WO2016039393A1 - Procédé de production d'un dérivé d'acide aminé - Google Patents

Procédé de production d'un dérivé d'acide aminé Download PDF

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WO2016039393A1
WO2016039393A1 PCT/JP2015/075653 JP2015075653W WO2016039393A1 WO 2016039393 A1 WO2016039393 A1 WO 2016039393A1 JP 2015075653 W JP2015075653 W JP 2015075653W WO 2016039393 A1 WO2016039393 A1 WO 2016039393A1
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group
salt
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雅彦 関
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株式会社エーピーアイ コーポレーション
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Publication of WO2016039393A1 publication Critical patent/WO2016039393A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/26—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and singly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C07C41/50—Preparation of compounds having groups by reactions producing groups
    • C07C41/52—Preparation of compounds having groups by reactions producing groups by substitution of halogen only
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/315—Compounds having groups containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms

Definitions

  • the present invention relates to an amino acid derivative and a method for producing an intermediate thereof. Specifically, the present invention relates to a method for producing (R) -N-benzyl-2-acetylamino-3-methoxypropionic acid amide (lacosamide) and an intermediate thereof.
  • Lacosamide is a useful drug for treating epilepsy and pain.
  • Patent Documents 1 and 2 and Non-Patent Document 1 disclose a method for producing lacosamide using methyl iodide and silver oxide as O-methylating agents.
  • Patent Document 3 discloses a method using dimethyl sulfate as an O-methylating agent.
  • Patent Documents 4 and 5 disclose a method for protecting an amino group before methylation of a hydroxyl group. All of these methods use expensive D-serine and its derivatives as starting materials, use expensive O-methylating agents and reagents for protection, Therefore, there is a demand for a method that can be manufactured industrially at a lower cost. Further, the method described in Patent Document 3 uses a large amount of dimethyl sulfate when industrially producing lacosamide on a large scale, which may cause safety or environmental problems, and is safer. An environmentally friendly manufacturing method is desired.
  • Patent Documents 6, 7 and 8 disclose a method of producing a racemic lacosamide or an intermediate thereof and optically resolving the same, or a method of separating optical isomers using an SMB (Simulated Moving Bed) separation apparatus. Yes.
  • SMB Simulated Moving Bed
  • An object of the present invention is to provide a method for industrially producing lacosamide having high optical purity in a high yield, inexpensively and safely.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • a compound represented by general formula [I] comprising a step of amidating a compound represented by formula (hereinafter also referred to as compound [III]) or a salt thereof:
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 1 and R 2 are each independently an alkyl group or an aralkyl group, and R 1 and R 2 may be linked by an alkyl chain.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • the production method according to [2] wherein the compound is obtained by reacting with a compound represented by formula (hereinafter also referred to as compound [V]) or a salt thereof.
  • compound [V] compound represented by formula
  • R 1 and R 2 are each independently an alkyl group or an aralkyl group, and R 1 and R 2 may be linked by an alkyl chain.
  • R 1 and R 2 are each independently an alkyl group or an aralkyl group, and R 1 and R 2 may be linked by an alkyl chain.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • the method includes a step of reacting with a compound represented by the formula:
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 1 and R 2 are each independently an alkyl group or an aralkyl group, and R 1 and R 2 may be linked by an alkyl chain.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • a compound represented by the formula or a salt thereof is hydrolyzed to give a general formula [XIV]:
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • a salt thereof is benzylamidated to give a general formula [XV]:
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • the compound represented by the formula or a salt thereof is reduced to give the formula [XVI]:
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • R 3 represents a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, the aryl group may be condensed with a benzene ring bonded is R 3,
  • R 4 is , An alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group).
  • R 5 , R 6 and R 7 are each independently an alkyl group.
  • high optical purity lacosamide can be industrially produced in a high yield, inexpensively and safely.
  • an intermediate useful in the production of lacosamide can be provided.
  • PMAD means (1′R, 2R) -2- (1-methylbenzyl) amino-3-methoxypropionic acid amide.
  • PMAD is an example of a compound represented by the general formula [I].
  • MAD means (R) -2-amino-3-methoxypropionic acid amide.
  • PMAN means (1′R) -2- (1′-methylbenzyl) amino-3-methoxypropionitrile.
  • PMAN is an example of a compound represented by the general formula [III].
