U.S. patent application number 11/650355 was filed with the patent office on 2007-08-30 for productioin of dolasetron.
Invention is credited to Janos Hajko, Adrienne Kovacsne-Mezei, Erika Magyar Molnarne, Csaba Peto, Csaba Szabo, Tivadar Tamas.
Application Number | 20070203175 11/650355 |
Document ID | / |
Family ID | 37913602 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070203175 |
Kind Code |
A1 |
Hajko; Janos ; et
al. |
August 30, 2007 |
Productioin of dolasetron
Abstract
The present invention provides an improved process for the
preparation of Dolasetron salts, in particularly Dolasetron
mesylate. Also provided are intermediates for the process and
methods of preparing the intermediates. Intermediates for preparing
Dolasetron according to the invention include
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo-
[3.3.1]nonane compounds (SAN compounds) and
endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0.sup.3,8]un-
decan-10-one compounds (SQO compounds).
Inventors: |
Hajko; Janos; (Debrecen,
HU) ; Tamas; Tivadar; (Debrecen, HU) ;
Kovacsne-Mezei; Adrienne; (Debrecen, HU) ; Molnarne;
Erika Magyar; (Debrecen, HU) ; Peto; Csaba;
(Debrecen, HU) ; Szabo; Csaba; (Debrecen,
HU) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
37913602 |
Appl. No.: |
11/650355 |
Filed: |
January 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60756690 |
Jan 5, 2006 |
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60800884 |
May 15, 2006 |
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60838758 |
Aug 17, 2006 |
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60861354 |
Nov 27, 2006 |
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60802842 |
May 22, 2006 |
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60818934 |
Jul 5, 2006 |
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60833515 |
Jul 24, 2006 |
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60836432 |
Aug 7, 2006 |
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60763683 |
Jan 30, 2006 |
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60784248 |
Mar 20, 2006 |
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60815199 |
Jun 19, 2006 |
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60852887 |
Oct 18, 2006 |
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Current U.S.
Class: |
514/294 ; 546/14;
546/94 |
Current CPC
Class: |
C07D 471/18 20130101;
A61P 25/06 20180101; C07F 7/1804 20130101; C07D 303/40 20130101;
C07D 451/14 20130101 |
Class at
Publication: |
514/294 ;
546/014; 546/094 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; C07D 471/14 20060101 C07D471/14; C07F 7/02 20060101
C07F007/02; C07D 453/00 20060101 C07D453/00 |
Claims
1. A quaternary ammonium salt of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one
compound (an OAN salt) of formula Vs, ##STR53## wherein R.sub.1 and
R.sub.2 are independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl,
and Z is an acid.
2. (canceled)
3. The quaternary ammonium salt of claim 1, wherein R.sub.1 and
R.sub.2 are methyl and Z is methanesulfonic acid.
4. The quaternary ammonium salt of claim 3, wherein the quaternary
ammonium salt is crystalline.
5. The quaternary ammonium salt of claim 4, wherein the quaternary
ammonium salt is crystalline OAN-MsOH is characterized by a powder
XRD diffraction pattern having peaks at about 8.5, 18.0, and 20.9
degrees two-theta, .+-.0.2 degrees two-theta.
6. (canceled)
7. The quaternary ammonium salt of claim 6, wherein the crystalline
OAN-MsOH is characterized having a PXRD pattern as depicted in FIG.
1.
8. A quaternary ammonium salt of
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-ol
(a HAN salt) of formula VIs, ##STR54## wherein R.sub.1 and R.sub.2
are independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl, and Z is
an acid.
9. (canceled)
10. The quaternary ammonium salt of claim 8, wherein R.sub.1 and
R.sub.2 are methyl and Z is methanesulfonic acid.
11. The quaternary ammonium salt of claim 10, wherein the
quaternary ammonium salt is crystalline.
12. The quaternary ammonium salt of claim 11, wherein the
quaternary ammonium salt is crystalline HAN-MsOH characterized by a
powder XRD diffraction pattern having peaks at about 7.3, 11.6, and
14.6 degrees two-theta, .+-.0.2 degrees two-theta.
13. (canceled)
14. (canceled)
15. A
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azab-
icyclo[3.3.1]nonane compound (a SAN compound) of formula X
##STR55## wherein R.sub.1 and R.sub.2 are independently C.sub.1-6
alkyl or C.sub.6-8 aryl, and R.sub.3R.sub.4R.sub.5 are
independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl, or
R.sub.3R.sub.4R.sub.5 together are a tert-butyldialkyl.
16. (canceled)
17. The compound of claim 15, wherein R.sub.1 and R.sub.2 are
methyl and R.sub.3R.sub.4R.sub.5 is tert-butyldimethyl.
18. An
endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0.sup-
.3,8]undecan-10-one compound (a SQO compound) of formula XII
##STR56## wherein R is a C.sub.1-6 alkyl or a C.sub.6-8 aryl, and
R.sub.3R.sub.4R.sub.5 are independently a C.sub.1-6 alkyl or a
C.sub.6-8 aryl, or R.sub.3R.sub.4R.sub.5 together are a
tert-butyldialkyl.
19. (canceled)
20. The compound of claim 18, wherein R is methyl, and
R.sub.3R.sub.4R.sub.5 are together tert-butyldimethyl.
21. The compound of claim 20, wherein the compound is
crystalline.
22. The compound of claim 21, wherein the compound is crystalline
SQO, characterized by a powder XRD diffraction pattern having peaks
at about 5.1, 10.1, 12.7, and 20.3 degrees two-theta, .+-.0.2
degrees two-theta.
23. (canceled)
24. (canceled)
25. A quaternary ammonium salt of
endo-5-hydroxy-8-azatricyclo[5.3.1.0.sup.3,8]undecan-10-one (a HQO
salt) of formula IIs, ##STR57## wherein Y an acid selected from the
group consisting of: hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric
acid, formic acid, acetic acid, propionic acid, trichloroacetic
acid, trifluoroacetic acid, maleic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, citric acid, mandelic acid,
benzoic acid, salicylic acid, naphthalene carboxylic and
dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid, naphthalene sulfonic and disulfonic acid.
26. The quaternary ammonium salt of claim 25, wherein Y is
Hydrochloric acid (HQO-HCl).
27. The quaternary ammonium salt of claim 26, wherein the salt is
crystalline.
28. (canceled)
29. The quaternary ammonium salt of claim 25, wherein Y is
Camphorsulfonic acid (HQO--CSA).
30. The quaternary ammonium salt of claim 29, wherein the salt is
crystalline.
31. (canceled)
32. A method for the preparation of a CCA-epoxide of formula IV
##STR58## comprising combining a CCA-ester of formula III,
##STR59## an oxidizing agent, a catalyst, and a solvent selected
from the group consisting of water, a water miscible organic
solvent, and mixtures thereof forming a mixture, to obtain the
CCA-epoxide of formula IV, wherein, R.sub.1 is a C.sub.1-6 alkyl or
C.sub.6-8 aryl.
33. The method of claim 32, wherein RI is methyl.
34. The method of claim 32, wherein the oxidizing agent is selected
from the group consisting of: hydroxyperoxide, dialkyl peroxide,
peroxyacid, peroxyester, diacyl peroxide, persulphate, perborate,
and perphosphate.
35. (canceled)
36. The method of claim 34, wherein the hydroperoxide is hydrogen
peroxide.
37. The method of claim 32, wherein the water miscible organic
solvent is selected from the group consisting of linear or branched
C.sub.1-4 alcohols.
38. (canceled)
39. The method of claim 32, wherein the solvent is a mixture of
water and a water immiscible organic solvent in the presence of a
phase transfer catalyst.
40. The method of claim 39, wherein the water immiscible organic
solvent is selected from the group consisting of a C.sub.1-8
halogenated hydrocarbon, a C.sub.2-8 ester, a C.sub.2-8 ether and a
C.sub.3-6 ketone.
41. The method of claim 32, wherein the catalyst is selected from
the group consisting of Zeolites and polyoxometalates.
42. The method of claim 41, wherein the metal moiety of the
polyoxometalates is selected from the group consisting of tungsten,
molybdenum, rhenium, vanadium and niobium.
43. (canceled)
44. (canceled)
45. The method of claim 32, wherein the reaction mixture is
maintained at a temperature of about 0.degree. C. to about
80.degree. C.
46. The method of claim 32, further comprising recovering the
CCA-epoxide of formula IV.
47. (canceled)
48. (canceled)
49. (canceled)
50. A method for the preparation of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one
compound (an OAN compound) of formula V ##STR60## comprising a)
combining a CCA-epoxide of formula IV, an oxidizing agent, and a
solvent selected from the group consisting of water, water miscible
organic solvent, and mixtures thereof to form a reaction mixture;
b) raising the pH of the reaction mixture; and c) reacting the
reaction mixture of step b) with a pH 4 buffer, a glycine C.sub.1-4
ester or salts thereof, and a substance containing a carbonyl
moiety selected from the group consisting of
1,3-acetonedicarboxylic acids, acetone and C.sub.1-4 esters thereof
to form an OAN compound of formula V, wherein R.sub.1 and R.sub.2
are independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl.
51. The method of claim 50, wherein R.sub.1 and R.sub.2 are
methyl.
52. The method of claim 50, wherein the water miscible organic
solvent is selected from the group consisting of: a C.sub.2-4
nitrile, a C.sub.3-6 ketone and a cyclic ether.
53. (canceled)
54. The method of claim 50, wherein the solvent is water.
55. The method of claim 50, wherein the oxidizing agent is selected
from the group consisting of: periodic acid and salts thereof, lead
tetraacetate, cerium and ammonium nitrate
(Ce(NH.sub.4).sub.2(NO.sub.3).sub.6).
56. (canceled)
57. The method of claim 50, wherein the reaction mixture is
maintained at a temperature of about 10.degree. C. to about
60.degree. C.
58. The method of claim 57, wherein the pH of the first reaction
mixture is of about 0.5 to about 7.
59. (canceled)
60. The method of claim 59, wherein the pH is raised by using a
water immiscible base selected from poly(4-vinylpyridine) and OH
resins.
61. The method of claim 50, wherein the pH 4 buffer is an
amine-free buffer selected from the group consisting of: citric
acid-sodium hydroxide-hydrochloric acid, citric acid-disodium
hydrogenphosphate, sodium acetate-acetic acid, potassium
diphthalate-sodium hydroxide, sodium dihydrogen phosphate and
potassium hydrogen phthalate.
62. (canceled)
63. (canceled)
64. (canceled)
65. (canceled)
66. The method of claim 64, wherein the glycine C.sub.1-4 ester is
glycin methylester hydrochloride.
67. The method of claim 50, wherein the substance comprising a
carbonyl moiety is 1,3-acetonedicarboxylic acid.
68. The method of claim 50, wherein the reaction mixture in step c)
is maintained at a temperature of about 0.degree. C to about
60.degree. C.
69. (canceled)
70. (canceled)
71. The method of claim 50, further comprising; combining the OAN
compound of formula V, an acid, and an organic solvent selected
from the group consisting of a C.sub.1-4 alcohol, a C.sub.2-8
ester, a linear, branched or cyclic C.sub.2-8 ether, a C.sub.3-6
ketone, a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8 halogenated
hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4 alkylcyanide, a
C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide, and mixtures
thereof, forming a mixture to obtain an OAN-salt of formula Vs
##STR61## wherein, R.sub.1 and R.sub.2 are independently a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, and Z is an acid.
72. The method of claim 71, wherein Z is methanesulfonic acid.
73. (canceled)
74. (canceled)
75. (canceled)
76. The method of claim 71, wherein the mixture of the OAN compound
of formula V, the solvent and the acid form is maintained at a
temperature of about 10.degree. C. to about 60.degree. C.
77. The method of claim 71, further comprising adding a base,
wherein the OAN compound of formula V is obtained as a purified
compound.
78. (canceled)
79. (canceled)
80. A method of preparing a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-ol
compound (a HAN compound) of formula VI ##STR62## comprising
combining an OAN salt of formula Vs, a reducing agent, and a
solvent selected from the group consisting of water, water miscible
organic solvents and mixtures thereof to form mixture, to obtain an
HAN compound of formula VI, wherein R.sub.1 and R.sub.2 are
independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl.
81. The method of claim 80, wherein R.sub.1 and R.sub.2 are
methyl.
82. The method of claim 80, wherein the OAN salt is OAN-MsOH.
83. The method of claim 80, wherein the water miscible organic
solvent is a C.sub.1-4 alcohol.
84. (canceled)
85. The method of claim 80, wherein the reducing reagent is a metal
hydride complex.
86. (canceled)
87. The method of claim 80, wherein the mixture comprising the OAN
salt, the water miscible organic solvent, and the reducing agent is
maintained at a temperature of about 25.degree. C. to about
35.degree. C.
88. The method of claim 80, further comprising recovering the HAN
compound of formula VI.
89. (canceled)
90. (canceled)
91. The method of claim 80, further comprising combining the HAN
compound of formula VI, an acid, and an organic solvent selected
from the group consisting of a C.sub.1-4 alcohol, a C.sub.2-8
ester, a linear, branched or cyclic C.sub.2-8 ether, a C.sub.3-6
ketone, a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8 halogenated
hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4 alkylcyanide, a
C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide, and mixtures
thereof, forming a mixture to obtain a HAN-salt of formula VIs
##STR63## wherein R.sub.1 and R.sub.2 are independently a C.sub.1-6
alkyl or a C.sub.6-8 aryl and Z is an acid.
92. (canceled)
93. The method of claim 91, further comprising adding a base,
wherein the HAN compound of formula V is obtained as a purified
compound.
94. (canceled)
95. (canceled)
96. (canceled)
97. (canceled)
98. A method of preparing a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo-
[3.3.1]nonane compound (a SAN compound) of formula X ##STR64##
comprising combining a HAN-salt of formula VIs ##STR65## a
silylating agent selected from a group consisting of: silanes,
silyl halogenides, silyl cyanides, silyl amines, silyl amides,
silyl trifluoromethanesulfonates (silyl triflates), and silazanes,
a base, and an aprotic organic solvent, forming a mixture to obtain
the SAN compound of formula X, wherein, R.sub.1 and R.sub.2 are
independently C.sub.1-6 alkyl or C.sub.6-8 aryl, and
R.sub.3R.sub.4R.sub.5 are independently C.sub.1-6 alkyl or
C.sub.6-8 aryl, or R.sub.3R.sub.4R.sub.5 together are a
tert-butyldialkyl, and Z is an acid.
