WO2014155264A1 - Process for the preparation of lacosamide using novel intermediates - Google Patents
Process for the preparation of lacosamide using novel intermediates Download PDFInfo
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- WO2014155264A1 WO2014155264A1 PCT/IB2014/060077 IB2014060077W WO2014155264A1 WO 2014155264 A1 WO2014155264 A1 WO 2014155264A1 IB 2014060077 W IB2014060077 W IB 2014060077W WO 2014155264 A1 WO2014155264 A1 WO 2014155264A1
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- ZEWWJSJMNBJIKR-CYBMUJFWSA-N CC(C)(C)OC(N[C@H](COC)C(NCc1ccccc1)=O)=O Chemical compound CC(C)(C)OC(N[C@H](COC)C(NCc1ccccc1)=O)=O ZEWWJSJMNBJIKR-CYBMUJFWSA-N 0.000 description 1
- VPPJLAIAVCUEMN-GFCCVEGCSA-N CC(N[C@H](COC)C(NCc1ccccc1)=O)=O Chemical compound CC(N[C@H](COC)C(NCc1ccccc1)=O)=O VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
Definitions
- the present invention relates to an industrially feasible and cost effective process for the preparation of Lacosamide having formula I.
- the present invention further provides novel intermediate, process for its preparation and use for the preparation of Lacosamide.
- Lacosamide is a drug that has been used in the treatment of epilepsy.
- a chemical name for Lacosamide is (i?)-2-acetamido-N-benzyl-3-methoxypropionamide, and it is the active ingredient in VIMPAT® (Lacosamide) tablets and injections, for the treatment of partial- onset seizures.
- Lacosamide, CAS Registry Number [175481-36-4] has the following formula
- U.S. Patent No. 5,654,301 discloses certain compounds, which are amino acid derivatives and includes Lacosamide. Various synthetic schemes for the preparation of these derivatives are disclosed. Lacosamide and its methods of preparation are disclosed in U.S. Reissue Patent No. RE 38,551.
- the patent 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 carhoxyiic acid groups).
- the other method disclosed in this patent involves protection of an amino group of D-serine with carbobenzyloxy chloride (Cbz-Ci), subsequent O-methylation at the hydroxy group followed by amidation at carboxylic acid group with benzylamine and finally removal of the 'Cbz !
- D-serine is N- protected with Boc group ('Boc' refers to t-butoxycarbonyl) and O-methylated with methylating agents such as methyl iodide or dimethyl sulphate.
- methylating agents such as methyl iodide or dimethyl sulphate.
- the resultant compound is reacted with benzylamine to get the corresponding amide which on N-deprotection of Boc group followed by acetylation gave Lacosamide of formula-I.
- Overall yield of Lacosamide by this route is 43.7% and hence this route is not commercially viable.
- the other drawback is the use of expensive reagents such as butyl lithium compound for O-methylation of N- Boc-D-serine, which requires cryogenic condition, special care and critical handling on industrial scale. Further, it also necessitates the use of very low temperature and anhydrous conditions, thus increases the overall production cost.
- a process for the preparation of Lacosamide is disclosed in US patent application No. 20090143472 using trityl group for N-protection of D-serine.
- the process of preparation of Lacosamide involves O-methylation of the N-trityl protected D-serine, benzylamine amidation, detritylation and finally acetylation to yield Lacosamide.
- Another method disclosed involves first benzyiamine amidation of the N-trityl protected D-serine, and then O-methylation, followed by detritylation and finally acetylation.
- the present invention (Scheme 1) relates to an improved process for the preparation of Lacosamide comprising the steps of: (a) protecting D-serine of formula II with N-proteeting agent of formula III in presence of a base
- R is selected from the group comprising of CcHsCH?.-, CH3-, €?3 ⁇ 4-, (CH 3 ) 2 CHCH 2 -, (CH. 3C- and
- Z is a leaving group such as halogen, ⁇ ⁇ ' ⁇ i : ) :(. ' ( )-
- Lacosamide (g) optionally purifying Lacosamide of formula I.
- step (a) of Scheme 1 protection of the compound of formula II is carried out with N- protecting agent of formula III in presence of a base in aqueous solution to obtain compound of formula IV.
- the N-protecting agent is selected from the group comprising of BOC anhydride, CbzCi or Fmoc-Cl, alkyl or aralkyi or haloalkyl chloroformate and the like.
- the base is selected from organic or inorganic base.
- the organi base is selected from the group comprising of triethylamine, di-isopropyl ethylamine, pyridine, piperidine, DMAP (4-dimethylaminopyridine), NMM (N-methyl morpholino). Pyrrolidine and the like.
- the inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate or bicarbonate and the like, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate more preferably sodium hydroxide, potassium hydroxide and lithium carbonate.
- step (b) of Scheme I the compound of formula IV is O-methylated with methylating agent such as dimethylsulphate methyl triflate, methyl p-toluene sulfonate, dimethyl carbonate, trimethyl oxonium tetrafluoroborate and the like in presence of inorganic base selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide in aqueous solution to obtain compound of formula V, whic is optionally purified by using appropriate solvent such as hydrocarbon, preferably cyclohexane, n-hexane, toluene, ethers such as MTBE or mixture thereof and / or crystallization.
- methylating agent such as dimethylsulphate methyl triflate, methyl p-toluene sulfonate, di
- step (c) of Scheme 1 compound of formula V is cyclized using paraformaldehyde or formalin in presence of acid catalyst such as acetic acid, PTSA (p-toluene sulphonic acid) or camphor sulfonic acid in an organic solvent to obtain compound of formula VI.
- acid catalyst such as acetic acid, PTSA (p-toluene sulphonic acid) or camphor sulfonic acid in an organic solvent to obtain compound of formula VI.
