U.S. patent application number 11/540519 was filed with the patent office on 2007-06-21 for oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues.
Invention is credited to Celal Ates, Anne-Catherine Burteau, Emile Cavoy, Violeta Marmon, John Surtees.
Application Number | 20070142647 11/540519 |
Document ID | / |
Family ID | 8178301 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070142647 |
Kind Code |
A1 |
Ates; Celal ; et
al. |
June 21, 2007 |
Oxopyrrolidine compounds, preparation of said compounds and their
use in the manufacturing of levetiracetam and analogues
Abstract
The present invention relates to an improved process for the
preparation of (S)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide
and analogues thereof. The invention also relates to compounds of
the general formula (6) ##STR1## wherein R.sup.1 is methyl or
ethyl; and R.sup.2 is C.sub.2-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl or C.sub.2-C.sub.4 alkynyl, optionally substituted by one
or more halogen, and their preparation processes.
Inventors: |
Ates; Celal;
(Louvain-la-Neuve, BE) ; Surtees; John;
(Jezus-Eik, BE) ; Burteau; Anne-Catherine;
(Grand-Leez (Gembloux), BE) ; Marmon; Violeta;
(Abingdon-Oxon, GB) ; Cavoy; Emile;
(Ham-sur-Heure, BE) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
8178301 |
Appl. No.: |
11/540519 |
Filed: |
October 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10486342 |
Feb 10, 2004 |
7122682 |
|
|
PCT/EP02/08717 |
Aug 5, 2002 |
|
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|
11540519 |
Oct 2, 2006 |
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Current U.S.
Class: |
548/556 ;
548/555 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 207/26 20130101; C07D 207/27 20130101; A61P 25/08
20180101 |
Class at
Publication: |
548/556 ;
548/555 |
International
Class: |
C07D 207/267 20060101
C07D207/267 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 10, 2001 |
EP |
01119396.8 |
Claims
1. A compound of formula (6) ##STR65## wherein R.sup.1 is methyl or
ethyl; and R.sup.2 is C.sub.2-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl or C.sub.2-C.sub.4 alkynyl, optionally substituted by one
or more halogen; as well as the stereoisomers and mixtures
thereof.
2. The compound according to claim 1, wherein the R.sup.2
substituent is present at position 4 on the ring structure,
according to the following general formula (7). ##STR66##
3. The compound according to claim 2, wherein R.sup.1 is methyl and
R.sup.2 is propyl or 2,2-difluorovinyl.
4. The compound according to claim 2, wherein R.sup.1 is ethyl and
R.sup.2 is propyl or 2,2-difluorovinyl.
5. The compound according to claim 2, wherein R.sup.1 is methyl and
R.sup.2 is a substituent selected from 2-fluoro-2-methylpropyl,
2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.
6. The compound according to claim 2, wherein R.sup.1 is ethyl and
R.sup.2 is a substituent selected from 2-fluoro-2-methylpropyl,
2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.
7. The compound according to claim 1, which is an S isomer,
according to the following formula (8) ##STR67##
8. A process for the manufacture of a compound according to claim
1, said process comprising following steps: (a) reaction of a
compound of formula (9) ##STR68## with an alcohol of formula
R.sup.1OH wherein R.sup.1 is as noted in claim 1, (b) reaction of
the corresponding compound of formula (10) thus obtained ##STR69##
with a R.sup.2-substituted-ethyl-4-bromobutyrate wherein R.sup.2 is
as noted in claim 1, (c) cyclisation of the corresponding compound
of formula (11) thus obtained ##STR70## with a catalyst, (d)
isolation of the resulting compound.
9. The process according to claim 8, wherein step (a) is performed
in the presence of thionyl chloride and an alcohol.
10. The process according to claim 8, wherein step (b) is performed
in the presence of a base and an alcohol.
11. The process according to claim 8, wherein the catalyst used in
step (c) is pyridinol.
12. The process for the manufacture of a compound according to
claim 1, said process comprising a step of cyclisation of the
compound of the formula (11) ##STR71## wherein R.sup.1 and R.sup.2
are as in claim 1.
13. A process for the manufacture of a compound according to claim
1, said process comprising following steps: (a) reaction of an
.alpha.-ketocarboxylic acid derivative of formula (12) ##STR72##
wherein R.sup.1 is as noted in claim 1, with a pyrrolidinone of
formula (13) ##STR73## wherein R.sup.2 is as noted in claim 1, (b)
reaction of the corresponding compound of formula (14) thus
obtained ##STR74## with hydrogen in the presence of an asymmetric
hydrogenation catalyst, and (c ) isolation of the resulting
compound.
14. A process for the manufacture of a compound according to claim
1, said process comprising following steps: (a) reaction of a
compound of formula (15) ##STR75## wherein R.sup.1' is
C.sub.1-C.sub.6 alkyl and X is Cl, Br, I, alkylsulphonate or
sulfate; with a pyrrolidone of formula (13) ##STR76## wherein
R.sup.2 is as in claim 1; (b) reaction of the corresponding
compound of formula (16) thus obtained ##STR77## with ethyl-X,
wherein X is Cl, Br, I, alkylsulphonate or sulfate in the presence
of an asymmetric alkylation catalyst or additive; (c) optionally,
when R.sup.1' is different from R.sup.1, reaction of the compound
obtained in step (b) with an alcohol of formula R.sup.1 OH, and (d)
isolation of the resulting compound of formula (6).
15. A process for the manufacture of a compound according to claim
1, said process comprising following steps: (a) reaction of a
compound of general formula (20) ##STR78## wherein R.sup.1 is as
defined in claim 1, with a pyrrolidone of general formula (13)
##STR79## wherein R.sup.2 is defined as in claim 1; (b) separation
of the corresponding compound of formula (21) thus obtained
##STR80## wherein R.sup.1 and R.sup.2 are defined as in claim 1;
(c) isolation of the resulting compound of formula (6).
16. A process for the manufacture of a compound of formula (22')
##STR81## wherein R.sup.2' is hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl, optionally
substituted by one or more halogen, said process comprising the
ammonolysis of the corresponding compound of formula (6') ##STR82##
wherein R.sup.1' is C.sub.1-C.sub.6 alkyl and R.sup.2' is hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4
alkynyl, optionally substituted by one or more halogen, in the
presence of water.
17. The process according to claim 16, wherein said ammonolysis is
performed in a mixture of water and an alcohol.
18. The process according claim 16, wherein said ammonolysis is
performed in a 30-80% (w/w) NH.sub.3 solution in water.
19. The process according to claim 16, wherein said ammonolysis is
performed at 0 to 25.degree. C.
20. The process according to claim 16, wherein the molar ratio of
NH.sub.3 to the compound of formula (6') is at least 4.
21. The process according to claim 16, wherein a compound of
formula (6') is used wherein R.sup.1' is methyl and R.sup.2' is
hydrogen.
22. The process according to claim 16, wherein a compound of
formula (6') is used wherein R.sup.1' is ethyl and R.sup.2' is
hydrogen.
23. The process according to claim 16, wherein a compound of
formula (6') is used wherein the R.sup.2' substituent is present at
position 4 on the ring structure, according to the following
general formula (7') ##STR83##
24. The process according to claim 16, wherein a compound of
formula (6') or (7') is used wherein R.sup.2' is selected from the
group of propyl, 2,2-difluorovinyl, 2-fluoro-2-methylpropyl,
2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.
