U.S. patent application number 11/432010 was filed with the patent office on 2007-02-22 for optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid.
Invention is credited to Ziv Dee-Noor, Lilach Hedvati, Gideon Pilarski, Claude Singer.
Application Number | 20070043241 11/432010 |
Document ID | / |
Family ID | 36940669 |
Filed Date | 2007-02-22 |
United States Patent
Application |
20070043241 |
Kind Code |
A1 |
Hedvati; Lilach ; et
al. |
February 22, 2007 |
Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid
Abstract
The invention relates to pure (R)--CMH and to the optical
resolution of CMH-racemate, a key intermediate in the synthesis of
(S)-Pregabalin. The invention also relates to the process for
optically purifying (R)--CMH and to the process for isolating
(S)--CMH from the mother liquor.
Inventors: |
Hedvati; Lilach; (Doar Na
Hefer, IL) ; Dee-Noor; Ziv; (Haifa, IL) ;
Singer; Claude; (Kfar Saba, IL) ; Pilarski;
Gideon; (Holon, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36940669 |
Appl. No.: |
11/432010 |
Filed: |
May 10, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60679784 |
May 10, 2005 |
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60689699 |
Jun 9, 2005 |
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60733009 |
Nov 2, 2005 |
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60735634 |
Nov 9, 2005 |
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60740950 |
Nov 29, 2005 |
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Current U.S.
Class: |
562/571 |
Current CPC
Class: |
C07C 233/05 20130101;
C07C 231/20 20130101; C07C 233/05 20130101; A61P 25/08 20180101;
C07C 229/08 20130101; C07C 227/16 20130101; C07C 231/20 20130101;
C07C 215/30 20130101 |
Class at
Publication: |
562/571 |
International
Class: |
C07C 237/02 20070101
C07C237/02 |
Claims
1. (R)--CMH containing less than about 0.2% area by HPLC of
(S)--CMH.
2. The (R)--CMH of claim 1, containing less than about 0.1% area by
HPLC of (S)--CMH.
3. A process for the optical resolution of
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),
##STR20## comprising: a) combining CMH-racemate, a solvent selected
from the group consisting of: ketone, ester, nitrile, C.sub.1-4
alcohol, water, or mixtures thereof, a chiral resolving reagent of
amino alcohol and salts thereof to obtain a precipitate; b)
isolating the precipitate; and c) adding a solvent selected from
the group consisting of: ketone, C.sub.1-8 alcohol, water or
mixtures thereof, and a strong mineral acid.
4. The process of claim 3, wherein the precipitate of (R)--CMH
contains less than about 7% area by HPLC of (S)--CMH.
5. The process of claim 4, wherein the precipitate of (R)--CMH
contains less than about 4% area by HPLC of (S)--CMH.
6. The process of claim 5, wherein the precipitate of (R)--CMH
contains less than about 0.2% area by HPLC of (S)--CMH.
7. The process of claim 6, wherein the precipitate of (R)--CMH
contains less than about 0.1% area by HPLC of (S)--CMH.
8. The process of claim 3, wherein the chiral resolving reagent of
amino alcohol and salts thereof is selected from the group
consisting of: ephedrine, ephedrine salt, norephedrine and
norephedrine salt.
9. The process of claim 8, wherein the salt is a hydrochloride,
nitrate or sulfate.
10. The process of claim 9, wherein the salt is a
hydrochloride.
11. The process of claim 8, wherein the chiral resolving reagent of
amino alcohol and salts thereof is ephedrine or ephedrine salt.
12. The process of claim 11, wherein the chiral resolving reagent
of amino alcohol and salts thereof is 1R, 2S-(-)-ephedrine.
13. The process of claim 8, wherein the chiral resolving reagent of
amino alcohol and salts thereof is a salt of ephedrine or of
norephedrine.
14. The process of claim 13, wherein a base is added.
15. The process of claim 14, wherein the base is either an organic
base or an inorganic base.
16. The process of claim 15, wherein the organic base is an
amine.
17. The process of claim 16, wherein the amine is tertiary or
secondary amine.
18. The process of claim 17, wherein the tertiary amine is
triethylamine or tributylamine.
19. The process of claim 18, wherein the tertiary amine is
triethylamine.
20. The process of claim 17, wherein the secondary amine is
diisopropylamine or n-dipropylamine.
21. The process of claim 15, wherein the inorganic base is alkali
metal hydrogen carbonates, alkali hydroxide or alkali
carbonate.
22. The process of claim 21, wherein the alkali hydroxide is either
NaOH or KOH.
23. The process of claim 22, wherein the alkali hydroxide is
NaOH.
24. The process of claim 21, wherein the alkali carbonate is either
K.sub.2CO.sub.3 or Na.sub.2CO.sub.3.
25. The process of claim 3, wherein the ketone is a C.sub.2 to
C.sub.6 ketone.
26. The process of claim 25, wherein the ketone is C.sub.2 to
C.sub.5 ketone.
27. The process of claim 3, wherein the ketone is either acetone or
methyl isobutyl ketone.
28. The process of claim 27, wherein the ketone is acetone.
29. The process of claim 3, wherein the C.sub.1-4 alcohol is
selected from the group consisting of: methanol, ethanol,
isopropanol, or isobutanol.
30. The process of claim 29, wherein the C.sub.1-4 alcohol is
methanol.
31. The process of claim 3, wherein the ester is a C.sub.3 to
C.sub.8.
32. The process of claim 31, wherein the ester is a C.sub.4 to
C.sub.6 ester.
33. The process of claim 31, wherein the ester is ethyl-acetate,
butylacetate or isopropylacetate.
34. The process of claim 33, wherein the ester is ethylacetate.
35. The process of claim 3, wherein the nitrile is
acetonitrile.
36. The process of claim 3, wherein the solvent is acetone or a
mixture of acetone and water.
37. The process of claim 3, wherein the strong mineral acid is HCl,
HBr, H.sub.2SO.sub.4 or H.sub.3PO.sub.4.
38. The process of claim 36, wherein the strong mineral acid is
HCl.
