U.S. patent application number 13/154807 was filed with the patent office on 2012-01-05 for intermediate compounds and their use in preparation of lacosamide.
Invention is credited to Chandra Has Khanduri, Mukesh Kumar MADHRA, Pankaj Kumar Singh.
Application Number | 20120004452 13/154807 |
Document ID | / |
Family ID | 40377199 |
Filed Date | 2012-01-05 |
United States Patent
Application |
20120004452 |
Kind Code |
A1 |
MADHRA; Mukesh Kumar ; et
al. |
January 5, 2012 |
INTERMEDIATE COMPOUNDS AND THEIR USE IN PREPARATION OF
LACOSAMIDE
Abstract
The present invention is concerned with novel compounds and
their use for the preparation of lacosamide. The present invention
also contemplates processes for the preparation of lacosamide
employing the novel compound of general Formula II, Formula IIa or
Formula IIb as intermediate. ##STR00001## Wherein R.sub.1 is --OH
or --OMe; R.sub.2 is --OH or --NH--CH.sub.2--C.sub.6H.sub.5.
Inventors: |
MADHRA; Mukesh Kumar;
(Karnal, IN) ; Singh; Pankaj Kumar; (Kanpur,
IN) ; Khanduri; Chandra Has; (Gurgaon, IN) |
Family ID: |
40377199 |
Appl. No.: |
13/154807 |
Filed: |
June 7, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12327124 |
Dec 3, 2008 |
|
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13154807 |
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Current U.S.
Class: |
562/441 ;
564/165 |
Current CPC
Class: |
C07C 237/06 20130101;
C07C 229/22 20130101; C07B 2200/07 20130101; C07C 231/14 20130101;
C07C 231/14 20130101; C07C 237/22 20130101 |
Class at
Publication: |
562/441 ;
564/165 |
International
Class: |
C07C 229/36 20060101
C07C229/36; C07C 237/20 20060101 C07C237/20 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 4, 2007 |
IN |
2542/DEL/2007 |
Claims
1. Use of compound of Formula II for the preparation of lacosamide.
##STR00029##
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 12/327,124 filed on Dec. 3, 2008, the contents
of which are incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to intermediate compounds and
their use in preparation of lacosamide.
BACKGROUND OF THE INVENTION
[0003] Lacosamide (SPM 927, also referred to as harkoseride or ADD
234037), is chemically
(R)-2-acetamido-N-benzyl-3-methoxypropionamide of Formula Ia. It
shows effects in the treatment of pain, epilepsy, fibromyalgia
syndrome, osteoarthritis and migraine. It is also known to be
useful for the treatment of CNS disorders in humans.
##STR00002##
[0004] Lacosamide and its methods of preparation are disclosed in
U.S. Reissue Pat. No. RE 38,551 (hereinafter referred to as the
'551 patent). This reference provides three general methods for the
preparation of lacosamide. The first two methods do not involve the
protection of active groups in intermediate compounds (such as
amino, hydroxy and carboxylic acid groups). The other method
disclosed in the '551 patent involves protection of an amino group
present in D-serine with carbobenzoxy chloride (Cbz-Cl), subsequent
O-methylation at the hydroxy group followed by benzylamination at
carboxylic (--COOH) group and finally removal of the `Cbz` group
followed by acetylation produces lacosamide.
[0005] An alternative method for the preparation of lacosamide is
disclosed in PCT publication WO 2006/037574 (hereinafter referred
to as '574 application) that involves O-methylation of
N-Boc-protected-D-serine ("Boc" refers to t-butoxycarbonyl)
directly in one step by avoiding simultaneous formation of the
methyl ester moiety.
[0006] In view of the preparation methods available for lacosamide,
there is a need for simple and cost effective processes for the
preparation of lacosamide that eliminates racemization of
intermediate compounds and final product and provides improved
efficiency per reaction volume in terms of yield, purity and chiral
purity.
SUMMARY OF THE INVENTION
[0007] A new method for the preparation of lacosamide that gives
excellent chiral purity and yield at low cost is provided. The new
method involves the use of particular intermediate compounds. The
intermediate compounds of the present invention comprise bulky
protecting groups that are capable of minimizing nucleophilic
attack at chiral carbon atom, which is otherwise responsible for
racemization, providing the chirally pure lacosamide in high yield.
The present invention makes use of a bulkier group than "Boc" and
"Cbz" during the present invention.
[0008] Thus, the novel intermediate compounds and use thereof for
the preparation of lacosamide are aspects of the present
invention.
[0009] Accordingly, the present invention is directed to compound
of Formula II
##STR00003##
wherein
[0010] R.sub.1 is --OH or --OMe;
[0011] R.sub.2 is --OH or --NH--CH.sub.2--C.sub.6H.sub.5 and
the
pharmaceutically acceptable salts, solvates, hydrates or
enantiomeric forms thereof.
[0012] The compound of Formula II is useful pharmaceutical
intermediate for the preparation of lacosamide.
[0013] The present invention also contemplates processes for the
preparation of lacosamide employing the compound of Formula II as
an intermediate.
[0014] The present invention also provides lacosamide substantially
free of (S)-2-acetamido-N-benzyl-3-methoxypropionamide.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The term "lacosamide" as used herein refers to the
R-enantiomeric form of
2-acetamido-N-benzyl-3-methoxypropionamide.
[0016] The term "O-methylation" as used herein refers to attachment
of a methyl group to the main chain of a given compound through an
oxygen bridge. Alternatively the "O-methylation" is a process of
converting an --OH group into an --OMe group in a given chemical
compound. The term "benzylamination" as used herein refers to
attaching an --NH--CH.sub.2--C.sub.6H.sub.5 group in a given
compound in such a way that the terminal --NH moiety can form an
amide group. The term "de-tritylation" as used herein refers to
removal of a trityl group from a given compound. The term
"acetylation" as used herein refers to attachment of a --COMe group
to the N.sup.2-amino group of a given compound. The term
"N.sup.2-amino" refers to the amino group located at the second
position in the main carbon chain of a given compound. The term
"trityl" as used herein refers to a triphenylmethyl group and "Me"
refers to a methyl group.
[0017] The term "alkoxy" as used herein refers to an --O-alkyl
group, wherein the alkyl group has C.sub.1-C.sub.6 carbon atoms
such as methyl, ethyl, propyl, butyl, isobutyl, isopropyl, t-butyl,
etc.