- the organic solvent is selected from the group comprising of chlorinated hydrocarbon such as dichloromethane or hydrocarbon such as, toluene, cyclohexane, heptane and the like; and ester such as ethyl acetate.
- the novel compound of formula VI is characterized by the 3 ⁇ 4 H- NMR, IR and mass spectra.
- the compound of formula VI is optionally prepared directly from D-Serine of formula II with or without isolating the compound of Formula IV and V.
- step (d) of Scheme 1 amidation of the compound of formula VI is carried out using benzylamine in presence or absence of base in an organic solvent to obtain compound of the formula VIII with or without isolation of compound of formula VII.
- the base is organic base.
- the organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tributylamine, dicyclohexylamine, piperidine, pyridine and the like.
- the organic solvent is selected from the group comprising of ether such as methyl- tert-butyl ether, THF and the like; hydrocarbon such as toluene and the like; polar solvent suc as DMSO, dimethylformamide, dimethyl acetamide or methanol.
- step (d) of Scheme 1 compound of formula VII is prepared in-situ after 2-3 hr of said reaction which upon further heating for 10-12 hr is converted to compound of formula VIII.
- the novel compound of formula VII is characterized by the 'H- MR, IR and mass spectra.
- step (e) of Scheme 1 the compound of formula VIII is deprotected with acid in presence of an organic solvent to obtain compound of formula IX.
- the organic solvent is selected from the group comprising of chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like; ether such as dioxane, THF, MTBE and the like; ester such as ethyl acetate, i-propyi acetate, t-butyl acetate and the like; alcohol such as methanol, ethanol and the like; hydrocarbon such as toluene, octane and the like.
- chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like
- ether such as dioxane, THF, MTBE and the like
- ester such as ethyl acetate, i-propyi acetate, t-butyl acetate and the like
- alcohol such as
- the acid is selected from inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like.
- inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like.
- the compound of formula IX is optionally prepared directly from compound of formula VII without isolating compound of formula VIII.
- the conversion of compound of fonnula VII to compound of formula IX is carried out with acid in presence of an organic solvent.
- the organic solvent is selected from the group comprising of chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like; ether such as dioxane, THF, MTBE and the like; ester such as ethyl acetate, i-propyl acetate, t-butyl acetate and the like; alcohol such as methanol, ethanol and the like; hydrocarbon such as toluene, octane and the like.
- chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like
- ether such as dioxane, THF, MTBE and the like
- ester such as ethyl acetate, i-propyl acetate, t-butyl acetate and the like
- alcohol such as methanol,
- the acid is selected from inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like.
- inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like.
- the compound of formula IX is optionally prepared directly from compound of formula VI with or without isolating compound of formula VII.
- step (f) of Scheme 1 the compound of formula IX is subjected to N-acetylation with acylating agents such as acetic anhydride or acetyl chloride in presence or absence of base in organic solvent to obtain Lacosamide of the formula I, which is optionally purified by methods known in prior art.
- Acylation is done optionally in presence of acylation catalyst such as DMAP etc.
- the organic solvent is selected from the group comprising of chlorinated solvent such as dichloromethane, dichloroethane, chloroform and the like.
- the base is selected from organic or inorganic base.
- the organic base is selected from the group comprising of triethylamine, di-isopropyl ethylamine, pyridine, DMAP (4-dimethylammopyridine), NMM (N-methyl morpholine), piperidine, pyrrolidine and the like.
- the inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate or bicarbonate and the like, preferably sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate more preferably sodium hydroxide.
- Lacosamide of formula I is optionally prepared directly from compound of formula VIII with or without isolating compound of formula IX,
- Lacosamide obtained from above process is optionally further purified by techniques already known in prior art such as crystallization.
- the solvent used for purification is selected from the group comprising of ester such as ethyl acetate, isopropyl acetate and the like; ether such as di-ethyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like;; chlorinated solvent such as dichloromethane arid the like; hydrocarbon such as toluene and the like; nitrile such as acetonitrile or mixtures thereof.
- Lacosamide obtained by the process of the invention is in fact substantially pure, and in particular substantially free from the impurities.
- the expression "substantially pure' ' means having a purity degree equal to or higher than 99%.
- the process for the preparation of Lacosamide described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples
- the reaction mixture was acidified to pH -1 -2 with 2% hydrochloric acid solution at 0-5°C and extracted with methylene chloride (300 ml). Separating organic layer, aqueous layer was extracted with methylene chloride (100 mL). The combined organic layer was concentrated under vacuum. The obtained residue was dissolved in methyl tert-butyl ether (83.25 mL) at 60-65°C. To the resulting solution was added H-hexane (466.2 mL) at 20-25°C and mixture was stirred for 10-12h. The solid was filtered and dried to provide the title compound as white solid.
- reaction mass was stirred at 5-10°C for 2-4h then diluted with water (650 mL) and DCM (650 mL) and acidified to pH ⁇ l -2 with 10% aq. HQ (-520 mL) at 0-5°C, Separating DCM layer, aqueous layer was extracted with DCM " (2x300 mL). The combined DCM layer was washed with water (1 00 mL). To the DCM layer was added paraformaldehyde (42.85g) and p-TSA (5.43 g) at 25-30°C. The mixture was stirred under reflux using a water separater for 8-1 Oh.
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention provides an improved and commercial process for the preparation of Lacosamide having formula (I). Further, the present invention also provides the novel intermediate compounds of formula (VI) and (VII) and their process for the preparation. Present process utilizes compound of formula (VI) and (VI)I as key novel intermediates for the preparation of Lacosamide.