39. The process of claim 3, wherein after the addition of the acid,
a pH of about 0 to about 4 is obtained.
40. The process of claim 39, wherein after the addition of the
acid, a pH of about 1 to about 3 is obtained.
41. The process of claim 3, wherein the ketone, which is added with
the strong mineral acid, is acetone.
42. The process of claim 3, wherein the C.sub.1-8 alcohol, which is
added with the strong mineral acid, is methanol.
43. The process of claim 3, wherein the solvent, which is added
with the strong mineral acid, is a mixture of water and ketone or
water and C.sub.1-8 alcohol.
44. A process for the optical resolution of
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),
##STR21## comprising: a) combining CMH-racemate, a solvent selected
from the group consisting of: ketone, ester, nitrile, C.sub.1-4
alcohol, water, or mixtures thereof, a chiral resolving reagent
selected from: ephedrine, ephedrine salt, norephedrine and
norephedrine salt to obtain a precipitate, wherein the precipitate
is of (R)--CMH-ephedrine salt of the following structure: ##STR22##
or of (R)--CMH-norephedrine salt of the following structure:
##STR23## b) isolating the precipiatate; and c) combining the
precipitate with a solvent selected from the group consisting of:
ketone, C.sub.1-8 alcohol, water or mixtures thereof, and with a
strong mineral acid to obtain a precipitate of (R)--CMH of the
following structure ##STR24##
45. A process for the optical resolution of
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),
##STR25## comprising: b) combining CMH-racemate, a solvent selected
from ketone, ester, nitrile, C.sub.1-4 alcohol, water, or mixtures
thereof, and 1R, 2S-(-)-ephedrine to obtain a a reaction mixture;
c) heating the reaction mixture to a temperature of about
50.degree. C. to about 140.degree. C.; d) cooling the reaction
mixture to a temperature of about 20.degree. C. to about
-20.degree. C. to obtain a precipitate, wherein the precipitate is
of (R)--CMH-ephedrine salt of the following structure: ##STR26## or
of (R)--CMH-norephedrine salt of the following structure: ##STR27##
e) isolating the precipitate; f) combining the precipitate with a
solvent selected from ketone, C.sub.1-8 alcohol, water or mixtures
thereof, and a strong mineral acid, to obtain a slurry; and g)
cooling the slurry to a temperature of about 10.degree. C. to about
2.degree. C. to obtain a precipitate of (R)--CMH of the following
structure ##STR28##
46. The process of claim 44, wherein the chiral resolving reagent
is ephedrine salt or norephedrine salt.
47. The process of claim 46, wherein the chiral resolving reagent
is combined with a base.
48. The process of claim 44, wherein the reaction mixture of step
b) is heated to a temperature of about 50.degree. C. to about
100.degree. C.
49. The process of claim 48, wherein the reaction mixture is
maintained for about 0.5 hour to about 5 hours.
50. The process of claim 44, wherein the reaction mixture obtained
in step b) is a solution.
51. The process of claim 45, wherein prior to step d), the solution
is maintained for about an hour to about 24 hours.
52. The process of claim 45, wherein the slurry is cooled to a
temperature of about 2.degree. C.
53. The process of claim 45, wherein the slurry is maintained at a
temperature of about 2.degree. C. to about ambient temperature.
54. The process of claim 53, wherein the slurry is maintained at a
temperature of about 2.degree. C. to about 10.degree. C.
55. The process of claim 53, wherein the slurry is maintained for
about 0.5 hours to about 24 hours.
56. The process of claim 44, wherein the precipitate of (R)--CMH is
recovered.
57. (R)--CMH-Ephedrine salt.
58. A process for optically purifying (R)--CMH comprising combining
(R)--CMH with water.
59. The process of claim 58, wherein the water is in an amount of
8-15 vol.
60. The process of claim 58, wherein the (R)--CMH has a specific
optical purity as measured by HPLC.
61. The process of claim 58, wherein the (R)--CMH has a purity of
about 90% to about 99% area by HPLC.
62. The process of claim 61, wherein the (R)--CMH has a purity of
about 96.5% to about 99% area by HPLC.
63. The process of claim 58, wherein the combination of (R)--CMH
and water results in a slurry.
64. The process of claim 63, wherein the slurry is stirred to
obtain a precipitate of (R)--CMH.
65. The process of claim 64, wherein the obtained slurry is stirred
at a temperature of about 2.degree. C. to about 30.degree. C. for
about one hour to about 24 hours.
66. The process of claim 65, wherein the obtained slurry is stirred
at a temperature of about 15.degree. C. to about 20.degree. C. for
about 0.5 hour to about 24 hours.
67. The process of claim 66, wherein the obtained slurry is stirred
for about one hour to about 2 hours.
68. The process of claim 58, wherein the (R)--CMH obtained by the
above process contains less than about 1% area by HPLC of
(S)--CMH.
69. The process of claim 68, wherein the (R)--CMH obtained by the
above process contains less than about 0.2% area by HPLC of
(S)--CMH.
70. The process of claim 69, wherein the (R)--CMH obtained by the
above process contains less than about 0.1% area by HPLC of
(S)--CMH.
71. The process of claim 64, wherein the precipitate is
recovered.
72. A process for isolating (S)--CMH from the remaining mother
liquor comprising: a) combining the mother liquor obtained after
the flirtation of (R)--CMH with water; b) heating to obtain a
solution; c) cooling the solution; d) combining the solution with
an acid to obtain a precipitate of CMH containing about a specific
amount of (S)--CMH; e) filtering the precipitate; f) combining the
precipitate with acetone and 1R, 2S-(-)-ephedrine, to obtain a
second precipitate in a mother liquor; g) removing the precipitate
from the mother liquor; h) evaporating the mother liquor to obtain
a residue; i) combining the residue with a solvent selected from
ketone, C.sub.1-8 alcohol, water or mixtures thereof, and with a
strong mineral acid to obtain a slurry; and j) recovering the
(S)--CMH.
73. The process of claim 72, wherein step f) further comprises
adding a base.
