to reflux to obtain a solution. The charcoal was
filtered at reflux and washed with n-butanol (5 ml).
[0126] The solution was maintained at 100.degree. C. and seeded to
induce crystallization. After 30 min at 100.degree. C., the mixture
was cooled to 0.degree. C. over 3 hrs, and after 1 hr at 0.degree.
C. the mixture was filtered. The product was washed with cold
butanol (3.times.3 ml). (Dry weight 8.8-8.9 g. Yield 88-89%. HPLC
purity 99.65-99.75% area).
Example 16
Preparation of (S)-Darifenacin Hydrobromide Via
(S)-darifenamine
[0127] 3-(S)-(+)-(1-Carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.1
g, 7.5 mmoles) and 2,3-dihydrobenzofuran-5-yl,acetaldehyde (1.4 g,
8.6 mmoles) were combined with toluene (20 ml) at room temperature,
and reacted for 15 hours to give (S)-darifenamine.
[0128] At this point, a solution of NaBH.sub.4 (0.57 g, 15 mmoles)
in ethanol (10 ml) was added slowly, and after 3 hours at room
temperature, HPLC analysis revealed formation of (S)-Darifenacin.
After washing with water, the solvent was eliminated by
distillation, and the obtained residue was dissolved in n-BuOH
followed by the addition of HBr 48% (1.5 g, 9 mmoles). Water was
eliminated under vacuum, and a slow crystallization was observed.
After cooling, the product was filtered and washed with n-BuOH to
give the title compound. (Dry weight 0.7 g).
[0129] The same reaction has been performed in presence of
molecular sieves and titanium isopropylate with similar
results.
Example 17
Purification of Darifenacin HBr
[0130] The product of Example 16 (3.6 g) was suspended in n-Butanol
(25 ml), and heated to reflux to obtain a solution. Charcoal (0.1
g) was added, and, after 5 minutes at reflux, was filtered off.
After cooling to room temperature, Darifenacin HBr was filtered,
washed, and dried at 45-50.degree. C. under vacuum for 10 hours.
(Dry solid 3.20 g; overall yield 68%; HPLC purity 99.86% area).
Example 18
2,3-Dihydrobenzofura-5-yl, acetaldehyde
[0131] In a four necked round bottomed flask equipped with
thermometer, mechanical stirrer and condenser, was charged under
N.sub.2, 2,3-Dihydrobenzofura-5-yl, carboxaldehyde (50 g, 0.33
moles) and 2-butylchloroacetate (66.5 g, 0.4415 moles). The
solution was warmed to 40-45.degree. C., followed by a dropwise
addition (in about 1 hour) of 288 ml of 17% (w/v) potassium
2-butylate solution in 2-butyl alcohol (0.43 moles). The reaction
was maintained at a temperature of 40-45.degree. C., and after 1
hour at 40-45.degree. C., HPLC analysis revealed almost complete
transformation of carboxaldehyde. The suspension was slowly added
to a solution of KOH 90% (24.5 g, 0.3937 moles) in water (47 ml),
followed by maintaining at 45-50.degree. C. After 1 hour at
45.degree. C., TLC analysis revealed complete hydrolysis, and a
thick suspension was obtained. At this point toluene (120 ml) and
water (180 ml) were added, and the suspension was cooled to
1-5.degree. C. Then, 75% H.sub.3PO.sub.4 (about 50 g) was added
drop-wise to obtain a pH in range of 5.4-5.8. During acidification
CO.sub.2 evolves and almost complete solid dissolution is observed.
After the phases are separated, the organic phase was washed with
water (200 ml) and then with sat NaCl, (100 ml). After solvent
elimination under vacuum, a residual oil (47 g) of the title
compound was obtained.
Example 19
2(2,3-Dihydrobenzofura-5-y) acetaldehyde, bisulfitic complex
[0132] In a four necked round bottomed flask equipped with
thermometer, and mechanical stirrer, was loaded
2,3-Dihydrobenzofura-5-yl, acetaldehyde, of example 18 (47 g, 0.29
moles) and toluene (500 ml) to obtain a solution. Then, water (100
ml) and Na.sub.2S.sub.2O.sub.5 (58.6 g) were added. The bisulfitic
adduct precipitated and after 3 hours at room temperature it was
filtered and washed twice with toluene (50 ml each). (Wet product:
95 g).
Example 20
2(2,3-Dihydrobenzofura-5-y) ethanol
[0133] The obtained wet bisulphitic adduct of example 19 was
suspended in water (150 ml), and the pH was adjusted to 10-10.2
with NaOH 30%. Na.sub.2CO.sub.3 10% (50 ml) and toluene (100 ml)
were added and, after cooling to 5-10.degree. C., a solution of
NaBH.sub.4 (5.8 g, 0.1526 moles)) in water (40 ml) was added
drop-wise over about 45-60 minutes, while maintaining the pH at
9.8-10.2. The temperature was raised to 15-20.degree. C. and after
1 hour the phases were separated. The aqueous phase was extracted
with toluene (25 ml), and the combined organic phases were washed
with water (50 ml). The solvent was eliminated under vacuum
distillation, and the obtained oil solidified to give the title
compound (26 g).