Description
The present invention relates to an industrially feasible and cost effective process for the preparation of Lacosamide having formula I. The present invention further provides novel intermediate, process for its preparation and use for the preparation of Lacosamide.
Formula I
Lacosamide
BACKGROUND OF THE INVENTION
Lacosamide is a drug that has been used in the treatment of epilepsy. A chemical name for Lacosamide is (i?)-2-acetamido-N-benzyl-3-methoxypropionamide, and it is the active ingredient in VIMPAT® (Lacosamide) tablets and injections, for the treatment of partial- onset seizures. Lacosamide, CAS Registry Number [175481-36-4] has the following formula
Formula I
Lacosamide
U.S. Patent No. 5,654,301 discloses certain compounds, which are amino acid derivatives and includes Lacosamide. Various synthetic schemes for the preparation of these derivatives are disclosed.
Lacosamide and its methods of preparation are disclosed in U.S. Reissue Patent No. RE 38,551. The patent 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 carhoxyiic acid groups). The other method disclosed in this patent involves protection of an amino group of D-serine with carbobenzyloxy chloride (Cbz-Ci), subsequent O-methylation at the hydroxy group followed by amidation at carboxylic acid group with benzylamine and finally removal of the 'Cbz! group followed by acetylation, to produce Lacosamide. The drawback of the process is the use of expensive reagent like methyl iodide and silver oxide for methylatkm reaction, besides requiring longer reaction times even up to 7 days for the completion. This leads to the formation of various impurities, in turn requires purification via column chromatography or solvent treatment, which not only makes the process costlier but also industrially inefficient. Moreover, the reagent methyl iodide is carcinogenic in nature and hence not preferable on industrial scale. An alternative method for the preparation of Lacosamide is disclosed in international Publication No. WO2006037574. In this disclosed method D-serine is N- protected with Boc group ('Boc' refers to t-butoxycarbonyl) and O-methylated with methylating agents such as methyl iodide or dimethyl sulphate. The resultant compound is reacted with benzylamine to get the corresponding amide which on N-deprotection of Boc group followed by acetylation gave Lacosamide of formula-I. Overall yield of Lacosamide by this route is 43.7% and hence this route is not commercially viable. The other drawback is the use of expensive reagents such as butyl lithium compound for O-methylation of N- Boc-D-serine, which requires cryogenic condition, special care and critical handling on industrial scale. Further, it also necessitates the use of very low temperature and anhydrous conditions, thus increases the overall production cost.
A process for the preparation of Lacosamide is disclosed in US patent application No. 20090143472 using trityl group for N-protection of D-serine. The process of preparation of Lacosamide involves O-methylation of the N-trityl protected D-serine, benzylamine
amidation, detritylation and finally acetylation to yield Lacosamide. Another method disclosed involves first benzyiamine amidation of the N-trityl protected D-serine, and then O-methylation, followed by detritylation and finally acetylation. In this process costly / environmental!}' unsafe / carcinogenic / pyrophoric reagents like trimethylsiiyl chloride, trityl chloride, hexamethyldisilazine, sodium hydride and methyl iodide are used. Therefore, this route is not commercially viable.
The known processes suffer from problems, such as a cumbersome purification of the product by column chromatography, low yields, use of costly, hazardous, environmentally unsafe, carcinogenic or pyrophoric reagents, etc. on industrial scale. In view of the preparation methods available for Lacosamide, there is a need for simple, industrially scalable, cost effective and environmentally-friendly processes for the preparation of Lacosaraide that is free from above mentioned drawbacks and achieves high yield and purity. The problem has been solved by the applicant by providing a novel process and via the use of novel intermediate, which allows a convenient and efficient synthesis of Lacosamide.
OBJECT OF THE INVENTION
It is a principal object of the present invention to improve upon limitations in the prior arts by providing a novel process for the preparation of Lacosamide.
It is another object of the present invention to provide a simple, commercially viable, economical and environment friendly process for preparing Lacosamide, in high yield and purity.
It is still another object of the present invention to provide an improved and commercially viable process for the preparation of Lacosamide, via novel intermediate of formula VI and VII.
It is yet another object of the present invention to provide a novel intermediate of formula VI and VII.
It is yet another object of the present invention to provide a process for the preparation of novel intermediate of formula VI and VII.
It is still another object of the present invention to provide Lacosamide substantially free impurities.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a novel and cost effective process for the manufacture of Lacosamide of formula I, as shown in Scheme 1 .
Scheme
c
Formula VIII Formula VII Formula VI
Deprotection Step e
Deprotection
O
O N Ph
\ N-Acetylation o >
O' NHAcH
NH2 Step f Formula I
Lacosamide
R = C6H5CH2-, CH3-, C2H5-, (CH3)2CHCH2-, (CH3)3C- Z = Halogen, (CH3)3CO- It has been unexpectedly found that Lacosamide is efficiently prepared from novel intermediate of fonnula VI as shown in Scheme 1 . This intermediate is easily isolable with better purity, which finally help in achieving Lacosamide in better yield and purity,
DESCRIPTION OF THE INVENTION
The present invention (Scheme 1) relates to an improved process for the preparation of Lacosamide comprising the steps of:
(a) protecting D-serine of formula II with N-proteeting agent of formula III in presence of a base
O
HO' ^ "OH
H2
D-Serine o
Formula II Formula ΙΠ with or without isolation of compound of formula IV;
Formula IV
wherein R is selected from the group comprising of CcHsCH?.-, CH3-,€?¾-, (CH3)2CHCH2-, (CH. 3C- and
Z is a leaving group such as halogen, · ί'ί i : ) :(.'( )-
(b) O-methylating compound of formula IV with methylating agent in presence of with or without isol ation of the compound of formula V;
Formula V
(c) subjecting the said compound of formula V to cyclization with paraformaldehyde or formalin in presence of acid catalyst to obtain compound of formula VI;
Formula VI
(d) condensing the compound of formula VI with benzylamine in organic solvent in presence or absence of a base to obtain compound of the formula VIII with or without isolation of compound of formula VII;
Formula VII Formula VIII
(e) deprotecting the compound of formula VII or formula VIII with acid or base in organic sol vent with or without isolation of compound of the formula IX;
Formula IX
(f) treating the said compound of formula IX with acylating agent in presence or absence of base in organic solvent to obtain Lacosamide of formula I and
Formula I
Lacosamide
(g) optionally purifying Lacosamide of formula I.