74. A process for preparing (S)-Pregabalin comprising preparing
(R)--CMH by the process of claim 3, and converting it to
(S)-Pregabalin.
75. The process of claim 74, wherein the conversion comprises:
reacting (R)--CMH with bromine in a Hoffman reaction under basic
conditions at a temperature of about 60.degree. C. to about
85.degree. C., to obtain a basic mixture, followed by an addition
of a strong mineral acid, to obtain an acidic mixture containing a
(S)-Pregabalin salt.
76. The process of claim 74, wherein (S)-Pregabalin contains less
than about 0.2% area by HPLC of (R)-Pregabalin.
77. The process of claim 76, wherein (S)-Pregabalin contains less
than about 0.1% area by HPLC of (R)-Pregabalin.
78. A-pharmaceutical composition comprising (S)-Pregabalin made by
the process of claim 74 and at least one pharmaceutically
acceptable excipient.
79. A process for preparing a pharmaceutical formulation comprising
combining (S)-Pregabalin made by the process of claim 74, with at
least one pharmaceutically acceptable excipient.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Nos. 60/679,784, filed May 10, 2005, 60/689,699, filed
Jun. 9, 2005, 60/733,009, filed Nov. 2, 2005, 60/735,634, filed
Nov. 9, 2005, and 60/740,950, filed Nov. 29, 2005, the contents of
which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to pure (R)--CMH, the
optical resolution of 3-carbamoylmethyl-5-methyl hexanoic
acid-racemate (CMH-racemate), the process for optically purifying
(R)--CMH and the process for isolating (S)--CMH from the mother
liquor.
BACKGROUND OF THE INVENTION
[0003] (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic
acid, a compound having the chemical structure, ##STR1## is also
known as .gamma.-amino butyric acid or (S)-3-isobutyl GABA.
(S)-Pregabalin has been found to activate GAD (L-glutamic acid
decarboxylase). (S)-Pregabalin has a dose dependent protective
effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is
useful in anticonvulsant therapy, due to its activation of GAD,
promoting the production of GABA, one of the brain's major
inhibitory neurotransmitters, which is released at 30 percent of
the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant,
and anxiolytic activity.
[0004] In the synthesis disclosed in U.S. Pat. No. 5,616,793,
(S)-Pregabalin is obtained after optical resolution of the
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid racemate (referred
to as CMH-racemate), which is accomplished by reaction of the
CMH-racemate with chiral phenylethylamine in a solvent mixture of
CHCl.sub.3 and ethanol to obtain the desired R-enantiomer of CMH
according to the following scheme: ##STR2## However, according to
Chemical Development of CI-1008. An Enantiomerically Pure
Anticonvulsant, ORGANIC PROCESS RESEARCH & DEVELOPMENT, 1997,
1, 26-38, this synthetic method was avoided because it requires the
use of chloroform.
[0005] In the synthesis disclosed in DRUGS OF THE FUTURE, 24 (8),
862-870 (1999), CMH-racemate is also resolved with
(R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of
(R)--CMH. Combining the salt with an acid liberates the R
enantiomer. Finally, Hoffmann degradation with Br.sub.2/NaOH
provides (S)-Pregabalin. However, the optical resolution is done
using a mixture of EtOH and chloroform, and therefore is
problematic.
[0006] Optical resolution of a racemic mixture, particularly of
carboxylic acids and amines, is performed via a diastereomeric
salt. An example of this method is depicted in the following
scheme, ##STR3## The salt is formed by reacting the racemic mixture
with a chiral resolving reagent. Then, a selective crystallization
of only one of the diastereomers is done to isolate the desired
diastereomer salt, while the undesired remains in the solution. The
crystalline salt is then isolated and the chiral resolving reagent
is removed to give the desired enantiomer. Accordingly, CMH which
has a carboxylic acid function can be reacted with an appropriate
chiral amine to obtain the salt of the desirable enantiomer
(R-enantiomer), which is then isolated followed by removing the
chiral amine to give (R)--CMH. ##STR4##
[0007] Thus, there is a need for an optical resolution process that
overcomes the limitations of the above resolution procedures.
SUMMARY OF THE INVENTION
[0008] In one embodiment, the present invention provides (R)--CMH
containing less than about 0.2% area by HPLC of (S)--CMH.
Preferably, the present invention provides (R)--CMH containing less
than about 0.1% area by HPLC of (S)--CMH.
[0009] In another embodiment, the present invention provides a
process for the optical resolution of
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as
CMH-racemate), ##STR5## comprising combining CMH-racemate, a
solvent selected from the group consisting of ketone, ester,
nitrile, C.sub.1-4 alcohol, water, or mixtures thereof, a chiral
resolving reagent of amino alcohol and salts thereof; recovering;
and adding a solvent selected from the group consisting of ketone,
C.sub.1-8 alcohol, water or mixtures thereof, and a strong mineral
acid, wherein; any individual stereoisomer of the chiral resolving
reagent may be used.
[0010] In yet another embodiment the present invention also
provides a process for the optical resolution CMH-racemate that
comprises two steps: the first is the preparation of the (R)--CMH
amine salt and the second, recovering (R)--CMH from the salt. The
process comprises combining CMH-racemate, a solvent selected from
the group consisting of ketone, ester, nitrile, C.sub.1-4 alcohol,
water, or mixtures thereof, a chiral resolving reagent selected
from ephedrine, ephedrine salt, norephedrine, and norephedrine salt
to obtain a precipitate, wherein the precipitate is of
(R)--CMH-ephedrine salt of the following structure: ##STR6## or of
(R)--CMH-norephedrine salt of the following structure: ##STR7##
[0011] The precipitate is further isolated and thereafter combined
with a solvent selected from the group consisting of ketone,
C.sub.1-8alcohol, water, or mixtures thereof, and with a strong
mineral acid to obtain a precipitate of (R)--CMH of the following
structure ##STR8##
[0012] In one embodiment the present invention provides a process
for the optical resolution of
(.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as
CMH-racemate) comprising combining CMH-racemate, a solvent selected
from ketone, ester, nitrile, C.sub.1-4 alcohol, water, or mixtures
thereof, and 1R, 2S-(-)-ephedrine to obtain a reaction mixture. The
obtained reaction mixture is then heated to a temperature of about
50.degree. C. to about 140.degree. C. The reaction mixture is then
cooled to a temperature of about ambient to about 2.degree. C. to
obtain a precipitate, wherein the precipitate is of
(R)--CMH-ephedrine salt of the following structure: ##STR9## or of
(R)--CMH-norephedrine salt of the following structure:
##STR10##
[0013] The precipitate is further isolated and thereafter combined
with a solvent selected from the group consisting of ketone,
C.sub.1-8 alcohol, water or mixtures thereof, and with a strong
mineral acid to obtain a slurry and the slurry is then cooled to a
temperature of about 10.degree. C. to about 2.degree. C. to obtain
a precipitate of (R)--CMH of the following structure ##STR11##
[0014] In another embodiment, the present invention provides
(R)--CMH-Ephedrine salt.