25. The process according to claim 16, wherein compound (6') is an
S isomer according to the following formula (8') ##STR84##
26. The process according to claim 16, wherein compound (6') is
obtained by a process comprising following steps: (a) reaction of a
compound of formula (9) ##STR85## with an alcohol of formula
R.sup.1'OH wherein R.sup.1' is as noted in claim 16, (b) reaction
of the corresponding compound of formula (10') thus obtained
##STR86## with a R.sup.2'-substituted-ethyl-4-bromobutyrate wherein
R.sup.2' is as noted in claim 16, (c) cyclisation of the
corresponding compound of formula (11') thus obtained ##STR87## in
the presence of a catalyst, and (d) isolation of the resulting
compound.
27. The process according to claim 16, wherein compound (6') is
obtained by a process comprising a step of cyclisation of a
compound of formula (11') ##STR88## wherein R.sup.1' and R.sup.2'
are as noted in claim 16.
28. The process according to claim 16, wherein compound (6') is
obtained by a process comprising following steps: (a) reaction of
an .alpha.-ketocarboxylic acid derivative of formula (12')
##STR89## wherein R.sup.1' is as noted in claim 16, with a
pyrrolidinone of formula (13') ##STR90## wherein R.sup.2' is as
noted in claim 16, (b) reaction of the corresponding compound of
formula (14') thus obtained ##STR91## with hydrogen in the presence
of an asymmetric hydrogenation catalyst, and (c) isolation of the
resulting compound.
29. The process according to claim 16, wherein compound (6') is
obtained by a process comprising following steps: (a) reaction of a
compound of formula (15') ##STR92## wherein R.sup.1' is as noted in
claim 16 and X is Cl, Br, I, alkylsulphonate or sulfate; with a
pyrrolidone of formula (13') ##STR93## wherein R.sup.2' is as in
claim 16, (b) reaction of the corresponding compound of formula
(16') thus obtained ##STR94## with ethyl-X, wherein X is Cl, Br, I,
alkylsulphonate or sulfate in the presence of an asymmetric
alkylation catalyst or additive, (c) isolation of the resulting
compound.
30. The process according to claim 16, wherein compound (6') is
obtained by a process comprising following steps: (a) reaction of a
compound of general formula (20') ##STR95## wherein R.sup.1' is as
noted in claim 16, with a pyrrolidone of general formula (13')
##STR96## wherein R.sup.2' is defined as in claim 16, (b)
separation of the corresponding compound of formula (21') thus
obtained, and ##STR97## (c) isolation of the resulting compound of
formula (6').
Description
[0001] This invention concerns a new and improved process for the
preparation of (S)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide
and analogues thereof, which is referred to under the International
Non-proprietary Name of Levetiracetam. Levetiracetam is known as a
useful therapeutic agent for the treatment or prevention of
epilepsy and other neurological disorders. This invention also
discloses novel intermediates and their use in manufacturing
processes of Levetiracetam and analogues thereof.
[0002] Levetiracetam or (S)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine
acetamide, a laevorotatory compound is disclosed as a protective
agent for the treatment and the prevention of hypoxic and ischemic
type aggressions of the central nervous system in the European
patent No. EP 0 162 036 B and has the following formula.
##STR2##
[0003] This compound is also effective in the treatment of
epilepsy, a therapeutic indication for which it has been
demonstrated that its dextrorotatory enantiomer
(R)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide completely
lacks activity (A. J. Gower et al., Eur. J. Pharmacol., 222, 1992,
193-203). A process for the preparation of this dextrorotatory
enantiomer has been described in the European patent No. 0165
919.
[0004] Manufacturing processes for Levetiracetam have been
described in both the European patent No. 0162 036 and in the
British patent No. 2 225 322. In the British patent No. 2 225 322
(S)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide is prepared by
hydrogenolysis of
(S)-.alpha.-[2-(methylthio)ethyl]-2-oxo-1-pyrolidineacetamide in
the presence of a desulfurizing reagent such as
NaBH.sub.4/NiCl.sub.2.6H.sub.2O, Raney nickel W-2 or, preferably,
Raney nickel T-1. However, this process cannot be conveniently
applied on an industrial scale for safety and environmental
reasons.
[0005] Another industrially applicable process was developed and
disclosed in a more recent patent application PCT/EPO1/01956. The
process described in said patent application PCT/EP01/01956 is
illustrated in Scheme 1 below. This process is based on the
asymmetric hydrogenation of a compound of formula (1), resulting in
Levetiracetam (compound of formula (2)). Said patent application
also describes the efficient asymmetric hydrogenation of related
compounds of general formula (3), providing the acid and esters of
general formula (4). ##STR3##
[0006] Me represents methyl, and Et represents ethyl.
[0007] However, it may be desired to convert the ester (4) directly
to Levetiracetam (2) by ammonolysis. A disadvantage of performing
said ammonolysis is that racemisation may occur, resulting in the
formation of the compound of formula (5) as described in Scheme 2.
below. ##STR4##
[0008] Moreover, the reaction time necessary to obtain a reasonable
conversion is generally very long. The reaction time may be
decreased by increasing the reaction temperature, but then the
extent of racemisation increases to unacceptable levels. No
compromise had until now been found between the reaction time, the
temperature and extent of racemisation.
[0009] It Is clear that an industrially viable process without the
above-mentioned disadvantage would be extremely desirable.
[0010] The process of the present invention largely overcomes the
major disadvantages such as the racemisation discussed above and
excessive hydrolysis. In addition, the present invention describes
novel intermediates and their use in processes for the preparation
of Levetiracetam and analogues thereof. The invention also relates
to new processes for preparing said intermediates.
[0011] According to a first aspect, the present invention relates
to a compound of formula (6): ##STR5## wherein R.sup.1 is methyl or
ethyl and R.sup.2 is C.sub.2-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl
or C.sub.2-C.sub.4 alkynyl, optionally substituted by one or more
halogen, preferably F, Cl, Br or I; as well as the stereoisomers
and mixtures thereof.
[0012] This invention relates to all stereoisomeric forms such as
geometrical and optical enantiomeric and diastereoisomeric forms of
the compounds of formula (6) and mixtures (including racemates)
thereof. The compounds of formula (6) and some of their
intermediates have at least one stereogenic center in their
structure, being the carbon atom attached to the nitrogen atom of
the pyrrolidine heterocycle. This stereogenic center is indicated
in formula (6) by an asterisk (*). This stereogenic center may be
present in a R or a S configuration, said R and S notation is used
in accordance with the rules described in Pure Appl. Chem., 45
(1976) 11-30. The compounds of formula (6) have at least a second
stereogenic center in their structure, being the carbon atom of the
pyrrolidine cycle to which the R.sup.2 substituent is attached.
This stereogenic center may be in a S or a R configuration.
Furthermore certain compounds of formula (6) which contain alkenyl
groups may exist as Z or E isomers. In each instance, the invention
includes both mixtures and separate individual isomers.
[0013] The compound of the formula (6) can be in the form of a
solvate, which is included within the scope of the present
invention. The solvates are for example hydrates, alcoholates and
the like. The compound of the formula (6) can also be in the form
of a salt, especially a pharmaceutical acceptable salt, which are
also included within the scope of the present invention.
[0014] According to a preferred embodiment, the present invention
relates to the compound of the general formula (6), wherein the
R.sup.2 substituent is present at position 4 on the ring structure,
as given in the following general formula (7) wherein R.sup.1 and
R.sup.2 are as noted above. ##STR6##
[0015] According to another preferred embodiment, the present
invention relates to the compound of formula (7), wherein the
R.sup.2 is a C2-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl,
optionally substituted by one or more halogen.
[0016] The term alkyl as used herein includes saturated monovalent
hydrocarbon radicals having straight, branched or cyclic moieties
or combinations thereof.