In step (a) of Scheme 1 , protection of the compound of formula II is carried out with N- protecting agent of formula III in presence of a base in aqueous solution to obtain compound of formula IV. The N-protecting agent is selected from the group comprising of BOC anhydride, CbzCi or Fmoc-Cl, alkyl or aralkyi or haloalkyl chloroformate and the like. The base is selected from organic or inorganic base. The organi base is selected from the group comprising of triethylamine, di-isopropyl ethylamine, pyridine, piperidine, DMAP (4-dimethylaminopyridine), NMM (N-methyl morpholino). Pyrrolidine and the like. The inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate or bicarbonate and the like, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate more preferably sodium hydroxide, potassium hydroxide and lithium carbonate.
In step (b) of Scheme I , the compound of formula IV is O-methylated with methylating agent such as dimethylsulphate methyl triflate, methyl p-toluene sulfonate, dimethyl carbonate, trimethyl oxonium tetrafluoroborate and the like in presence of inorganic base selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide in aqueous solution to obtain compound of formula V, whic is optionally purified by using appropriate solvent such as hydrocarbon, preferably cyclohexane, n-hexane, toluene, ethers such as MTBE or mixture thereof and / or crystallization.
The compound of formula V is optionally prepared directly from protection of the compound of formula II with or without isolating the compound of formula IV and subsequently followed by O-methylation.
In step (c) of Scheme 1 , compound of formula V is cyclized using paraformaldehyde or formalin in presence of acid catalyst such as acetic acid, PTSA (p-toluene sulphonic acid) or camphor sulfonic acid in an organic solvent to obtain compound of formula VI. The organic solvent is selected from the group comprising of chlorinated hydrocarbon such as dichloromethane or hydrocarbon such as, toluene, cyclohexane, heptane and the like; and ester such as ethyl acetate. The novel compound of formula VI is characterized by the ¾H- NMR, IR and mass spectra.
The compound of formula VI is optionally prepared directly from D-Serine of formula II with or without isolating the compound of Formula IV and V.
In step (d) of Scheme 1 , amidation of the compound of formula VI is carried out using benzylamine in presence or absence of base in an organic solvent to obtain compound of the formula VIII with or without isolation of compound of formula VII. The base is organic base. The organic base is selected from the group comprising of triethylamine, diisopropylethylamine, tributylamine, dicyclohexylamine, piperidine, pyridine and the like. The organic solvent is selected from the group comprising of ether such as methyl- tert-butyl ether, THF and the like; hydrocarbon such as toluene and the like; polar solvent suc as DMSO, dimethylformamide, dimethyl acetamide or methanol.
In step (d) of Scheme 1, compound of formula VII is prepared in-situ after 2-3 hr of said reaction which upon further heating for 10-12 hr is converted to compound of formula VIII. The novel compound of formula VII is characterized by the 'H- MR, IR and mass spectra.
In step (e) of Scheme 1, the compound of formula VIII is deprotected with acid in presence of an organic solvent to obtain compound of formula IX. The organic solvent is selected from the group comprising of chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like; ether such as dioxane, THF, MTBE and the like; ester such as ethyl acetate, i-propyi acetate, t-butyl acetate and the like; alcohol such as methanol, ethanol and the like; hydrocarbon such as toluene, octane and the like. The acid
is selected from inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like. The compound of formula IX is optionally prepared directly from compound of formula VII without isolating compound of formula VIII.
The conversion of compound of fonnula VII to compound of formula IX is carried out with acid in presence of an organic solvent. The organic solvent is selected from the group comprising of chlorinated solvents such as dichloromethane, dichloroethane, chloroform and the like; ether such as dioxane, THF, MTBE and the like; ester such as ethyl acetate, i-propyl acetate, t-butyl acetate and the like; alcohol such as methanol, ethanol and the like; hydrocarbon such as toluene, octane and the like. The acid is selected from inorganic acid such as hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate, perchloric acid or organic acid such as acetic acid, trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid, camphor sulfonic acid and the like.
The compound of formula IX is optionally prepared directly from compound of formula VI with or without isolating compound of formula VII.
In step (f) of Scheme 1, the compound of formula IX is subjected to N-acetylation with acylating agents such as acetic anhydride or acetyl chloride in presence or absence of base in organic solvent to obtain Lacosamide of the formula I, which is optionally purified by methods known in prior art. Acylation is done optionally in presence of acylation catalyst such as DMAP etc. The organic solvent is selected from the group comprising of chlorinated solvent such as dichloromethane, dichloroethane, chloroform and the like. The base is selected from organic or inorganic base. The organic base is selected from the group comprising of triethylamine, di-isopropyl ethylamine, pyridine, DMAP (4-dimethylammopyridine), NMM (N-methyl morpholine), piperidine,
pyrrolidine and the like. The inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate or bicarbonate and the like, preferably sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate more preferably sodium hydroxide. Lacosamide of formula I is optionally prepared directly from compound of formula VIII with or without isolating compound of formula IX,
Lacosamide obtained from above process is optionally further purified by techniques already known in prior art such as crystallization. The solvent used for purification is selected from the group comprising of ester such as ethyl acetate, isopropyl acetate and the like; ether such as di-ethyl ether, methyl-tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohol such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like;; chlorinated solvent such as dichloromethane arid the like; hydrocarbon such as toluene and the like; nitrile such as acetonitrile or mixtures thereof.