99. The method of claim 98, wherein R.sub.1 and R.sub.2 are methyl,
R.sub.3R.sub.4R.sub.5 together are tert-butyldimethyl.
100. The method of claim 98, wherein the a-protic organic solvent
is selected from the group consisting of a C.sub.1-8 halogenated
hydrocarbon, a C.sub.2-8 ester, a C.sub.2-8 ether, a C.sub.6-8
aromatic hydrocarbon, a C.sub.3-10 amide, and a C.sub.3-6
ketone.
101. (canceled)
102. The method of claim 98, wherein the amount of base is about 2
to about 10 mole equivalent of base per mole equivalent of the
HAN-salt.
103. The method of claim 98, wherein the base is selected from the
group consisting of: sodium hydroxide, sodium carbonate, sodium
bicarbonate, potassium hydroxide, potassium carbonate potassium
bicarbonate, trialkyl amines, and N-containing heterocycles.
104. (canceled)
105. (canceled)
106. The method of claim 98, wherein the base is added at a
temperature of about 15.degree. C. to about 55.degree. C.
107. The method of claim 98, wherein the silylating agent is
selected from the group consisting of triethylsilane,
triisopropylsilane, and triphenylsilane.
108. The method of claim 98, wherein the silylating agent is
trialkylsilyl halogenide.
109. (canceled)
110. The method of claim 108, wherein the silylating agent is added
in an amount of about 1 to about 4 mole equivalent of sylilating
agent per mole equivalent of the HAN-salt.
111. The method of claim 98, wherein the mixture is maintained at a
temperature of about 20.degree. C. to about 60.degree. C.
112. The method of claim 98, further comprising recovering SAN of
formula X.
113. (canceled)
114. (canceled)
115. A method of preparing an
endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0.sup.3,8]un-
decan-10-one compound (a SQO compound) of formula XII ##STR66##
comprising, a) mixing a SAN compound of formula X, a metal
alkoxide, and a polar aprotic organic solvent to form a mixture; b)
heating the mixture; and c) reacting the heated mixture of step b)
with a weak acid, forming-the SQO compound of formula XII, wherein,
R is a C.sub.1-6 alkyl or a C.sub.6-8 aryl, and
R.sub.3R.sub.4R.sub.5 are independently a C.sub.1-6 alkyl or a
C.sub.6-8 aryl, or R.sub.3R.sub.4R.sub.5 together are a
tert-butyldialkyl.
116. The method of claim 115, wherein R is methyl and
R.sub.3R.sub.4R.sub.5 together are tert-butyldimethyl.
117. (canceled)
118. The method of claim 115, wherein the polar a-protic organic
solvent is THF.
119. The method of claim 115, wherein the metal alkoxide is
selected from the group consisting of lithium alcoholates, sodium
alcoholates and potassium alcoholates; wherein the alcoholate
moiety contains 1 to 4 carbons.
120. (canceled)
121. The method of claim 115, wherein the mixture is heated to a
temperature of about 40.degree. C. to about 120.degree. C.
122. The method of claim 121, wherein the heated mixture is cooled
to a temperature of about 0.degree. C. to about 30.degree. C.
123. The method of claim 115, wherein the weak acid is selected
from the group consisting of acetic acid, formic acid, propionic
acid, maleic acid, fumaric acid, succinic acid, oxalic acid,
tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic
acid, naphthalene carboxylic and dicarboxylic acids,
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
acid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic
acid, naphthalene sulfonic and disulfonic acids
124. The method of claim 123, wherein the acid is acetic acid.
125. (canceled)
126. The method of claim 115, further comprising recovering the SQO
compound of formula XII.
127. (canceled)
128. (canceled)
129. A method of preparing
endo-5-hydroxy-8-azatricyclo[5.3.1.0.sup.3,8]undecan-10-one (HQO)
of formula II ##STR67## comprising mixing a SQO compound of formula
XII, water or a water-miscible organic solvent, and an acid
selected from the group consisting of hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
perchloric acid, fluoroboric acid, methanesulfonic acid,
ethanesulfonic acid, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid,
naphthalene sulfonic and disulfonic acids, to obtain the HQO
compound.
130. The method of claim 129, wherein the water-miscible organic
solvent is dimethylformamide, dimethylacetamide, dimethyl
sulfoxide, or diglyme.
131. The method of claim 129, wherein the solvent is water.
132. The method of claim 129, wherein the SQO compound of formula
XII is combined with the solvent at a temperature of about
10.degree. C. to about 50.degree. C.
133. (canceled)
134. The method of claim 129, wherein the mixture is heated to a
temperature of about 80.degree. C. to about 100.degree. C.
135. The method of claim 129, further comprising recovering HQO of
formula II.
136. The method of claim 129, wherein HQO is prepared comprising
combining a SAN compound of formula X, in stead of the SQO compound
of formula XII.
137. (canceled)
138. The method of claim 129, further comprising combining HQO, an
alcohol and an acid selected from the group consisting of:
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, perchloric acid, fluoroboric acid, formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, maleic acid, fumaric acid, succinic acid, oxalic acid,
tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic
acid, naphthalene carboxylic and dicarboxylic acids,
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene
sulfonic, and disulfonic acid to obtain a HQO salt of formula
IIs.
139. The method of claim 138, further comprising the step of adding
a base to obtain purified HQO.
140. The method of claim 138, wherein the alcohol is a C.sub.1-4
alcohol.
141. (canceled)
142. (canceled)
143. (canceled)
144. (canceled)
145. (canceled)
146. (canceled)
147. (canceled)
148. (canceled)
149. (canceled)
150. A method of preparing a Dolasetron salt of formula VIIIs,
comprising a) combining a CCA-ester of formula III, an oxidizing
agent selected from the group consisting of: hydroperoxides,
dialkyl peroxides, peroxyacids, peroxyesters, diacyl peroxides,
persulphate, perborate and perphosphate, a catalyst and a solvent
selected from the group consisting of water, water miscible organic
solvents and mixtures thereof, to form CCA-epoxide of formula IV;
b) admixing CCA-epoxide with an oxidizing agent, and a solvent
selected from the group consisting of water and a water miscible
organic solvent; c) raising the pH; d) admixing with a pH 4 buffer,
a glycine C.sub.1-4 ester or salts thereof, and a substance
comprising a carbonyl moiety selected from the group consisting of
1,3 acetonedicarboxylic acids, acetone and a C.sub.1-4 ester
thereof, to form OAN of formula V; e) admixing with a reducing
agent, and a solvent selected from the group consisting of water,
water miscible organic solvents and mixtures thereof, to form HAN
of formula VI; f) admixing with a silylating agent selected from a
group consisting of: silanes, silyl halogenides, silyl cyanides,
silyl amines, silyl amides, silyl trifluoromethanesulfonates (silyl
triflates), and silazanes, a base, and an aprotic organic solvent
to form SAN of formula X; g) admixing with a metal alkoxide, and a
polar a-protic organic solvent to form a reaction mixture; h)
heating the reaction mixture; i) quenching with a weak acid
selected from the group consisting of acetic acid, formic acid,
acetic acid, propionic acid, maleic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, citric acid, mandelic acid,
benzoic acid, and salicylic acid forming SQO of formula XII; j)
admixing with a solvent selected from a group consisting of: water,
and water-immiscible organic solvent, and an acid selected from the
group consisting of hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric
acid, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids to form HQO of formula II; k) admixing with an
anhydride, 3-indole carboxylic acid, a halogenated hydrocarbon, and
a catalyst to obtain Dolasetron base; and l) reacting Dolasetron
base with an acid to obtain the DLS-salt of formula VIIIs.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of the following
U.S. Provisional Patent Application No. 60/756,690, filed Jan. 5,
2006; 60/800,884, filed May 15, 2006; 60/838,758, filed Aug. 17,
2006; 60/861,354, filed Nov. 27, 2006; 60/802,842, filed May 22,
2006; 60/818,934, filed Jul. 5, 2006; 60/833,515, filed Jul. 24,
2006; 60/836,432, filed Aug. 7, 2006; 60/763,683, filed Jan. 30,
2006; 60/784,248, filed Mar. 20, 2006; 60/815,199, filed Jun. 19,
2006; 60/852,887, filed October 18, 2006. The contents of these
applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to an improved process for the
preparation of Dolasetron salts, in particularly Dolasetron
mesylate, and intermediates thereof.
BACKGROUND OF THE INVENTION
[0003] Dolasetron mesylate monohydrate,
(2',6.alpha.,8.alpha.,9.alpha..beta.)-octahydro-3-oxo-2,6-methano-2H-quin-
olizin-8-yl-1H-indole-3-carboxylate monomethanesulfonate
monohydrate, (referred to as DLS-MsOH--H.sub.2O) a compound having
the chemical structure, ##STR1##
Dolasetron Mesylate Monohydrate
[0004] is a serotonin receptor (5-HT.sub.3) antagonist used as an
antiemetic and antinauseant agent in chemo- and radiotherapies.
[0005] DLS-MsOH-H.sub.2O developed by Merrell Dow Pharmaceuticals
is marketed as tablets for oral administration and as sterile
solution for intravenous administration by Aventis, under the name
Anzemet.RTM..
[0006] DLS-MsOH and its monohydrate form can be prepared by a multi
step synthesis, as described in EP patent No. 0339669 ("the EP '669
patent") as illustrated in the following scheme ##STR2##
[0007] Accordingly, step (c) of the reaction involves oxidation
with a molar equivalent of an expensive oxidizing reagent,
3-chloroperbenzoic acid (referred to as mCPBA), which transforms to
3-chlorobenzoic acid (referred to as mCBA), waste that is disposed
at the end of the reaction. Removal of mCBA is problematic, hence,
leading to a contaminated product. CCA-epoxide is also contaminated
by other aromatic impurities, such as [(3-ClPh)C(O)O].sub.2 (the
corresponding peroxide ) in an amount of 5%. Therefore, the
oxidation reaction as described above is non-economic for scale-up.
Also, the reaction in steps (e) and (f) are done by using periodic
acid in ethyl acetate in step (e), and water as a solvent in step
(f). Since, the reagents and the reduction products have low
solubility in ethylacetate; the reaction disclosed in the above
patent is slower. Also, the reaction in ethylacetate is more
dangerous. In addition, since two different solvents are used in
steps (e) and (f), a work-up procedure, which can lead to a
decomposition of the sensitive
3-methoxycarbonyl-1,5-glutardialdehyde (the product of the
oxidation step), is required.
[0008] A similar process is apparently described in EP patent No.
0266730, comprising an oxidation reaction, as described in step (c)
of the above scheme, to the corresponding diol, instead of to the
epoxide, as apparently disclosed in EP patent No. 0339669. The diol
is then transformed to DLS-base in a similar way.
[0009] Hence, there is a need in the art for an improved process
for the preparation of Dolasetron salts, preferably, Dolasetron
Mesylate.
SUMMARY OF THE INVENTION
[0010] In one embodiment, the present invention provides a
quaternary ammonium salt of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one
compound (referred to as an OAN compound salt) of formula Vs;
##STR3## wherein R.sub.1 and R.sub.2 are independently a C.sub.1-6
alkyl or a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl, more
preferably, methyl, and Z is an acid, preferably, methanesulfonic
acid.
[0011] In another embodiment, the present invention provides
crystalline methanesulfonate salt of
7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-o-
ne (referred to as OAN-MsOH).
[0012] In yet another embodiment, the present invention provides a
quaternary ammonium salt of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol
compound (referred to as a HAN compound salt) of formula VIs;
##STR4## wherein R.sub.1, R.sub.2 and Z are described before.
[0013] In one embodiment, the present invention provides
crystalline methanesulfonate salt of
7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol
(referred to as HAN-MsOH).
[0014] In yet another embodiment, the present invention provides a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo-
[3.3.1]nonane compound (referred to as a SAN compound) of formula
X; ##STR5## wherein R.sub.1 and R.sub.2 are independently a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl,
more preferably, methyl, and R.sub.3R.sub.4R.sub.5 are
independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl, or together
are a tert-butyldialkyl, preferably, tert-butyldimethyl.
[0015] In one embodiment, the present invention provides an
endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0.sup.3,8]un-
decan-10-one
(trans-hexahydro-4-alkoxycarbonyl-8-trialkylsilyloxy-2,6-methano-2H-quino-
lizin-3(4H)-one) compound (referred to as a SQO compound) of
formula XII ##STR6## wherein R is a C.sub.1-6 alkyl or a C.sub.6-8
aryl, preferably, a C.sub.1-4 alkyl, more preferably, methyl, and
R.sub.3R.sub.4R.sub.5 are independently a C.sub.1-6 alkyl or a
C.sub.6-8 aryl, or together are a tert-butyldialkyl, preferably,
tert-butyldimethyl.
[0016] In another embodiment, the present invention provides
crystalline
endo-9-methoxycarbonyl-5-tert-butyldimethylsilyloxy-8-azatricyclo[5.3.1.0-
.sup.3,8]undecan-10-one
(trans-hexahydro-4-methoxycarbonyl-8-tert-butyldimethylsilyloxy-2,6-metha-
no-2H-quinolizin-3(4H)-one) (referred to as SQO).
[0017] In yet another embodiment, the present invention provides a
quaternary ammonium salt of
endo-5-hydroxy-8-azatricyclo[5.3.1.0.sup.3,8]undecan-10-one
(trans-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one)
(referred to as a HQO-salt) of formula IIs; ##STR7## wherein Y is
an acid selected from the group consisting of hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid,
fluoroboric acid, formic acid, acetic acid, propionic acid,
trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaric
acid, succinic acid, oxalic acid, tartaric acid, citric acid,
mandelic acid, benzoic acid, salicylic acid, naphthalene carboxylic
and dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid, naphthalene sulfonic and disulfonic
acids.
[0018] In one embodiment, the present invention provides a process
for the preparation of a CCA-epoxide of formula IV ##STR8##
comprising combining a CCA-ester of formula III, ##STR9## an
oxidizing agent selected from a group consisting of hydroperoxide,
dialkyl peroxide, peroxyacid, peroxyester, diacyl peroxide,
persulphate, perborate, and perphosphate, a catalyst, and a solvent
selected from the group consisting of water, a water miscible
organic solvent, and mixtures thereof, to obtain a CCA-epoxide of
formula IV; wherein, R.sub.1 is C.sub.1-6 alkyl or C.sub.6-8 aryl,
preferably, C.sub.1-4 alkyl, more preferably, methyl.