[0017] The term alkenyl as used herein includes both branched and
unbranched unsaturated hydrocarbon radicals having at least one
double bond.
[0018] The term alkynyl as used herein includes both branched and
unbranched hydrocarbon radicals having at least one triple
bond.
[0019] According to a more preferred embodiment, the invention
relates to the compound of the general formula (7), wherein R.sup.1
is methyl and R.sup.2 is propyl according to the following formula:
##STR7##
[0020] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is methyl and R.sup.2 is 2,2-difluorovinyl
according to the following formula: ##STR8##
[0021] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is propyl according to the
following formula: ##STR9##
[0022] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is 2,2-difluorovinyl according
to the following formula: ##STR10##
[0023] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is methyl and R.sup.2 is 2-fluoro-2-methylpropyl
according to the following formula: ##STR11##
[0024] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is 2-fluoro-2-methylpropyl
according to the following formula: ##STR12##
[0025] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is methyl and R.sup.2 is 2,2-difluoropropyl
according to the following formula: ##STR13##
[0026] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is 2,2-difluoropropyl
according to the following formula: ##STR14##
[0027] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is methyl and R.sup.2 is cyclopropylmethyl
according to the following formula: ##STR15##
[0028] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is cyclopropylmethyl according
to the following formula: ##STR16##
[0029] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is methyl and R.sup.2 is 2,2,2-trifluoroethyl
according to the following formula: ##STR17##
[0030] According to yet another more preferred embodiment, the
invention relates to the compound of the general formula (7),
wherein R.sup.1 is ethyl and R.sup.2 is 2,2,2-trifluoroethyl
according to the following formula: ##STR18##
[0031] According to another preferred embodiment, the compound of
general formula (6) or (7) is the S isomer as illustrated in the
following formula (8) wherein R.sup.1 and R.sup.2 are as noted
above. ##STR19##
[0032] In this preferred embodiment the compounds of formula (8)
include compounds wherein the second stereogenic center, that is
the carbon atom of the pyrrolidine heterocycle to which the R.sup.2
substituent is attached, is in a S or in a R configuration and
their mixtures. Furthermore certain compounds of formula (8) which
contain alkenyl groups may exist as Z or E isomers. In each
instance, the invention includes both mixtures and separate
individual isomers.
[0033] The invention also relates to new processes for the
manufacture of said compound of the general formula (6) as defined
above.
[0034] According to a first process, named the "Late Ring-Closure
route or LRC route", said compound of general formula (6) of the
invention as defined above may be manufactured by a process
comprising following steps: (a) reaction of a compound of formula
(9) ##STR20## with an alcohol of formula R.sup.1OH wherein R.sup.1
is defined as above, (b) reaction of the corresponding compound of
formula (10) thus obtained ##STR21## with a
R.sup.2-substituted-ethyl-4-bromobutyrate wherein R.sup.2 is
defined as above, (c) cyclisation of the corresponding compound of
formula (11) thus obtained ##STR22## with a catalyst, and (d)
isolation of the resulting compound.
[0035] In this process, the compound of formula (9) is an
enantiomerically pure or an enantiomerically enriched compound, the
chiral centre (either configuration) being denoted by an asterisk
(*). By enantiomerically enriched compound is meant a compound
containing more than 50%, preferably more than 55%, most preferably
more than 60%, of one of the enantiomers. By enantiomerically pure
compound is meant a compound containing at least 90%, preferably at
least 95%, most preferably at least 98%, of one of the
enantiomers.
[0036] The first step (step a) of this first process is preferably
effectuated in the presence of an alcohol (for instance methanol or
ethanol) and thionyl chloride. The second step (step b) is the
mono-N-alkylation of the amino-ester of formula (10) with a
R.sup.2-substituted ethyl 4-bromobutyrate (4-EBB) and is preferably
effectuated in the presence of an alcohol (for instance methanol,
ethanol or isopropanol). The alcohol is preferably isopropanol. The
use of isopropanol resulted in a major amount of the monoalkylated
ester (11) and a small amount of a dialkylated product which may be
separated by column chromatography. Alternatively, the
monoalkylated product may be precipitated as its hydrochloride salt
by means of gaseous HCl. The hydrochloride of the mono-alkylated
product (solid) is next neutralised with aqueous sodium carbonate
and extracted with an organic solvent. The second step is
preferably performed in the presence of base, most preferably
sodium carbonate. The catalyst used in the third step (step c) in
the first process is preferably 2-pyridinol. This reaction is
non-racemising and provides enantiomerically enriched or pure
(S)-isomers of compounds of formula (8) in the case where the (S)
enantiomer of compound (9) is used as starting material.
[0037] According to an alternative process, said compound of
general formula (6) of the invention as defined above may be
manufactured by a process comprising the step of cyclisation of the
compound of formula (11), wherein R.sup.1 and R.sup.2 are as
defined above. This process is carried out according to Scheme 4.
below: ##STR23##
[0038] According to a second process, said compounds of formula (6)
of the invention as defined above may also be manufactured by a
process comprising following steps: (a) reaction of an
.alpha.-ketocarboxylic acid derivative of formula (12) ##STR24##
wherein R.sup.1 is as defined above, with a pyrrolidinone of
formula (13) ##STR25## wherein R.sup.2 is as defined above, (b)
reaction of the corresponding compound of formula (14) thus
obtained ##STR26## with hydrogen in the presence of an asymmetric
hydrogenation catalyst, and (c) isolation the resulting
compound.
[0039] This process has as a major advantage that it is much more
rapid, simpler, and comprising fewer steps than the first `LRC`
route as discussed above. All details of this process are disclosed
in the application PCT/EP01/01956 where it is described for
compounds of a more general formula. Said application is hereby
further incorporated by reference.
[0040] According to a third process, said compounds of the general
formula (6) of the invention as defined above may also be
manufactured by a process comprising following steps: (a) reaction
of a compound of formula (15) ##STR27## wherein R.sup.1' is
C.sub.1-C.sub.6 alkyl and X is Cl, Br, I, alkylsulphonate or
sulfate; with a pyrrolidone of general formula (13). ##STR28##
wherein R.sup.2 is as noted as above; (b) reaction of the
corresponding compound of formula (16) thus obtained ##STR29## with
ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate and an
asymmetric alkylation catalyst or additive; (c) optionally, when
R.sup.1' is different from R.sup.1, reaction of the compound
obtained from step (b) with an alcohol of formula R.sup.1OH, and
(d) isolating the resulting compound of formula (6).
[0041] According to this third process, R.sup.1' is preferably
C3-C4 alkyl, especially terbutyl.
[0042] According to this third process, the asymmetric alkylation
catalyst or additive is preferably a chiral amine, most preferably
selected from (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine (17),
(R)-2-methoxyethoxyethyl-1-phenyl-2-piperidinoethylamine (18) and
(S)-1-methyl-2-anilinomethyl pyrrolidine (19). ##STR30##
[0043] Step (b) of this third process is preferably performed in
the presence of a base (such as mineral, organic or organometallic
bases). The base is preferably butyllithium.
[0044] Step (c) of this process is preferably acid or base
catalysed.
[0045] This process has the advantage that it comprises only few
reaction steps. Another advantage is that it may be performed using
inexpensive and readily available raw materials.
[0046] According to a fourth process, the compound of the general
formula (6) as defined above may also be prepared by a process
comprising following steps: (a) reaction of a compound of general
formula (20) ##STR31## wherein R.sup.1 is as defined above, with a
pyrrolidone of general formula (13) wherein R.sup.2 is defined as
above; (b) separation of the corresponding compound of general
formula (21) thus obtained ##STR32## wherein R.sup.1 and R.sup.2
are defined as above; (c) isolation of the resulting compound of
general formula (6).