  • MAA means methoxyacetaldehyde dimethyl acetal.
  • MAA is an example of a compound represented by the general formula [IV].
  • CAA means chloroacetaldehyde dimethyl acetal.
  • CAA is an example of a compound represented by the general formula [VI].
  • AME means methyl acrylate.
  • MCA means (R) -2-amino-3-methoxypropionic acid.
  • AMCA means (R) -2-acetylamino-3-methoxypropionic acid.
  • LACO means (R) -2-acetamino-3-methoxy-N-benzylpropionic acid amide (lacosamide).
  • AMOD means (R) -2-acetylamino-3-methoxypropionamide.
  • PMCA means (2R, 1′R) -2- (1′-methylbenzyl) amino-3-methoxypropionic acid.
  • PMCA is an example of a compound represented by the general formula [XIV].
  • PMBA means (2R, 1′R) -N-benzyl-2- (1′-methylbenzyl) amino-3-methoxypropionic acid amide.
  • PMBA is an example of a compound represented by the general formula [XV].
  • HMBA means (R) —N-benzyl-2-amino-3-methoxypropionic acid amide.
  • PEA means ⁇ -methylbenzylamine.
  • PEA is an example of a compound represented by the general formula [V]. The absolute configuration of PEA may be R-form or S-form, but R-form (R-PEA) is preferred.
  • DCM means dichloromethane.
  • DMF means N, N′-dimethylformamide.
  • DMA means N, N-dimethylacetamide.
  • DMSO means dimethyl sulfoxide.
  • NMP N-methyl-2-pyrrolidone.
  • THF tetrahydrofuran.
  • DCC means N, N′-dicyclohexylcarbodiimide.
  • EDC means 1,2-dichloroethane.
  • CDI means 1,1-carbonyldiimidazole.
  • Me means a methyl group.
  • Et means an ethyl group.
  • Ac means an acetyl group.
  • Bn means a benzyl group.
  • examples of the “alkyl group” include linear or branched alkyl groups having 1 to 12 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and an isopropyl group. Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • a lower alkyl group having 1 to 6 carbon atoms is preferable, and a methyl group or an ethyl group is particularly preferable.
  • alkoxy group examples include linear or branched alkoxy groups having 1 to 12 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group.
  • examples of the “aryl group” include aryl groups having 6 to 14 carbon atoms, such as phenyl group, 1-naphthyl group, 2-naphthyl group, 2-anthryl group and the like. Is mentioned.
  • examples of the “aryloxy group” include aryloxy groups having 6 to 14 carbon atoms, such as phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like. Can be mentioned.
  • examples of the “aralkyl group” include aralkyl groups having 7 to 40 carbon atoms, such as benzyl group, phenethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, Examples include 2-anthrylmethyl group and trityl group.
  • examples of the “alkyl chain” include an alkyl chain having 1 to 12 carbon atoms, such as a methylene group, an ethylene group, and an isopropylidene group.
  • examples of the “acetylating agent” include acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like.
  • R 1 and R 2 are each independently an alkyl group or an aralkyl group, and R 1 and R 2 may be linked by an alkyl chain.
  • R 1 and R 2 are preferably both methyl groups.
  • R 3 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl group or an aryloxy group, and the aryl group may be condensed with a benzene ring to which R 3 is bonded.
  • the R 3 in the case where "the aryl group, R 3 may be condensed with the benzene ring which is bonded", for example, biphenylenyl group, and a fluorenyl group.
  • R 3 is preferably a hydrogen atom.
  • R 4 is an alkyl group, an aryl group, an aralkyl group, —COOR 5 or —CONR 6 R 7 (wherein R 5 , R 6 and R 7 are each independently an alkyl group) .) R 4 is preferably a methyl group.
  • Step 1 Production of compound [II] or a salt thereof
  • Compound [II] or a salt thereof can be produced by reducing compound [I] or a salt thereof.
  • the reduction is preferably performed in the presence of a noble metal catalyst.
  • a noble metal catalyst As the salt of compound [I] or [II], an acid salt is preferred, and for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, mandelate can be used, Hydrochloride is preferable.
  • the noble metal catalyst palladium carbon, palladium black, palladium barium sulfate, palladium calcium carbonate, platinum carbon, rhodium carbon, ruthenium carbon and the like can be used, and preferably palladium carbon.