[0019] In another embodiment, the present invention provides a
process for the preparation of a DLS-salt of formula VIIIs,
##STR10## comprising preparing a CCA-epoxide of formula IV by the
process of the invention; and converting it to a DLS-salt of
formula VIIIs, wherein X is an acid selected from the group
consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, perchloric acid, fluoroboric acid,
formic acid, acetic acid, propionic acid, trichloroacetic acetic,
trifluoroacetic acid, maleic acid, fumaric acid, succinic acid,
oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic
acid, salicylic acid, naphthalene carboxylic and dicarboxylic
acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids, preferably, methane sulfonic acid.
[0020] In yet another embodiment, the present invention provides a
process for the preparation of an OAN compound of formula V
##STR11## comprising combining a CCA-epoxide of formula IV, an
oxidizing agent, and a solvent selected from the group consisting
of water, a water miscible organic solvent, and mixtures thereof,
to form a reaction mixture; raising the pH of the reaction mixture;
and adding to the resulting product a pH 4 buffer, a glycine
C.sub.1-4 ester or salts thereof, and a substance comprising a
carbonyl moiety selected from the group consisting of
1,3-acetonedicarboxylic acids, acetone and C.sub.1-4 esters
thereof, to form an OAN compound of formula V, wherein R.sub.1 and
R.sub.2 are independently, C.sub.1-6 alkyl or C.sub.6-8 aryl,
preferably, C.sub.1-4 alkyl, more preferably, methyl.
[0021] In one embodiment, the present invention provides a process
for the 10 preparation of a DLS-salt of formula VIIIs, comprising
preparing an OAN compound of formula V by the process of the
invention; and converting it to a DLS-salt of formula VIIIs.
[0022] In another embodiment, the present invention provides a
process for the preparation of an OAN compound salt of formula Vs
##STR12## comprising combining an OAN compound of formula V, an
acid, and an organic solvent selected from the group consisting of
a C.sub.1-4 alcohol, a C.sub.2-8 ester, a linear, branched or
cyclic C.sub.2-8 ether, a C.sub.3-6 ketone, a C.sub.5-8 aliphatic
hydrocarbon, a C.sub.1-8 halogenated hydrocarbon, a C.sub.1-4
nitroalkane, a C.sub.1-4 alkylcyanide, a C.sub.6-8 aromatic
hydrocarbon, a C.sub.3-10 amide, and mixtures thereof to form an
OAN salt; wherein R.sub.1 and R.sub.2 are independently, C.sub.1-6
alkyl or C.sub.6-8 aryl, preferably, C.sub.1-4 alkyl, more
preferably, methyl, and Z is an acid, preferably, methanesulfonic
acid.
[0023] In yet another embodiment, the present invention provides a
process for purifying an OAN compound of formula V comprising
combining an OAN compound of formula V, an acid, and an organic
solvent selected from the group consisting of a C.sub.1-4 alcohol,
a C.sub.2-8 ester, a linear, branched or cyclic C.sub.2-8 ether, a
C.sub.3-6 ketone, a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8
halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4
alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide,
and mixtures thereof; and adding a base to obtain a purified OAN
compound.
[0024] In one embodiment, the present invention provides a process
for the preparation of a DLS-salt of formula VIIIs comprising
preparing an OAN compound salt of formula Vs by the process of the
invention, and converting it to a DLS-salt of formula VIIIs.
[0025] In another embodiment, the present invention provides a
process for the preparation of a HAN compound of formula VI
##STR13## comprising combining an OAN compound salt of formula Vs,
a reducing agent, and a solvent selected from the group consisting
of water, water miscible organic solvents and mixtures thereof,
forming a HAN compound of formula VI.
[0026] In yet another embodiment, the present invention provides a
process for the preparation of a HAN compound salt of formula VIs
##STR14## comprising combining a HAN compound of formula VI,
##STR15## an acid, and an organic solvent selected from the group
consisting of a C.sub.1-4 alcohol, a C.sub.2-8 ester, a linear,
branched or cyclic C.sub.2-8 ether, a C.sub.3-6 ketone, a C.sub.5-8
aliphatic hydrocarbon, a C.sub.1-8 halogenated hydrocarbon, a
C.sub.1-4 nitroalkane, a C.sub.1-4 alkylcyanide, a C.sub.6-8
aromatic hydrocarbon, a C.sub.3-10 amide and mixtures thereof,
forming a HAN salt, wherein, Z is an acid, preferably
methanesulfonic acid, R.sub.1 and R.sub.2 are independently,
C.sub.1-6 alkyl or C.sub.6-8 aryl, preferably, C.sub.1-4 alkyl,
more preferably, methyl.
[0027] In yet another embodiment, the present invention provides a
process for the preparation of a DLS-salt of formula VIIIs
comprising preparing a HAN compound of formula VI by the process of
the invention, and converting it to a DLS-salt of formula
VIIIs.
[0028] In one embodiment, the present invention provides a process
for purifying a HAN compound of formula VI comprising combining a
HAN compound of formula VI, an acid, and an organic solvent
selected from the group consisting of a C.sub.1-4 alcohol, a
C.sub.2-8 ester, a linear, branched or cyclic C.sub.2-8 ether, a
C.sub.3-6 ketone, a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8
halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4
alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide,
and mixtures thereof; and adding a base to obtain a purified HAN
compound.
[0029] In another embodiment, the present invention provides a
process for the preparation of a DLS-salt of formula VIIIs
comprising preparing a HAN compound salt of formula VIs by the
process of the invention, and converting it to a DLS-salt of
form.
[0030] In yet another embodiment, the present invention provides a
process for the preparation of a SAN compound of formula X
##STR16## comprising combining a HAN-salt of formula VIs ##STR17##
a silylating agent selected from a group consisting of: silanes,
silyl halogenides, silyl cyanides, silyl amines, silyl amides,
silyl trifluoromethanesulfonates (silyl triflates), and silazanes,
a base, and an aprotic organic solvent to obtain the SAN compound
of formula X, wherein R.sub.1 and R.sub.2 are independently,
C.sub.1-6 alkyl or C.sub.6-8 aryl, preferably, C.sub.1-4 alkyl,
more preferably methyl, R.sub.3R.sub.4R.sub.5 are independently a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, or together are a
tert-butyldialkyl, preferably tert-butyldimethyl, and Z is an acid,
preferably methanesulfonic acid.
[0031] In one embodiment, the present invention provides a process
for the preparation of a DLS-salt of formula VIIIs, comprising
preparing a SAN compound of formula X by the process of the
invention, and converting it to a DLS-salt of formula VIIIs.
[0032] In another embodiment, the present invention also provides a
process for the preparation a SQO compound of formula XII ##STR18##
comprising mixing a SAN compound of formula X, a metal alkoxide,
and a polar aprotic organic solvent to form a mixture; heating the
mixture; and reacting it with a weak acid forming the SQO compound
of formula XII, wherein, R is a C.sub.1-6 alkyl or C.sub.6-8 aryl,
preferably a C.sub.1-4 alkyl, more preferably methyl, and
R.sub.3R.sub.4R.sub.5 are independently a C.sub.1-6 alkyl or a
C.sub.6-8 aryl, or together are a tert-butyldialkyl, preferably,
tert-butyldimethyl.
[0033] In yet another embodiment, the present invention provides a
process for the preparation of a DLS-salt of formula VIIIs,
comprising preparing a SQO compound of formula XII by the process
of the invention, and converting it to a DLS-salt of formula
VIIIs.
[0034] In one embodiment, the present invention also provides a
process for preparing HQO of formula II ##STR19## comprising mixing
a SQO compound of formula XII, water and an acid selected from the
group consisting of hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric
acid, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids to obtain HQO of formula II.
[0035] In another embodiment, the present invention further
provides a process for the preparation of a DLS-salt of formula
VIIIs, comprising preparing HQO of formula II by the process of the
invention, and converting it to a DLS-salt of formula VIIIs.
[0036] In yet another embodiment, the present invention provides
another process for the preparation of a HQO-salt of formula IIs
comprising combining HQO, an alcohol and an acid selected from the
group consisting of: hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric
acid, formic acid, acetic acid, propionic acid, trichloroacetic
acid, trifluoroacetic acid, maleic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, citric acid, mandelic acid,
benzoic acid, salicylic acid, naphthalene carboxylic and
dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid, naphthalene sulfonic, and disulfonic acids,
forming a HQO salt of formula IIs.
[0037] In one embodiment, the present invention provides a process
for purifying HQO of formula II comprising a) combining HQO of
formula II, an alcohol and an acid selected from the group
consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, perchloric acid, fluoroboric acid,
formic acid, acetic acid, propionic acid, trichloroacetic acid,
trifluoroacetic acid, maleic acid, fumaric acid, succinic acid,
oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic
acid, salicylic acid, naphthalene carboxylic and dicarboxylic
acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
benzenesulfonic acid, naphthalene sulfonic, and disulfonic acids;
and b) adding a base, to obtain a purified HQO of formula II.
[0038] In one embodiment, the present invention provides a process
for the preparation of a DLS-salt of formula VIIIs, comprising
preparing a HQO-salt of formula IIs by the process of the
invention, and converting it to a DLS-salt of formula VIIIs.
[0039] In yet another embodiment, the present invention provides a
process for the preparation of a DLS-salt of formula VIIIs,
comprising the steps of a) combining a CCA-ester of formula III, an
oxidizing agent selected from the group consisting of:
hydroperoxides, dialkyl peroxides, peroxyacids, peroxyesters,
diacyl peroxides, persulphate, perborate and perphosphate, a
catalyst and a solvent selected from the group consisting of water,
water miscible organic solvents and mixtures thereof, to form a
first intermediate mixture; b) adding to the first intermediate
mixture an oxidizing agent, and a solvent selected from the group
consisting of water and a water miscible organic solvent, to form a
second intermediate mixture; c) raising the pH of the second
intermediate mixture; d) reacting the products in the second
reaction mixture with a pH 4 buffer, a glycine C.sub.1-4 ester or
salts thereof, and a substance comprising a carbonyl moiety
selected from the group consisting of 1,3 acetonedicarboxylic
acids, acetone and a C.sub.1-4 ester thereof, to form a third
reaction mixture; e) adding to the third intermediate mixture a
reducing agent, and a solvent selected from the group consisting of
water, water miscible organic solvents and mixtures thereof, to
form a fourth intermediate mixture; f) adding to the fourth
intermediate mixture a silylating agent selected from a group
consisting of: silanes, silyl halogenides, silyl cyanides, silyl
amines, silyl amides, silyl trifluoromethanesulfonates (silyl
triflates), and silazanes, a base, and an aprotic organic solvent
to form a fifth intermediate mixture; g) adding to the fifth
intermediate mixture a metal alkoxide, and a polar aprotic organic
solvent to form a sixth intermediate mixture; h) heating the sixth
intermediate mixture; i) reacting the products in the sixth
intermediate mixture with a weak acid forming a seventh
intermediate mixture; j) adding to the seventh intermediate mixture
water and an acid to form an eight intermediate mixture; k) mixing
the eight intermediate mixture with an anhydride, 3-indole
carboxylic acid, a halogenated hydrocarbon, and a catalyst; and 1)
reacting the product from step k) with an acid to obtain the
DLS-salt of formula VIIIs.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 illustrates powder X-ray diffraction pattern for
OAN-MsOH.
[0041] FIG. 2 illustrates powder X-ray diffraction pattern for
HAN-MsOH.
[0042] FIG. 3 illustrates powder X-ray diffraction pattern for
SQO.
[0043] FIG. 4 illustrates powder X-ray diffraction pattern for
HQO-HCl.
[0044] FIG. 5 illustrates powder X-ray diffraction pattern for
HQO-CSA.
[0045] FIG. 6 illustrates powder X-ray diffraction pattern for
HQO-base.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention offers novel intermediates in the
syntheses of Dolasetron salts, and processes for preparing them.
The invention also offers the use of these intermediates in novel
processes for preparing Dolasetron salts, especially, the mesylate
salt.
[0047] The present invention provides a process for the preparation
of a DLS-salt of formula VIIIs, comprising the steps of a)
combining a CCA-ester of formula III, an oxidizing agent selected
from the group consisting of: hydroperoxides, dialkyl peroxides,
peroxyacids, peroxyesters, diacyl peroxides, persulphate, perborate
and perphosphate, a catalyst and a solvent selected from the group
consisting of water, water miscible organic solvents and mixtures
thereof, to form CCA-epoxide of formula IV; b) admixing CCA-epoxide
with an oxidizing agent, and a solvent selected from the group
consisting of water and a water miscible organic solvent; c)
raising the pH of the mixture; d) admixing the mixture with a pH 4
buffer, a glycine C.sub.1-4 ester or salts thereof, and a substance
comprising a carbonyl moiety selected from the group consisting of
1,3 acetonedicarboxylic acids, acetone and a C.sub.1-4 ester
thereof, to form OAN of formula V; e) admixing the material of the
previous step with a reducing agent, and a solvent selected from
the group consisting of water, water miscible organic solvents and
mixtures thereof, to form HAN of formula VI; f) admixing the
material of the previous step with a silylating agent selected from
a group consisting of: silanes, silyl halogenides, silyl cyanides,
silyl amines, silyl amides, silyl trifluoromethanesulfonates (silyl
triflates), and silazanes, a base, and an aprotic organic solvent
to form SAN of formula X; g) admixing the material of the previous
step with a metal alkoxide, and a polar a-protic organic solvent to
form a reaction mixture; h) heating the reaction mixture; i)
quenching the reaction mixture with a with a weak acid forming SQO
of formula XII; j) admixing the material of the previous step with
a solvent selected from a group consisting of: water, and
water-immiscible organic solvent, and an acid to form HQO of
formula II; k) admixing the material of the previous step with an
anhydride, 3-indole carboxylic acid, a halogenated hydrocarbon, and
a catalyst to obtain Dolasetron base; and 1) reacting Dolasetron
base with an acid to obtain the DLS-salt of formula VIIIs.
Preferably, the weak acid in step i) is selected from the group
consisting of acetic acid, formic acid, acetic acid, propionic
acid, maleic acid, fumaric acid, succinic acid, oxalic acid,
tartaric acid, citric acid, mandelic acid, benzoic acid, and
salicylic acid. Preferably, the acid in step j) is selected from
the group consisting of hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid,
fluoroboric acid, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids. Preferably, the acid in step l) is selected
from the group consisting of hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid,
fluoroboric acid, formic acid, acetic acid, propionic acid,
trichloroacetic acetic, trifluoroacetic acid, maleic acid, fumaric
acid, succinic acid, oxalic acid, tartaric acid, citric acid,
mandelic acid, benzoic acid, salicylic acid, naphthalene carboxylic
and dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids, preferably, methane sulfonic acid. In the
alternative, the weak acid in step i) can be a (strong) acid as in
step j), in which instant the step j) of this process may be
omitted.