[0015] In yet another embodiment, the present invention provides a
process for improving the optical purity of (R)--CMH comprising
combining (R)--CMH with water.
[0016] In one embodiment, the present invention provides a process
for isolating (S)--CMH from the remaining mother liquor comprising
combining the mother liquor obtained after the filtration of
(R)--CMH with water, and heating to dissolution. The solution is
then cooled and combined with an acid to obtain a precipitate of
CMH containing about a specific amount of (S)--CMH. The precipitate
is then filtered and resolved again with acetone, and ephedrine as
a chiral resolving reagent to obtain a second precipitate of
R--CMH-ephedrine salt that is then removed. The remaining mother
liquor, which contains (S)--CMH-ephedrine salt, is then evaporated
to dryness, and the residue is treated with an acid to obtain
(S)--CMH, which is further recovered
[0017] In another embodiment, the present invention provides a
process for preparing (S)-Pregabalin comprising preparing (R)--CMH
by the process of the present invention, and converting it to
(S)-Pregabalin.
DETAILED DESCRIPTION OF THE INVENTION
[0018] As used herein, the term "chiral resolving reagent" refers
to an acidic or basic structure re that can lead to the
precipitation of the diastereomer containing the desired enantiomer
in high chemical and optical yields.
[0019] As used herein, the term "racemate" refers to a mixture that
contains an equal amount of enantiomers.
[0020] The present invention provides (R)--CMH containing less than
about 0.2% area by HPLC of (S)--CMH. Preferably, the present
invention provides (R)--CMH containing less than about 0.1% area by
HPLC of (S)--CMH.
[0021] The process of the present invention performs resolution at
the stage of CMH-racemate, of the following structure ##STR12##
without using carcinogenic solvents as chloroform, while also
recycling the undesired enantiomer. However, some processes of the
prior art perform the optical resolution on Pregabalin itself
while, recycling (R)-Pregabalin is very difficult, thus leading to
a non-efficient and non-economical process.
[0022] The present invention provides a process for the optical
resolution of (.+-.)-3-(carbamoylmethyl)-5-methylhexanoic acid
(referred to as CMH-racemate), ##STR13## comprising combining
CMH-racemate, a solvent selected from the group consisting of
ketone, ester, nitrile, C.sub.1-4 alcohol, water, or mixtures
thereof, a chiral resolving reagent of amino alcohol and salts
thereof to obtain a precipitate; isolating the precipitate; and
adding a solvent selected from the group consisting of ketone,
C.sub.1-8 alcohol, water or mixtures thereof, and a strong mineral
acid, wherein; any individual stereoisomer of the chiral resolving
reagent may be used.
[0023] The present invention also provides a process for the
optical resolution CMH-racemate that comprises two steps: the first
is the preparation of the (R)--CMH amine salt and the second,
recovering (R)--CMH from the salt. The process comprises combining
CMH-racemate, a solvent selected from the group consisting of
ketone, ester, nitrile, C.sub.1-4 alcohol, water, or mixtures
thereof, a chiral resolving reagent selected from ephedrine,
ephedrine salt, norephedrine, and norephedrine salt to obtain a
precipitate, wherein the precipitate is of (R)--CMH-ephedrine salt
of the following structure: ##STR14## or of (R)--CMH-norephedrine
salt of the following structure: ##STR15##
[0024] The precipitate is further isolated and thereafter combined
with a solvent selected from the group consisting of ketone,
C.sub.1-8 alcohol, water, or mixtures thereof, and with a strong
mineral acid to obtain a precipitate of (R)--CMH of the following
structure ##STR16##
[0025] The present invention provides a process for the optical
resolution of CMH-racemate comprising combining CMH-racemate, a
solvent selected from ketone, ester, nitrile, C.sub.1-4 alcohol,
water, or mixtures thereof, and 1R, 2S-(-)-ephedrine to obtain a
reaction mixture. The obtained reaction mixture is then heated to a
temperature of about 50.degree. C. to about 140.degree. C. The
reaction mixture is then cooled to a temperature of about
20.degree. C. to about -20.degree. C. to obtain a precipitate,
wherein the precipitate is of (R)--CMH-ephedrine salt of the
following structure: ##STR17## or of (R)--CMH-norephedrine salt of
the following structure: ##STR18##
[0026] The precipitate is further isolated and thereafter combined
with a solvent selected from the group consisting of ketone,
C.sub.1-8 alcohol, water or mixtures thereof, and with a strong
mineral acid to obtain a slurry and the slurry is then cooled to a
temperature of about 10.degree. C. to about 2.degree. C. to obtain
a precipitate of (R)--CMH of the following structure ##STR19##
[0027] Preferably, the chiral resolving reagent of amino alcohol
and salts thereof is selected from the group consisting of
ephedrine, ephedrine salt, norephedrine, and norephedrine salt.
More preferably, the chiral resolving reagent is ephedrine or
ephedrine salt. Most preferably, the chiral resolving reagent is
1R,2S-(-)-ephedrine.