  • the amount of the noble metal catalyst used is 0.05 to 10 mmol, preferably 0.1 to 0.5 mmol, relative to 1 mmol of compound [I] or a salt thereof.
  • Hydrogen, formic acid, ammonium formate, triethylammonium formate, etc. can be used as the reducing agent used for the reduction of compound [I] or a salt thereof, preferably hydrogen.
  • compound [I] or a salt thereof can be reduced by reacting in the presence of a noble metal catalyst in a hydrogen atmosphere.
  • the hydrogen pressure is usually 1 atm to 100 atm, preferably 3 atm to 15 atm.
  • compound [I] or a salt thereof can be reduced by reacting these reducing agents with a noble metal catalyst.
  • the amount of formic acid, ammonium formate, or triethylammonium formate to be used is 1 mmol-100 mmol, preferably 1 mmol-20 mmol, relative to 1 mmol of compound [I] or a salt thereof.
  • the reduction can be performed in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but water, methanol, ethanol, isopropanol, THF, dioxane, toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, etc., preferably water, methanol Ethanol or isopropanol. You may mix and use a solvent.
  • the amount of the solvent to be used is generally 1 mL to 20 mL, preferably 3 mL to 10 mL, per 1 mmol of compound [I] or a salt thereof.
  • the temperature during the reduction is usually 5 ° C.
  • the reduction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours.
  • the reduction can be performed in the presence or absence of an acid.
  • examples of the acid include acetic acid, butanoic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, tartaric acid, mandelic acid, etc. These may be used as a mixture.
  • hydrochloric acid sulfuric acid or methanesulfonic acid
  • hydrochloric acid particularly preferred is hydrochloric acid.
  • the amount of the acid used is 0.05 to 10 mmol, preferably 0.1 to 0.5 mmol, relative to 1 mmol of compound [I] or a salt thereof.
  • the pressure during the reaction is usually atmospheric pressure.
  • Step 2 Production of Compound [I] or a Salt thereof (Part 1)
  • Compound [I] or a salt thereof can be produced by amidating compound [III] or a salt thereof. Specifically, it can be produced by reacting with hydrogen peroxide in the presence of an alkali metal carbonate.
  • an acid salt is preferable.
  • hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, mandelate and the like can be used, preferably hydrochloric acid. Salt.
  • the alkali metal carbonate lithium carbonate, sodium carbonate, and potassium carbonate are preferable, and potassium carbonate is particularly preferable.
  • the amount of alkali metal carbonate used is 0.01 mmol to 10 mmol, preferably 0.1 mmol to 0.5 mmol, relative to 1 mmol of compound [III] or a salt thereof.
  • hydrogen peroxide an aqueous solution having a concentration of 5% to 45%, preferably 20% to 30% can be used.
  • the amount of hydrogen peroxide to be used is 1 mmol to 10 mmol, preferably 1.5 mmol to 3 mmol, relative to 1 mmol of compound [III] or a salt thereof.
  • the amidation is preferably performed in the presence of a solvent.
  • the solvent is not particularly limited as long as amidation proceeds, but DMSO, methylene chloride, toluene, chlorobenzene and the like can be used, and DMSO is particularly preferable. Further, DMSO and a solvent such as methylene chloride, toluene, or chlorobenzene may be mixed and used.
  • the amount of the solvent to be used is generally 0.5 mL to 100 mL, preferably 1 mL to 3 mL, relative to 1 mmol of compound [III] or a salt thereof.
  • the reaction temperature is usually ⁇ 10 ° C. to 100 ° C., preferably 5 ° C. to 50 ° C.
  • the reaction time is usually 0.1 hour to 48 hours, preferably 0.5 hour to 30 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Compound [I] or a salt thereof is useful as a starting material or an intermediate for producing lacosamide.
  • Step 3 Production of compound [III] or a salt thereof
  • Compound [III] or a salt thereof can be produced by reacting compound [IV] with an acid and then reacting the obtained compound with compound [V] or a salt thereof (Strecker reaction). Specifically, (Step 3-1) reacting compound [IV] with an acid to produce methoxyacetaldehyde, (Step 3-2) the produced aldehyde with an inorganic cyanide compound and compound [V] or a salt thereof. It can be produced by reacting.