[0048] The process can be illustrated by the following scheme:
##STR20##
[0049] The present invention provides a quaternary ammonium salt of
a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one
compound (referred to as an OAN-salt) of formula Vs; ##STR21##
wherein R.sub.1 and R.sub.2 are independently a C.sub.1-6 alkyl or
a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl, more preferably,
methyl, and Z is an acid, preferably, methanesulfonic acid.
[0050] When R.sub.1 and R.sub.2 are methyl, and Z is
methanesulfonic acid, said compound of formula Vs refers to the
methanesulfonate salt of
7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-o-
ne (referred to as OAN-MsOH) of the following formula.
##STR22##
[0051] The present invention further provides crystalline OAN-MsOH.
The crystalline OAN-MsOH of the present invention may be
characterized by a powder XRD diffraction pattern having peaks at
about 8.5, 18.0, and 20.9 degrees two-theta, .+-.0.2 degrees
two-theta. Crystalline OAN-MsOH may be further characterized by a
powder XRD diffraction pattern having peaks at about 14.7, 22.7,
24.3, 25.0, 26.3 and 27.9 degrees two-theta, .+-.0.2 degrees
two-theta. Crystalline OAN-MsOH may be also substantially
identified by the PXRD pattern as depicted in FIG. 1.
[0052] The present invention also provides a quaternary ammonium
salt of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol
compound (referred to as a HAN-salt) of formula VIs; ##STR23##
wherein R.sub.1, R.sub.2 and Z are described before.
[0053] When R.sub.1 and R.sub.2 are methyl, and Z is
methanesulfonic acid, said compound of formula VIs refers to the
methanesulfonate salt of
7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol
(referred to as HAN-25 MsOH) of the following formula.
##STR24##
[0054] The present invention provides crystalline HAN-MsOH. The
crystalline HAN-MsOH of the present invention may be characterized
by a powder XRD diffraction pattern having peaks at about 7.3,
11.6, and 14.6 degrees two-theta, .+-.0.2 degrees two-theta. The
crystalline HAN-MsOH may be further characterized by a powder XRD
diffraction pattern having peaks at about 15.9, 17.9, 19.0, 20.4,
21.9, 29.0 and 29.4 degrees two-theta, .+-.0.2 degrees two-theta.
The crystalline HAN-MsOH may be also substantially identified by
the PXRD pattern as depicted in FIG. 2.
[0055] The present invention further provides a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo-
[3.3.1]nonane compound (referred to as a SAN compound) of formula
X; ##STR25## wherein R.sub.1 and R.sub.2 are described before.
[0056] When R.sub.1 and R.sub.2 are methyl, and
R.sub.3R.sub.4R.sub.5 is tert-butyldimethyl, said compound of
formula X refers to
7-methoxycarbonyl-9-(methoxycarbonylmethyl)-3-tert-butyldimethylsilyloxy--
9-azabicyclo[3.3.1]nonane (referred to as SAN) of the following
formula. ##STR26##
[0057] The present invention also provides an
endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0.sup.3,8]un-
decan-10-one
(trans-hexahydro-4-alkoxycarbonyl-8-trialkylsilyloxy-2,6-methano-2H-quino-
lizin-3(4H)-one) compound (referred to as a SQO compound) of
formula XII ##STR27## wherein R is a C.sub.1-6 alkyl or a C.sub.6-8
aryl, preferably, a C.sub.1-4 alkyl, more preferably, methyl, and
R.sub.3R.sub.4R.sub.5 are independently a C.sub.1-6 alkyl or a
C.sub.6-8 aryl, preferably, tert-butyldialkyl, more preferably,
tert-butyldimethyl.
[0058] Preferably, when R is methyl and R.sub.3R.sub.4R.sub.5 is
tert-butyldimethyl, said compound of formula XII refers to
endo-9-methoxycarbonyl-5-tert-butyldimethylsilyloxy-8-azatricyclo[5.3.1.0-
.sup.3,8]undecan-10-one
(trans-hexahydro-4-methoxycarbonyl-8-tert-butyldimethylsilyloxy-2,6-metha-
no-2H-quinolizin-3(4H)-one) (referred to as SQO) of the following
formula. ##STR28##
[0059] The present invention provides crystalline SQO. The
crystalline SQO of the present invention may be characterized by an
XRD diffraction pattern having peaks at about 5.1, 10.1, 12.7, and
20.3 degrees two-theta, .+-.0.2 degrees two-theta. The crystalline
SQO may be further characterized by an XRD diffraction pattern
having peaks at about 15.2, 17.0, 17.6, 18.3, 19.1, and 19.8
degrees two-theta, .+-.0.2 degrees two-theta. The crystalline SQO
may be also substantially identified by the PXRD pattern as
depicted in FIG. 3.
[0060] The present invention further provides a quaternary ammonium
salt of endo-5-hydroxy-8-azatricyclo[5.3.1.0.sup.3,8]undecan-10-one
(trans-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one)
(referred to as a HQO-salt) of formula IIs; ##STR29## wherein Y is
an acid selected from the group consisting of: hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,
perchloric acid, fluoroboric acid, formic acid, acetic acid,
propionic acid, trichloroacetic acetic, trifluoroacetic acid,
maleic acid, fumaric acid, succinic acid, oxalic acid, tartaric
acid, citric acid, mandelic acid, benzoic acid, salicylic acid,
naphthalene carboxylic and dicarboxylic acids, methanesulfonic
acid, ethanesulfonic acid, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids, preferably, methanesulfonic acid.
[0061] Preferably, when Y is HCl, said HQO-salt of formula IIs
corresponds to HQO-HCl of the following formula. ##STR30##
[0062] The present invention provides crystalline HQO-HCl salt. The
crystalline HQO-HCl salt of the present invention may be
characterized by a powder XRD diffraction pattern as depicted in
FIG. 4.
[0063] The present invention also provides a process for the
preparation of a CCA-epoxide of formula IV ##STR31## comprising
combining a CCA-ester of formula III, ##STR32## an oxidizing agent
selected from the group consisting of: a hydroperoxide, a dialkyl
peroxide, a peroxyacid, a peroxyester, a diacyl peroxide, a
persulphate, a perborate, a perphosphate, and a dimethyldioxiran, a
catalyst, and a solvent selected from the group consisting of
water, water miscible organic solvents, and mixtures thereof, to
obtain the CCA-epoxide of formula IV, wherein R.sub.1 is a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl,
more preferably, methyl.
[0064] When R.sub.1 is methyl, said CCA-ester of formula III
corresponds to CCA-methylester of the following formula, ##STR33##
and said CCA-epoxide of formula IV corresponds to CCA-epoxide of
the following formula. ##STR34##
[0065] Preferably, the CCA-ester of formula III is combined with a
solvent selected from the group consisting of water, water miscible
organic solvents, and mixtures thereof, to obtain a solution.
[0066] Preferably, the water miscible organic solvent is selected
from the group consisting of linear or branched C.sub.1-4 alcohols.
Preferably, the C.sub.1-4 alcohol is a C.sub.1-3 alcohol, more
preferably, a C.sub.1-2 alcohol, most preferably, methanol. In the
alternative, a mixture of water and a water immiscible organic
solvent may be used in the presence of a phase transfer catalyst.
Preferably, the water immiscible organic solvent is selected from
the group consisting of a C.sub.1-8 halogenated hydrocarbon, a
C.sub.2-8 ester, a C.sub.2-8 ether and a C.sub.3-6 ketone. A
preferred C.sub.1-8 halogenated hydrocarbon is a C.sub.1-4
halogenated hydrocarbon, more preferably a C.sub.1-2 halogenated
hydrocarbon. Preferably, the C.sub.1-2 halogenated hydrocarbon is
dichloromethane, 1,2-dichloroethane or chloroform, more preferably
dichloromethane. A preferred C.sub.2-8 ester is a C.sub.2-6 ester,
more preferably, a C.sub.4-6 ester. Preferably, the C.sub.4-6 ester
is ethyl acetate, n-butyl acetate or isobutyl acetate, more
preferably ethyl acetate. A preferred C.sub.2-8 ether is a
C.sub.2-6 ether, more preferably, a C.sub.4-6 ether. Preferably,
the C.sub.4-6 ether is diethyl ether, diisopropyl ether or
tert-butyl methyl ether, more preferably tert-butyl methyl ether. A
preferred C.sub.3-6 ketone is a C.sub.4-6 ketone. Preferably, the
C.sub.4-6 ketone is methyl ethyl ketone (2-butanone), 2-pentanone,
3-pentanone or 3,3-dimethyl-2-butanone, more preferably
2-pentanone. The most preferred solvent is dichloromethane.
Further, the phase transfer catalyst is preferably a quaternary
ammonium salt, more preferably the phase transfer catalyst is
tetrabutyl ammonium bromide.
[0067] Preferably, the solution is combined with an oxidizing agent
selected from the group consisting of: a hydroperoxide, a dialkyl
peroxide, a peroxyacid, a peroxyester, a diacyl peroxide, a
persulphate, a perborate, a perphosphate, and a dimethyldioxiran,
and a catalyst, to obtain a mixture.
[0068] Preferably, the hydroperoxide is RO--OH, wherein R is either
H or an alkyl group. Preferably, the alkyl group is a C.sub.1-6
alkyl, more preferably t-butyl. A preferred dialkyl peroxide is
RO--OR, wherein R is a C.sub.1-6 alkyl, preferably t-butyl.
Preferably, the peroxyacid is RCO--O--OH. More preferably, the
RCO--O--OH is selected from the group consisting of: peracetic
acid, trifluoroperacetic acid, perlauric acid, perbenzoic acid, and
3,5-dinitroperbenzoic acid. Preferably, the peroxyester is
RCO--O--OR', wherein R is phenyl or methyl, and R' is an C.sub.1-6
alkyl, preferably t-butyl. A preferred diacyl peroxide is
RCO--O--O--COR, wherein R is phenyl or methyl. A preferred
persulphate is peroxydisulphuric acid (M.sub.2S.sub.2O.sub.8) in
the form of a potassium, sodium or ammonium (M=K, Na, NH.sub.4)
salt, peroxymonosulfuric acid (Caro's acid), and Oxone.RTM.
(potassium monopersulfate triple salt:
KHSO.sub.5--KHSO.sub.4--K.sub.2SO.sub.4 (2:1:1)"). The more
preferred oxidizing agent is hydroperoxide, most preferably,
hydrogen peroxide. Preferably, an aqueous solution of hydrogen
peroxide is used. A preferred concentration of the solution is of
about 3% to about 50%, more preferably of about 20% to about 40%,
most preferably of about 30% to about 35%.
[0069] Preferably, the catalyst is selected from the group
consisting of Zeolites and polyoxometalates. Preferably, the metal
moiety of the polyoxometalates is selected from the group
consisting of tungsten, molybdenum, rhenium, vanadium and niobium.
More preferably, the catalyst is either sodium tungstate dihydrate
or sodium molybdenate dihydrate.
[0070] A preferred amount of the catalyst is about 0.01 mole % to
about 50 mole % per mole of the CCA-ester, more preferably about 1
mole % to about 10 mole % per mole of the CCA-ester, most
preferably about 2 mole % per mole of the CCA-ester.
[0071] In preparing the CCA epoxide of formula IV, the reaction
mixture is maintained at a temperature of about 0.degree. C. to
about 80.degree. C., preferably about 30.degree. C. to about
80.degree. C., more preferably, at a temperature of about
15.degree. C. to about 65.degree. C., most preferably at a
temperature of about 60.degree. C. to about 65.degree. C. The
reaction mixture is preferably, maintained at such temperature for
a period of about 0.5 hours to about 24 hours, more preferably for
about 1 to about 10 hours, most preferably for about 2 hours to
about 4 hours.
[0072] The progress of the reaction may be monitored by
gas-chromatography (referred to as GC) or by thin-layer
chromatography (referred to as TLC). When monitored by TLC, an
eluent of n-hexane and ethylacetate in a ratio of 1:1 may be
used.
[0073] The process for preparing a CCA-ester of formula IV may
further comprise a recovery step. The CCA-epoxide of formula IV may
be recovered comprising the steps of adjusting the temperature of
the reaction mixture to a temperature of about 20.degree. C. to
about 30.degree. C.; extracting the product with a water immiscible
organic solvent, preferably, dichloromethane; and evaporating the
solvent.
[0074] The process for preparing a CCA-ester of formula IV may
further comprise a process for converting it to a DLS-salt of
formula VIIIs, ##STR35## wherein, X is an acid selected from the
group consisting of: hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, perchloric acid, fluoroboric
acid, formic acid, acetic acid, propionic acid, trichloroacetic
acetic, trifluoroacetic acid, maleic acid, fumaric acid, succinic
acid, oxalic acid, tartaric acid, citric acid, mandelic acid,
benzoic acid, salicylic acid, naphthalene carboxylic and
dicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid,
camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic
and disulfonic acids, preferably, methane sulfonic acid. This
conversion to a DLS salt of formula VIIIs may be carried out by the
process of the invention or any other known process converting the
CCA epoxide of formula IV to a DLS salt of formula VIIIs as
described for example in EP 0339699, example 9.
[0075] When X is methane sulfonic acid, said DLS-salt of formula
VIIIs corresponds to DLS-MsOH of the following formula.
##STR36##
[0076] The process of the present invention provides an OAN
compound of formula V prepared by a process comprising an oxidation
reaction followed by Robinson-Schopf reaction, wherein both
reactions are done in water, and therefore can be done
concurrently, i.e., without isolation of the oxidation product,
prior to the Robinson-Schopf reaction. The oxidation applies the
use of periodic acid in water, in which the reagents and the
reduction products have high solubility; hence, the reaction is
fast. Also, using water allows controlling the exothermic nature of
the reaction, thus, reducing the danger.
[0077] The present invention further provides a process for the
preparation of an OAN compound of formula V ##STR37## comprising
combining a) a CCA-epoxide of formula IV, an oxidizing agent, and a
solvent selected from the group consisting of water, water miscible
organic solvents, and mixtures thereof, to form a reaction mixture;
b) raising the pH of the reaction mixture; c) and adding to the
reaction mixture of step b) a pH 4 buffer, glycine C.sub.1-4 ester
or salts thereof, and a substance comprising carbonyl moiety
selected from the group consisting of 1,3-acetonedicarboxylic acid,
acetone and a C.sub.1-4 ester thereof, to form the OAN compound of
formula V, wherein R.sub.1 and R.sub.2 are independently a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl,
more preferably, methyl.