[0028] Preferably, the salt of ephedrine or norephedrine is a
hydrochloride, nitrate, or sulfate. More preferably, the salt is a
hydrochloride.
[0029] Optionally, a base is further added with the resolving
reagent. When the chiral resolving reagent is the salt of ephedrine
or of norephedrine, a base must also be used. Preferably, the base
is either an organic base or an inorganic base. Preferably, the
organic base is an amine. Preferably, the amine is tertiary or
secondary amine. Preferably, the tertiary amine is triethylamine or
tributylamine. Preferably, the secondary amine is diisopropylamine
or n-dipropylamine. The more preferred organic base is
triethylamine. Preferably, the inorganic base is alkali metal
hydrogen carbonates, alkali hydroxide or alkali carbonate.
Preferably, the alkali hydroxide is either NaOH or KOH. Preferably,
the alkali carbonate is either K.sub.2CO.sub.3 or Na.sub.2CO.sub.3.
The more preferred inorganic base is NaOH.
[0030] Preferably, the ketone is a C.sub.2 to C.sub.6 ketone, more
preferably a C.sub.2 to C.sub.5 ketone, more preferably, acetone or
methylisobutyl ketone, most preferably, aetone. Preferably, the
C.sub.1-4 alcohol is selected from the group consisting of
methanol, ethanol, isopropanol, or isobutanol. More preferably, the
C.sub.1-4 alcohol is methanol. Preferably, the ester is selected
from a C.sub.3 to C.sub.8, more preferably a C.sub.4 to C.sub.6
ester, such as a C.sub.2 to C.sub.4 alkylacetate. More preferably,
the ester is selected from the group consisting of ethyl acetate,
butylacetate and isopropyl acetate. Most preferably, the ester is
Ethylacetate. Preferably, the nitrile is acetonitrile. The most
preferred solvent is acetone or a mixture of acetone and water.
[0031] Preferably, the mixture is heated to a temperature of about
50.degree. C. to about 100.degree. C. obtain a reaction mixture,
which is maintained at this temperature for about 0.5 hour to about
5 hours, more preferably, for about 0.5 hour to about 2 hours.
Preferably, the reaction mixture is a solution.
[0032] The obtained reaction mixture is cooled to a temperature of
about 20.degree. C. to about -20.degree. C., and is preferably
maintained for about an hour to about 24 hours, more preferably,
for an hour to about 12 hours.
[0033] Preferably, the isolation is by recovering.
[0034] Preferably, the strong mineral acid is HCl, HBr,
H.sub.2SO.sub.4, or H.sub.2PO.sub.3. The more preferred strong
mineral acid is HCl.
[0035] Preferably, after the addition of the acid, a pH of about 0
to about 4 is obtained, more preferably, a pH of about 1 to about 3
is obtained.
[0036] Preferably, the slurry is cooled to a temperature of about
2.degree. C.
[0037] Preferably, the slurry is maintained at a temperature of
about 2.degree. C. to about ambient temperature, more preferably,
of about 2.degree. C. to about 10.degree. C., for about 0.5 hours
to about 24 hours, more preferably, for about 0.5 hours to about 2
hours.
[0038] Preferably, the (R)--CMH is further recovered.
[0039] (R)--CMH, (R)--CMH-ephedrine salt and (R)--CMH-norephedrine
salt may be recovered by known methods in the art, such as
filtering, washing, and drying in a vacuum oven. After the
filtration step, the remaining mother liquor is obtained.
[0040] The (R)--CMH obtained by the process of the invention
contains less than about 7% area by HPLC, more preferably, less
than about 4% area by HPLC, most preferably, less than about 0.2%
area by HPLC and even most preferably, less than 0.1% area by HPLC
of (S)--CMH.
[0041] The present invention provides (R)--CMH-Ephedrine salt.
[0042] The present invention provides a process for optically
purifying (R)--CMH comprising combining (R)--CMH with water.
Preferably, the water is in an amount of 8-15 vol.
[0043] Preferably, the (R)--CMH has a specific optical purity as
measured by HPLC. The combination of (R)--CMH and water results in
a slurry. Preferably, the obtained slurry is stirred to obtain a
precipitate of (R)--CMH. Preferably, the obtained slurry is stirred
at a temperature of about 2.degree. C. to about 30.degree. C. for
about one hour to about 24 hours, more preferably, at a temperature
of about 15.degree. C. to about 20.degree. C. for about 0.5 hour to
about 24 hours, most preferably, at a temperature of about
20.degree. C. for about one hour to about 2 hours.
[0044] The starting (R)--CMH may be obtained by the processes
described before, having a purity of about 90% to about 99% area by
HPLC, more preferably, of about 96.5% to about 99% area by
HPLC.
[0045] (R)--CMH obtained by the above process contains less than
about 1% area by HPLC, more preferably, less than about 0.2% area
by HPLC, most preferably, less than 0.1% area by HPLC of
(S)--CMH.
[0046] Preferably, the precipitate is recovered. The precipitate
may be recovered by any method known in the art, such as filtering,
washing, and drying.
[0047] The present invention provides a process for isolating
(S)--CMH from the remaining mother liquor comprising combining the
mother liquor obtained after the flirtation of (R)--CMH with water,
and heating to dissolution. The solution is then cooled and
combined with an acid to obtain a precipitate of CMH containing
about a specific amount of (S)--CMH. The precipitate is then
filtered and resolved again with acetone, and 1R, 2S-(-)-ephedrine
to obtain a second precipitate of R--CMH-ephedrine salt that is
then removed. The remaining mother liquor, which contains
(S)--CMH-ephedrine salt, is then evaporated to dryness, and the
residue is treated with an acid to obtain (S)--CMH, which is
further recovered.
[0048] Preferably, when the precipitate is resolved again with
acetone and ephedrine a base is also added.
[0049] The precipitate of (S)--CMH may be recovered by known
methods in the art, such as filtering, washing and drying in a
vacuum oven.