Lacosamide obtained by the process of the invention is in fact substantially pure, and in particular substantially free from the impurities. The expression "substantially pure'' means having a purity degree equal to or higher than 99%. The process for the preparation of Lacosamide described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples
Example 1: Preparation of N-Boc O-methyl Serine:
To a stirred aqueous solution of sodium hydroxide (23.1 g of NaOH in 150 ml of water) was added D-serine (30 g) lot wise at 2G-25°C and BOC anhydride (74.7 g) at 10-15°C. The traction mixture was stirred at 20-25 C'C for 10 hours. Sodium hydroxide pellets (11.4
g) was added to the reaction mixture at 5-10°C and stirred for another 30 mins. To the resulting reaction mixture was slowly added dimethylsulphate (340 ml) and aqueous solution of sodium hydroxide (91.0 g NaOH in 1 10 mL of water) at 5-10°C over 4 hours and then stirred for 10 hrs. The reaction mixture was acidified to pH -1 -2 with 2% hydrochloric acid solution at 0-5°C and extracted with methylene chloride (300 ml). Separating organic layer, aqueous layer was extracted with methylene chloride (100 mL). The combined organic layer was concentrated under vacuum. The obtained residue was dissolved in methyl tert-butyl ether (83.25 mL) at 60-65°C. To the resulting solution was added H-hexane (466.2 mL) at 20-25°C and mixture was stirred for 10-12h. The solid was filtered and dried to provide the title compound as white solid.
Weight: 34.5 g
Yield: 55.29%.
Example 2: Preparation of (R)-tert-butyl-4-(methoxymethyl)-5-oxazolidinone:
A mixture N-Boc-O-methyl serine (1 0.0 g), para-formaldehyde (8.23 g) and />-toluene suiphonic acid (0.52 g) in toluene (300 mL) was heated under reflux using water separater at 120~ 130°C for 2-3h. The reaction mixture was allowed to cool to room temperature. To the reaction raixture was added activated charcoal (1.0 g), hyflo (5.0 g) followed by aqueous sodium hydrogen carbonate solution (100 mL) and stirred for 30 min then filtered. Organic layer was separated from the filtrate, washed with DM water (2x50 mL) and concentrated under reduce pressure to afford title compound.
Weight: 7.0 g
Yield: 66.66%
FT-IR (CHCI3): 2979, 2931 , 2823, 1808, 1709, 1477, 1458, 1403, 1 169, 1 135
ESI-MS (m/z}i 231.72 (M+i); 253.92 (M+23)
1H-NMR (CDC! ;, S): 1.46 (s, (CH3)3C); 3.30 (s, OCH3); 3.72-3.86 (m, CH?; OCH3); 4.2 (bs, C I I }: 5.15 (s, N-CiL-O), 5.42 (s, N-C! h-O )
Example 3: Preparation of (R)-tert-buryl 4-(methoxymethyl)-5-oxazolidinone:
The solution of N-Boc O-methyl Serine ( 1.0 g) in toluene ( 10 mL), para toluene suiphonic acid (0.086 g) and formalin (0.74 g) was charged into a round bottom flask
fitted with dean-stark, thermometer and stirred at 120-130°C for 3-4h. To cooled solution activated charcoal (0.2 g), hyfio (1.0 g) and aqueous sodium hydrogen carbonate solution (5 mL) was added to it and stirred for 30 min. The reaction mixture was filtered through hyflo and separated organic layer was washed with water (2x5 mL) and concentrated under reduce pressure to yield title compound (0.8 g, 76.19%).
Example 4: Preparation of (R)-tert-butyl 4-(methoxymethyl)-5-oxazolidinone:
To aqueous solution of sodium hydroxide (28.6 g of NaOH in 250 ml of water) was added D-serine (50.0 g) lot wise at 20-25°C. To this solution, BOC anhydride (134.95 g) was added and stirred for 14-16h hours at 25~30°C. The reaction mass was cooled to 0- 5°C and aq. NaOH solution (19.0 g NaOH dissolved in 25 mL DM water) was dropwise added. Then another lot of aq. sodium hydroxide solution (123.85g sodium hydroxide dissolved in 175 mL DM water) and dimethyl sulphate (360.37 g) simultaneously dropwise added in 3-4h at 0~5°C. The reaction mass was stirred at 5-10°C for 2-4h then diluted with water (650 mL) and DCM (650 mL) and acidified to pH~l -2 with 10% aq. HQ (-520 mL) at 0-5°C, Separating DCM layer, aqueous layer was extracted with DCM" (2x300 mL). The combined DCM layer was washed with water (1 00 mL). To the DCM layer was added paraformaldehyde (42.85g) and p-TSA (5.43 g) at 25-30°C. The mixture was stirred under reflux using a water separater for 8-1 Oh. The reaction mass was cooled to 20-30°C and filtered over hyflo bed and washed the bed with DCM ( 150 mL). The combined filtrate and washing was washed with 3%> aq. sodium bicarbonate (3x250mL) and concentrated under vacuum at 40-45 °C to obtain an oily residue. The residual DCM was removed with toluene (25 mL) under vacuum at 50-60°C to provide the title compound (87.0 g). Example 5: Preparation of (R)-tert-biityl (l-(benzylamino)-3-methoxy-l-oxopropan- 2-yl)(hydroxymethyl)carbamate:
A mixture of (4i?)-3-(tert-butyloxycarbonyl)-4-(methoxymethyl)-5-oxazolidinone (0.5 g), benzyl amine (0.46 g) and triethylamine (0.36g) in MTBE (2 mL) was stirred at 60-65°C for l-2h. After completion, the reaction mixture was diluted with MTBE and acidified with 20% aqueous potassium bisulfate (~ 5 mL) solution at 10-15°C. The organic layer
was washed with water (2x10 mL) and concentrated under reduced pressure to get the title compound which was further purified using column chromatography (50% hexane/ethylacetate) to provide the title compound as a colorless oil.