[0047] According to this fourth process, the compound of the
general formula (6) as defined above may be isolated by industrial
chiral chromatographic separation (batch, MCC (Multi Column
Chromatography) or SMB (simulated moving bed)) of a compound of
general formula (21) according to Scheme 7. below. ##STR33##
[0048] The chromatographic process can be carried out using either
the batch or MCC process. Each enantiomer can be separated using a
chiral stationary phase to yield enantiomerically pure
products.
[0049] Commercially available chromatographic columns are for
example sold by DAICEL Company or SHISEIDO Company. The preferred
DAICEL columns such as the columns sold under the trademark
CHIRALPAK AD, CHIRALPAK AS and CHIRALPAK OD were found to be
efficient to this end when mobile phases such as mixtures of
alkanes with alcohols were used or even a pure alcohol or mixtures
of alcohols. The alkane or mixtures of alkanes particularly
referred to are: hexane, isohexane or heptane. The alcohol or
mixtures of alcohols particularly referred to are: propanol,
isopropanol, ethanol or methanol. There is a preference for the use
of heptane among the alkanes and there is a preference for the use
of ethanol and methanol among the alcohols. There is a preference
for the following mixtures: 50% to 95% for the alkane and 50% to 5%
for alcohol(s), or 100% of alcohol.
[0050] The preferred SHISEIDO columns such as the columns sold
under the trademark CERAMOSPHER CHIRAL RU-2 or CERAMOSPHER CHIRAL
RU-1 were found to be efficient for the separation when alcohols
were used as mobile phase. The alcohols referred to are: propanol,
isopropanol, ethanol or methanol. There is a preference for the use
of ethanol and methanol among the alcohols.
[0051] The extrapolation of small-scale batch separations of this
type to an industrial scale proceeds without difficulty in either
batch or continuous mode.
[0052] According to a second aspect, the present invention also
relates to a process for the manufacture of a compound of the
general formula (22') wherein R.sup.2' is hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl,
optionally substituted by one or more halogen, said process
comprising the ammonolysis of the corresponding compound of formula
(6') ##STR34## wherein R.sup.1' is C.sub.1-C.sub.6 alkyl and
R.sup.2' is hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl or C.sub.2-C.sub.4 alkynyl, optionally substituted by one
or more halogen, in the presence of water.
[0053] Surprisingly, it has been found that performing said
ammonolysis in the presence of water greatly overcomes the
disadvantages such as racemisation as described in the background
art, and encountered when using an organic solvent (e.g. methanol).
Other advantage of this invention Is minimisation of potential
hydrolytic side-reaction.
[0054] According to a preferred embodiment, said ammonolysis as
described above is performed in a mixture of water and an alcohol.
Preferred alcohols are methanol, ethanol, isopropanol and butanol.
Most preferably a mixture of water and methanol is used. Using a
mixture of water and an alcohol, especially methanol, offers the
additional advantage that the level of hydrolysis is even more
decreased.
[0055] According to a preferred embodiment, said ammonolysis of the
invention as described above is performed with NH.sub.3.
Preferably, a 10-95% (w/w) NH.sub.3 solution in water is used. Most
preferably, a 30-80% (w/w) NH.sub.3 solution in water, especially a
50% NH.sub.3 solution in water, is used.
[0056] According to yet another preferred embodiment, said
ammonolysis of the invention as described above is performed at 0
to 40.degree. C., most preferably at a temperature of 0 to
25.degree. C., especially at a temperature of about 3 to 10.degree.
C.
[0057] In the process according to the invention, the molar ratio
of NH.sub.3 to the compound of formula (6') is generally at least
1, preferably at least 4, most preferably at least 6. The molar
ratio does preferably not exceed 100.
[0058] According to a preferred embodiment of the process for the
manufacture of the compound of formula (22'), a compound of the
general formula (6') is used wherein R.sup.1' is methyl, ethyl or a
C.sub.3-C.sub.4 alkyl. Especially preferred are compounds of
general formula (6') wherein R.sup.1' is methyl or ethyl and most
preferably wherein R.sup.1' is methyl.
[0059] According to another preferred embodiment of the process for
the manufacture of the compound of formula (22'), a compound of the
general formula (6') is used wherein R.sup.2' is hydrogen.
[0060] According to a more preferred embodiment of the process for
the manufacture of the compound of formula (22') a compound of the
general formula (6') is used wherein R.sup.1' is methyl and
R.sup.2' is hydrogen according to the following formula:
##STR35##
[0061] The above compound is referred to as PBM (methyl
2-(2-oxo-pyrrolidin-1-yl) butyrate).
[0062] According to yet another embodiment of the process for the
manufacture of the compound of formula (22'), a compound of the
general formula (6') is used wherein R.sup.1' is ethyl and R.sup.2'
is hydrogen according to the following formula: ##STR36##
[0063] The above compound is referred to as PBE (ethyl
2-(2-oxo-pyrrolidin-1-yl) butyrate).
[0064] According to yet another embodiment of the process for the
manufacture of the compound of formula (22'), a compound of the
general formula (6') is used wherein the R.sup.2' substituent is
present at position 4 on the ring structure, as given in the
following general formula (7') wherein R.sup.1' and R.sup.2' are as
noted above. ##STR37##
[0065] According to another preferred embodiment of the process
according to the invention, the compound of formula (6') is the S
isomer as illustrated in the following formula (8') wherein
R.sup.1' and R.sup.2' are as noted above. ##STR38##
[0066] The use of an S isomer of formula (8') in the process
according to the invention permits to obtain compounds of formula
(22') being S isomers. Compounds of formula (6') wherein R.sup.2'
is different from hydrogen possess a second stereogenic center,
being the carbon atom of the pyrrolidine ring to which the R.sup.2'
substituent is attached. In this case, this stereogenic center may
be in an S- or R-form or mixtures of both forms may be used.
[0067] According to a more preferred embodiment of the process for
the manufacture of the compound of formula (22'), a compound of the
general formula (6'), (7') or (8') is used, wherein R.sup.2' is
selected from the group of hydrogen, propyl, 2,2-difluorvinyl,
2-fluoro-2-methylpropyl, 2,2-difluoropropyl, cyclopropylmethyl and
2,2,2-trifluoroethyl.
[0068] The ammonolysis process according to the invention permits
high conversion rates. The ammonolysis process according to the
invention offers also the advantage that the amount of racemisation
and hydrolysis is very low, even negligible. A simple
crystallisation of the crude products from this ammonolysis in an
organic solvent may give pure compounds, such as pure
Levetiracetam.
[0069] The compound of formula (6') used as starting material in
the process for the manufacture of a compound of formula (22'), can
be manufactured by any process suitable therefore.
[0070] According to a first variant, the compound of formula (6')
is manufactured by a first new process comprising following steps:
(a) reaction of a compound of formula (9) ##STR39## with an alcohol
of formula R.sup.1' OH wherein R.sup.1' is defined as above. (b)
reaction of the corresponding compound of formula (10') thus
obtained ##STR40## with a
R.sup.2'-substituted-ethyl-4-bromobutyrate wherein R.sup.2' is
defined as above, (c) cyclisation of the corresponding compound of
formula (11') thus obtained ##STR41## in the presence of a
catalyst, and (d) isolation of the resulting compound.
[0071] In this process, the compound of formula (9) is an
enantiomerically enriched or an enantiomerically pure compound, the
chiral centre (either configuration) being denoted by an asterisk
(*).