[0050] The present invention provides a process for preparing
(S)-Pregabalin comprising preparing (R)--CMH by the process of the
present invention, and converting it to (S)-Pregabalin. Preferably,
the conversion of (R)--CMH to (S)-Pregabalin comprises reacting
(R)--CMH with bromine in a Hoffman reaction under basic conditions
at a temperature of about 60.degree. C. to about 85.degree. C., to
obtain a basic mixture, followed by an addition of a strong mineral
acid, to obtain an acidic mixture containing a complex of
(S)-Pregabalin with the strong mineral acid, as disclosed in
Co-application No. 60/689,699, or by any other process known to one
skilled in the art.
[0051] Preferably, the (S)-Pregabalin contains less than about 0.2%
area by HPLC of (R)-Pregabalin. More preferably, (S)-Pregabalin
contains less than about 0.1% area by HPLC of (R)-Pregabalin.
[0052] The present invention provides a pharmaceutical composition
comprising (S)-Pregabalin made by the process of the present
invention and at least one pharmaceutically acceptable
excipient.
[0053] The present invention provides a process for preparing a
pharmaceutical formulation comprising combining (S)-Pregabalin made
by the process of the present invention, with at least one
pharmaceutically acceptable excipient.
[0054] The present invention provides the use of (S)-Pregabalin
made by the process of the present invention for the manufacture of
a pharmaceutical composition.
[0055] Methods of administration of a pharmaceutical composition of
the present invention can be administered in various preparations
depending on the age, sex, and symptoms of the patient. The
pharmaceutical compositions can be administered, for example, as
tablets, pills, powders, liquids, suspensions, emulsions, granules,
capsules, suppositories, injection preparations (solutions and
suspensions), and the like.
[0056] Pharmaceutical compositions of the present invention can
optionally be mixed with (S)-Pregabalin obtained in the present
invention and other active ingredients. In addition, pharmaceutical
compositions of the present invention can contain inactive
ingredients such as diluents, carriers, fillers, bulking agents,
binders, disintegrants, disintegration inhibitors, absorption
accelerators, wetting agents, lubricants, glidants, surface active
agents, flavoring agents, and the like.
[0057] Diluents increase the bulk of a solid pharmaceutical
composition, and may make a pharmaceutical dosage form containing
the composition easier for the patient and care giver to handle.
Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g. AVICEL.RTM.), microfine cellulose,
lactose, starch, pregelatinized starch, calcium carbonate, calcium
sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium
carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g. EUDRAGIT.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0058] Solid pharmaceutical compositions that are compacted into a
dosage form, such as a tablet, may include excipients whose
functions include helping to bind the active ingredient and other
excipients together after compression. Binders for solid
pharmaceutical compositions include acacia, alginic acid, carbomer
(e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl
cellulose, gelatin, guar gum, hydrogenated vegetable oil,
hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL.RTM.),
hydroxypropyl methyl cellulose (e.g. METHOCEL.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON.RTM.,
PLASDONE.RTM.), pregelatinized starch, sodium alginate and
starch.
[0059] The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach may be increased by the
addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. AC-DI-SOL.RTM.,
PRIMELLOSE.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. KOLLIDON.RTM., POLYPLASDONE.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
EXPLOTAB.RTM.) and starch.
[0060] Glidants can be added to improve the flowability of a
non-compacted solid composition and to improve the accuracy of
dosing. Excipients that may function as glidants include colloidal
silicon dioxide, magnesium trisilicate, powdered cellulose, starch,
talc, and tribasic calcium phosphate.
[0061] When a dosage form such as a tablet is made by the
compaction of a powdered composition, the composition is subjected
to pressure from a punch and dye. Some excipients and active
ingredients have a tendency to adhere to the surfaces of the punch
and dye, which can cause the product to have pitting and other
surface irregularities. A lubricant can be added to the composition
to reduce adhesion and ease the release of the product from the
dye. Lubricants include magnesium stearate, calcium stearate,
glyceryl monostearate, glyceryl palmitostearate, hydrogenated
castor oil, hydrogenated vegetable oil, mineral oil, polyethylene
glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, stearic acid, talc and zinc stearate.
[0062] Flavoring agents and flavor enhancers make the dosage form
more palatable to the patient. Common flavoring agents and flavor
enhancers for pharmaceutical products that may be included in the
composition of the present invention include maltol, vanillin,
ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol,
and tartaric acid.
[0063] Solid and liquid compositions may also be dyed using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0064] In liquid pharmaceutical compositions of the present
invention, the (S)-Pregabalin and any other solid excipients are
dissolved or suspended in a liquid carrier such as water, vegetable
oil, alcohol, polyethylene glycol, propylene glycol or
glycerin.
[0065] Liquid pharmaceutical compositions may contain emulsifying
agents to disperse uniformly throughout the composition an active
ingredient or other excipient that is not soluble in the liquid
carrier. Emulsifying agents that may be useful in liquid
compositions of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol,
and cetyl alcohol.
[0066] Liquid pharmaceutical compositions of the present invention
may also contain a viscosity enhancing agent to improve the
mouth-feel of the product and/or coat the lining of the
gastrointestinal tract. Such agents include acacia, alginic acid
bentonite, carbomer, carboxymethylcellulose calcium or sodium,
cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate,
sodium starch glycolate, starch tragacanth and xanthan gum.
[0067] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar
may be added to improve the taste.
[0068] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and
ethylenediamine tetraacetic acid may be added at levels safe for
ingestion to improve storage stability.
[0069] According to the present invention, a liquid composition may
also contain a buffer such as guconic acid, lactic acid, citric
acid or acetic acid, sodium guconate, sodium lactate, sodium
citrate or sodium acetate. Selection of excipients and the amounts
used may be readily determined by the formulation scientist based
upon experience and consideration of standard procedures and
reference works in the field.
[0070] When preparing injectable (parenteral) pharmaceutical
compositions, solutions and suspensions are sterilized and are
preferably made isotonic to blood. Injection preparations may use
carriers commonly known in the art. For example, carriers for
injectable preparations include, but are not limited to, water,
ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol,
polyoxylated isostearyl alcohol, and fatty acid esters of
polyoxyethylene sorbitan. One of ordinary skill in the art can
easily determine with little or no experimentation the amount of
sodium chloride, glucose, or glycerin necessary to make the
injectable preparation isotonic. Additional ingredients, such as
dissolving agents, buffer agents, and analgesic agents may be
added.