[0018] In a first aspect, a compound of the general Formula II is
provided,
##STR00004##
wherein R.sub.1 is --OH or --OMe; and R.sub.2 is --OH or
--NH--CH.sub.2--C.sub.6H.sub.5 and pharmaceutically acceptable
salt, solvate, hydrate or enantiomeric form thereof.
[0019] In an embodiment of this aspect, the compound of Formula II
can exist independently as the R-enantiomer (Formula IIa),
S-enantiomer (Formula IIb) or mixture.
##STR00005##
[0020] In another embodiment of the present aspect, the R.sub.1 and
R.sub.2 are --OH.
[0021] In another embodiment of the present aspect, the R.sub.1 is
--OH and R.sub.2 is --NH--CH.sub.2--C.sub.6H.sub.5.
[0022] In another embodiment of the present aspect, the R.sub.1 is
--OMe and R.sub.2 is --OH.
[0023] In another embodiment of the present aspect, the R.sub.1 is
--OMe and R.sub.2 is --NH--CH.sub.2--C.sub.6H.sub.5.
[0024] In another embodiment of the present aspect, the compound of
Formula II is N-trityl-D-serine; O-methyl-N-trityl-D-serine;
N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide or
N-benzyl-N.sup.2-trityl-D-serinamide.
[0025] The compound disclosed herein should be substantially pure,
i.e., substantially free from impurities. For example, the compound
can be about 85% pure (w/w), or, for example, greater than about
90% pure (w/w), or, for example, than about 99% pure (w/w).
[0026] In another embodiment of this aspect, the compounds
presented herein can be enantiomerically pure, e.g., at least about
98% enantiomerically pure. One enantiomer substantially free of
other enantiomer can be prepared. One enantiomer having no
detectable amount of other enantiomer is another aspect of this
disclosure.
[0027] The present aspect also contemplates use of compound of
Formula II, Formula IIa or Formula IIb for the preparation of
lacosamide.
[0028] In a second aspect, a process for the preparation of
2-acetamido-N-benzyl-3-methoxypropionamide of Formula I is
provided.
##STR00006##
comprising the steps of: [0029] a) O-methylating the compound of
Formula III
[0029] ##STR00007## [0030] to produce a compound of Formula IV
[0030] ##STR00008## [0031] wherein R.sub.2 is --OH or
--NH--CH.sub.2--C.sub.6H.sub.5; [0032] b) optionally
benzylaminating the compound of Formula IV to produce a compound of
Formula V;
[0032] ##STR00009## [0033] c) de-tritylating the compound of
Formula V to produce the compound of Formula VI;
##STR00010##
[0034] d) acetylating the compound of Formula VI to produce the
compound of Formula I.
[0035] In an embodiment of this aspect, the O-methylation step a)
is performed by means of a methylating agent. Methylating agents
such as methyl iodide, dimethyl sulfate, trimethyl
silyldiazomethane, dimethyl sulfoxide (DMSO), for example, can be
used for this purpose. The O-methylation can be performed, under,
for example, Williamson conditions by treating the compound of
Formula III with QX, wherein Q is alkoxy and X is a leaving group,
such as, for example, the tosyl (p-toluenesulfonyl) mesyl
(methanesulfonyl) group. The O-methylation can also be performed
either by using an organometailic compound with the methylating
agent or by a phase-transfer reaction, for example, as described in
PCT application WO 2006/37574. The O-methylation is generally
performed in the presence of a base. The base can be, for example,
hydride, hydroxide and/or oxides of metals, for example, hydride,
hydroxide and/or oxides of sodium, potassium, calcium, silver, etc.
can be used as base. The O-methylation can optionally be performed
in the presence of a catalyst. Compounds including for example,
imidazole, dimethylaminopyridine (DMAP), pyridine etc. can be used
as catalysts in the reaction. The solvents that can be used for the
O-methylation reaction are generally organic solvents. For example,
polar organic solvents, e.g., tetrahydrofuran (THF), dimethyl
sulfoxide (DMSO), acetonitrile (MeCN) etc. can be used.
[0036] Accordingly, a solution of compound of Formula in polar
organic solvent is mixed with a solution containing base, catalyst
and polar organic solvent. The methylating agent is then added to
this mixture. The reaction is usually allowed to proceed for at
least 2 hours at -20 to 0.degree. C., and preferably for 2.5-5
hours at -18.degree. C. to -3.degree. C., most preferably for 3-4
hours at -15.degree. C. to -5.degree. C. Also, the reaction may be
performed at higher or lower temperatures such as any temperature
between -20.degree. C. and 0.degree. C. if the reaction time is
adapted accordingly. The O-methylated compound of Formula IV is
then isolated from the mixture and purified with non-polar
solvent.
[0037] Methyl iodide can be used as the methylating agent, sodium
hydride or potassium hydroxide as the base, imidazole as the
catalyst and THF or DMSO as the solvent for the O-methylation
purpose. Non-polar solvent may be used for the purification of the
O-methylated compound of Formula IV. Preferably, non-polar
solvents, e.g., hexane, heptane, ethers, like petroleum ether,
diethyl ether, di-isopropyl ether etc. can be used for the
purification purpose.
[0038] In another embodiment of this aspect, the O-methylated
compound of Formula IV can be optionally subjected to a
benzylamination reaction (step-b). The benzylaminating agent used
for this purpose is benzylamine (C.sub.6H.sub.5CH.sub.2NH.sub.2).
The carbonyl moiety present in the compound of Formula IV forms an
amide group with the --NH.sub.2 moiety of benzylamine in this
reaction. The reaction can be performed with benzylamine optionally
in a mixed-anhydride condition. The mixed-anhydride coupling
reaction conditions are described by, for example, Anderson, et,
at. JACS (1967), 89, 5012-5017, the contents of which are
incorporated herein by reference. The carbonyl group present in
Formula IV needs activation before the benzylamination reaction.
Some of the examples of compounds that can act as an activator of
the carbonyl group are optionally substituted alkyl or aryl
chloroformates such as methyl chloroformate, isobutyl chloroformate
(IBCF), phenyl chloroformate, nitro-phenyl chloroformate, etc.;
azoles such as 1-hydroxybenzotriazole (HOBT) and the like; or
imides such as 1,3-dicyclohexylcarbodi-imide (DCC),
1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide (EDC) and the like.