[0078] When R.sub.1 and R.sub.2 are methyl, said OAN compound of
formula V corresponds to OAN of the following formula.
##STR38##
[0079] Combining a CCA-epoxide of formula IV, an oxidizing agent,
and a solvent selected from the group consisting of water, water
miscible organic solvents, and mixtures thereof, to form a reaction
mixture; and raising the pH of the reaction mixture, may be
designated as an oxidation reaction.
[0080] Preferably, combining a CCA-epoxide of formula IV with an
oxidizing agent, and a solvent selected from the group consisting
of water, water miscible organic solvent and mixtures thereof
provides a first reaction mixture.
[0081] Preferably, the water miscible organic solvent is selected
from the group consisting of: a nitrile, a ketone and an ether. A
preferred nitrile is a C.sub.2-4 nitrile. Preferably, the C.sub.2-4
nitrile is acetonitrile, propionitrile or butyronitrile. A
preferred ketone is a C.sub.3-6 ketone. Preferably, the C.sub.3-6
ketone is acetone, methyl ethyl ketone or diethyl ketone.
Preferably, the ether is a cyclic ether. A preferred cyclic ether
is THF, 1,4-dioxane or 1,3-dioxolane. The preferred solvent is
water.
[0082] Preferably, the oxidizing agent is selected from the group
consisting of: periodic acid and salts thereof, lead tetraacetate,
cerium and ammonium nitrate (Ce(NH.sub.4).sub.2(NO.sub.3).sub.6).
More preferably, the oxidizing agent is periodic acid. Preferably,
the oxidizing agent is added in the form of a solution when the
solvent is water.
[0083] Preferably, the first reaction mixture is maintained at a
temperature of about 10.degree. C. to about 60.degree. C., more
preferably at a temperature of about 10.degree. C. to about
15.degree. C. Preferably, the first mixture is maintained for a
period of about 0.5 hours to about 24 hours, and more preferably
for about 1 to about 3 hours. Maintaining the first reaction
mixture is preferably done while stirring.
[0084] The first reaction mixture is, preferably, acidic.
Preferably, the pH of the acidic first reaction mixture is of about
0.5 to about 7, more preferably of about 0.5 to about 2.
[0085] Preferably, the pH of the maintained first reaction mixture
is increased to about 2 to about 7. The pH is raised, preferably to
about 3.5 to about 4.5. Preferably, the pH is raised by using a
water immiscible base, more preferably either poly(4-vinylpyridine)
or OH resins, and even more preferably, OH resins. The water
immiscible base is, preferably, filtered off, more preferably
through Celite, providing an aqueous solution of the product of the
oxidation reaction. Preferably, adjusting the pH is performed at a
temperature of about 15.degree. C. to about 35.degree. C., more
preferably at about room temperature.
[0086] The reaction may be run stepwise or concurrently, i.e.,
without isolation of the oxidation product prior to the
Robinson-Schopf reaction. Preferably, the process is run
concurrently.
[0087] Preferably, after adjusting the pH, a pH 4 buffer, a glycine
C.sub.1-4 ester or salts thereof, and a substance comprising
carbonyl moiety selected from the group consisting of a
1,3-acetonedicarboxylic acids, acetone and C.sub.1-4 esters
thereof, are added to obtain a second reaction mixture.
[0088] Preferably, the pH 4 buffer is an amine-free buffer.
Preferably, the amine-free buffer is selected from the group
consisting of: a citric acid-sodium hydroxide-hydrochloric acid
buffer, a citric acid-disodium hydrogenphosphate buffer, a sodium
acetate-acetic acid buffer, a potassium diphthalate-sodium
hydroxide buffer, sodium dihydrogen phosphate and potassium
hydrogen phthalate. More preferably, the amine-free buffer is
potassium hydrogen phthalate. Preferably, the buffer is used in an
amount of about 1 to about 10 mole equivalents, more preferably
about 2 to 5 mole equivalents, most preferably about 3 mole
equivalents, per mole equivalent of the CCA-epoxide.
[0089] Preferably, the glycine C.sub.1-4 ester is a methyl ester. A
preferred salt of the glycine C.sub.1-4 ester is glycine
hydrochloride. More preferably, the glycine C.sub.1-4 ester or
salts thereof, is glycin methylester hydrochloride.
[0090] Preferably, the C.sub.1-4 ester of 1,3-acetonedicarboxylic
acid is selected from the group consisting of symmetrical and mixed
C.sub.1-4 ester derivatives. The preferred substance comprising a
carbonyl moiety is 1,3-acetonedicarboxylic acid.
[0091] Preferably, the second reaction mixture is maintained at a
temperature of about 0.degree. C. to about 60.degree. C., more
preferably, at about 10.degree. C. to about 40.degree. C., most
preferably at about room temperature. The second mixture is
maintained, preferably for about 10 to about 72 hours, and more
preferably for about 12 to about 24 hours, most preferably for
about 18 hours. Maintaining the second reaction mixture is
preferably done while stirring.
[0092] The process for preparing the OAN compound of formula V may
further comprise a recovery step. The recovery may be done by any
known process. The OAN compound of formula V may be recovered by
filtering off the undissolved solid particles from the second
reaction mixture, preferably, through Celite, followed by washing
with water, and combining the filtrate with an inorganic base to
obtain a pH of about 7 to about 9, more preferably, of about 7.5 to
about 8. Preferably, the inorganic base is selected from the group
consisting of sodium hydroxide, sodium carbonate, sodium
bicarbonate, potassium hydroxide, potassium carbonate and potassium
bicarbonate, more preferably is sodium bicarbonate. The basic
filtrate is then extracted with a water immiscible organic solvent,
preferably a C.sub.2-5 acetate, more preferably isobutylacetate,
and the solvent is evaporated.
[0093] The present invention also provides a process for the
preparation of a DLS-salt of formula VIIIs comprising preparing the
OAN compound of formula V by the process of the invention, and
converting it to a DLS-salt of formula VIIIs. This conversion to a
DLS salt of formula VIIIs may be carried out by the process of the
invention or any other known process converting an OAN compound of
formula V to a DLS salt of formula VIIIs as described for example
in EP 0339699, examples 4 and 9.
[0094] The present invention provides a process for the preparation
of an OAN-salt of formula Vs ##STR39## comprising reacting the OAN
compound of formula V, an acid, and an organic solvent selected
from the group consisting of a C.sub.1-4 alcohol, a C.sub.2-8
ester, a linear, branched or cyclic C.sub.2-8 ether, a C.sub.3-6
ketone and a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8
halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4
alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide
and mixtures thereof, wherein, R.sub.1 and R.sub.2 are described
before, and Z is an acid, preferably, methanesulfonic acid.
[0095] The present invention further provides a process for
purifying the OAN compound of formula V comprising reacting the OAN
compound of formula V, an acid, and an organic solvent selected
from the group consisting of a C.sub.1-4 alcohol, a C.sub.2-8
ester, a linear, branched or cyclic C.sub.2-8 ether, a C.sub.3-6
ketone and a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8
halogenated hydrocarbon, a C.sub.1-4nitroalkane, a C.sub.1-4
alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide
and mixtures thereof; and adding a base.
[0096] The OAN compound of formula V used as a starting material
may be a crude OAN compound or a concentrated solution of a crude
OAN compound, obtained in the recovery process of the OAN
compound.
[0097] Preferably, the OAN compound of formula V is dissolved in an
organic solvent selected from the group consisting of a C.sub.1-4
alcohol, a C.sub.2-8 ester, a linear, branched or cyclic C.sub.2-8
ether, a C.sub.3-6 ketone and a C.sub.5-8 aliphatic hydrocarbon, a
C.sub.1-8 halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a
C.sub.1-4 alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a
C.sub.3-10 amide and mixtures thereof, prior to adding the
acid.
[0098] Preferably, the C.sub.1-4 alcohol is a C.sub.1-3 alcohol.
Preferably, the C.sub.1-3 alcohol is methanol, n-propanol,
isopropanol or ethanol. A preferred C.sub.2-8 ester is a C.sub.2-6
ester, more preferably, a C.sub.2-4 ester. A preferred C.sub.2-4
ester is ethyl acetate, propylacetate, n-butyl acetate, or
isobutylacetate. A preferred linear, branched or cyclic C.sub.2-8
ether is a C.sub.2-7 ether, more preferably, a C.sub.2-5 ether. A
preferred C.sub.2-5 ether is 1,4-dioxane, diisopropyl ether,
t-butyl methyl ether or tetrahydrofuran. Preferably, the C.sub.3-6
ketone is a C.sub.3-5 ketone. Preferably, the C.sub.3-5 ketone is
methyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone,
3,3-dimethyl-2-butanone or acetone. Preferably, the C.sub.5-8
aliphatic hydrocarbon is a C.sub.5-7 aliphatic hydrocarbon, more
preferably, a C.sub.6-7 aliphatic hydrocarbon. A preferred
C.sub.6-7 aliphatic hydrocarbon is either n-hexane, or n-heptane. A
preferred C.sub.1-8 halogenated hydrocarbon is a C.sub.1-6
halogenated hydrocarbon, more preferably a C.sub.1-4 halogenated
hydrocarbon, most preferably a C.sub.1-2 halogenated hydrocarbon. A
preferred C.sub.1-2 halogenated hydrocarbon is dichloroethane,
chloroform or dichloromethane. A preferred C.sub.1-4 nitroalkane is
a C.sub.1-2 nitroalkane. Preferably, the C.sub.1-2 nitroalkane is
nitromethane or nitroethane. Preferably, the C.sub.1-4 alkylcyanide
is a C.sub.1-3 alkylcyanide. A preferred C.sub.1-3 alkylcyanide is
either propionitrile or acetonitrile. A preferred C.sub.6-8
aromatic hydrocarbon is a C.sub.6-7 aromatic hydrocarbon.
Preferably, the C.sub.6-7 aromatic hydrocarbon is toluene. A
preferred C.sub.3-10 amide is a C.sub.3-6 amide. Preferably, the
C.sub.3-6 amide is dimethylformamide. The more preferred solvent is
a mixture of a C.sub.2-4 ester and a C.sub.1-3 alcohol, more
preferably, of isobutylacetate and ethanol. Preferably, the mixture
contains isobutylacetate and ethanol in a ratio of about 1:1,
respectively.
[0099] Preferably, the acid is either an organic acid or an
inorganic acid. The organic acid is selected from the group
consisting of carboxylic acids and sulfonic acids. Preferably, the
carboxylic acid is selected from the group consisting of: formic
acid, acetic acid, propionic acid, trichloroacetic acetic,
trifluoroacetic acid, maleic acid, fumaric acid, succinic acid,
oxalic acid, tartaric acid, citric acid, mandelic acid, benzoic
acid, salicylic acid, naphthalene carboxylic and dicarboxylic
acids. More preferably, the carboxylic acid is tartaric acid. A
preferred sulfonic acid is selected from the group consisting of:
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
acid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic
acid, naphthalene sulfonic and disulfonic acids. More preferably,
the sulfonic acid is either methane sulfonic acid or
camphorsulfonic acid. Preferably, the inorganic acid is selected
from the group consisting of: hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and
fluoroboric acid. The more preferred inorganic acid is hydrochloric
acid. The more preferred acid is methane sulfonic acid.
[0100] Combining the OAN compound of formula V, the solvent and the
acid provides a mixture. Preferably, the mixture is maintained at a
temperature of about 10.degree. C. to about 60.degree. C., more
preferably, at a temperature of about 20.degree. C. to about
50.degree. C., most preferably at a temperature of about 30.degree.
C. to about 40.degree. C. The mixture is preferably maintained at
such temperature for about 1 hour to about 24 hours, and more
preferably, for about 2 to about 12 hours. Maintaining the reaction
mixture is preferably done while stirring.
[0101] Preferably, reacting the OAN compound with an acid provides
the corresponding OAN-salt of formula Vs. Preferably, the OAN-salt
of formula Vs precipitates from the reaction mixture. Preferably,
in the process of purifying the OAN compound of formula V, the
precipitate is reacted with a base providing the OAN compound of
formula V back again. Preferably, the precipitate is recovered
prior to reacting with a base.
[0102] Preferably, the base is selected from the group consisting
of sodium hydroxide, sodium carbonate, sodium bicarbonate,
potassium hydroxide, potassium carbonate and potassium bicarbonate.
More preferably, the base is sodium bicarbonate.
[0103] The process for preparing an OAN-salt of formula Vs may
further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0104] The present invention provides a process for the preparation
of a HAN compound of formula VI ##STR40## comprising combining an
OAN salt of formula Vs, a reducing agent, and a solvent selected
from the group consisting of water, water miscible organic solvents
and mixtures thereof to obtain the HAN compound of formula VI.
[0105] Preferably, the OAN-salt of formula Vs is OAN-MsOH. When the
OAN-salt is used as a starting material, it is combined with a
water miscible organic solvent, providing a suspension. Preferably,
the suspension is prepared at a temperature of about 15.degree. C.
to about 35.degree. C., preferably of about 20.degree. C. to about
25.degree. C. Optionally, the OAN compound of formula V may be used
as a starting material. When, the OAN compound of formula V is used
as a starting material, it is combined with a water miscible
organic solvent, providing a solution. Preferably, the water
miscible organic solvent is a C.sub.1-4 alcohol, more preferably, a
C.sub.1-3 alcohol, most preferably, a C.sub.1-2 alcohol. A
preferred C.sub.1-2 alcohol is methanol.
[0106] Preferably, the reducing reagent is a metal hydride complex,
preferably lithium borohydride, selectricde or sodium borohydride,
more preferably, sodium borohydride. The reducing agent may be used
in a basic aqueous solution or as a solid. When the OAN compound of
formula V is the starting material, a basic aqueous solution of the
reducing agent may be used. Preferably, the basic aqueous solution
is an aqueous solution of an alkali hydroxide, more preferably an
aqueous solution of sodium hydroxide. Preferably, the basic aqueous
solution contains about 30% to about 50% by weight, preferably
about 30%, of sodium hydroxide.
[0107] Preferably, the solution of the OAN compound of formula V in
a C.sub.1-4 alcohol and the basic aqueous solution of the reducing
agent are combined at a temperature of about 0.degree. C. to about
10.degree. C., preferably about 0.degree. C. to about 5.degree. C.