[0071] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable administration in any given case will depend on the
nature and severity of the condition being treated, the most
preferred route of the present invention is oral. The dosages may
be conveniently presented in unit dosage form and prepared by any
of the methods well-known in the pharmaceutical arts.
[0072] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges, as
well as liquid syrups, suspensions and elixirs.
[0073] The dosage form of the present invention may be a capsule
containing the composition, preferably a powdered or granulated
solid composition of the invention, within either a hard or soft
shell. The shell may be made from gelatin and optionally contain a
plasticizer such as glycerin and sorbitol, and an opacifying agent
or colorant.
[0074] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0075] A composition for tableting or capsule filling may be
prepared by wet granulation. In wet granulation, some or all of the
active ingredients and excipients in powder form are blended and
then further mixed in the presence of a liquid, typically water,
that causes the powders to clump into granules. The granulate is
screened and/or milled, dried and then screened and/or milled to
the desired particle size. The granulate may then be tableted, or
other excipients may be added prior to tableting, such as a glidant
and/or a lubricant.
[0076] A tableting composition may be prepared conventionally by
dry blending. For example, the blended composition of the actives
and excipients may be compacted into a slug or a sheet and then
comminuted into compacted granules. The compacted granules may
subsequently be compressed into a tablet.
[0077] As an alternative to dry granulation, a blended composition
may be compressed directly into a compacted dosage form using
direct compression techniques. Direct compression produces a more
uniform tablet without granules. Excipients that are particularly
well suited for direct compression tableting include
microcrystalline cellulose, spray dried lactose, dicalcium
phosphate dihydrate, and colloidal silica. The proper use of these
and other excipients in direct compression tableting is known to
those in the art with experience and skill in particular
formulation challenges of direct compression tableting.
[0078] A capsule filling of the present invention may comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, however, they are not subjected to a
final tableting step.
[0079] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable route in any given case will depend on the nature and
severity of the condition being treated, the most preferred route
of the present invention is oral. The dosages can be conveniently
presented in unit dosage form and prepared by any of the methods
well-known in the pharmaceutical arts.
[0080] While the present invention is described with respect to
particular examples and preferred embodiments, it is understood
that the present invention is not limited to these examples and
embodiments. The present invention as claimed therefore includes
variations from the particular examples and preferred embodiments
described herein, as will be apparent to one of skill in the
art.
Instruments
[0081] HPLC TABLE-US-00001 Enantiomeric purity of
R-3-(Carbamoylmethyl)-5-methylhexanoic acid (CMH) by chiral HPLC
HPLC Column & packing DAICEL Chiralpak AD-H 250*4.6 mm 5 .mu.m
P.N. 19325 Eluent: n-Heptane:Ethanol:TFA 850:150:1 TFA from J. T.
Baker 9470-01 recommended Stop time: 25 min Flow: 0.5 ml/min
Detector: 208 nm. Injection volume: 50 .mu.l. Diluent 85:15
n-Heptane:Ethanol Column temperature 10.degree. C. Autosampler
temperature 15.degree. C. Typical relative retention times are:
R-CMH-R-(+)-3-(Carbamoylmethyl)-5-methylhexanoic acid RRT = 1.00
S-CMH-S-(-)-3-(Carbamoylmethyl)-5-methylhexanoic acid RRT =
1.14
EXAMPLES
Example 1
Optical Resolution of (R)--CMH-Ephedrine Salt
[0082] A 250 ml flask was charged with 100 ml of acetone, 10 ml of
methanol, 10 g of CMH-racemate, and 4.4 g of 1R, 2S-(-)-ephedrine.
The resulting clear solution was evaporated to dryness, and 100 ml
of acetone was added to the residue. After stirring for 1 hour at
room temperature, the precipitate was filtered, washed with 40 ml
of acetone, and dried at 45.degree. C. at a pressure of 10 mm Hg.
The (R)--CMH-ephedrine salt was found to have an optical purity of
99.3% area by HPLC.
Example 2
Optical Resolution of (R)--CMH-Ephedrine Salt
[0083] A 100 ml flask was charged with 40 ml of acetone, 5 g of
CMH-racemate, and 4.4 g of 1R, 2S-(-)-ephedrine. The mixture was
heated to dissolution, and then cooled to 10.degree. C. After
stirring for 1 hour at 10.degree. C., the resulting precipitate was
filtered, washed with 10 ml of acetone, and dried at 45.degree. C.
at a pressure of 10 mm Hg. The (R)--CMH-ephedrine salt was found to
have an optical purity of 97% area by HPLC.
Example 3
Optical Resolution of (R)--CMH-Ephedrine Salt
[0084] A 100 ml flask was charged with acetone (80 ml),
CMH-racemate (10 gr), Triethylamine (5.4 gr) and 1R,
2S-(-)-Ephedrine hydrochloride (10.79 gr). The mixture was heated
to reflux and stirred at reflux for 2 h. The mixture was cooled to
10.degree. C., and after stirring for 1 h at 10.degree. C. the
precipitate was filtered, washed with acetone (10 ml) and dried at
45.degree. C. under 10 mm Hg. (R)--CMH-ephedrine salt was obtained
(9.95 gr), 90.2% optical pure.
Example 4
Preparation of (R)--CMH from (R)--CMH-Ephedrine Salt
[0085] A 100 ml flask was charged with water (22 ml), HCl--32% (2
ml) and CMH-ephedrine salt (GP-4328, 6 gr). The mixture was stirred
at room temperature for 15 min, then was cooled to 2.degree. C.,
and stirred for 2 h. The precipitate was filtered, washed with
water (5 ml) and dried at 45.degree. C. under 10 mm Hg. (R)--CMH
was obtained (1 gr), 93.6% optical pure.