[0072] This first new process as such for the manufacture of a
compound of formula (6') is another aspect of the present
invention.
[0073] The first step (step a) of this process is preferably
performed in the presence of an alcohol (for instance methanol or
ethanol) and thionyl chloride. The second step (step b) of this
process is the mono-N-alkylation of the amino-ester of formula
(10') with a R.sup.2'-substituted ethyl 4-bromobutyrate (4-EBB) and
is preferably performed in the presence of an alcohol (for instance
methanol, ethanol or isopropanol). The alcohol is preferably
isopropanol. The use of isopropanol presents the further advantage
that transesterification did not occur. Moreover, the use of
isopropanol resulted in a major amount of the monoalkylated ester
(11') and only a small amount of a dialkylated product which may be
separated by column chromatography. Alternatively, the
monoalkylated product may be precipitated as its hydrochloride salt
by means of gaseous HCl. The hydrochloride of the mono-alkylated
product (solid) is next neutralised with aqueous sodium carbonate
and extracted with an organic solvent. The second step is
preferably performed in the presence of base, preferably sodium
carbonate. The catalyst used in the third step (step c) in the
process is preferably 2-pyridinol. This reaction is non-racemising
and provides enantiomerically pure (S)-compounds of formula (8') in
the case where the (S) enantiomer of compound (9) is used as
starting material.
[0074] According to an alternative process, said compound of
general formula (6') of the invention as defined above may be
manufactured by a process comprising the step of cyclisation of the
compound of formula (11'), wherein R.sup.1' and R.sup.2' are as
defined above. This process is carried out according to Scheme 4'.
below: ##STR42##
[0075] According to a second variant, the compound of formula (6')
is manufactured by a second process comprising the following steps:
(a) reaction of an .alpha.-ketocarboxylic acid derivative of
formula (12') ##STR43## wherein R.sup.1' is as defined above with a
pyrrolidinone of formula (13') ##STR44## wherein R.sup.2' is as
defined above, (b) reaction of the corresponding compound of
formula (14') thus obtained ##STR45## wherein R.sup.1' and R.sup.2'
are defined as above, with hydrogen in the presence of an
asymmetric hydrogenation catalyst; (c) isolation of the resulting
compound.
[0076] This second process has as a major advantage that it is much
more rapid and simpler, comprising fewer steps than the first `LRC`
route as discussed above. All details of this process are disclosed
in the application PCT/EP01/01956 where it is described for
compounds of a more general formula. Said application is hereby
further incorporated by reference.
[0077] According to a third variant, compounds of the general
formula (6') as defined above are manufactured by a third new
process comprising following steps: (a) reaction of a compound of
formula (15') ##STR46## wherein R.sup.1' is as noted above and X is
Cl, Br, I, alkylsulphonate or sulfate; with a pyrrolidone of
general formula (13') ##STR47## wherein R.sup.2' is as noted as
above; (b) reaction of the corresponding compound of formula (16')
thus obtained ##STR48## with ethyl-X, wherein X is Cl, Br, I,
alkylsulphonate or sulfate in the presence of an asymmetric
alkylation catalyst or additive; (c) isolation of the resulting
compound of formula (6').
[0078] According to this third variant, R.sup.1' is preferably
C.sub.3-C.sub.4 alkyl, especially tertbutyl.
[0079] This third new process as such for the manufacture of a
compound of formula (6') is another aspect of the present
invention.
[0080] According to this third process, the asymmetric alkylation
catalyst or additive is preferably a chiral amine, most preferably
selected from (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine (17),
(R)-2-methoxyethoxyethyl-1-phenyl-2-piperidinoethylamine (18) and
(S)-1-methyl-2-anilinomethyl pyrrolidine (19). ##STR49##
[0081] Step (b) of this process is preferably performed in the
presence of a base (such as mineral, organic or organometallic
bases). This base is most preferably butyllithium.
[0082] Especially when R.sup.1' is not methyl or ethyl, this third
process may comprise an additional reaction step wherein the
compound obtained from step (b) is reacted with an alcohol of
formula R.sup.1OH wherein R.sup.1 is methyl or ethyl, preferably in
the presence of an acid, so that a compound of formula (6') is
formed wherein R.sup.1' is methyl or ethyl.
[0083] This third process has the advantage that it comprises only
few reaction steps. Another advantage is that it may be performed
using inexpensive and readily available raw materials.
[0084] According to a fourth variant, the compound of the general
formula (6') as defined above is prepared by a fourth new process
comprising following steps:
(a) reaction of a compound of general formula (20')
[0085] (a) reaction of a compound of general formula (20')
##STR50## wherein R.sup.1' is as noted above, with a pyrrolidone of
general formula (13') ##STR51## wherein R.sup.2' is defined as
above: (b) separation of the corresponding compound of general
formula (21') thus obtained wherein R.sup.1' and R.sup.2' are
defined as above; and ##STR52## (c) isolation of the resulting
compound of general formula (6').
[0086] This fourth new process as such for the manufacture of a
compound of formula (6') is another aspect of the present
invention.
[0087] According to this fourth process, the compound of the
general formula (6') as defined above is preferably isolated by
industrial chiral chromatographic separation (batch, MCC (Multi
Column Chromatography) or SMB (simulated moving bed)) of a compound
of general formula (21') according to Scheme 7'. below.
##STR53##
[0088] According to this fourth process, (S)-PBE and (S)-PBM can be
separated using chiral HPLC by means of commercially available
chiral stationary phases. These separations can more particularly
be performed using chromatographic columns sold by DAICEL Company
or SHISEIDO Company. The chromatographic process can be carried out
using either the batch or MCC process. Each enantiomer can be
separated using a chiral stationary phase to yield enantiomerically
pure (S)-PBM and (S)-PBE.
[0089] The preferred DAICEL columns such as the columns sold under
the trademark CHIRALPAK AD, CHIRALPAK AS and CHIRALPAK OD were
found to be efficient to this end when mobile phases such as
mixtures of alkanes with alcohols were used or even a pure alcohol
or mixtures of alcohols. The alkane or mixtures of alkanes
particularly referred to are: hexane, isohexane or heptane. The
alcohol or mixtures of alcohols particularly referred to are:
propanol, isopropanol, ethanol or methanol. There is a preference
for the use of heptane among the alkanes and there is a preference
for the use of ethanol and methanol among the alcohols. There is a
preference for the following mixtures: 50% to 95% for the alkane
and 50% to 5% for alcohol(s), or 100% of alcohol.
[0090] The preferred SHISEIDO columns such as the columns sold
under the trademark CERAMOSPHER CHIRAL RU-2 or CERAMOSPHER CHIRAL
RU-1 were found to be efficient for the separation when alcohols
were used as mobile phase. The alcohols referred to are: propanol,
isopropanol, ethanol or methanol. There is a preference for the use
of ethanol and methanol among the alcohols.
[0091] The extrapolation of small-scale batch separations of this
type to an industrial scale proceeds without difficulty in either
batch or continuous mode.
[0092] The optimum conditions as determined by chiral HPLC for the
separation of both PBE & PBM are presented in Tables I and III
below. An estimated productivity for PBE and PBM using the MCC
process is also given in Tables II and IV. TABLE-US-00001 TABLE I
Examples of separation by chiral HPLC: PBM Phase provider Phase
Solvents k'l Alpha Resolution Daicel Chiralpak .RTM. AD Ethanol
50%/i-Hexane 50% 0.499 1.19 1.06 Daicel Chiralpak .RTM. AD Ethanol
2%/Methanol 8%/Hexane 90% 2.432 1.45 2.1 Daicel Chiralpak .RTM. AD
Acetonitrile 100% 0.549 1.3 0.79 Daicel Chiralpak .RTM. AD Ethanol
10%/Heptane 90% 3.901 1.24 1.19 Daicel Chiralpak .RTM. AD Ethanol
5%/Methanol 5% Heptane 90% 3.646 1.41 1.92 Daicel Chiralpak .RTM.