Preferably, the solution of the reducing reagent is added drop-wise
to the solution of the OAN compound in a C.sub.1-4 alcohol.
[0108] When the OAN-salt of formula Vs is the starting material, a
solid reducing agent may be used. Preferably, the suspension of the
OAN-salt of formula Vs in a C.sub.1-4 alcohol and the reducing
agent are combined at a temperature of about 15.degree. C. to about
35.degree. C., preferably about 20.degree. C. to about 25.degree.
C. Preferably, the reducing reagent is added portion-wise to the
suspension of the OAN-salt in a C.sub.1-4 alcohol. Preferably, the
portion-wise addition of the reducing agent is done while
maintaining the temperature at about 15.degree. C. to about
35.degree. C., preferably about 25.degree. C. to about 35.degree.
C.
[0109] Combining the above substances leads to a mixture.
Preferably, the mixture is maintained for about a half hour to
about 2 hours, preferably for about a half hour to about an hour at
such temperature, prior to recovering the HAN compound of formula
VI.
[0110] When the OAN compound of formula V is used as a starting
material, the mixture is maintained at a temperature of about
0.degree. C. to about 5.degree. C., for about an hour, and when the
starting material is OAN-salt of formula Vs, the mixture is
maintained at a temperature of about 25.degree. C. to about
35.degree. C., for about a half an hour. The reaction may be
monitored by TLC using ethylacetate as an eluent.
[0111] The process for preparing the HAN compound of formula VI may
further comprise a recovery step. The recovery may be carried out
by any known method. The HAN compound of formula VI may be
recovered by a process comprising adding an acid, preferably a
water miscible organic acid, more preferably acetic acid, to the
reaction mixture, to give a precipitate. The precipitate is then
combined with water and with a halogenated hydrocarbon, preferably
a C.sub.1-2 halogenated hydrocarbon, to give a solution, optionally
followed by filtration. The aqueous phase is then extracted, and
the solvent is evaporated form the combined organic phase,
providing a crude HAN compound. Optionally, after adding acetic
acid, the mixture is evaporated and the residue is combined with
ethylacetate. The undissolved particles are then, filtered off, and
the filtrate is concentrated, providing a crude HAN compound.
[0112] The present invention further provides a process for the
preparation of a HAN-salt of formula VIs, ##STR41## comprising
reacting the HAN compound of formula VI, ##STR42## an acid, and an
organic solvent selected from the group consisting of a C.sub.1-4
alcohol, a C.sub.2-8 ester, a linear, branched or cyclic C.sub.2-8
ether, a C.sub.3-6 ketone and a C.sub.5-8 aliphatic hydrocarbon, a
C.sub.1-8 halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a
C.sub.1-4 alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a
C.sub.3-10 amide, and mixtures thereof, wherein, Z, R.sub.1 and
R.sub.2 are described before.
[0113] When R.sub.1 and R.sub.2 are methyl, said HAN compound of
formula VI corresponds to HAN of the following formula, ##STR43##
and when R.sub.1 and R.sub.2 are methyl Z is methane sulfonic acid,
said HAN-salt of formula VIs corresponds to HAN-MsOH of the
following formula. ##STR44##
[0114] The process for preparing the HAN compound of formula VI may
further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0115] The present invention also provides a process for purifying
the HAN compound of formula VI comprising combining the HAN
compound of formula VI, an acid, and an organic solvent selected
from the group consisting of a C.sub.1-4 alcohol, a C.sub.2-8
ester, a linear, branched or cyclic C.sub.2-8 ether, a C.sub.3-6
ketone and a C.sub.5-8 aliphatic hydrocarbon, a C.sub.1-8
halogenated hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4
alkylcyanide, a C.sub.6-8 aromatic hydrocarbon, a C.sub.3-10 amide,
and mixtures thereof; and adding a base.
[0116] The HAN compound of formula VI used as a starting material
may be a crude HAN compound.
[0117] Preferably, the HAN compound of formula VI is dissolved in
an organic solvent selected from the group consisting of a
C.sub.1-4 alcohol, a C.sub.2-8 ester, linear, branched or cyclic
C.sub.2-8 ethers, a C.sub.3-6 ketone and a C.sub.5-8 aliphatic
hydrocarbon, a C.sub.1-8 halogenated hydrocarbon, a C.sub.1-4
nitroalkane, a C.sub.1-4 alkylcyanide, a C.sub.6-8 aromatic
hydrocarbon, a C.sub.3-10 amide, and mixtures thereof, prior to
adding the acid.
[0118] Preferably, the C.sub.1-4 alcohol is a C.sub.1-3 alcohol.
Preferably, the C.sub.1-3 alcohol is methanol, ethanol, n-propanol,
or isopropanol. A preferred C.sub.2-8 ester is a C.sub.2-6 ester,
more preferably a C.sub.4-6 ester. A preferred C.sub.4-6 ester is
ethyl acetate, propyl acetate, butyl acetate, or isobutyl acetate.
A preferred linear, branched or cyclic C.sub.2-8 ether is a
C.sub.2-7 ether, more preferably a C.sub.2-6 ether. A preferred
C.sub.2-6 ether is tetrahydrofuran, 1,4-dioxane, diisopropyl ether,
or t-butyl methyl ether. Preferably, the C.sub.3-6 ketone is a
C.sub.3-5 ketone. Preferably, the C.sub.3-5 ketone is acetone,
methyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone, or
3,3-dimethyl-2-butanone. Preferably, the C.sub.5-8 aliphatic
hydrocarbon is a C.sub.5-7 aliphatic hydrocarbon, more preferably a
C.sub.6-7 aliphatic hydrocarbon. A preferred C.sub.6-7 aliphatic
hydrocarbon is either n-hexane, or n-heptane. A preferred C.sub.1-8
halogenated hydrocarbon is a C.sub.1-6 halogenated hydrocarbon,
more preferably a C.sub.1-4 halogenated hydrocarbon, most
preferably a C.sub.1-2 halogenated hydrocarbon. A preferred
C.sub.1-2 halogenated hydrocarbon is dichloromethane,
dichloroethane, or chloroform. A preferred C.sub.1-4 nitroalkane is
a C.sub.1-2 nitroalkane. Preferably, the C.sub.1-2 nitroalkane is
nitromethane or nitroethane. Preferably, the C.sub.1-4 alkylcyanide
is a C.sub.1-3 alkylcyanide. A preferred C.sub.1-3 alkylcyanide is
either acetonitrile or propionitrile. A preferred C.sub.6-8
aromatic hydrocarbon is a C.sub.6-7 aromatic hydrocarbon.
Preferably, the C.sub.6-7 aromatic hydrocarbon is toluene. A
preferred C.sub.3-10 amide is a C.sub.3-6 amide. Preferably, the
C.sub.3-6 amide is dimethylformamide. The more preferred solvent
for dissolving the HAN compound of formula VI is a C.sub.2-4 ester,
most preferably, ethylacetate.
[0119] Preferably, the acid is the same as the acid in the process
for preparing the purified OAN compound of formula V. The more
preferred acid is methane sulfonic acid.
[0120] Combining the HAN compound of formula VI, the solvent and
the acid provides a mixture. Preferably, the mixture is maintained
at a temperature of about 10.degree. C. to about 60.degree. C.,
more preferably, at a temperature of about 20.degree. C. to about
50.degree. C., most preferably at a temperature of about 30.degree.
C. to about 40.degree. C. The mixture is preferably maintained at
such temperature for about 0.5 hours to about 24 hours, and more
preferably for about 1 hour to about 3 hours, most preferably for
about 2 hours. Maintaining the reaction mixture is preferably done
while stirring.
[0121] Preferably, reacting the HAN compound with an acid provides
a corresponding HAN-salt of formula VIs. Preferably, the HAN-salt
of formula VIs precipitates from the reaction mixture. Preferably,
in a process for purifying the HAN compound of formula VI, the
HAN-salt of formula VIs is reacted with a base, providing the HAN
compound of formula VI back again. Preferably, the precipitate is
recovered prior to reacting with a base.
[0122] Preferably, the base is selected from the group consisting
of sodium hydroxide, sodium carbonate, sodium bicarbonate,
potassium hydroxide, potassium carbonate and potassium bicarbonate.
More preferably, the base is sodium bicarbonate.
[0123] The process for preparing a HAN-salt of formula VIs may
further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0124] The present invention further provides a process for the
preparation of a
7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo-
[3.3.1]-nonane compound (referred to as a SAN compound) of formula
X ##STR45## wherein R.sub.1 and R.sub.2 are independently a
C.sub.1-6 alkyl or a C.sub.6-8 aryl, preferably, a C.sub.1-4 alkyl,
more preferably, methyl, and R.sub.3R.sub.4R.sub.5 are
independently a C.sub.1-6 alkyl or a C.sub.6-8 aryl, preferably,
tert-butyldialkyl, more preferably, tert-butyldimethyl comprising
combining a HAN compound of formula VI or a salt thereof ##STR46##
a silylating agent selected from the group consisting of: silanes,
silyl halogenides, silyl cyanides, silyl amines, silyl amides,
silyl trifluoromethanesulfonates (silyl triflates), silazanes, a
base, and an a-protic organic solvent forming a mixture to obtain
the SAN compound of formula X, wherein, R.sub.1 and R.sub.2 and Z
are described before.
[0125] When R.sub.1 and R.sub.2 are methyl, and Z is MsOH, said
compound of formula VIs corresponds to HAN-MsOH of the following
formula, ##STR47## and said compound of formula X corresponds to
SAN of the following formula. ##STR48##
[0126] Preferably, the HAN-salt of formula VI is combined with an
a-protic organic solvent. Preferably, the a-protic organic solvent
is selected from a group consisting of a C.sub.1-8 halogenated
hydrocarbon, a C.sub.2-8 ester, a C.sub.2-8 ether, C.sub.6-8
aromatic hydrocarbon, C.sub.3-10 amide, and a C.sub.3-6 ketone to
obtain a suspension. A preferred C.sub.1-8 halogenated hydrocarbon
is a C.sub.1-5 halogenated hydrocarbon, more preferably, a
C.sub.1-3 halogenated hydrocarbon. Preferably, the a C.sub.1-3
halogenated hydrocarbon is dichloromethane, 1,2-dichloroethane or
chloroform. A preferred C.sub.2-8 ester is a C.sub.4-6 ester.
Preferably, the C.sub.4-6 ester is ethyl acetate, n-butyl acetate
or isobutyl acetate. A preferred C.sub.2-8 ether is a C.sub.4-6
ether. Preferably, the C.sub.4-6 ether is diethyl ether,
diisopropyl ether or tert-butyl methyl ether. A preferred C.sub.6-8
aromatic hydrocarbon is a C.sub.6-7 aromatic hydrocarbon.
Preferably, the C.sub.6-7 aromatic hydrocarbon is toluene. A
preferred C.sub.3-10 amide is a C.sub.3-6 amide. Preferably, the
C.sub.3-6 amide is dimethylformamide. A preferred C.sub.3-6 ketone
is a C.sub.4-6 ketone. Preferably, the C.sub.4-6 ketone is methyl
ethyl ketone (2-butanone), 2-pentanone, 3-pentanone or
3,3-dimethyl-2-butanone. The preferred solvent is
dichloromethane.
[0127] The base is added to the suspension, providing a solution.
Preferably, about 2 to about 10 mole equivalent of base per mole
equivalent of the HAN-salt is used. More preferably, about 3 to
about 6 mole equivalent of base per mole equivalent of the HAN-salt
is used. Preferably, the base is selected from the group consisting
of: sodium hydroxide, sodium carbonate, sodium bicarbonate,
potassium hydroxide, potassium carbonate potassium bicarbonate,
trialkyl amines, and N-containing heterocycles. Preferably, the
trialkylamine is triethylamine, diisopropylethyl amine or tributyl
amine. A preferred N-containing heterocycle is piperidine,
pyridine, pyrimidine, piperazine, triazine, pyrrolidine, imidazole,
or triazole. The preferred base is an N-containing heterocycle,
more preferably, imidazole.
[0128] Preferably, the base is added at a temperature of about
15.degree. C. to about 55.degree. C., more preferably, at
20.degree. C. to about 25.degree. C.
[0129] Preferably the silane is selected from the groups consisting
of triethylsilane, triisopropylsilane, and triphenylsilane.
Preferably the silyl halogendie is selected from the group
consisting of trimethylsily chloride, tert-butyldimethylsilyl
chloride, and tert-butyldiphenylsilyl chloride. Preferably the
silyl cyanide is selected from the group consting of trimethylsilyl
cyanide, triethylsilyl cyanide, and tert-butyldimethylsilyl
cyanide. Preferably the silyl amine is trimethylsilyldiethylamine
or triethylsilyldiethylamine. Preferably the silyl amide is
selected from the group consisting of
N-methyl-N-trimethylsilylacetamide,
N-methyl-N-triethylsilylacetamide, and
tert-butyldimethylsilyl-N-methyltrifluoroacetamide. Preferably the
silyl triflate is selected from the group consisting of
trimethylsilyl trifluoromethanesulfonate, triethylsilyl
trifluoromethanesulfonate, and tert-butyldimethylsilyl
trifluoromethanesulfonate. Preferably the silazane is
hexamethyldisilazane or hexaethyldisilazane. Preferably, the
silylating agent is trialkylsilyl halogenide. Preferably, the alkyl
group is t-butyldimethyl. The preferred silylating agent is
tert-butyldimethylsilyl chloride. Preferably, the silylating agent
is added to the solution, providing a reaction mixture.
[0130] Preferably, about 1 to about 4 mole equivalent of silylating
agent per mole equivalent of the HAN-salt is used. More preferably,
about 1.5 to about 2.5 mole equivalent of sylilating agent per mole
equivalent of the HAN-salt is used. Preferably, the mixture is
maintained at a temperature of about 0.degree. C. to about
80.degree. C., more preferably, more preferably at a temperature of
about 20.degree. C. to about 60.degree. C., most preferably, at
about 40.degree. C. to about 60.degree. C. Preferably, the mixture
is maintained for about 0.5 hours to about 24 hours, and more
preferably, for about 4 to about 12 hours.
[0131] The progress of the reaction may be monitored by HPLC or by
TLC. When monitored by TLC, an eluent of ethyl acetate is used.
[0132] The process for preparing the SAN compound of formula X may
further comprise a recovery step. The SAN compound of formula X may
be recovered by extracting the product with water, and evaporating
the solvent.