  • the salt of compound [V] is preferably an acid salt, and for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, and mandelate are preferable.
  • Step 3-1 As the acid, acetic acid, butanoic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, tartaric acid, mandelic acid and the like can be used. You may mix and use. Hydrochloric acid is preferred.
  • the amount of the acid to be used is generally 0.1 mmol-10 mmol, preferably 1 mmol-3 mmol, relative to 1 mmol of compound [IV].
  • the concentration of the acid in the reaction system is usually 0.01 mol / L to 16 mol / L, preferably 0.5 mol / L to 6 mol / L.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but alcohols such as methanol, ethanol, and isopropanol, methyl acetate, ethyl acetate, acetonitrile, toluene, DCM, DMF, DMA, NMP, water, and the like can be used. Is preferred. Further, water and a solvent other than water may be mixed and used.
  • the amount of the solvent to be used is generally 1 mL to 100 mL, preferably 5 mL to 20 mL, per 1 mmol of compound [IV].
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C.
  • the reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Compound [III] or a salt thereof is useful as a starting material or an intermediate for producing lacosamide.
  • Step 3-2 After the reaction in Step 3-1, an inorganic cyanide compound and compound [V] or a salt thereof are further added.
  • the compound [III] or a salt thereof can be produced by reacting the aldehyde produced in Step 3-1 with an inorganic cyanide compound and the compound [V] or a salt thereof in the presence or absence of an acid.
  • the inorganic cyanide compound hydrogen cyanide, lithium cyanide, sodium cyanide, potassium cyanide and the like can be used. From the viewpoint of safety and economy, lithium cyanide, sodium cyanide and potassium cyanide are preferable, and particularly preferable. Is sodium cyanide.
  • the amount of the inorganic cyanide compound used is 1 mmol to 10 mmol, preferably 1 mmol to 2 mmol, relative to 1 mmol of the compound [IV].
  • the amount of compound [V] or a salt thereof used is 1 mmol to 10 mmol, preferably 1 mmol to 2 mmol, relative to 1 mmol of compound [IV].
  • As the acid acetic acid, butanoic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, tartaric acid, mandelic acid and the like can be used. You may mix and use.
  • Hydrochloric acid is preferred.
  • the amount used is 1 mmol to 10 mmol, preferably 1 mmol to 2 mmol, with respect to 1 mmol of the inorganic cyanide compound.
  • the acid may be present in the reaction system from the previous step.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but alcohols such as methanol, ethanol, and isopropanol, methyl acetate, ethyl acetate, acetonitrile, toluene, DCM, DMF, DMA, NMP, water, and the like can be used. Is preferred. Further, water and a solvent other than water may be mixed and used.
  • the amount of the solvent to be used is generally 1 mL to 100 mL, preferably 5 mL to 20 mL, per 1 mmol of compound [V] or a salt thereof.
  • the reaction temperature is usually ⁇ 50 ° C. to 120 ° C., preferably 10 ° C. to 80 ° C.
  • the reaction time is usually 0.1 hour to 168 hours, preferably 1 hour to 48 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Compound [IV] can be commercially available, but can also be produced at lower cost by methoxylation of compound [VI] as in Step 4 below.
  • compound [IV] can be produced by reacting commercially available compound [VI] such as chloroacetaldehyde dimethyl acetal with sodium methoxide.
  • the amount of sodium methoxide to be used is generally 1 mmol-100 mmol, preferably 1 mmol-10 mmol, relative to 1 mmol of compound [VI].
  • the solvent is not particularly limited as long as the reaction proceeds, but methanol, THF, toluene and the like can be used. You may mix and use a solvent. Preferred is methanol or THF, and particularly preferred is methanol.
  • the amount of the solvent to be used is generally 0.1 mL to 100 mL, preferably 0.5 mL to 5 mL, particularly preferably 1 mL to 3 mL, relative to 1 mmol of compound [VI].
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 10 ° C. to 120 ° C.
  • the reaction time is usually 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Step 5 Production of Compound [I] or a Salt thereof (Part 2)
  • Compound [I] or a salt thereof can be produced by halogenating compound [VII] or a salt thereof and then reacting with compound [V] or a salt thereof. Specifically, first, compound [VII] or a salt thereof is reacted with a halogen.
  • a halogen bromine is particularly preferable.