AS i-Propanol 10%/i-Hexane 90% 9.408 1.28 2.6 Daicel Chiralpak
.RTM. AS Ethanol 10%/i-Hexane 90% 3.035 1.17 1.65 Daicel Chiralpak
.RTM. AS Propanol 10%/i-Hexane 90% 2.987 1.14 1.34 Daicel Chiralpak
.RTM. OD-H Ethanol 5%/i-Hexane 95% 2.49 1.23 2.97 Daicel Chiralpak
.RTM. OD-H Propanol 5%/i-Hexane 95% 1.94 1.22 2.58 Shiseido
Ceramospher Chiral RU-1 Methanol 100% 4.69 1.28 1.56 Shiseido
Ceramospher Chiral RU-2 Methanol 100% 3.747 1.29 1.5 Shiseido
Ceramospher Chiral RU-2 Ethanol 100% 4.853 1.32 1.19
[0093] TABLE-US-00002 TABLE II Estimated productivity using MCC
process: PBM Phase provider Phase Solvents Productivity (kg/kg/day)
Daicel Chiralpak .RTM. AD Ethanol 2%/Methanol 8%/i-Hexane 90%
0.17
[0094] Productivity as presented in the above table is expressed as
Kg of racemic PBM engaged per Kg of chiral stationary phase per
day. TABLE-US-00003 TABLE III Examples of separation by chiral
NPLC: PBE Phase provider Phase Solvents k'l Alpha Resolution Daicel
Chiralpak .RTM. AD Ethanol 50%/i-Hexane 50% 0.449 1.3 1.15 Daicel
Chiralpak .RTM. AD Ethanol 2%/Methanol 8%/Hexane 90% 1.955 1.9 3.32
Daicel Chiralpak .RTM. AD Acetonitrile 100% 0.554 1.8 2.05 Daicel
Chiralpak .RTM. AD Ethanol 10%/Heptane 90% 3.076 1.5 4.4 Daicel
Chiralpak .RTM. AD Ethanol 5%/Methanol 5% Heptane 90% 2.971 1.7
2.93 Daicel Chiralpak .RTM. AD Methanol 5%/Benzine 95% 3.227 1.7
2.99 Daicel Chiralpak .RTM. AD i-Propanol 10%/i-Hexane 90% 5.029
2.16 7.39 Daicel Chiralpak .RTM. AD Ethanol 10%/i-Hexane 90% 1.764
1.9 5.97 Daicel Chiralpak .RTM. AD Propanol 10%/i-Hexane 90% 1.733
1.86 5.46 Daicel Chiralpak .RTM. AD Ethanol 5%/i-Hexane 95% 1.878
1.13 1.66 Daicel Chiralpak .RTM. AD Propanol 5%/i-Hexane 95% 1.44
1.14 1.56 Shiseido Ceramospher Chiral Ru-1 Methanol 100% 5.047 1.89
3.57 Shiseido Ceramospher Chiral Ru-2 Methanol 100% 3.869 1.84 3.21
Shiseido Ceramospher Chiral Ru-2 Ethanol 100% 3.97 2.01 1.94
[0095] TABLE-US-00004 TABLE IV Estimated productivity using MCC
process: PBE Phase provider Phase Solvents Productivity (kg/kg/day)
Daicel Chiralpak .RTM. AD Ethanol 10%/Heptane 90% 0.84
[0096] Productivity as presented in the above table is expressed as
Kg of racemic PBE engaged per Kg of chiral stationary phase per
day.
[0097] In the implementation of the processes according to the
invention, the reaction products may be isolated from the reaction
medium and, if necessary, further purified according to
methodologies generally known in the art such as, for example
extraction, crystallisation, distillation and chromatography, or
any combination of the same.
[0098] Stereoisomerically pure forms of said compounds of the
invention (and said intermediates) can be obtained by the
application of procedures known to a chemist skilled in the art.
For example, diastereoisomers can be separated by physical methods
such as selective crystallisation or chromatographic techniques,
e.g. counter current distribution, liquid chromatography and
related methods. Enantiomers can be obtained from racemic mixtures
by first converting said racemic mixtures with suitable resolving
agents such as, for example, chiral acids, to mixtures of
diastereolsomeric salts or compounds; then physically separating
said mixtures of diastereoisomeric salts or compounds by, for
example, selective crystallisation or chromatographic techniques,
e.g. liquid chromatography and related methods; and finally
converting said separated diastereomeric salts or compounds into
the corresponding enantiomers.
[0099] Alternatively, pure stereochemically isomeric forms may be
obtained by using enantioselective reactions according to
procedures known by the person skilled in the art.
[0100] Another alternative manner of separating the enantiomeric
forms of the compounds of formula (6) or (6') and intermediates
involves liquid chromatography, in particular liquid chromatography
using a chiral stationary phase.
[0101] According to another aspect, the present invention also
relates to any compounds obtained by a process of the invention as
defined above. In particular, the invention comprises Levetiracetam
obtained by said processes. More particularly, the present
invention also relates to new compounds obtainable by the processes
according to the invention such as compounds of formula (22')
wherein R.sup.2' is 2-fluoro-2-methylpropyl or cyclopropylmethyl.
More specifically the present invention also relates to the (4S)
and (4R) diastereoisomers of
(2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyirolidinyl]butanamide
and of
(2S)-2-[4-cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide, and
pharmaceutical compositions containing such compounds and their use
as pharmaceuticals.
[0102] The following examples serve to illustrate the invention and
therefore should not be taken to limit the scope thereof.
EXAMPLES
Example 1
[0103] Step 1-Synthesis of methyl (S)-aminobutyrate hydrochloride
##STR54##
[0104] 5.0 g of (S)-amino butyric acid (23) was suspended in 50 ml
of methanol and stirred at 0-5.degree. C. 6.35 g of thionyl
chloride was added dropwise over 45 min to form a clear solution.
After stirring for 20 hours at room temperature, the reaction was
concentrated under reduced pressure to dryness and the almost
colourless residue solidified to give the required product which
was dried in an oven at 50.degree. C. under vacuum (7.6g; 102%
crude yield). The same reaction was scaled-up from 200 g of the
amino acid and provided 296 g (99.5% yield) of product (24).
[0105] Analysis gave the following results:
[0106] 1H NMR (DMSO-d.sub.6): d 0.94 (3H, t) 1.88 (2H, q) 3.75 (3H,
s) 3,9 (1H, m) 8.8 (3H, m).
[0107] m.p.: 107.degree. C.-110.degree. C.
[0108] IR: 2876 cm.sup.-1, 1742 cm.sup.-1.
[0109] TLC: SiO.sub.2, 20 %MeOH/80 %EtOAc/1 %NH.sub.4OH, UV &
IR.
[0110] (TLC is an abbreviation for thin layer chromatography).
[0111] Step 2-Synthesis of methyl
(S)-aminobutyrate-N(4-ethylbutyrate) ##STR55##
[0112] 2.0 g of (S)-aminobutyrate hydrochloride salt (24) was
dissolved and stirred at room temperature in 20 ml of 2-propanol,
followed by addition of 2.8 g of sodium carbonate and the reaction
was then heated to reflux. When reflux temperature was reached, 2.8
g of 4-BBE (ethyl-4-bromobutyrate) was added dropwise over a period
of 10 min, with reflux and stirring being maintained for 24 hrs.