The benzylamination reaction can be performed in presence of a
base. The base selected for the purpose is generally a
nitrogen-containing base. Some examples of suitable bases are
morpholine, N-methyl morpholine (NMM), triethylamine, diethylamine,
isopropylamine (IPA) etc. The solvent used for benzylamination
reaction can be an organic solvent. The organic solvent can be, for
example, an aliphatic, alicyclic or aromatic solvent. Some examples
of solvent are dichloromethane, trichloromethane,
tetrachloromethane, ethyl acetate, toluene, tetrahydrofuran (THF),
oxirane, acetone and the like.
[0039] Accordingly, the base and solution of the activator compound
in organic solvent are mixed with a solution of compound of Formula
in organic solvent, sequentially. The benzylaminating agent is then
added to the mixture. The reaction is usually allowed to proceed
for at least 1 hour at -20.degree. C. to 40.degree. C. and
preferably for 1.5 hours at -18.degree. C. to 35.degree. C., most
preferably for 2-3 hours at -15.degree. C. to 30.degree. C. Also,
the reaction may be performed at higher or tower temperatures such
as any temperature between -20.degree. C. and 40.degree. C. if the
reaction time is adapted accordingly. The benzylaminated compound
of Formula V is then isolated and/or purified with non-polar
solvent.
[0040] Typically, benzylamine as benzylaminating agent, isobutyl
chloroformate (IBCF) as an activator of carbonyl group, N-methyl
morpholine (NMM) as base and tetrahydrofuran (THF) or ethyl acetate
as solvent are used for the benzylamination. Non-polar solvents may
be used for the isolation/purification of benzylaminated compound
of Formula V. Non-polar solvents such as hexane, heptane, ether
like petroleum ether, diethyl ether, di-isopropyl ether etc, can be
used for the isolation/purification.
[0041] In another embodiment of this aspect, the O-methylated and
benzylaminated compound of Formula V is then subjected to
de-tritylation reaction (step-c). The de-tritylation can be
performed using de-tritylating agents like acids. Strong as well as
mild acidic conditions can be suitable for the de-tritylation
reaction. Mild acids e.g., acetic acid, etc. or strong acids e.g.,
hydrochloric acid, sulphuric acid, trifluoroacetic acid, etc, can
be used. Organic solvents (aromatic or aliphatic) can be used
during the reaction. Aromatic solvents e.g., toluene, xylene etc.,
and aliphatic solvents like chlorinated solvents e.g.,
dichloromethane, chloroform etc.; alcohols e.g., methanol, ethanol,
isopropanol, etc. can be used for the de-tritylation purpose. Basic
compounds can be used to neutralize the reaction medium. A solution
of strong or mild basic compounds is suitable for neutralization.
Some examples of these basic compounds are ammonia, ammonium
hydroxide, ammonium carbonate, ammonium bicarbonate sodium
bicarbonate, sodium carbonate, sodium hydroxide, potassium
bicarbonate, potassium carbonate, potassium hydroxide, calcium
bicarbonate, calcium hydroxide, calcium carbonate, magnesium
hydroxide, magnesium carbonate, magnesium bicarbonate, etc.
[0042] Accordingly, the acid is added to the solution of compound
of Formula V in organic solvent and the de-tritylation reaction is
allowed to proceed for about 1 hour at 15.degree. C. to 40.degree.
C., preferably for 20-50 minutes at 20.degree. C. to 35.degree. C.,
most preferably for 30-40 minutes at 25.degree. C. to 30.degree. C.
Also, the reaction may be performed at higher or lower temperatures
such as any temperature between 15.degree. C. and 40.degree. C. if
the reaction time is adapted accordingly. After completion of the
reaction, a solution of the base compound is added to the reaction
mixture. The de-tritylated compound of Formula VI is then isolated
from the reaction mixture and optionally purified.
[0043] Hydrochloric acid or acetic acid as de-tritylating agent,
dichloromethane or ethanol as organic solvent and aqueous ammonia
solution as base can be used for neutralization. The de-tritylated
compound of Formula VI is isolated and optionally purified using
organic solvents e.g., dichloromethane, toluene, ethanol, etc.
[0044] In another embodiment of present aspect, the de-tritylated
compound of Formula VI can be acetylated to produce the compound of
Formula I (step-d). For this purpose, acetic anhydride, acetyl
chloride, acetic acid or the like and derivatives thereof may be
used as an acetylating agent. The acetylation can be performed in
the presence or absence of a base. The base can be a
nitrogen-containing base e.g., pyridine, dimethylaminopyridine,
etc. The acetylation reaction can be performed in presence of
organic solvents e.g., dichloromethane, toluene, ethyl acetate,
etc.
[0045] Accordingly, base is added to the solution of compound of
Formula VI in organic solvent and acetylating agent is then slowly
added to the mixture. The reaction is allowed to proceed for up to
2 hours at temperature ranging from 5.degree. C. to 40.degree. C.
The compound of Formula I is then isolated from the reaction
mixture and purified.
[0046] Acetic anhydride as acetylating agent, dichloromethane or
ethyl acetate as organic solvent and dimethylaminopyridine as base
can be used for the acetylation. The compound of Formula I, so
formed, is purified with the help of suitable organic solvents such
as dichloromethane, toluene, ethanol, ethyl acetate, etc.
[0047] The compound of Formula III of present aspect can be
prepared by reacting the corresponding serine compound with trityl
chloride. The hydroxy and/or carboxylic group of the corresponding
serine compound can be protected by a silyl protecting group like,
for example, trimethylsilyl, hexamethyldisilazane, etc. and then
the free amino group in the compound can be selectively tritylated.
Subsequently, the silyl protecting group can be removed by
hydrolysis reaction, providing high yields of the compound of
Formula III.
[0048] In another embodiment of present aspect, a racemic serine
compound may be utilized as the starting material. Following the
procedure outlined herein would provide the racemic mixture, which
can be resolved into the R or S enantiomer by standard techniques
known in the art.
[0049] In a further embodiment of present aspect, the process
outlined herein starting from serine compound in its racemic, R or
S enantiomeric form provides the final compound of Formula I in
corresponding racemic, R or S form, respectively. If necessary, the
optical purity of the product may be enhanced by further separation
of the S-enantiomer from the R-enantiomer, by standard techniques
known in the art. D-serine (i.e., R-enantiomer) derivatives or
L-serine (i.e., S-enantiomer) derivatives or mixtures of D- and
L-serine derivatives in any ratio may be used in the method of the
present aspect.