Weight: 0.4g
Yield: 54.79%
Purity: 90%
FT-IR (CHCI3): 3398, 2978, 2928, 1701 , 1655, 1542, 1477, 1455, 1368, 1219
ESI-MS (m/z)i 360.96 (M+23), 376.94 { .V! 39). 320.88 ( VI -OH )
1H-NMR (CDCI3, $: 1.42 (s, (CH3)3C); 3.35 (s, OCH3); 3.80-3.85 (m, CH2, OCH3); 4.35 (s, CH); 4.40 (s, NH CH2Ph); 4.77 (s, N-CH2-0), 4.92 (s, N-CH2-0)
Example : Preparation of (R)-it?ri-butyl-(l-(benzylamino)-3-methoxy-l-oxopropaii- 2-yl)carbamate:
A mixture of (i?)-tert-butyl-4-(methoxymethyl)-5-oxazolidinone (7.0 g), benzyl amine (6.5 g) and triethylamine (5.1 1 g) in methyl tert-butyl ether (15 mL) was stirred at 60- 65°C for 10- 12h. After completion of the reaction, methyl tert-butyl ether was added to reaction mixture and acidified with 20% aqueous potassium hydrogen sulphate solution (~ 30 mL) at 10~15°C. The organic layer was washed with water (2x 15 mL) and concentrated under reduced pressure to get the title compound.
Weight: 9.0 g
Yield: 96.45%
Example 7: Preparation of (jR)-ii?ri-butyl-(l-(benzylamino)-3-methoxy-l-oxopropaii- 2-yl)carbamate:
A solution of ( ?)-tert-butyl-4-(methoxymethyl)-5-oxazolidinone (30.5 g) and benzyl amine (10.75 g) in toluene (1 10 mL) was stirred at 70-75°C for 24-26h. The reaction mixture was cooled to 10-15°C and acidified with 20% aqueous potassium hydrogen sulphate solution. Organic layer was washed with water and concentrated under vacuum to afford the title compound.
Weight: 12.3 g
Yield: 85.63%
Example 8: Preparation of (J?)-tert-b st\ -(l-(beiiz\7!am!Oo)-3-Miethoxy-l-oxopropaii- 2-yl)earbaniate:
A solution of (i?)-tert-butyl 4-(methoxymethyl)-5-oxazolidinone (87.0 g) and benzyl amine (104.5 g) in toluene (900 niL) was stirred under reflux at 120-130°C for 20-22h. The reaction mixture was cooled to 0-5°C and acidified with 20% aqueous potassium hydrogen sulphate solution (500 mL). Organic layer was washed 10% aqueous potassium hydrogen sulphate solution (500 mL). Organic layer was washed with water and concentrated under vacuum to afford title compound.
Weight: 106.0g
Yield: 91.73%
Purity: 96.30
Example 9: Preparation of (R)-N-benzyl-2-amino-3-methoxypropionamide:
To a solution of (i?)-teri-butyl-(l -(benzylamino)-3-rnethoxy-l -oxopropan-2- yl)carbamate (9.0 g) in methylene chloride (90 mL) was added concentrated hydrochloric acid (18.5 mL) at 0-5°C and stirred at 25-30°C for 2 hrs. Reaction mixture was diluted with water (20 mL) at 0-5°C and stirred for half an hour. The aqueous layer was basified with 20% aqueous sodium hydroxide solution at 0-5°C and the reaction mixture was extracted in methylene chloride. The combined organic layer was washed with water and concentrated under vacuum to obtain the title compound.
Weight: 6, lg
Yield: 100%,
Example 10: Preparation of Lacosamide:
To a solution of (i?)-N-benzyl-2-amino-3-methoxypropionamide (6.1 g) in methylene chloride (61 mL) was added acetic anhydride (3.3 g) at 20~25°C and stirred for 3-4h. The reaction mixture was washed with 5% aqueous sodium carbonate solution (40 mL), followed by 5% aqueous potassium hydrogen sulphate solution (~20 mL) and water (-20 mL). The organic layer was concentrated under vacuum to obtain a solid residue which was dissolved in methyl tert-butyl ether (30 mL) at 60-65c'C and then stirred at room
temperature for an hour. The solid obtained was filtered, washed with methyl tert-butyl ether and dried to get the title compound.
Weight: 3.75g
Yield: 51.22% Example 11: Preparation of Lacosamide:
To a solution of (i?)~tert-butyl-(l -(benzylainino)-3-methoxy-l-oxopropan-2-yl) carbamate ( 06.0 g) in DCM (600 mL) was added cone. HC1 (189.38 mL) at 0-5°C and stirred for 4- 5h. The reaction mixture was decomposed with water (250 mL) at 0-5°C. The aqueous layer was washed with DCM (150 mL). To the aqueous layer was added with DCM (400 mL) and acidified with 20% aq. sodium hydroxide (-375 mL) to pH -9.0-10.0 with solution. Aqueous layer was extracted the with DCM (3x200 mL) and DCM layer was washed with water (100 mL). To the DCM" layer was added acetic anhydride (38.86g) at 30-! 5°C and stirred at 25-30°C for 4-6 h. The reaction mixture was quenched with 2N HC1 (300 mL) at 25-30°C arid stirred for 20-30 min. The organic layer was washed with 20% aq. sodium bicarbonate solution (300 mL) then with DM Water (300 mL). The DCM layer was charcoalized, filtered over hyflo bed arid washed the hyflo bed with DCM (300 mL). The combined filtrate arid washing was concentrated under vacuum at 40-45°C to obtain solid residue which was stirred in ethyl acetate (750 mL) at 70-75°C for I h and then at 25-30°C for 12-14h. The solid was filtered, washed with ethyl acetate and dried under vacuum at 40-45°C for 12-14h to get title compound.