  • the amount of halogen to be used is generally 1 mmol-5 mmol, preferably 1 mmol-2 mmol, particularly preferably 1 mmol-1.5 mmol, relative to 1 mmol of compound [VII] or a salt thereof.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, and examples thereof include methanol, DCM, chloroform, toluene and the like. You may mix and use a solvent.
  • the reaction temperature is usually ⁇ 10 ° C. to 100 ° C., preferably 5 ° C. to 40 ° C.
  • the reaction time is usually 0.1 hour to 24 hours, preferably 0.5 hour to 5 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • compound [I] or a salt thereof is produced by reacting the produced halide [VIII] or a salt thereof with compound [V] or a salt thereof.
  • the reaction is preferably performed in the presence of a base.
  • Compound [V] or a salt thereof is generally 1 mmol to 10 mmol, preferably 1 mmol to 5 mmol, particularly preferably 1 mmol to 2 mmol, relative to 1 mmol of compound [VII] or a salt thereof.
  • the base include triethylamine, pyridine, potassium carbonate, sodium hydroxide and the like.
  • the amount of the base to be used is generally 2 mmol to 10 mmol, preferably 2 mmol to 6 mmol, particularly preferably 2 mmol to 4 mmol, relative to 1 mmol of compound [VII] or a salt thereof.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, and examples thereof include methanol, ethanol, isopropanol, DCM, chloroform, toluene, and THF. You may mix and use a solvent.
  • the reaction temperature is usually ⁇ 10 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • the reaction time is usually 0.1 hour to 72 hours, preferably 1 hour to 8 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • compound [XII] lacosamide
  • a salt thereof is produced from compound [II] or a salt thereof by the following method A (step 6 ⁇ 7 ⁇ 8) or method B (step 9 ⁇ 10).
  • method A step 6 ⁇ 7 ⁇ 8> Step 6: Production of compound [X] or a salt thereof
  • Compound [X] or a salt thereof can be produced by hydrolyzing compound [II] or a salt thereof. Specifically, compound [II] or a salt thereof is reacted with an acid to be hydrolyzed.
  • an acid acetic acid, butanoic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, tartaric acid, mandelic acid and the like can be used. You may mix and use.
  • Preferred is hydrochloric acid or sulfuric acid.
  • the concentration of the acid used is usually 1% to 98%.
  • the amount of the acid used is 1 mmol to 1000 mmol, preferably 2 mmol to 100 mmol, particularly preferably 3 mmol to 10 mmol, relative to 1 mmol of compound [II] or a salt thereof.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to 120 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 5 hours to 30 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • the salt of compound [X] is preferably an acid salt, and for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, and mandelate are preferable.
  • the obtained compound [X] or a salt thereof can be used in the next step as it is, but may be used in the next step after purification.
  • a conventionally known method can be adopted, and it is preferable to purify using an ion exchange resin such as Dowex 50X4.
  • Step 7 Production of compound [XI] or a salt thereof
  • Compound [XI] or a salt thereof can be produced by acetylating compound [X] or a salt thereof. Specifically, compound [X] or a salt thereof is reacted with an acetylating agent in the presence of a base.
  • an acetylating agent acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like can be used, and these may be used in combination. In particular, acetic anhydride or acetyl chloride is preferred.
  • the amount of the acetylating agent to be used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [X] or a salt thereof.
  • the base triethylamine, pyridine, 4-N, N-dimethylaminopyridine, N-methylmorpholine, N-methylimidazole, sodium hydroxide, potassium carbonate, etc. can be used. Also good.
  • the amount of the base used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [X] or a salt thereof.
  • the reaction can also be carried out in the presence of a solvent.
  • the solvent water, THF, toluene, ethyl acetate or the like can be used.
  • the amount of the solvent used is 1 mL to 20 mL, preferably 3 mL to 10 mL, relative to 1 mmol of compound [X] or a salt thereof.
  • the reaction temperature is usually ⁇ 10 ° C. to 80 ° C., preferably ⁇ 5 ° C. to 30 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 3 hours to 10 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • the salt of compound [XI] is preferably an acid salt, for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, and mandelate, but an amine salt such as dicyclohexylamine is preferred.
  • an acid salt for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, and mandelate
  • an amine salt such as dicyclohexylamine is preferred.