[0050] A third aspect of the present invention provides a process
for the preparation of lacosamide comprising:
[0051] O-methylating the compound of Formula IIIa
##STR00011##
[0052] to produce the compound of Formula IVa
##STR00012##
[0053] wherein R.sub.2 is --OH or
--NH--CH.sub.2--C.sub.6H.sub.5.
[0054] The O-methylation method, reagents (methylating agent, base,
catalyst, etc.), solvents, process conditions (e.g., temperature,
reaction time, etc.) and purification methods are already described
herein above for the conversion of the compound of Formula III to
give the compound of Formula IV can also be applied in this aspect
for the O-methylation of the compound of Formula to give the
compound of Formula IVa.
[0055] The optional benzylamination reaction of the compound of
Formula IVa, subsequent de-tritylation and N.sup.2-acetylation of
the compound can afford lacosamide.
[0056] In an embodiment of this aspect, racemization is avoided
during the process of the present aspect.
[0057] In an embodiment of this aspect, the lacosamide obtained by
following the process of this aspect is substantially chirally
pure. The substantial chiral purity refers to the purity in which
no detectable amount of corresponding S-enantiomer is present in
lacosamide.
[0058] In another embodiment of this aspect, lacosamide prepared by
following the process of this aspect is substantially free of
impurities. Lacosamide having at least about 99% purity, preferably
at least about 99.8% purity and most preferably at least about
99.9% purity can be obtained by the process of present aspect.
[0059] In a fourth aspect, a process for the preparation of
lacosamide is provided comprising the steps of: [0060] a)
O-methylating the compound of Formula VII
[0060] ##STR00013## [0061] to produce a compound of Formula
VIII;
[0061] ##STR00014## [0062] b) benzylaminating the compound of
Formula VIII to produce a compound of Formula Va;
[0062] ##STR00015## [0063] c) de-tritylating the compound of
Formula Va to produce a compound of Formula VIa; and
[0063] ##STR00016## [0064] d) acetylating the compound of Formula
VIa to produce a compound of Formula Ia.
[0065] The O-methylation, benzylamination, de-tritylation,
acetylation steps (with respect to method, reaction agents,
solvents, catalyst, bases, etc.) and process conditions (e.g.,
temperature, reaction time, etc.) are described herein for the
preparation of 2-acetamido-N-benzyl-3-methoxypropionamide of
Formula I can also be applied in this aspect, but for the
preparation of lacosamide comprising the steps of this aspect.
[0066] In an embodiment of this aspect, racemization is avoided
during the process of the present aspect.
[0067] In another embodiment of this aspect, the lacosamide
obtained by following the process of this aspect is substantially
chirally pure. The substantial chiral purity refers to the purity
in which no detectable amount of corresponding S-enantiomer is
present in lacosamide.
[0068] In another embodiment of this aspect, lacosamide prepared by
following the process of this aspect is substantially free of
impurities. Lacosamide having at least about 99% purity, preferably
at least about 99.8% purity and most preferably at least about
99.9% purity can be obtained by the process of present aspect.
[0069] In a fifth aspect, a process for the preparation of
lacosamide is provided comprising the steps of: [0070] a)
benzylaminating the compound of Formula VII
[0070] ##STR00017## [0071] to produce a compound of Formula IX;
[0071] ##STR00018## [0072] b) O-methylating the compound of Formula
IX to produce a compound of Formula Va;
[0072] ##STR00019## [0073] c) de-tritylating the compound of
Formula Va to produce a compound of Formula VIa; and
[0073] ##STR00020## [0074] d) acetylating the compound of Formula
VIa to produce a compound of Formula Ia.
[0075] The O-methylation, benzylamination, de-tritylation,
acetylation steps (with respect to method, reaction agents,
solvents, catalyst, bases, etc.) and process conditions (e.g.,
temperature, reaction time, etc.) are described herein for the
preparation of 2-acetamido-N-benzyl-3-methoxypropionamide of
Formula I can also be applied in this aspect, but for the
preparation of lacosamide comprising the steps of this aspect.
[0076] In an embodiment of this aspect, racemization is avoided
during the process.
[0077] In another embodiment of this aspect, the lacosamide
obtained by following the process of this aspect is substantially
chirally pure. The substantial chiral purity refers to the purity
in which no detectable amount of corresponding S-enantiomer is
present in lacosamide.
[0078] In another embodiment of this aspect, lacosamide prepared by
following the process of this aspect is substantially free of
impurities. Lacosamide having at least about 99% purity, preferably
at least about 99.8% purity and most preferably at least about
99.9% purity can be obtained by the process of present aspect.
[0079] In a sixth aspect, substantially chirally pure lacosamide is
provided.
[0080] In an embodiment of this aspect, lacosamide having chiral
purity of more than about 99.8% is preferred. More preferably,
lacosamide having chiral purity of at least about 99.9% and most
preferably lacosamide having no detectable amount of corresponding
S-enantiomer (i.e., 100% chiral purity) is an object of this
aspect.
[0081] In a seventh aspect, a composition comprising a
pharmaceutically effective amount of substantially chirally pure
lacosamide along with pharmaceutically acceptable carrier, diluent
and/or excipient is provided.
[0082] While the present invention has been described in terms of
its specific aspects, certain modifications and equivalents will be
apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
[0083] In the following section, aspects are described by way of
examples to illustrate the processes of the invention. However,
these do not limit the scope of the present invention. Several
variants of these examples would be evident to persons ordinarily
skilled in the art.