[0133] The SAN compound of formula X may also be prepared from the
HAN compound of formula VI ##STR49## using similar conditions as
used when the HAN-salt of formula VIs is the starting material,
however, a smaller amount of base and of a silylated agent may be
used and the most preferred solvent is dichloromethane. Preferably,
when the HAN compound of formula VI is the starting material, about
1 to about 5 mole equivalent of base per mole equivalent of the HAN
compound is used, more preferably, about 1 to about 3 mole
equivalent of base per mole equivalent of the HAN compound is used.
Preferably, about 1 to about 3 mole equivalent of silylating agent
per mole equivalent of the HAN compound is used. More preferably,
about 1 to about 2 mole equivalent of silylating agent per mole
equivalent of the HAN compound is used.
[0134] The process for preparing the SAN compound of formula X may
further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0135] The present invention provides a process for the preparation
of a SQO compound of formula XII ##STR50## comprising mixing a SAN
compound of formula X, a metal alkoxide, and a polar a-protic
organic solvent to form a mixture; heating the mixture; and
reacting this mixture with a weak acid, forming the SQO compound of
formula XII, wherein, R, R.sub.3R.sub.4 and R.sub.5 are described
before.
[0136] When R is methyl, and R.sub.3R.sub.4R.sub.5 are
tert-butyldimethyl said compound of formula XII corresponds to SQO
of the following formula. ##STR51##
[0137] A preferred polar a-protic organic solvent is selected from
the group consisting of a C.sub.2-8 ether having a boiling point of
about 60.degree. C. to about 100.degree. C. Preferably, the
C.sub.2-8 ether having a boiling point of about 60.degree. C. to
about 100.degree. C. is tetrahydrofuran (referred to as THF),
2-methyltetrahydrofuran, tetrahydropyran, monoglyme, diisopropyl
ether, or methyl t-butyl ether. The more preferred polar aprotic
organic solvent is THF.
[0138] Preferably, the SAN compound of formula X is dissolved in a
polar a-protic organic solvent, prior to adding the metal
alkoxide.
[0139] Preferably, the metal alkoxide is selected from the group
consisting of lithium alcoholates, sodium alcoholates and potassium
alcoholates; wherein the alcoholate moiety contains 1 to 4 carbons.
More preferably, the metal alkoxide is potassium tert-butoxide.
[0140] Combining the SAN compound of formula X, the polar a-protic
organic solvent and the metal alkoxide provides a solution.
Preferably, the solution is heated to a temperature of about
40.degree. C. to about 120.degree. C., more preferably, to a
temperature of about 60.degree. C. to about 80.degree. C. The
solution is heated, preferably, for about 0.5 hours to about 8
hours, and more preferably, for about 1 hour to about 3 hours.
Heating the solution is preferably done under stirring.
[0141] While heating, the solution is concentrated, preferably, by
distillation of the polar a-protic organic solvent, providing a
mixture. The mixture is, preferably, cooled to a temperature of
about 0.degree. C. to about 30.degree. C., more preferably, to a
temperature of about 15.degree. C. to about 25.degree. C., prior to
reacting with the acid.
[0142] Preferably, the weak acid is selected from the group
consisting of acetic acid, formic acid, propionic acid, maleic
acid, fumaric acid, succinic acid, oxalic acid, tartaric acid,
citric acid, mandelic acid, benzoic acid, salicylic acid,
naphthalene carboxylic and dicarboxylic acids, methanesulfonic
acid, ethanesulfonic acid, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid,
naphthalene sulfonic and disulfonic acids. Preferably, the acid is
a water miscible organic acid, preferably acetic acid, more
preferably acetic acid combined with water, providing a diluted
aqueous solution of acetic acid. Preferably, the acid is added to
the cooled mixture, providing an acidic mixture, prior to
recovering the SQO compound of formula XII. Preferably, the pH of
the acidic mixture is of about 4 to about 6, more preferably, of
about 5 to about 6.
[0143] The process for preparing the SQO compound of formula XII
may further comprise a step of recovering it. The recovery may be
carried out by any known method. The SQO compound of formula XII
may be recovered by a process comprising combining the acidic
mixture with a base, providing a slight basic mixture;
concentrating the slight basic mixture; precipitating the SQO
compound of formula XII; and recovering it.
[0144] Preferably, the pH of the slightly basic mixture is of about
7 to about 8. Preferably, the base is selected from a group
consisting of sodium hydroxide, sodium carbonate, sodium
bicarbonate, potassium hydroxide, potassium carbonate and potassium
bicarbonate. The more preferred base is sodium bicarbonate.
[0145] Preferably, the basic mixture is concentrated by removing
the polar a-protic organic solvent. Preferably, removal of the
polar a-protic organic solvent is done by distillation. The removal
of the polar a-protic organic solvent provides a concentrated
aqueous mixture. Preferably, the precipitation of the SQO compound
of formula XII is done by cooling the concentrated aqueous mixture
to about 0.degree. C. to about 10.degree. C., preferably about
2.degree. C. to about 8.degree. C. The cooled concentrated aqueous
mixture is maintained, preferably, for about 3 hours to about 24
hours, and more preferably, for about 8 hours to about 18 hours,
prior to filtering the precipitate. The filtered SQO compound of
formula XII is washed with water, and dried.
[0146] The process for preparing the SQO compound of formula XII
may further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0147] The present invention also provides a process for preparing
HQO of formula II ##STR52## comprising mixing a SQO compound of
formula XII, a solvent selected from the group consisting of water
and a water-miscible organic solvent, and an acid to obtain
HQO.
[0148] Preferably, the acid is selected from the group consisting
of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, perchloric acid, fluoroboric acid, methanesulfonic
acid, ethanesulfonic acid, trifluoromethanesulfonic acid,
p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid,
naphthalene sulfonic and disulfonic acids.
[0149] Preferably, the SQO compound of formula XII is combined with
water or a water-miscible organic solvent to obtain a suspension.
Preferably, the water-miscible organic solvent is
dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or
diglyme, more preferably dimethylformamide. Preferably, the SQO
compound of formula XII is combined with water at a temperature of
about 10.degree. C. to about 50.degree. C., more preferably, at
20.degree. C. to about 25.degree. C.
[0150] Preferably, the acid is added to the suspension providing a
solution. Preferably, the addition of the acid provides an acidic
solution. Preferably, the acidic solution has a pH of about 0.5 to
about 3, more preferably, of about 1 to about 2.
[0151] The acidic solution is heated, preferably, to a temperature
of about 80.degree. C. to about 100.degree. C. The heated solution
is maintained, preferably, for about 3 hours to about 24 hours, and
more preferably, for about 6 hours to about 10 hours. Heating the
solution is preferably done while stirring.
[0152] The progress of the reaction may be monitored by HPLC or by
TLC. When monitored by TLC, an eluent of methylene chloride and
methanol in a ratio of 1:1 is used.
[0153] The process for preparing HQO of formula II may further
comprise a recovery step. The recovery may be carried out by any
known method. HQO of formula II may be recovered by cooling the
heated acidic solution, adding a base to the cooled acidic mixture,
extracting the product with a water immiscible organic solvent, and
evaporating the water immiscible organic solvent to obtain HQO of
formula II.
[0154] Preferably, the heated solution is cooled to a temperature
of about 0.degree. C. to about 30.degree. C., more preferably, to a
temperature of about 15.degree. C. to about 25.degree. C.
[0155] Preferably, a base is added to the cooled solution.
Preferably, the base is selected from the group consisting of
sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium
hydroxide, potassium carbonate and potassium bicarbonate. The more
preferred base is sodium hydroxide. Preferably, the addition of the
base provides a basic mixture. Preferably, the basic mixture has a
pH of about 8 to about 13, more preferably, of about 11 to about
12.
[0156] The preferred water immiscible organic solvent is selected
from the group consisting of a C.sub.2-8 ester, a linear, branched
or cyclic C.sub.2-8 ether, a C.sub.3-6 ketone and a C.sub.5-8
aliphatic hydrocarbon, and a C.sub.1-8 halogenated hydrocarbon. The
most preferred water immiscible organic solvent is methylene
chloride. A preferred C.sub.2-8 ester is a C.sub.4-6 ester.
Preferably, the C.sub.4-6 ester is ethyl acetate, n-butyl acetate
or isobutyl acetate. A preferred C.sub.2-8 ether is a C.sub.4-6
ether. Preferably, the C.sub.4-6 ether is diethyl ether,
diisopropyl ether or tert-butyl methyl ether. A preferred C.sub.3-6
ketone is a C.sub.4-6 ketone. Preferably, the C.sub.4-6 ketone is
methyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone or
3,3-dimethyl-2-butanone. A preferred C.sub.5-8 aliphatic
hydrocarbon is a C.sub.6-7 aliphatic hydrocarbon. Preferably, the
C.sub.6-7 aliphatic hydrocarbon is n-hexane or n-heptane. A
preferred C.sub.1-8 halogenated hydrocarbon is a C.sub.1-2
halogenated hydrocarbon. Preferably, the C.sub.1-2 halogenated
hydrocarbon is dichloromethane, 1,2-dichloroethane or
chloroform.
[0157] Optionally, HQO of formula II may be prepared directly from
the SAN compound of formula X, i.e., without isolating the SQO
compound of formula XII. Preferably, the reaction may include the
same steps as described in the process for preparing the SQO
compound of formula XII, but using a strong acid instead of a weak
acid, and heating. Preferably, the stron acid is selected from the
group consisting of methanesulfonic acid, sulfuric acid, phosphoric
acid, hydrochloric acid, hydrobromic acid, and triflic acid.
[0158] This process for preparing HQO of formula II from the SQO
compound of formula XII or directly from the SAN compound of
formula X may further comprise a process for converting it to a
DLS-salt of formula VIIIs.
[0159] Preferably, reacting SAN with an acid provides the
corresponding salt of HQO, a HQO-salt of formula IIs. Preferably,
the HQO-salt of formula IIs precipitates in the reaction mixture.
Preferably, the HQO-salt of formula IIs is reacted with a base,
providing HQO of formula II back again. Preferably, the precipitate
is recovered prior to reacting with a base.
[0160] Preferably, the base is selected from the group consisting
of sodium hydroxide, sodium carbonate, sodium bicarbonate,
potassium hydroxide, potassium carbonate, and potassium
bicarbonate, more preferably sodium bicarbonate.
[0161] The present invention also provides another process for the
preparation of a HQO-salt of formula IIs comprising combining HQO,
an alcohol and an acid selected from the group consisting of:
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, perchloric acid, fluoroboric acid, formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, maleic acid, fumaric acid, succinic acid, oxalic acid,
tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic
acid, naphthalene carboxylic and dicarboxylic acids,
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene
sulfonic, and disulfonic acid to obtain a HQO salt of formula
IIs.
[0162] The present invention provides a process for purifying HQO
of formula II by a process comprising combining HQO of formula II,
an alcohol and an acid selected from the group consisting of:
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, perchloric acid, fluoroboric acid, formic acid,
acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic
acid, maleic acid, fumaric acid, succinic acid, oxalic acid,
tartaric acid, citric acid, mandelic acid, benzoic acid, salicylic
acid, naphthalene carboxylic and dicarboxylic acids,
methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic
acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene
sulfonic, and disulfonic acid forming a mixture, and adding a base
to obtain purified HQO.
[0163] Preferably, the alcohol is a C.sub.1-4 alcohol, more
preferably, ethanol.
[0164] Preferably, the acid is an organic acid, more preferably, a
sulfonic acid, most preferably, methanesulfonic acid.
[0165] The process for preparing a HQO-salt of formula IIs can
further comprise a process for converting it to a DLS-salt of
formula VIIIs.
[0166] HQO-salt of formula IIs may be converted to a DLS-salt of
formula VIIIs comprising converting it to the free base, HQO of
formula II; reacting HQO with a base to form a reaction mixture;
mixing the reaction mixture with an anhydride, indole-3-carboxylic
acid, an organic solvent, and a catalyst to form a mixture; and
reacting the mixture with an acid, to obtain the DLS-salt of
formula VIIIs.
[0167] Preferably, the base is selected from the group consisting
of sodium hydroxide, sodium carbonate, sodium bicarbonate,
potassium hydroxide, potassium carbonate and potassium bicarbonate.
The more preferred base is sodium bicarbonate.
[0168] Preferably, the organic solvent is selected from the group
consisting of a C.sub.1-2 halogenated hydrocarbon, a C.sub.6-8
aromatic hydrocarbon, a C.sub.1-4 nitroalkane, a C.sub.1-4 alkyl
cyanide, trifluoroacetic acid and mixtures thereof. A preferred
C.sub.1-2 halogenated hydrocarbon is dichloromethane,
1,2-dichloroethane or chloroform, more preferably dichloromethane.
A preferred C.sub.6-8 aromatic hydrocarbon is benzene, toluene or
xylol, more preferably toluene. Preferably, the C.sub.1-4
nitroalkane is a C.sub.1-2 nitroalkane, either nitromethane or
nitroethane, more preferably nitromethane. Preferably, the
C.sub.1-4 alkyl cyanide is a C.sub.1-2 alkyl cyanide, either
acetonitrile or propionitrile, more preferably acetonitrile.
[0169] Preferably, the anhydride is either trifluoroaceticanhydride
or methyl chlorocarbonate, more preferably,
trifluoroaceticanhydride.
[0170] Preferably, indole-3-carboxylic acid is added drop-wise,
more preferably, over a period of about 10 minutes to about 30
minutes, preferably about 15 minutes.
[0171] Preferably, the catalyst is either a saturated
trisubstituted amine or an aromatic amine. Preferably, the
saturated trisubstituted amine is either a trialkyl amine or
4-dialkylaminopyridine amine. Preferably, the trisubstituted amine
is 4-dimethylaminopyridine or diisopropylethylamine, more
preferably, 4-dimethylaminopyridine.
[0172] Preferably, HQO and the catalyst are added at the same time
to a solution of the anhydride, the organic solvent and the
3-indole-carboxylic acid, providing a reaction mixture. Preferably,
the reaction mixture is heated to a temperature of about 25.degree.
C. to about 40.degree. C., more preferably to about 30.degree. C.
to about 35.degree. C., for about 2 to about 18 hours, more
preferably for about 2 hours, and preferably while stirring,
providing Dolasetron base.
[0173] Dolasetron base may be recovered by removing the solvent to
obtain a precipitate and filtering off the precipitate.