Example 5
Optical Resolution of (R)--CMH-Ephedrine Salt
[0086] A 100 ml flask was charged with acetone (80 ml),
CMH-racemate (10 gr), NaOH (2.14 gr) and 1R, 2S-(-)-Ephedrine
hydrochloride (10.79 gr). The mixture was heated to reflux and
stirred at reflux for 2 h. The mixture was cooled to 10.degree. C.,
and after stirring (1 h) at 10.degree. C. the precipitate was
filtered, washed with acetone (10 ml) and dried at 45.degree. C.
under 10 mm Hg. (R)--CMH-ephedrine salt was obtained (9.65 gr),
94.6% optical pure.
Example 6
Preparation of (R)--CMH from (R)--CMH-Ephedrine Salt
[0087] A 100 ml flask was charged with water (22 ml), HCl--32% (2
ml) and (R)--CMH-ephedrine salt (6 gr, optical purity of 94.6%).).
The mixture was stirred at RT for 15 min, then was cooled to
2.degree. C., and stirred for 2 h. The precipitate was filtered,
washed with water (5 ml) and dried at 45.degree. C. under 10 mm Hg.
(R)--CMH was obtained (2.1 gr), 98.5% optical pure.
Example 7
Optical Resolution of (R)--CMH-Ephedrine Salt
[0088] A 1 L flask was charged with acetone (480 ml), CMH-racemate
(60 gr), NaOH (12.84 gr) and 1R, 2S-(-)-Ephedrine hydrochloride
(64.74 gr). The mixture was heated to reflux and stirred at reflux
for 2 h. The mixture was cooled to 10.degree. C., and after
stirring (1 h) at 10.degree. C. the precipitate was filtered,
washed with acetone (60 ml) and dried at 45.degree. C. under 10 mm
Hg. (R)--CMH-ephedrine salt was obtained (56 gr), 98.8% optical
pure.
Example 8
Preparation of (R)--CMH from (R)--CMH-Ephedrine Salt
[0089] A 0.5 L flask was charged with water (216 ml), and
(R)--CMH-ephedrine salt (54 gr, optical purity of 99.7%). The
mixture was stirred at RT until dissolution, and HCl--32% (15 ml)
was added to obtain pH=1. The solution was cooled to 2.degree. C.,
stirred for 1 h, after which the precipitate was filtered, washed
with water (54 ml) and dried at 45.degree. C. under 10 mm Hg.
(R)--CMH was obtained (20 gr), 99.7% optical pure.
Example 9
Slurry of (R)--CMH in Water (Improve Optical Purity)
[0090] A mixture of (R)--CMH (40 gr, 96.5% optical pure) in water
(400 ml) was stirred for 1 h at RT. The solid was filtered, washed
with water (80 ml) and dried at 45.degree. C. under 10 mm Hg.
(R)--CMH was obtained (34.5 gr), 99.7% optical pure.
Example 10
Preparation of (R)--CMH (All Steps)
[0091] A 1 L flask was charged with acetone (320 ml), CMH-racemate
(40 gr), NaOH (8.56 gr) and 1R, 2S-(-)-Ephedrine hydrochloride
(43.16 gr). The mixture was heated to reflux and stirred at reflux
for 1 h. The mixture was cooled to 2.degree. C., and after stirring
(1 h) at 2.degree. C. the precipitate was filtered. Water (320 ml)
was added to the wet solid and the mixture was heated until
dissolution. After cooling to RT, HCl--32% (10 ml) was added. The
solution was cooled to 2.degree. C., stirred for 1 h, after which
the precipitate was filtered. Water (320 ml) was added to the cake
and the mixture was stirred at 20.degree. C. for 1 h. The
precipitate was filtered, washed with water (20 ml) and dried at
45.degree. C. under 10 mm Hg. (R)--CMH was obtained (12.5 gr),
98.4% optical pure.
Example 11
Preparation of (R)--CMH (All Steps)
[0092] 1 l flask was charged with acetone (1600 ml), water (40 ml),
CMH-racemate (200 gr), and 1R, 2S-(-)-Ephedrine (186.1 gr). The
mixture was heated to reflux and stirred at reflux for 1 h. The
solution was cooled to 2.degree. C. (during a period of 6 h), and
after stirring (10 h) at 2.degree. C. the precipitate was filtered
and washed with acetone (400 ml).
[0093] Water (800 ml) was added to the wet solid and then HCl--32%
(50 ml) was added dropwise to pH 2. The mixture was cooled to
2.degree. C., stirred for 2 h, after which the precipitate was
filtered and washed with water (100 ml).
[0094] Water (1000 ml) was added to the cake and the mixture was
stirred at 25.degree. C. for 1 h. The precipitate was filtered,
washed with water (100 ml) and dried at 45.degree. C. under 10 mm
Hg. R--CMH was obtained (72 gr), 99.94% optical pure.
Example 12
Preparation of (S)--CMH
[0095] The mother liquor residue of example 10, containing (S)--CMH
and a residue of (R)--CMH, was dissolved in water and was heated to
dissolution. After cooling to RT, HCl--32% (12 ml) was added and
mixture was stirred for 30 min at RT. The precipitate, of (R)--CMH
was filtered and washed with water (20 ml), while the (S)--CMH
remained in the filtrate.
[0096] A 0.5 L flask was charged with the later cake of the
filtered (R)--CMH, acetone (150 ml), NaOH (4.3 gr) and 1R,
2S-(-)-Ephedrine hydrochloride (21.5 gr). The mixture was stirred
at RT for 1 h and the precipitate, of (R)--CMH-ephedrine salt, was
filtered. The filtrate containing the remaining (S)--CMH-ephedrine
salt, was evaporated to dryness. The residue (44 gr) was dissolved
in water (100 ml) and HCl--32% was added until pH=1. The mixture
was stirred for 30 min at RT, then the precipitate was filtered,
washed with water (20 ml) and dried at 45 .degree. C. under 10 mm
Hg. (S)--CMH was obtained (11.4 gr), 99.0% optical pure.
* * * * *