Example 1
Preparation of N-Trityl-D-Serine
##STR00021##
[0084] Example 1a
Preparation of N-trityl-D-serine
[0085] To dichloromethane (500 ml), D-serine (50 g) was added at
ambient temperature under nitrogen atmosphere to form a suspension
and then trimethylsilyl chloride (180.91 g) was added to the
suspension in 10-15 minutes at ambient temperature. The reaction
mixture was refluxed at 35.degree. C. to 40.degree. C. for 20
minutes and then it was cooled to ambient temperature. To the
reaction mixture, a solution of triethyl amine (168.50 g)
dichloromethane (50 ml) was added in 30-45 minutes at 25.degree. C.
to 30.degree. C. The mixture was refluxed for 45 minutes at
35.degree. C. to 40.degree. C. and then cooled to 0.degree. C. To
this mixture, a solution of anhydrous methanol (22.83 g)
dichloromethane (50 ml) was added at 0.degree. C. and the mixture
was allowed to reach at room temperature. Triethylamine (48.14 g)
was slowly added to it at 25.degree. C. to 30.degree. C. and then
trityl chloride (132.63 g) was added in 3 lots to the mixture at an
interval of 10 minutes. The reaction mixture was then stirred for 3
hours under nitrogen at ambient temperature. After completion of
the reaction, methanol (76.12 g) was added at ambient temperature
in 10-15 minutes and the solvent was recovered under vacuum at
40.degree. C. to 45.degree. C. The crude product obtained was
washed with water (750 ml) and filtered. The filtered product was
further washed with 5% citric acid solution (750 ml) and filtered.
The solid product obtained was partitioned between water (750 ml)
and hexanes (200 ml) and then filtered. The filtered solid was
washed with hexanes (200 ml) and dried to obtain the titled
product. Yield=135 gm.
Example 1b
Preparation of N-trityl-D-serine
[0086] To dichloromethane (400 ml), D-serine (50 g) was added at
ambient temperature under nitrogen atmosphere to form a suspension
and then trimethylsilyl chloride (61.92 g) and hexamethyldisilazane
(107.5 ml) were added to the suspension in 10-15 minutes at ambient
temperature. The reaction mixture was refluxed at 35.degree. C. to
40.degree. C. for 3 hours and then it was cooled to 0.degree. C. To
this mixture, a solution of anhydrous methanol (22.83 g) in
dichloromethane (50 ml) was added at 0.degree. C. and the mixture
was allowed to reach at room temperature. Triethylamine (48.14 g)
was slowly added to it at 25.degree. C. to 30.degree. C. and then
trityl chloride (132.63 g) was added in 3 lots to the mixture at an
interval of 10 minutes. The reaction mixture was then stirred for
overnight under nitrogen at ambient temperature. After completion
of the reaction, methanol (76.12 g) was added at ambient
temperature in 10-15 minutes and the solvent was recovered under
vacuum at 40.degree. C. to 45.degree. C. Hexane (400 ml) and 5%
citric acid solution (750 ml) was added to the recovered solid and
filtered. The solid product obtained was washed with water (750 ml)
and hexanes (200 ml) and then filtered. The filtered solid was
washed with hexanes (200 ml) and dried to obtain the titled
product. Yield=125 gm.
Example 1c
Preparation of N-trityl-D-serine
[0087] To dichloromethane (400 ml), D-serine (50 g) was added at
ambient temperature under nitrogen atmosphere to form a suspension
and then hexamethyldisilazane (134.15 ml) was added to the
suspension in 10-15 minutes at ambient temperature. Catalytic
amount of ammonium chloride (1 gm) was added. The reaction mixture
was refluxed at 35.degree. C. to 40.degree. C. for 3 hours and then
it was cooled to 0.degree. C. To this mixture, a solution of
anhydrous methanol (22.83 g) dichloromethane (50 ml) was added at
0.degree. C. and the mixture was allowed to reach at room
temperature. Triethylamine (48.14 g) was slowly added to it at
25.degree. C. to 30.degree. C. and then trityl chloride (132.63 g)
was added in 3 lots to the mixture at an interval of 10 minutes.
The reaction mixture was then stirred for overnight under nitrogen
at ambient temperature. After completion of the reaction, methanol
(76.12 g) was added at ambient temperature in 10-15 minutes and the
solvent was recovered under vacuum at 40.degree. C. to 45.degree.
C. Toluene (400 ml) and 5% citric acid solution (750 ml) was added
to the recovered solid and filtered. The solid product obtained was
washed with water (750 ml) and hexanes (200 ml) and then filtered.
The filtered solid was washed with toluene (200 ml) and dried to
obtain the titled product. Yield=100 gm; Mass: (-EI): 346 (M-1);
242.9 (-Tr).
Example 2
Preparation of O-methyl-N-trityl-D-serine
##STR00022##
[0089] To a mixture of sodium hydride (20.14 g), imidazole (1.959
g) and tetrahydrofuran (150 ml), a solution of Example 1 product
(i.e., N-trityl-D-serine, 50 g) tetrahydrofuran (500 ml) was added
and the mixture was stirred for 45 minutes at -15.degree. C. Methyl
iodide (40.8 g) was added to the mixture in 15 minutes at
-15.degree. C. to -5.degree. C. and the reaction mixture was
stirred at -5.degree. C. for 3 hours. The temperature was raised to
0.degree. C., water was added to it and then the tetrahydrofuran
was recovered completely under vacuum at 40.degree. C. Hexane (250
ml) was added to it and stirred for 15 minutes. The layers were
separated and the aqueous layer was neutralized with acetic acid
till pH=6.0. Dichloromethane (2.times.150 ml) was added to the
aqueous layer and extracted. Organic layer was separated and
solvent recovered under vacuum at 35.degree. C. to 40.degree. C. to
obtain an oily residue. Hexane (100 ml) was added to the oily
residue and the solution was stirred for 15 minutes. The product
formed was isolated and dried to obtain compound of Formula VIII.
Yield=40 gm.
Spectroscopic Data of O-methyl-N-trityl-D-serine
[0090] [.alpha.].sub.D.sup.23=+13.9 (c=1, EtOH)
[0091] .sup.1H NMR (CDCl.sub.3) .delta.: 7.42-7.25, (m, 15 Ph);
6.48 (Br s, NH, OH); 3.4-3.5 (m, CH.sub.2--OCH.sub.3); 3.1 (s,
OCH.sub.3) 2.36-2.41 (m CH--NH)
[0092] Mass: 369.9 (M-1);
[0093] IR (KBr): 3300, 3294, 2927, 2826, 1655, 1527, 1455, 1360,
1251, 1181, 1106, 971, 734 cm.sup.-1
Example 3
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
##STR00023##
[0094] Example 3a
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0095] To a solution of Example 2 product (i.e.,
O-methyl-N-trityl-D-serine, 50 g) in tetrahydrofuran (500 ml),
N-methyl morpholine (20.9 g) was added at -15.degree. C. in 5-10
minutes. The reaction mixture was stirred for 15 minutes and then
isobutylchloroformate (18.8 g) diluted with tetrahydrofuran was
added to it at 15.degree. C. under nitrogen atmosphere in 15-20
minutes. The solution was stirred for 15 minutes and benzyl amine
(14.7 g) was added to it at -0.15.degree. C. in 15 minutes. The
solution was allowed to cool to room temperature and stirred for 2
hours. The solvent was recovered from the solution. Dichloromethane
(250 ml) was added to the crude product and stirred for 5 minutes
to dissolve. The dichloromethane layer was washed or stirred for 5
minutes with water (250 ml). The layers were separated and the
dichloromethane layer was again washed with 5% NaHCO.sub.3 (250
ml). The layers were separated and then the dichloromethane layer
was sequentially washed with 5% citric acid solution (250 ml) and
then with water (250 ml). The solvent was recovered at 40.degree.