The reaction medium was allowed to cool to room temperature, the
salts were filtered and rinsed with 50 ml of 2-propanol. Following
this alkylation the desired product (25) may be isolated and
purified either by chromatography or via the hydrochloride salt
(25') as depicted in Scheme 10. above and as described in Methods A
and B below.
[0113] (Method A): The filtrate was concentrated under reduced
pressure to give 3.0 g of a pale yellow liquid. This liquid was
purified by chromatography through 125 g of silica and eluted with
a 50/50 mixture of hexane/ethyl acetate to provide the required
2.45 g (81% yield) mono alkylated ester (25) (Method B):
Chromatography can be avoided if the corresponding hydrochloride
salt is generated, precipitated and filtered from a mixture of
isopropanol and DIPE (di-isopropylether). Treatment of this salt
(25') with sodium carbonate in water and extraction with ethyl
acetate and concentration provides the pure free base (25) (the
required mono alkylated ester) as a liquid.
[0114] Analysis gave the following results:
[0115] .sup.1H NMR (CDCl.sub.3):d 0.9 (3H, t) 1.2 (2H, t) 1.4 (1H,
s) 1.5-1.7 (4H, m) 2.3-2.7 (4H, m) 3.15 (1H, t) 3.7 (3H, s) 4.1
(2H, q).
The identity of the product is confirmed by GC-MS, TLC.
[0116] IR:2938 cm.sup.-1, 1730 cm.sup.-1.
[0117] TLC:SiO.sub.2, 50%Hexane/50%EtOAc, UV & IR.
[0118] Step 3-Synthesis of methyl (S)-pyrrolidino-butyrate (26)
[(S)-PBM)] ##STR56##
[0119] 1.0 g of compound (25) and 2-pyridinol (0.02g; 5 mol %) were
magnetically stirred in 5 ml of toluene at reflux for 24 hrs. The
reaction mixture was allowed to cool to room temperature and TLC
analysis showed almost complete conversion. The reaction mixture
was then evaporated under reduced pressure to leave crude (S)-PBM
(26) as a pale brown liquid (1.0 g).
[0120] The identity of the product was confirmed by GC-MS, TLC,
HPLC (Chiral and Achiral) using external references.
[0121] Step 4-Ammonolysis of (S)-PBM to give Levetiracetam.
##STR57##
[0122] 11.3 g of ammonia gas was condensed in 13.2 ml of water at
approximately 0.degree. C. and the temperature was maintained at
0-5.degree. C. Then 20 g of (S)-PBM (26) was added dropwise over a
period of 10 min and reaction mixture was maintained at 5.degree.
C. and stirred for minimum 8 hrs (reaction was complete as
indicated by TLC). The reaction mixture was then evaporated to
dryness under vacuum and dried by means of toluene (2.times.50 ml)
to give minimum 17 g (92%) of crude (S)-pyrrolidinobutyramide
(crude Levetiracetam) as an off-white to beige solid.
[0123] Analysis gave the following results (chiral and achiral
HPLC): The extent of racemisation was 0.0%. The extent of
hydrolysis was measured to 2.5%.
Example 2
[0124] ##STR58##
[0125] 17.3 g of ammonia gas were condensed in 22 ml of water at
0.degree. C. and temperature maintained at 0-5.degree. C. Then 20 g
of (S)-PBE obtained via SMB separation of the corresponding racemic
mixture were added dropwise over a period of 2 min and the reaction
mixture was maintained at 5.degree. C. and stirred for 96 hrs
(reaction was complete as judged by TLC). The reaction mixture was
then evaporated to dryness under vacuum and dried by means of
toluene (2.times.100 ml) to give minimum 14.8 g (87%) of crude
(S)-pyrrolidinobutyramide as a brown orange solid. Analysis gave
the following results (chiral and achiral HPLC): The extent of
racemisation was 1.6% with 6.6% hydrolysis.
Example 3
[0126] 10.3 g of ammonia gas were condensed in 13.2 ml water at
0.degree. C. and the temperature of the system was maintained at
0-5.degree. C. 20 g of (S)-PBE obtained via asymmetric
hydrogenation was then added dropwise over a period of 10 min,
maintaining the reaction mixture at 5.degree. C. The system was
then stirred for 96 hrs, with TLC indicating completion of
reaction. The reaction mixture was then evaporated to dryness under
vacuum and dried by means of toluene (2.times.50 ml) to give
minimum 15.7 g (92%) of crude (S)-pyrrolidinobutyramide as a brown
orange solid. Analyses gave the following results (chiral and
achiral HPLC): The extent of racemisation was 0.2% with 3.4%
hydrolysis.
Example 4
[0127] ##STR59##
[0128] A reaction flask was charged with the chiral amine (34)
(1.07 equivalent (eq.); and anhydrous toluene (15 vol) with
stirring under an inert atmosphere. The solution was cooled below
-70.degree. C. and BuLi (2.5 M in hexane, 1.04 eq.) was added
dropwise. The reaction mixture was stirred for 30 min at this
temperature, then at -10.degree. to 0.degree. C. for 10 min. A
solution of t-butyl 2-(2-oxopyrrolidin-1-yl)-acetate (32) (600 mg,
1 eq., 1 wt) in toluene (5 vol) was added slowly, keeping the
reaction temperature below -70.degree. C. The reaction mixture was
stirred at -40 to -50.degree. C. for 30 min. Ethyl iodide 2.5 eq.,
1 vol) was then added and the reaction mixture was stirred at -50
to -40.degree. C. for 3 hrs. After being kept in the freezer at
approximately -40.degree. C. overnight, the reaction mixture was
diluted with pH 7 buffer (KH.sub.2PO.sub.4/KOH, 1 M, 33 vol) and
dichloromethane (33 vol). The aqueous phase was extracted with
dichloromethane (3.times.16 vol) and the combined organic extracts
were then dried over MgSO.sub.4 and concentrated in vacuo to give
crude material. Purification of this crude product using flash
chromatography (SiO.sub.2, 40 wt) with hexane/EtOAc eluent gave the
desired alkylated product (33) in 78% yield.
[0129] 1H-NMR in CDCl.sub.3: .delta.0.85t(3H), 1,4s(9H), 1.5-1.7
m(1H), 1.9-2.0 m(3H), 2.45 m(2H), 3.25 m (1H), 3.5 m(1H), 4.5
dd(1H)
[0130] HPLC analysis: t-Butyl 2-(2-oxopyrrolidin-1-yl)-butanoate
(25 mg) was accurately weighed into a 25 ml volumetric flask.
Mobile phase (99:1 hexane/isopropanol, 20 ml,) was added and the
sample was dissolved using ultrasonication. After cooling to
ambient temperature the concentration was adjusted with mobile
phase to give a working concentration of 1 mg/ml. The analysis was
conducted using a column sold under the trademark CHIRACEL OD
(4.6.times.250 mm, DAICEL), flow rate of 1 ml/min, UV detection at
250 nm and injection volume of 20 .mu.l at ambient temperature. The
relative retention times of the two enantiomers was 17.9 and 22.3
minutes
[0131] TLC conditions: SiO.sub.2 in EtOAc; visualisation with
KMnO.sub.4.
Example 5
[0132] 1. Evaluation of type of solvent most suitable for
ammonolysis of (S)-PBE.