[0174] Dolasetron may be converted to Dolasetron salt by combining
Dolasetron with an acid. Preferably, Dolasetron may be converted to
Dolasetron mesylate monohydrate by combining Dolasetron, a mixture
of acetone and water, and methane sulfonic acid.
[0175] Combining Dolasetron and the mixture of acetone and water
provides a suspension, in which the solid dissolves when adding
methane sulfonic acid. After complete dissolution, a precipitate of
DLS-MsOH is obtained. The precipitate may be maintained in a
fridge, and recovered by filtration, washing and drying.
[0176] Having thus described the invention with reference to
particular preferred embodiments and illustrative examples, those
in the art can appreciate modifications to the invention as
described and illustrated that do not depart from the spirit and
scope of the invention as disclosed in the specification. The
Examples are set forth to aid in understanding the invention but
are not intended to, and should not be construed to limit its scope
in any way.
EXAMPLES
Example 1
Preparation of CCA-Epoxide of Formula IV
[0177] CCA-Me ester (37.8 g, 0.3 mol) was dissolved in 60 ml of
methanol followed by the addition of hydrogen peroxide (30-35%, 43
ml, 1.3 equiv.) and sodium tungstate dihydrate (2 g, 2 mol %). The
yellow reaction mixture was refluxed slightly (at 60-65.degree. C.)
for 2-4 hours until the reaction was completed (GC or TLC: eluent
n-hexane-ethyl acetate 1:1, visualized by iodine). After cooling it
was extracted with methylene chloride (3.times.100 ml). The
combined organic phases were dried on sodium sulfate and evaporated
to dryness. The product was 40.5 g colorless oil (95% yield).
Example 2
Preparation of OAN of Formula V
[0178] To a well-stirred solution of periodic acid (32 g, 0.14 mol)
in water (200 ml) was added CCA-epoxide (19 g, 0.14 mol), and the
reaction mixture was stirred at 10-15.degree. C. for 1 hour. After
completion, the reaction mixture having a pH of 1, was cooled and
the pH was adjusted to 3.5-4 by the addition of OH-resin (or
poly(4-vinylpyridine)), followed by stirring the mixture for 10-15
min at room temperature. The solid material was filtered through a
layer of Celite and washed with water (2.times.150 ml). To the
aqueous solution were added sequentially at room temperature (86 g,
0.42 mol, 3 equiv) potassium hydrogen phthalate, (21 g, 0.17 mol,
1.2 equiv) glycine methyl ester hydrochloride and (25 g, 0.17 mol,
1.2 equiv) 1,3-acetonedicarboxylic acid. The dark red reaction
mixture was stirred at room temperature for 18 h (overnight). The
undissolved solid was filtered through a layer of Celite, washed
with a small volume of water (2.times.50 ml). To the solution was
added, in portions, solid sodium hydrogen carbonate (until pH
7.5-8), then the solution was extracted with isobutyl acetate
(5.times.200 ml). The combined organic phases were dried on sodium
sulfate and evaporated to dryness or to a reduced volume of about
40 ml.
[0179] TLC: n-hexane-ethyl acetate 1:1, visualized by UV-light
and/or iodine.
Example 3
Preparation of OAN-MsOH Salt of Formula Vs
[0180] Crude OAN (600 g) was dissolved in isopropanol (3 L) at room
temperature followed by the addition of (144 ml, 1 equiv)
methanesulfonic acid, under stirring. The mixture was warmed to
30-40.degree. C., and stirred for overnight. The precipitated oil
solidified. The salt was filtered at room temperature, washed with
isopropanol (600+2.times.300 ml) and dried.
[0181] The overall yield (from CCA-epoxyide): 35-40% (purity:
<90%).
Example 4
Preparation of OAN-MsOH Salt of Formula Vs
[0182] OAN solution in isobutyl acetate (1.2 L, containing 600 g of
OAN) was combined with ethanol (1.2 L) at room temperature followed
by the addition of (144 ml, 1 equiv) methanesulfonic acid, under
stirring. The mixture was stirred for 3 hours. The salt was
filtered, washed with a mixture of isobutyl acetate-ethanol 1:1 (
12.times.300 ml) and dried.
[0183] The overall yield (from CCA-epoxyide): 35-40%.
Example 5
Preparation of HAN of Formula VI
[0184] Sodium borohydride (71 g, 1.4 equiv.) was dissolved in a
mixture of water (500 ml) and aqueous solution of sodium hydroxide
(30%, 14 ml). OAN (361 g, 1.34 mol) was dissolved in methanol (3.6
L), and the solution was cooled to 0-5.degree. C. The solution of
sodium borohydride was added drop-wise to the solution of OAN in
methanol, and the mixture was stirred at 0-5.degree. C. for about 1
hour. The reaction was monitored by TLC (eluent:ethyl acetate).
After completion of reaction acetic acid (80 ml) was added under
stirring while cooling (foaming, warning and precipitating). Water
(0.5 L) and methylene chloride (1 L) were added (filtration can be
necessary). The aqueous phase was extracted with (2.times.1 L) of
methylene chloride. The combined organic phases were dried on
sodium sulfate and evaporated to dryness. The yield was 70%.
Example 6
Preparation of HAN of Formula VI
[0185] (14.6 g, 40 mmol) OAN-MsOH was suspended at 20-25.degree. C.
in (300 ml) ethanol, then to this suspension (4.2 g, 2.8 equiv)
sodium borohydride was added in portions in order to keep the inner
temperature between 25-35.degree. C. After addition of the reducing
agent the reaction mixture was stirred for additional 30 minutes.
The conversion was monitored by TLC (eluent:ethyl acetate), when it
was complete (4.5 ml) acetic acid was added (pH 6-7) and the
mixture was evaporated to dryness on rotavapor at 35-40.degree. C.
The residue was mixed with ethyl acetate (60 ml), the unsolved
material was filtered off and the filtered material was washed with
ethyl acetate (2.times.20 ml). The filtrate was concentrated on
rotavapor at 35-40.degree. C., to obtain 10.2 g (94%) of crude
HAN.
Example 7
Preparation of HAN-MsOH Salt of Formula VIs
[0186] Crude HAN (17 g) was dissolved in ethyl acetate (100 ml) at
room temperature and (3.6 ml, 1.1 equiv) of methanesulfonic acid
was added under stirring. The mixture was heated to 30-40.degree.
C., and was stirred for 2 hours. The precipitated oil solidified.
The salt was filtered at room temperature, washed with ethyl
acetate (2.times.30 ml) and dried. Yield was 80%.
Example 8
Preparation of HQO--CSA Salt of Formula IIs
[0187] To a solution of HQO (0.18 g, 1 mmol) in (3 ml) ethanol was
added camphorsulfonic acid (0.23 g) in (2.5 ml) ethanol. The
mixture was stirred for 20 minutes, filtered, then the solid
material was washed with ethyl acetate and dried.
Example 9
Example 13: Preparation of DLS-Base with Catalyst
[0188] To a solution of 52.9 ml (1.3 equiv) trifluoroacetic
anhydride in 1.0 L of dry dichloromethane 47.5 g (1.3 equiv)
indole-3-carboxylic acid was added in portions within 15 minutes.
The reaction mixture was cooled to 20-25.degree. C. and after 5
minutes 48.5 g (0.27 mol) HQO and 0.33 g (1 mol %)
4-dimethylaminopyridine were added in one portion. The reaction
mixture was heated to 30-35.degree. C. and stirred for 2 hours,
then 26.5 ml (0.7 equiv) trifluoroacetic anhydride was added. The
reaction mixture was stirred for additional 2 hours, then diluted
with 800 ml of 10% sodium carbonate. From the mixture
dichloromethane was distilled off. The precipitated solid was
filtered, washed with water (3.times.100 ml) and dried. Yield is
97%.
[0189] Crude Dolasetron base (84 g) was dissolved in isobutyl
acetate (2.6 L) at 95-100.degree. C. Charcoal (4.2 g) was added to
the solution, and after 10 minutes of stirring it was filtered off,
and washed with isobutyl acetate (0.26 L). The solution was
evaporated under reduced pressure to obtain a residue weighing
0.5-0.6 kg, which allowed to cool to room temperature, and then
further cooled in a fridge overnight. The precipitated crystals
were filtered off, washed with isobutyl acetate (2.times.50 ml),
and dried overnight at 40-45.degree. C. under reduced pressure.
Yield was 88%.
Example 10
Preparation of DLS-Base Without Catalyst
[0190] Indole-3-carboxylic acid (17.7 g, 1.1 equiv.) was added in
portions to a solution of trifluoroacetic anhydride (20 ml, 1.4
equiv.) in a mixture toluene (360 ml) and trifluoroacetic acid (90
ml), at room temperature (20-25.degree. C.), during 15 minutes.
After 5-minutes of stirring,
endo-5-hydroxy-8-azatricyclo[5.3.1.0.sup.3,8]-undecan-10-one (18.12
g, 0.1 mol), was added in one portion. The reaction mixture heated
to 30-35.degree. C., the solid phase dissolved. The solution was
stirred for 2 hours without external heating. The trifluoroacetic
acid was removed by evaporation under reduced pressure until
starting of crystallization. 10% of an aqueous solution of sodium
carbonate (360 ml) was added, then toluene was removed by
evaporation under reduced pressure. The precipitated Dolasetron
base monohydrate was collected by filtration, washed with water
(3.times.60 ml), and dried overnight at 40.degree. C. under reduced
pressure. The dry product was weighed as 33.63 g (98%).
[0191] The dried crude Dolasetron base was dissolved in isobutyl
acetate (1 L) at 95-100.degree. C. Charcoal (1.7 g) was added to
the solution, and after 10 minutes of stirring it was filtered off,
and washed with isobutyl acetate (0.1 L). The solution was
evaporated under reduced pressure to obtain a residue weighing
0.20-0.25 kg, which allowed to cool to room temperature, and then
further cooled in a fridge overnight. The precipitated crystals
were filtered off, washed with isobutyl acetate (2.times.20 ml),
and dried overnight at 40-45.degree. C. under reduced pressure.
Yield was 88%.
Example 11
Preparation of DLS-MsOH of Formula VIII
[0192] Methanesulfonic acid (2.85 ml, 1 equiv) was added to a
stirred suspension of Dolasetron base (14.24 g, 43.9 mmol) in a
mixture of acetone-water 95:5 (100 ml). The solid dissolved
immediately, after some minutes the salt precipitated in
crystalline form. The mixture was put into fridge, after 4 hours
the salt was filtered off, washed with same solvent mixture
(2.times.15 ml), dried overnight in an air-ventilated oven at
40.degree. C. The yield was 15.63 g (81%).
Example 12
Preparation of SAN from HAN
[0193] In a 250-ml flask HAN (41 mmol) was dissolved in methylene
chloride (120 ml). The solution was mixed with 1.5 equiv (7 g) of
imidazole at 20-25.degree. C. After complete dissolution, to this
solution 1.3 equiv (12.4 g) of tert-butyldimethylsilyl chloride was
added and the reaction mixture was stirred for 6 hours. The
conversion was monitored by TLC (eluent:ethyl acetate). The
reaction mixture was washed with water (2.times.40 ml). The
combined aqueous layer was washed with methylene chloride (120 ml).
The combined organic phase was dried on sodium sulfate, evaporated
to dryness on rotavapor at 40-45.degree. C. The product was about
19 g of oil.
Example 13
Preparation of SAN from HAN-Mesylate
[0194] In a 500-ml flask HAN-mesylate (70 mmol) was mixed with
methylene chloride (260 ml). To the suspension 4.5 equiv (21 g) of
imidazole was added at 20-25.degree. C. After complete dissolution,
to this solution 2 equiv (21 g) of tert-butyldimethylsilyl chloride
was added and the reaction mixture was stirred for 2 days at
40-45.degree. C. The conversion was monitored by TLC (eluent:ethyl
acetate). The reaction mixture was diluted with methylene chloride
(260 ml), washed with water (2.times.130 ml). The combined organic
phase was dried on sodium sulfate, evaporated to dryness on
rotavapor at 40-45.degree. C. The product is about 32 g of oil.
Example 14
Preparation of SQO
[0195] In a 250-ml flask the crude SAN (ca 19 g, theoretically 41
mmol) was dissolved in THF (190 ml) and potassium tert-butoxide
(9.2 g, 2 equiv) was added under stirring. The solution was heated
to reflux for 2 hours, and 95 ml of THF was distilled off during
this reflux period. The mixture was cooled to 20-25.degree. C. and
aqueous acetic acid (5.4 ml/94 mmol/of acetic acid in 80 ml of
water) was added, then the pH is adjusted to 7-8 by addition of
solid sodium hydrogencarbonate (6-7 g). The rest of THF was
distilled off, then the aqueous mixture was cooled to 20-25.degree.
C., and stored in the fridge (2-8.degree. C.) overnight. The
precipitated material was filtered off, washed with water, and
dried in vacuum. The product was 7.5 g of white solid.
Example 15
Preparation of HQO from SQO
[0196] In a 250-ml flask SQO (10.6 g) was suspended in 22 ml of
water at 20-25.degree. C. and 3 equiv (4.5 ml) cc HCl was added.
The obtained clear solution (pH 1) was stirred for 6 hours at
reflux temperature. The conversion was monitored by TLC (eluent:
1:1 methylene chloride-methanol). The reaction mixture was cooled
to 20-25.degree. C. and the pH of the solution was adjusted to 12
by addition of solid sodium hydroxide under cooling. The solution
was extracted with methylene chloride (5.times.50 ml). The combined
organic phase was dried on sodium sulfate, and evaporated to
dryness on rotavapor at 30-35.degree. C. The residue was 4.7 g of
white solid.
Example 16
Preparation of HQO from SAN
[0197] In a 250-ml flask the crude SAN (ca 4 g, theoretically 10
mmol) was dissolved in THF (50 ml) and potassium tert-butoxide (1.6
g, 1.4 equiv) was added under stirring. The solution was heated to
reflux for 2 hours, and 25 ml of THF was distilled off during this
reflux period. The mixture was cooled to 20-25.degree. C., diluted
with water (15 ml), and the pH was adjusted to 1 with concentrated
HCl. The rest of THF was distilled out, and the mixture was
refluxed for 6 hours, then cooled to 20-25.degree. C. The pH of the
solution was adjusted to 12 by addition of solid sodium hydroxide
under cooling. The basic solution was extracted with methylene
chloride (5.times.30 ml). The combined organic phase was dried on
sodium sulfate, and evaporated to dryness. The residue was 0.82 g
of brownish solid.
* * * * *