C. to 45.degree. C. to get oil. Ethyl acetate was added to the oil
and the mixture was heated to 60.degree. C. to 65.degree. C. to
dissolve. The clear solution so formed was cooled up to room
temperature and then hexanes (350 ml) were added to it. It was
stirred for 1 hour at room temperature, filtered and then dried to
get compound of Formula Va. Yield=30 gm.
Example 3b
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0096] To a solution of Example 2 product (i.e.,
O-methyl-N-trityl-D-serine, 50 g) in ethyl acetate (500 ml),
N-methyl morpholine (20.9 g) was added at -15.degree. C. in 5-10
minutes. The reaction mixture was stirred for 15 minutes and then
isobutylchloroformate (18.8 g) already diluted with tetrahydrofuran
was added to it at -15.degree. C. under nitrogen atmosphere in
15-20 minutes. The solution was stirred for 15 minutes and benzyl
amine (14.7 g) was added to it at -15.degree. C. in 15 minutes. The
solution was allowed to cool to room temperature and stirred for 2
hours. The solvent was recovered from the solution. Dichloromethane
(250 ml) was added to the crude product and stirred for 5 minutes
to dissolve. The dichloromethane layer was washed or stirred for 5
minutes with water (250 ml). The layers were separated and the
dichloromethane layer was again washed with 5% NaHCO.sub.3 (250
ml). The layers were separated and then the dichloromethane layer
was sequentially washed with 5% citric acid solution (250 ml) and
then with water (250 ml). The solvent was recovered at 40.degree.
C. to 45.degree. C. to get oil. Ethyl acetate was added to the oil
and the mixture was heated to 60.degree. C. to 65.degree. C. to
dissolve. The clear solution so formed was cooled up to room
temperature and then hexanes (350 ml) were added to it. It was
stirred for 1 hour at room temperature, filtered and then dried to
get compound of Formula Va. Yield=31 gm.
Spectroscopic Data of
N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0097] [.alpha.].sub.D.sup.23=-91.7 (c=1, EtOH)
[0098] .sup.1H NMR: 78 (m, NH) 7.41-7.43 (m, 5 Ph); 7.16-7.36 (m,
15 Ph); 4.3-4.5 (m, CH.sub.2--NH); 3.49-3.50 (CHH--OCH.sub.3)
3.46-3.47 (m, CHH--OCH.sub.3); 3.06 (s, OCH.sub.3) 2.01-2.06 (m,
CH--NH); IR (KBr): 3294, 3024, 2829, 1622, 1527, 1428, 1370
cm.sup.-1; Mass: 451 (M+1); 243.3 (Tr).
Example 4
Preparation of N-benzyl-O-methyl-D-serinamide
##STR00024##
[0099] Example 4a
Preparation of N-benzyl-O-methyl-D-serinamide
[0100] To a solution of Example 3 product (i.e.
N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide, 50 g) in
dichloromethane (100 ml), hydrochloric acid (36%) was added at room
temperature. This solution was stirred for 30 minutes at room
temperature and then the solvent was completely recovered under
vacuum at 40.degree. C. Water (250 ml) was added to it at room
temperature and the aqueous layer was neutralized with aqueous
ammonia (20 ml). The aqueous layer was extracted with toluene
(2.times.200 ml). The toluene was then completely recovered under
vacuum at 50.degree. C. to 55.degree. C. to get an oil. Yield=15
gm.
Example 4b
Preparation of N-benzyl-O-methyl-D-serinamide
[0101] To a solution of Example 3 product (i.e.,
N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide, 50 g) in absolute
ethanol (100 ml), acetic acid (1.25 mole eq.) was added at room
temperature. This solution was stirred for 30 minutes at room
temperature and then the solvent was completely recovered under
vacuum at 40.degree. C. Water (250 ml) was added to it at room
temperature and the aqueous layer was neutralized with aqueous
ammonia (20 ml). The aqueous layer was extracted with toluene
(2.times.200 ml). The toluene was then completely recovered under
vacuum at 50.degree. C. to 55.degree. C. to get an oil. Yield=18
gm.
Spectroscopic Data of N-benzyl-O-methyl-D-serinamide
[0102] IR (liq. film); 3352, 3311, 3064, 2964, 2927, 2826, 1655,
1527, 1455, 1360, 1251, 1181, 1106, 971, 734, 700 cm.sup.-1;
.sup.1H NMR (CDCl.sub.3) .delta.: 1.85 (br, s, NH.sub.2); 3.34 (s,
OCH.sub.3) 3.56-3.62 (m, CHOCH.sub.2), 4.39 (dd, NHCHH), 4.45 (dd,
NHCHH); 7.20-7.36 (m, 5 PhH) 7.80-7.88 (m, NH); MS (+CI): 209
(M.sup.++1).