  • Step 8 Production of Compound [XII] (Lacosamide) or a Salt thereof (Part 1)
  • Compound [XII] (lacosamide) or a salt thereof can be produced by benzylamidating compound [XI] or a salt thereof. Specifically, compound [XI] or a salt thereof is reacted with an activator in the presence or absence of a base, and then reacted with benzylamine to give compound [XII] (lacosamide) or a salt thereof. To manufacture.
  • the activator alkyl chlorocarbonates such as methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, CDI, DCC, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like can be used.
  • the amount of the activator used is 1 mmol to 10 mmol, preferably 1 mmol to 2 mmol, relative to 1 mmol of compound [XI] or a salt thereof.
  • the base N-methylmorpholine, triethylamine, N-methylimidazole and the like can be used, and these may be used in combination.
  • the amount of the base used is 1 mmol to 10 mmol, preferably 1 mmol to 2 mmol, relative to 1 mmol of compound [XI] or a salt thereof.
  • the temperature for the reaction with the activator is usually ⁇ 50 ° C. to 100 ° C., preferably ⁇ 25 ° C. to 25 ° C.
  • the reaction time is usually 0.1 hour to 24 hours, preferably 0.5 hour to 5 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • the amount of benzylamine used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [XI] or a salt thereof.
  • the temperature for the reaction with benzylamine is usually ⁇ 50 ° C. to 100 ° C., preferably ⁇ 25 ° C. to 40 ° C.
  • the reaction time is usually 0.1 hour to 24 hours, preferably 0.5 hour to 10 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Step 9 Production of compound [XIII] or a salt thereof
  • Compound [XIII] or a salt thereof can be produced by acetylating compound [II] or a salt thereof. Specifically, compound [II] or a salt thereof is reacted with an acetylating agent in the presence of a base.
  • an acetylating agent acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like can be used, and these may be used in combination.
  • the amount of the acetylating agent to be used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [II] or a salt thereof.
  • the base triethylamine, sodium hydroxide, potassium carbonate and the like can be used, and these may be used in combination.
  • the amount of the base used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [II] or a salt thereof.
  • the reaction can also be carried out in the presence of a solvent.
  • a solvent water, THF, toluene, ethyl acetate or the like can be used.
  • the amount of the solvent used is 1 mL to 20 mL, preferably 3 mL to 10 mL, relative to 1 mmol of compound [II] or a salt thereof.
  • the reaction temperature is usually ⁇ 10 ° C.
  • the reaction time is usually 0.5 hours to 48 hours, preferably 3 hours to 30 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • the salt of compound [XIII] is preferably an acid salt, for example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, mandelate, and amine salts such as dicyclohexylamine. Can also be obtained as
  • Step 10 Production of Compound [XII] (Lacosamide) or a Salt thereof (Part 2)
  • Compound [XII] (lacosamide) or a salt thereof can be produced by benzylamidating compound [XIII] or a salt thereof. Specifically, compound [XIII] or a salt thereof is reacted with benzylamine in the presence of a catalyst.
  • a catalyst As the catalyst, boronic acid, methylboronic acid, phenylboronic acid, 3,4,5-trifluorophenylboronic acid, phenylboronic acid having a substituent such as 2-iodophenylboronic acid, copper (II) acetate, etc. are used. These may be used as a mixture.
  • the amount of the catalyst used is 0.01 mmol to 1 mmol, preferably 0.05 mmol to 0.3 mmol, relative to 1 mmol of compound [XIII] or a salt thereof.
  • the amount of benzylamine to be used is 1 mmol to 10 mmol, preferably 1 mmol to 3 mmol, relative to 1 mmol of compound [XIII] or a salt thereof.
  • the reaction temperature is usually 10 ° C. to 200 ° C., preferably 25 ° C. to 150 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 5 hours to 30 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • compound [XII] (lacosamide) or a salt thereof can be produced from compound [I] or a salt thereof by the following method C (steps 11 ⁇ 12 ⁇ 13 ⁇ 14).
  • Method C steps 11 ⁇ 12 ⁇ 13 ⁇ 14>
  • Step 11 Production of compound [XIV] or a salt thereof
  • Compound [XIV] or a salt thereof can be produced by reacting compound [I] or a salt thereof with an acid.
  • an acid hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid and the like can be used, and these may be used in combination. Hydrochloric acid is preferred.