Weight: 49.35 g
Yield: 58.23%
Purity: 99.91% Example 12: Purification of Lacosamide:
The crude Lacosamide (3.0 g) was dissolved in ethyl acetate (25.2 mL) under reflux and solution was allowed to cool at 40-42°C and stirred for 8h. Reaction mixture was further stirred at 20-25°C for 3h and at 0-5°C for another 2h. The solid was filtered, washed with ethyl acetate and dried to get the title compound.
Weight: 2.0 e
Yield: 66.6%
Example 13: Purification of Lacosamide:
The crude Lacosamide (70.0 g) was dissolved in ethyl acetate (700 mL) under reflux and stirred for Ih. The solution was cooled to 25-30°C over 3-4h and stirred for 3-4h. The solid was filtered, washed with ethyl acetate and dried to get the title compound.
Weight: 59.5 g
Yield: 85%
Purity: 99.95%
Claims
We Claim:
An improved process for the preparation of Lacosamide of Formula I comprising the steps of;
Formula I
Lacosamide
(a) protecting D-serine of formula II with N -protecting agent of formula III in presence of a base
-Serine Y O
Formula Π Formula IN with or without isolation of compound of formula IV;
Formula IV
wherein R is selected from the group comprising of C6H5CH2-, CH3-, C2H5
(CH3)2CHCH2-, {( I S :} :(.·- and
Z is a leaving group such as halogen, (CH^CO-
(b) O-methylating compound of formula IV with methylating agent in presence of a base with or without isolation of the compound of formula V;
Formula V
wherein is as defined above,
(c) subjecting the said compound of formula V to cyclization with paraformaldehyde or formalin in presence of acid catalyst to obtain compound of formula VI;
Formula VI
wherein R is as defined above,
(d) condensing the compound of formula VI with benzyiamine in organic solvent in presence or absence of a base to obtain compound of the formula VIII with or without isolation of compound of formula VII;
Formula VII Formula VIII wherein R is as defined above,
(e) deprotecting the compound of formula VII or formula VIII with acid or base in organic solvent with or without isolation of compound of formula IX;
\
O' N Ph
H
NH2
Formula IX
(f) treating the said compound of formula IX with acylating agent in presence or absence of base in organic solvent to obtain Lacosamide of formula I.
(g) optionally purifying Lacosamide of formula L
The process according to claim 1 , wherein N-protecting agent in step (a) is selected from the group comprising of BOC anhydride, CbzCl, Fmoc-Cl and alkyl / aralkyl / haloaiky] chloroformate.
The process according to claim 1 , wherein base in step (a) is selected from organic or inorganic base, wherein organic base is selected from the group comprising of triethylamine, di-isopropylethylamine, pyridine, piperidine, DMAP, NMM and pyrrolidine and inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide, potassium hydroxide, lithium carbonate.
The process according to claim 1, wherein methylating agent in step (b) is selected from the group comprising of dimethylsulphate, methyl inflate, methyl p-toluene sulfonate, dimethyl carbonate and trimethyl oxonium tetrafluoroborate.
The process according to claim 1 , wherein base in step (b) is inorganic base selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide.
56. The process according to claim 1, wherein acid catalyst in step (c) is selected from the group comprising of acetic acid, p-toluene sulphonic acid and camphor sulfonic acid.
7. The process according to claim 1, wherein organic solvent in step (c) is selected from the group comprising of chlorinated solvent such as dichloromethane; hydrocarbon such as0 toluene, cyciohexane and heptane; and ester such as ethyl acetate.
8. The process according to claim 1 , wherein base in step (d) is organi base selected from the group comprising of triethylamine, di-isopropylethylamine, tributylamine, dicyclohexylamine, piperidine and pyridine.
5
9. The process according to claim 1, wherein organic solvent in step (d) is selected from the group comprising of ether such as methyl-tert-butyl ether, THF; hydrocarbon such as toluene; polar solvent such as DMSO, dimethylformamide, dimethyl acetamide and methanol.
0
10. The process according to claim 1 , wherein acid in step (e) is inorganic acid or organic acid, wherein inorganic acid is selected from the group comprising of hydrochloric acid (aqueous or gaseous), hydrogen bromide, hydrogen fluoride, hydrogen phosphate and perchloric acid; and organic acid is selected from the group comprising of acetic acid,5 trifluoroacetic acid, para-toluene sulfonic acid, methanesuifonic acid and camphor sulfonic acid.
11. The process according to claim 1 , wherein organic solvent in step (e) is selected from the group comprising of chlorinated solvents such as dichloromethane, dichioroethane and0 chloroform; ether such as dioxane, THF and MTBE; ester such as ethyl acetate, i-propyl acetate and t-butyl acetate; alcohol such as methanol and ethanol; hydrocarbon such as toluene and octane.
12. The process according to claim 1 , wherein acylating agents in step (f) is selected from the5 group comprising of acetic anhydride and acetyl chloride.
13. The process according to claim 1 , wherein organic solvent in step (f) is selected from the group comprising of chlorinated solvents such as dichloromethane, dichioroethane and chloroform.