Example 5
Preparation of N-benzyl-N.sup.2-trityl-D-serinamide
##STR00025##
[0103] Example 5a
Preparation of N-benzyl-N.sup.2-trityl-D-serinamide
[0104] N-trityl-D-serine (50 g), prepared by following Example 1,
was mixed with tetrahydrofuran (500 ml) and the solution was cooled
to -15.degree. C. N-methyl morpholine (15.72 g) was added to it at
-15.degree. C. in 5-10 minutes. The solution was stirred for 15
minutes and isobutylchloroformate (20.84 g) diluted with
tetrahydrofuran was added to it in 15-20 minutes at -15.degree. C.
under nitrogen atmosphere. The solution was stirred for 15 minutes
and benzyl amine (18.51 g) was added to it in 15 minutes at
-15.degree. C. The solution was further stirred for 45 minutes at
-15.degree. C. The solution was allowed to cool to room temperature
and stirred for 2 hours. The solvent was recovered from the
solution. Dichloromethane (250 ml) was added to the crude product
and stirred for 5 minutes to dissolve. The dichloromethane layer
was washed or stirred for 5 minutes with water (250 ml). The layers
were separated and the dichloromethane layer was again washed with
5% NaHCO.sub.3 (250 ml). The layers were separated and then the
dichloromethane layer was sequentially washed with 5% citric acid
solution (250 ml) and then with water (250 ml). The solvent was
recovered at 40.degree. C. to 45.degree. C. to get oil. Ethyl
acetate (150 ml) was added to the oil and the mixture was heated to
60.degree. to 65.degree. C. to dissolve. The clear solution so
formed was cooled up to room temperature and then hexanes (350 ml)
were added to it. It was stirred for 1 hour at room temperature,
filtered and then dried to get the compound of Formula IX. Yield=45
gm.
Example 5b
Preparation of N-benzyl-N.sup.2-trityl-D-serinamide
[0105] N-trityl-D-serine (50 g), prepared by following Example 1,
was mixed with ethyl acetate (500 ml) and the solution was cooled
to -15.degree. C. N-methyl morpholine (15.72 g) was added to it at
-15.degree. C. in 5-10 minutes. The solution was stirred for 15
minutes and isobutylchloroformate (20.84 g) diluted with
tetrahydrofuran was added to it in 15-20 minutes at -15.degree. C.
under nitrogen atmosphere. The solution was stirred for 15 minutes
and benzyl amine (18.51 g) was added to it in 15 minutes at
-15.degree. C. The solution was further stirred for 45 minutes at
-15.degree. C. The solution was allowed to cool to room temperature
and stirred for 2 hours. The solvent was recovered from the
solution. Dichloromethane (250 ml) was added to the crude product
and stirred for 5 minutes to dissolve. The dichloromethane layer
was washed or stirred for 5 minutes with water (250 ml). The layers
were separated and the dichloromethane layer was again washed with
5% NaHCO3 (250 ml). The layers were separated and then the
dichloromethane layer was sequentially washed with 5% citric acid
solution (250 ml) and then with water (250 ml). The solvent was
recovered at 40.degree. C. to 45.degree. C. to get oil. Ethyl
acetate (150 ml) was added to the oil and the mixture was heated to
60.degree. C. to 65.degree. C. to dissolve. The clear solution so
formed was cooled up to room temperature and then hexanes (350 ml)
were added to it. It was stirred for 1 hour at room temperature,
filtered and then dried to get the compound of Formula IX.
Yield=45.5 gm.
Example 6
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
##STR00026##
[0106] Example 6a
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0107] To a mixture of sodium hydride (6.59 g), imidazole (1.564 g)
and tetrahydrofuran (150 ml), a solution of Example 5 product (i.e.
N-benzyl-N.sup.2-trityl-D-serinamide, 50 g) in tetrahydrofuran (500
ml) was slowly added at -15.degree. C. and the mixture was stirred
for 45 minutes at -15.degree. C. Methyl iodide (24.38 g) was slowly
added to the mixture for 15 minutes at -15.degree. C. to -5.degree.
C. and the formed reaction mixture was stirred at -5.degree. C. for
3 hours. The reaction mixture was cooled to 0.degree. C. water was
added to it and then the tetrahydrofuran was recovered completely
under vacuum at 40.degree. C. Hexane (250 ml) was added to it and
stirred for 15 minutes. The layers were separated and the aqueous
layer was neutralized with acetic acid till pH=6.0. Dichloromethane
(2.times.150 ml) was added to the aqueous layer and layers were
separated. Oily product was recovered under vacuum at 35.degree. C.
to 40.degree. C. from the organic layer. Hexane (100 ml) was added
to the oily product and the solution formed was stirred for 15
minutes, filtered and dried to get the titled product of Formula
Va.
[0108] Yield=30 gm.
Example 6b
Preparation of N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0109] To a mixture of DMSO (8 g) and pulverized KOH (0.308 g),
Example 5 product (i.e., N-benzyl-N.sup.2-trityl-D-serinamide, 2 g)
was added in one lot. It was stirred for 3 hours at ambient
temperature. Methyl iodide (0.97 g) was slowly added to the mixture
for 15 minutes at ambient temperature and stirred for 30 minutes.
The reaction mixture was cooled to 0.degree. C., water was added to
it and the product was isolated with toluene. Oily product was
recovered under vacuum at 35.degree. C. to 40.degree. C. from the
organic layer. Hexane (100 ml) was added to the oily product and
the solution formed was stirred for 15 minutes, filtered and dried
to get the titled product of Formula Va. Yield=1 gm.
Spectroscopic Data of
N-benzyl-O-methyl-N.sup.2-trityl-D-serinamide
[0110] [.alpha.].sub.D.sup.23=91.7 (c=1, EtOH)
[0111] .sup.1H NMR: 78 (m, NH) 7.41-7.43 (m, 5 Ph); 7.16-7.36 (m,
15 Ph); 4.3-4.5 (m, CH.sub.2--NH); 3.49-3.50 (CHH--OCH.sub.3)
3.46-3.47 (m, CHH--OCH.sub.3); 3.06 (s, OCH.sub.3) 2.01-2.06 (m,
CH--NH); IR (KBr): 3294, 3024, 2829, 1622, 1527, 1428, 1370
cm.sup.-1; Mass: 451 (M+1); 243.3 (Tr).
Example 7
Preparation of Lacosamide
##STR00027##
[0112] Example 7a
Preparation of Lacosamide
[0113] N-benzyl-O-methyl-D-serinamide (50 g), prepared by
sequentially following Example 1 to Example 4, was mixed with
dichloromethane (500 ml) at ambient temperature and stirred to get
clear solution. To this solution, dimethylaminopyridine (1.04 g)
was added at ambient temperature. The solution was cooled to
10.degree. to 5.degree. C. and then acetic anhydride (24.48 g) was
slowly added to it for 10-15 minutes at 10.degree. to 5.degree. C.
The solution was stirred for 10 minutes at 10.degree. to 5.degree.