  • the amount of hydrochloric acid to be used is generally 1 mmol-100 mmol, preferably 1 mmol-10 mmol, per 1 mmol of compound [I] or a salt thereof.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but water, dioxane, acetic acid and the like can be used, and these may be used as a mixture. Preferably it is water.
  • the amount of the solvent (preferably water) to be used is generally 0.1 mL to 30 mL, preferably 0.5 mL to 3 mL, relative to 1 mmol of compound [I] or a salt thereof.
  • the reaction temperature is usually 5 ° C to 200 ° C, preferably 25 ° C to 120 ° C.
  • the reaction time is usually 0.5 to 72 hours, preferably 5 to 48 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Step 12 Production of compound [XV] or a salt thereof
  • Compound [XV] or a salt thereof can be produced by benzylamidation of compound [XIV] or a salt thereof. Specifically, compound [XV] or a salt thereof is reacted with benzylamine in the presence of a base and a condensing agent to produce compound [XV] or a salt thereof.
  • a base N-methylmorpholine, triethylamine, N-methylimidazole and the like can be used, and these may be used in combination. N-methylmorpholine is preferred.
  • the amount of the base to be used is generally 1 mmol-5 mmol, preferably 1 mmol-3 mmol, relative to 1 mmol of compound [XIV] or a salt thereof.
  • the condensing agent alkyl chlorocarbonates such as methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, EDC hydrochloride, CDI, DCC and the like can be used, and these may be used in combination. EDC hydrochloride is preferable.
  • the amount of the condensing agent to be used is generally 1 mmol-5 mmol, preferably 1 mmol-3 mmol, relative to 1 mmol of compound [XIV] or a salt thereof.
  • HOBt (1-hydroxybenzotriazole), HOSu (N-hydroxysuccinimide), and the like. These additives can promote condensation and suppress side reactions. HOBt is preferable.
  • the amount of the additive to be used is generally 1 mmol-5 mmol, preferably 1 mmol-3 mmol, relative to 1 mmol of compound [XIV] or a salt thereof.
  • the amount of benzylamine to be used is generally 1 mmol-5 mmol, preferably 1 mmol-3 mmol, relative to 1 mmol of compound [XIV] or a salt thereof.
  • the reaction can be carried out in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but DCM, toluene, THF, ethyl acetate and the like can be used. DCM is preferred.
  • the amount of the solvent to be used is generally 0.1 mL to 30 mL, preferably 0.5 mL to 3 mL, per 1 mmol of compound [XIV] or a salt thereof.
  • the reaction temperature is generally ⁇ 20 ° C. to 100 ° C., preferably ⁇ 10 ° C. to 40 ° C.
  • the reaction time is usually 0.5 to 72 hours, preferably 5 to 48 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • Step 13 Production of compound [XVI] or a salt thereof
  • Compound [XVI] or a salt thereof can be produced by reducing or acid-treating compound [XV] or a salt thereof.
  • the reduction is preferably performed in the presence of a noble metal catalyst.
  • a noble metal catalyst palladium carbon, palladium black, palladium barium sulfate, palladium calcium carbonate, platinum carbon, rhodium carbon, ruthenium carbon and the like can be used, and preferably palladium carbon.
  • the amount of the noble metal catalyst used is 0.0001 mmol to 1 mmol, preferably 0.0005 mmol to 0.05 mmol, relative to 1 mmol of compound [XV] or a salt thereof.
  • a reducing agent used for the reduction of compound [XV] or a salt thereof hydrogen, formic acid, ammonium formate, triethylammonium formate, or the like can be used.
  • hydrogen used as a reducing agent
  • compound [XV] or a salt thereof can be reduced by reacting in the presence of a noble metal catalyst in a hydrogen atmosphere.
  • the hydrogen pressure is usually 1 atm to 100 atm, preferably 1 atm to 20 atm.
  • compound [XV] or a salt thereof can be reduced by reacting these reducing agents with a noble metal catalyst.
  • the amount of formic acid, ammonium formate, or triethylammonium formate to be used is 1 mmol-100 mmol, preferably 1 mmol-20 mmol, relative to 1 mmol of compound [XV] or a salt thereof.