Example 21
Preparing 5-(2-chloroethyl)-2,3-dihydrobenzofuran of formula II in
DMF toluene and in a mixture of dimethylformamide (DMF) and
toluene
[0134] TABLE-US-00002 Level of 2- Level of 5-(2- (benzofuran-5-
chloroethyl)-2,3- Temperature yl)ethanol of formula benzofuran of
formula Solvent (.degree. C.) V (area % by HPLC) I (area % by HPLC)
DMF 20.degree. C. nd 0.3 DMF 0-5.degree. C. nd 0.44 Toluene/
55.degree. C. 0.01 1.15 DMF 99:1 Toluene 60.degree. C. 0.03 0.21
Toluene 60.degree. C. nd 0.19 Toluene 60.degree. C. nd 0.14 * nd =
not determined
Example 22
Correlation Between the Levels of the Oxidized Impurities in the
Intermediates for Preparing Darifenacin Hydrobromide to the Level
of Oxidized Darifenacin
[0135] TABLE-US-00003 Level of Level of Level of Level of impurity
impurity impurity impurity Level of (area % by (area (area (area %
impurity (w/w HPLC) % by HPLC) % by HPLC) by HPLC) % by HPLC)
BF-AcOH BF-AcOMe BF-EtOH BF-EtCl Oxidized darifenacin 0.18 0.17
0.16 0.18 0.09 0.50 0.53 0.47 0.30 0.49 * BF-AcOH is
benzofuran-5-acetic acid; BF-AcOMe is benzofuran-5-methylester
acetic acid; BF-EtOH is benzofuran-ethanol; and BF-EtCl is
5-(2-chloroethyl)-benzofuran.
Comparative Example 23
Example 1 from U.S. Pat. No. 5,096,890 (col. 6, 1.56 to col. 7,
1.51)
(A) Preparation of
3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl-
)ethyl]pyrrolidine
[0136] ##STR59##
[0137] A mixture containing
3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.33 g-see
Preparation 8), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.25 g-see
Preparation 13), anhydrous potassium carbonate (0.3 g) and
acetonitrile (10 ml) was heated under reflux for 2 hours. The
mixture was partitioned between dichloromethane (50 ml) and 10%
aqueous potassium carbonate (10 ml), the layers were separated, and
the aqueous layer extracted with dichloromethane (3.times.20 ml).
The combined dichloromethane extracts were dried (MgSO.sub.4) and
concentrated in vacuo to leave a gum which was purified by column
chromatography on silica eluting with dichloromethane containing
methanol (0% up to 8%). The product-containing fractions were
combined and concentrated in vacuo to leave an oil which was
crystallised from diisopropyl ether to give the title compound as a
colourless powder, yield 0.17 g, m.p. 131.degree.-132.degree.
C.
[0138] Analysis %: Found: C,78.90; H,7.70; N,6.28. Calculated for
C.sub.28H.sub.30N.sub.2O.sub.2: C,78.84; H,7.90; N,6.57.
[0139] .sup.1H N.m.r. (CDCl.sub.3) .delta.=7.50-7.20 (m, 11H); 7.00
(s, 1H); 6.90 (d, 1H); 6.70 (d, 1H); 5.45-5.30 (brs, 1H); 4.60-4.50
(t, 2H); 3.60-3.45 (m, 1H); 3.25-3.15 (t, 2H); 3.05-2.50 (m, 8H);
2.10-1.95 (m, 2H) ppm.
(B) A similar procedure starting with
3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.95 g-see
Preparation 10(B)) gave
3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5--
y l)ethyl]pyrrolidine as a foam, yield 1.9 g,
[.alpha.].sub.D.sup.25-20.6.degree. (c 1.0, CH.sub.2Cl.sub.2).
(C) A similar procedure starting with
3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.8 g-see
Preparation 11) gave
3-(R)-(+)-(1-carbamoyl-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5--
y l)ethyl]pyrrolidine as a foam, yield 1.7 g,
[.alpha.].sub.D.sup.25+18.1 (c 1.0, CH.sub.2Cl.sub.2).
[0140] While it is apparent that the invention disclosed herein is
well calculated to fulfill the objects stated above, it will be
appreciated that numerous modifications and embodiments may be
devised by those skilled in the art. Therefore, it is intended that
the appended claims cover all such modifications and embodiments as
falling within the true spirit and scope of the present
invention.
* * * * *