[0133] The ammonolysis of (S)-PBE was investigated in the presence
of water, toluene, methanol and ethyl acetate. It was shown that
the ammnonolysis of (S)-PBE can only be successfully realized in
the presence of water. When using methanol, the reaction is very
slow and when using the other solvents mentioned above the extent
of reaction is minimal.
[0134] 2. Evaluation of optimum reaction temperature for the
ammonolysis of (S)-PBE to form Levetiracetam.
[0135] The ammonolysis of (S)-PBE was carried out either at room
temperature or at 40.degree. C. using (S)-PBE (1 equivalent) in the
presence of water (6,5 volume) and various concentrations of
NH.sub.3 (15, 10, 7, 5, and 2 equivalents). The reactions were
carried out at room temperature and 40.degree. C., being followed
by TLC for at least 24 hours. At the end of the reaction the extent
of racemisation and hydrolysis was determined by HPLC.
[0136] It was shown that: [0137] good conversion was obtained,
especially when at least 4 equivalents of NH.sub.3 (per eq. of
(S)-PBE) were used; [0138] the extent of racemisation did not
exceed 8% at 40.degree. C. and decreased with reaction temperature.
At temperatures between 0 and 25.degree. C., the extent of
racemisation was less than 3%; [0139] the amount of hydrolysis was
low, especially at higher molar ratios of NH.sub.3 to (S)-PBE.
[0140] 3. Evaluation of different concentrations of NH.sub.3 for
ammonolysis of (S)-PBE.
[0141] Six experiments were performed in a 100 ml reactor while
varying the concentration of NH.sub.3 and reaction temperature.
(S)-PBE (1 equivalent) was mixed with 10 equivalents of NH.sub.3
from either a commercial solution of NH.sub.3 (28% w/w) or a more
concentrated solution (.+-.50% w/w). The temperatures used were
either 5, 10 or 20.degree. C. The reaction was followed by TLC
until no (S)-PBE remained and the extent of hydrolysis and
racemisation was determined by HPLC.
[0142] It was shown that: [0143] a more concentrated solution of
NH.sub.3 did not substantially influence the extent of
racemisation. [0144] the extent of racemisation was always less
than 3% at all reaction temperatures which were tested, [0145] the
extent of racemisation increases only very moderately between 5 and
20.degree. C., [0146] the extent of hydrolysis was low, especially
when using concentrated NH.sub.3 solution (.+-.50% w/w). [0147] the
extent of racemisation is always lower at lower reaction
temperature.
[0148] In summary, the following conclusions can be made: [0149]
the ammonolysis can easily be performed in the presence of water
(containing preferably at least 4 equivalents of NH.sub.3), this
reaction does not require any catalyst and may be performed in less
than 24 hours. [0150] the extent of racemisation is low (less than
3% when reaction temperature is less than 20.degree. C.), and
concentration of NH.sub.3 was found to have only a minor influence
on the racemisation, [0151] the extent of hydrolysis can be reduced
in an even more substantial way when using a more concentrated
solution of NH.sub.3 (.+-.50% w/w) at low reaction temperature
(reaction takes less than 48 hours).
Example 6
[0152] (S)-PBE was reacted under the conditions specified in Table
VI. The results are summarised in Table VI. below. TABLE-US-00005
TABLE VI ##STR60## ##STR61## HPLC Analysis area % Reaction
conditions Levetiracetam No (S)-PBE NH.sub.3 H.sub.2O Time
T.degree. acid or (S)-Amide (R)-Amide Exp. (g.) (eq.) (Vol.) (hrs)
(.degree. C.) (% area) (% area) (% area) 6 20 6.2 0.66 96 h 00 5
3.44 97.85 2.00
[0153] The starting material contained 1.6% of the (R)-enantiomer
and 98.4% of the (S)-enantiomer. The difference in enantiomeric
purity between the starting material and the final amides obtained
was 0.4%. This result corresponds to the degree of racemisation
accompanied by said ammonolysis.
[0154] The product obtained from the experiment described above was
recrystallised in eight volumes of acetone and filtered at
2.degree. C. to give the final product,
(S)-(-)-.alpha.-ethyl-2-oxo-1-pyrrolidine acetamide or
Levetiracetam in 69.1% yield. The recrystallised product contained
0.11% of the (R)-amide product and 0.08% of hydrolysed product.
Example 7
[0155] (S)-PBM was reacted under the conditions specified In Table
VIII. The results are summarised in Table VIII. below.
TABLE-US-00006 TABLE VIII ##STR62## ##STR63## HPLC Analysis area %
Reaction conditions Levetiracetam Opposite No (S)-PBE NH.sub.3
H.sub.2O Time T.degree. acid (S)-Amide (R)-Amide Exp. (g.) (eq.)
(Vol.) (hrs) (.degree. C.) (% area) (% area) (% area) 22 22 6.0
0.66 16 h 40 5 3.68 96.31 2.53
[0156] The starting material contained 96.3% of the (S)-enantiomer
and 3.5% of the (R)-enantiomer. The difference in enantiomeric
purity between the final product Levetiracetam and the starting
material (S)-PBM was approximately 0.2%, indicating indeed that the
amnmonolysis is accompanied by a negligible racemisation in this
case.
[0157] The final product obtained from the experiment above was
recrystallized from eight volumes of acetone and filtered at
4.degree. C. Levetiracetam is obtained in 73.3% yield. The
recrystallized product contained 1.64% of the opposite enantiomeric
amide and 0.03% of the hydrolysed product. Recrystallisation in the
presence of acetone as described allows production of Levetiracetam
of a sufficient quality for commercial purposes.
[0158] The same reaction was finally performed on an increased
scale according to Scheme 18. below. Racemisation was as previously
observed negligible (0.2%) . ##STR64##
[0159] In summary, it has been shown that Levetiracetam may be
obtained via ammonolysis of (S)-PBE in concentrated NH.sub.3 (50%
in water) and at 5.degree. C. Scaling-up of this reaction has been
successfully demonstrated in 0.6 volumes of water in the presence
of 6 equivalents of NH.sub.3. The extent of racemisation varies
between 0.4 and 2.0%, that of hydrolysis between 3.5 and 6.6%, with
a reaction time of approximately 96 hours.
[0160] Alternatively, Levetiracetam may equally be obtained via
ammonolysis of (S)-PBM in 0.6 volumes of water containing 6
equivalents of NH.sub.3 and at 5.degree. C. The reaction time is
much shorter and can be realised in 8 to 10 hours. The extent of
racemisation varies between 0.0 and 0.2% and that of hydrolysis
ranges from 1.8 to 3.6%.
Example 8
[0161] 8.1 Preparation of methyl
(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate
[0162] A reaction flask was charged with 2 g of methyl
(Z)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]-2-butenoate, 20 ml of
anhydrous and degassed methanol and 27 mg of
(S,S)-Me-DUPHOS/Rh(BF.sub.4). The reaction flask was purged with
hydrogen and the hydrogen pressure was adjusted to 10 atm. This
reaction mixture was stirred during about 20 hours at room
temperature and then concentrated. 1.96 g of methyl
(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate was
obtained.
[0163] 8.2 Ammonolysis
[0164] Ammonia gas was condensed in 2 ml water at 0-5.degree. C.
and the temperature of the system was maintained at 0-5.degree. C.
0.68 g of methyl
(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate obtained such
as described above was then added dropwise, maintaining the
reaction mixture at 0-5.degree. C. The system was then stirred for
6 hrs, with TLC indicating completion of reaction. After standing
overnight at ambient temperature the reaction mixture was
concentrated at 40.degree. C. under vacuum and further dried by
azyeotropic distillation with toluene to give 150 mg of crude
(2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanamide.
* * * * *