C. and raised to room temperature (25.degree.-30.degree. C.) in
over 30 minutes. The solution was further stirred for 30 minutes at
room temperature. The reaction mixture was washed with 8% sodium
bicarbonate (250 ml) solution. It was again washed with water (250
ml). The layers were separated and solvent was completely recovered
under vacuum at 40.degree. C. to 48.degree. C. to get a solid
product. Yield 50 gm; mp: 142.degree. C.-143.degree. C. Chiral
purity of lacosamide by HPLC, 99.98%.
Example 7b
Preparation of Lacosamide
[0114] N-benzyl-O-methyl-D-serinamide (50 g), prepared by
sequentially following Example 1 to Example 4, was mixed with ethyl
acetate (500 ml) at ambient temperature and stirred to get clear
solution. To this solution, dimethylaminopyridine (1.04 g) was
added at ambient temperature. The solution was cooled to 10.degree.
to 5.degree. C. and then acetic anhydride (24.48 g) was slowly
added to it for 10-15 minutes at 10.degree. to 5.degree. C. The
solution was stirred for 10 minutes at 10.degree. to 5.degree. C.
and raised to room temperature (25.degree. to 30.degree. C.) in
over 30 minutes. The solution was further stirred for 30 minutes at
room temperature. The reaction mixture was washed with 8% sodium
bicarbonate (250 ml) solution. It was again washed with water (250
ml). The layers were separated and solvent was completely recovered
under vacuum at 40.degree. C. to 48.degree. C. to get a solid
product. Yield=49.5 gm; mp: 142.degree. C.-143.degree. C. Chiral
purity of lacosamide by HPLC, 99.98%.
Example 8
Preparation of Lacosamide
##STR00028##
[0115] Example 8a
Preparation of Lacosamide
[0116] N-benzyl-O-methyl-D-serinamide (50 g), prepared by
sequentially following Example 1, 5, 6 and 4, was mixed with
dichloromethane (500 ml) at ambient temperature and stirred to get
clear solution. To this solution, dimethylaminopyridine (1.04 g)
was added at ambient temperature. The solution was cooled to
10.degree. to 5.degree. C. and then acetic anhydride (24.48 g) was
slowly added to it for 10-15 minutes at 10.degree. to 5.degree. C.
The solution was stirred for 10 minutes at 10.degree. to 5.degree.
C. and raised to room temperature (25.degree.-30.degree. C.) in
over 30 minutes. The solution was further stirred for 30 minutes at
room temperature. The reaction mixture was washed with 8% sodium
bicarbonate (250 ml) solution. It was again washed with water (250
ml). The layers were separated and solvent was completely recovered
under vacuum at 40.degree. C. to 48.degree. C. to get solid
product. Yield=49 gm; mp: 142.degree. C.-143.degree. C. Chiral
purity of lacosamide by HPLC, 99.98%.
Example 8b
Preparation of Lacosamide
[0117] N-benzyl-O-methyl-D-serinamide (50 g), prepared by
sequentially following Example 1, 5, 6 and 4, was mixed with ethyl
acetate (500 ml) at ambient temperature and stirred to get clear
solution. To this solution, dimethylaminopyridine (1.04 g) was
added at ambient temperature. The solution was cooled to 10.degree.
to 5.degree. C. and then acetic anhydride (24.48 g) was slowly
added to it for 10-15 minutes at 10.degree. to 5.degree. C. The
solution was stirred for 10 minutes at 10.degree. to 5.degree. C.
and raised to room temperature (25.degree. to 30.degree. C.) in
over 30 minutes. The solution was further stirred for 30 minutes at
room temperature. The reaction mixture was washed with 8% sodium
bicarbonate (250 ml) solution. It was again washed with water (250
ml). The layers were separated and solvent was completely recovered
under vacuum at 40.degree. C. to 48.degree. C. to get solid
product. Yield=49.5 gm; mp: 142.degree. C.-143.degree. C. Chiral
purity of lacosamide by HPLC, 99.98%.
Example 9
Preparation of Lacosamide
[0118] N-benzyl-O-methyl-D-serinamide (92 g), was mixed with
dichloromethane (368 ml) at ambient temperature and stirred for 10
minutes to get a clear solution. To this solution,
dimethylaminopyridine (0.47 g) was added at ambient temperature.
Acetic anhydride (45.09 g) was slowly added over 15-20 minutes at
ambient temperature. The solution was stirred for 2 hours at room
temperature. The reaction mixture was washed with sodium hydroxide
(19.16 gm dissolved in 291 ml water), and deionized water (276 ml).
The layers were separated and solvent was completely recovered
under vacuum at 35.degree. C. to 40.degree. C. to get crude
product. Yield=82.6 gm; Chiral purity=100%.
[0119] 5 gm of the crude product was dissolved in toluene (35 ml)
and heated to 80.degree. C. It was then cooled to room temperature
and stirred for 30 minutes. The material was cooled further to
0.degree. C. and stirred for 30 minutes at the same temperature.
The mixture was filtered, and washed with chilled toluene
(2.times.10 ml). The filtrate was suck-dried for 15 minutes and
dried under vacuum at 45.degree. C. to 50.degree. C. Dried wt==4.5
gm; Chiral purity of lacosamide by HPLC, 100.00%,
Example 10
Preparation of Lacosamide
[0120] N-benzyl-O-methyl-D-serinamide (5 g), was mixed with DCM (25
ml) at ambient temperature and stirred for 10 minutes to get a
clear solution. To this solution, dimethylaminopyridine (0.025 g)
was added at ambient temperature. Acetic anhydride (2.695 g) was
slowly added over 10-12 minutes at ambient temperature. The
solution was stirred for 30 minutes at room temperature. The
reaction mixture was washed with 5% sodium bicarbonate (15 ml)
solution, deionized water (15 ml), and brine (10 ml). The layers
were separated and solvent was completely recovered under vacuum at
35.degree. C. to 40.degree. C. to get crude product. Yield=5.9
gm.
[0121] 1 gm of the crude product was dissolved in ethyl acetate (6
ml) and heated to reflux to get a clear solution. The mixture was
cooled to room temperature in 1 hour, cooled further to 5.degree.
C. in 15 minutes, then stirred for 1 hour at 5.degree. C. to
10.degree. C. The solid was filtered, and washed with chilled ethyl
acetate (3.0 ml). The material was suck-dried for 15 minutes, and
finally dried under vacuum at 50.degree. C. to 55.degree. C. Dried
wt=0.5 g. Chiral purity of lacosamide by HPLC, 100.00%.
* * * * *