1014. The process according to claim 1 , wherein base in step (f) is selected from organic or inorganic base, wherein organic base is selected from the group comprising of triethylamine, di-isopropylethylamine, pyridine, piperidine, DMAP, NMM and pyrrolidine and inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, potassium
15 hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide, potassium hydroxide, lithium carbonate.
15. The process according to claim 1 , wherein purification in step (g) is carried out using 20 solvent selected from the group comprising of ester such as ethyl acetate, and isopropyl acetate; ether such as di-ethyl ether, methyl-tert-butyl ether, tetrahydrofuran and dioxane; alcohol such as methanol, ethanol, propanol, isopropanol, butanol and t-butanol; chlorinated solvent such as dichloromethane; hydrocarbon such as toluene; nitrile such as acetonitrile; or mixtures thereof.
16. A process for the preparation of Lacosamide of Formula I comprising the steps of:
Formula I
Lacosamide
D-Serine
Formula Π without isolation of compound of formul
(b) O-methylating compound of formula IV with dimethyl sulfate in presence of sodium hydroxide without isolation of the compound of formula V;
Formula V
(c) subjecting the said compound of formula V to eyclizati n with paraformaldehyde in presence of p-toluene sulphonic acid to obtain compound of formula VI;
Formula VI
Formula VII I
(e) deprotecting the compound of formula VII or formula VIII with cone. HC1 without isolation of compound of the formula IX;
Formula IX
(f) treating the said compound of formula IX with acetic anhydride to obtain Lacosamide of formula I.
Forrnu!a VI compound of formula VII
O
' Ph
HOH2C Boc
Formula VII
Formula VI
wherein R is selected from the group comprising of C6H5CH2-, CH3-, ( ' -·! ~. (CH3)2CHCH2-, (CH3)3C- comprising the steps of:
(a) protecting D-serine of formula II with N-protecting agent of formula III in presence of a base
L ,Z
Y o
Formula Π Formula
with or without isolation of compound of formula IV;
Formula IV
wherein, R is defined as above and
Z is such as halogen, (CE ^CO-
(b) O-methylating compound of formula IV with methyiating agent in presence of a base with or without isolation of the compound of formula V;
Formula V
wherein, R is defined as above
(c) subjecting the said compound of formula V to cyciization with paraformaldehyde or formalin in presence of acid catalyst to obtain compound of formula VI.
1020. The process according to claim 19, wherein N-protecting agent in step (a) is selected from the group comprising of BOC anhydride, CbzCl, Fmoc-Cl and alkyl / aralkyl / haloalkyl chloro formate.
21. The process according to claim 19, wherein base in step (a) is selected from organic or 15 inorganic base, wherein organic base is selected from the group comprising of triethylaraine, di-isopropylethylamine, pyridine, piperidine, DMAP, NMM and pyrrolidine; inorganic base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, 20 sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide, potassium hydroxide, lithium carbonate.
22. The process according to claim 19, wherein methylating agents in step (b) is selected from the group comprising dimethvlsulphate, methyl triflate, methyl p-toluene sulfonate,
25 dimethyl carbonate and trimethyl oxonium tetrafiuoroborate.
23. The process according to claim 19, wherein base in step (b) is inorganic base selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate preferably sodium hydroxide, lithium hydroxide, sodium carbonate,
30 potassium carbonate, sodium bicarbonate and potassium bicarbonate and more preferably sodium hydroxide.
24. The process according to claim 19, wherein acid catalyst in step (c) is selected from the group comprising of acetic acid, p-toluene sulphonic acid and camphor sulfonic acid.
25. The process according to claim 19, wherein organic solvent in step (c) is selected from the group comprising of chlorinated solvent such as dichloromethane; hydrocarbon such as toluene, cyclohexane and heptanes; and ester such as ethyl acetate.
Formula VI
Formula VII
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Cited By (1)
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CN105523957A (en) * | 2016-01-15 | 2016-04-27 | 齐鲁天和惠世制药有限公司 | Method for preparing Lacosamide by one-pot method |
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US5654301A (en) | 1985-02-15 | 1997-08-05 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
US6437145B1 (en) * | 1995-02-21 | 2002-08-20 | Degussa-Huls Ag | Method of producing oxazolidinones, the use thereof and oxazolidinones |
USRE38551E1 (en) | 1996-03-15 | 2004-07-06 | Research Corporation Technologies, Inc. | Anticonvulsant enantiomeric amino acid derivatives |
WO2006037574A1 (en) | 2004-10-02 | 2006-04-13 | Schwarz Pharma Ag | Improved synthesis scheme for lacosamide |
US20090143472A1 (en) | 2007-12-04 | 2009-06-04 | Mukesh Kumar Madhra | Intermediate compounds and their use in preparation of lacosamide |
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2014
- 2014-03-24 WO PCT/IB2014/060077 patent/WO2014155264A1/en active Application Filing
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Publication number | Priority date | Publication date | Assignee | Title |
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US5654301A (en) | 1985-02-15 | 1997-08-05 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
US6437145B1 (en) * | 1995-02-21 | 2002-08-20 | Degussa-Huls Ag | Method of producing oxazolidinones, the use thereof and oxazolidinones |
USRE38551E1 (en) | 1996-03-15 | 2004-07-06 | Research Corporation Technologies, Inc. | Anticonvulsant enantiomeric amino acid derivatives |
WO2006037574A1 (en) | 2004-10-02 | 2006-04-13 | Schwarz Pharma Ag | Improved synthesis scheme for lacosamide |
US20090143472A1 (en) | 2007-12-04 | 2009-06-04 | Mukesh Kumar Madhra | Intermediate compounds and their use in preparation of lacosamide |
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