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WO2014155264A1 - Procédé pour la préparation de lacosamide utilisant de nouveaux intermédiaires - Google Patents

Procédé pour la préparation de lacosamide utilisant de nouveaux intermédiaires Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
formula
compound
group
base
acid
Prior art date
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Ceased
Application number
PCT/IB2014/060077
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English (en)
Inventor
Sujay Biswas
Vikas Bansal
Nitin Kumar GUPTA
Dharam Vir
Rohit CHAKRAVARTY
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Jubilant Pharmova Ltd
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Jubilant Life Sciences Ltd
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Publication of WO2014155264A1 publication Critical patent/WO2014155264A1/fr
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention porte sur un procédé amélioré et industriel pour la préparation de lacosamide répondant à la formule I. En outre, la présente invention porte également sur les nouveaux composés intermédiaires représentés par les formules VI et VII et sur leur procédé de préparation. Le présent procédé utilise les composés de formules VI et VII comme nouveaux intermédiaires clés pour la préparation de lacosamide.
PCT/IB2014/060077 2013-03-25 2014-03-24 Procédé pour la préparation de lacosamide utilisant de nouveaux intermédiaires Ceased WO2014155264A1 (fr)

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IN908DE2013 2013-03-25
IN908/DEL/2013 2013-03-25

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WO2014155264A1 true WO2014155264A1 (fr) 2014-10-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105523957A (zh) * 2016-01-15 2016-04-27 齐鲁天和惠世制药有限公司 一锅法制备拉科酰胺的方法
CN117304049A (zh) * 2023-09-25 2023-12-29 江西亿森源植物香料有限公司 一种n,2,3-三甲基-2-异丙基丁酰胺清凉剂的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (fr) 2004-10-02 2006-04-13 Schwarz Pharma Ag Schema de synthese ameliore pour le lacosamide
US20090143472A1 (en) 2007-12-04 2009-06-04 Mukesh Kumar Madhra Intermediate compounds and their use in preparation of lacosamide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (fr) 2004-10-02 2006-04-13 Schwarz Pharma Ag Schema de synthese ameliore pour le lacosamide
US20090143472A1 (en) 2007-12-04 2009-06-04 Mukesh Kumar Madhra Intermediate compounds and their use in preparation of lacosamide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105523957A (zh) * 2016-01-15 2016-04-27 齐鲁天和惠世制药有限公司 一锅法制备拉科酰胺的方法
CN117304049A (zh) * 2023-09-25 2023-12-29 江西亿森源植物香料有限公司 一种n,2,3-三甲基-2-异丙基丁酰胺清凉剂的制备方法

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