  • the reduction can be performed in the presence of a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but water, methanol, ethanol, isopropanol, THF, dioxane, toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, etc., preferably water, methanol Ethanol or isopropanol. You may mix and use a solvent.
  • the amount of the solvent to be used is generally 0 mL to 100 mL, preferably 0.1 mL to 50 mL, per 1 mmol of compound [XV] or a salt thereof.
  • the temperature during the reduction is usually ⁇ 10 ° C. to 150 ° C., preferably 25 ° C. to 110 ° C.
  • the reduction time is usually 0.1 to 96 hours, preferably 6 to 36 hours.
  • the reduction can be performed in the presence or absence of an acid. When reducing in the presence of an acid, hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid can be used as the acid.
  • the amount of the acid used is 0.1 mmol to 100 mmol, preferably 1 mmol to 10 mmol, relative to 1 mmol of compound [XV] or a salt thereof.
  • Examples of the acid used for the acid treatment of the compound [XV] or a salt thereof include hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, etc., preferably hydrochloric acid or sulfuric acid It is.
  • the amount of the acid to be used is generally 0.1 mmol-100 mmol, preferably 1 mmol-10 mmol, per 1 mmol of compound [XV] or a salt thereof.
  • the temperature during the acid treatment is usually ⁇ 10 ° C. to 110 ° C., preferably 0 ° C. to 60 ° C.
  • the acid treatment time is usually 0.1 hour to 48 hours, preferably 1 hour to 24 hours.
  • the pressure during the acid treatment is usually normal pressure.
  • Step 14 Production of Compound [XII] (Lacosamide) or a Salt thereof (Part 3)
  • Compound [XII] (lacosamide) or a salt thereof can be produced by reacting compound [XVI] or a salt thereof with an acetylating agent.
  • an acetylating agent acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like can be used.
  • acetic anhydride, acetyl chloride or N-acetylimidazole is used as the acetylating agent, it can be carried out in the presence of a base.
  • Examples of the base include triethylamine, pyridine, and p- (N, N-dimethylamino) pyridine.
  • acetic acid When acetic acid is used as the acetylating agent, it can be carried out in the presence of an organic compound such as DCC, EDC hydrochloride, or isobutyl chlorocarbonate.
  • This reaction can be performed using a solvent.
  • the solvent is not particularly limited as long as the reaction proceeds, but water, methanol, ethanol, isopropanol, THF, dioxane, toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, methylene chloride, and the like can be used.
  • You may mix and use a solvent Preferred are water, THF, methylene chloride, a mixture of water and THF, and a mixture of water and methylene chloride.
  • the amount of the solvent to be used is generally 0 mL to 100 mL, preferably 0.1 mL to 50 mL, per 1 mmol of compound [XVI] or a salt thereof.
  • the reaction temperature is -75 ° C to 120 ° C, preferably -25 ° C to 50 ° C.
  • the reaction time is 0.1 to 96 hours, preferably 0.2 to 24 hours.
  • the pressure during the reaction is usually atmospheric pressure.
  • the obtained compound [XII] (lacosamide) or a salt thereof can be recrystallized after completion of the reaction.
  • the solvent for recrystallization include DMF, DMA, NMP, acetonitrile, methanol, ethanol, isopropanol, THF, dioxane, toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, and the like, preferably ethyl acetate or Butyl acetate.
  • the amount of solvent used for recrystallization is 0.1 mL to 100 mL, preferably 3 mL to 12 mL, relative to 1 mmol of compound [XII] or a salt thereof.
  • the recrystallization temperature is usually ⁇ 10 ° C. to 120 ° C., preferably ⁇ 5 ° C. to 50 ° C.
  • the recrystallization time is usually 0.1 hour to 96 hours, preferably 1 hour to 36 hours.
  • the compound obtained by each of the above production methods can be used in the next production method as it is as a reaction mixture or as a crude product, but can also be isolated from the reaction mixture according to a conventional method and recrystallized. It can be easily purified by separation means such as distillation, chromatography and the like.
  • Compounds [I], [II], [III], [V], [VII], [VIII], [IX], [X], [XI], [XII], [XIII], [XIV] of the present invention ], [XV] and [XVI] include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Can be mentioned.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, mandelic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
  • solvates include hydrates and alcohol solvates (eg, methanol solvates and ethanol solvates).
  • a more preferable production method of lacosamide includes the following synthesis route (a), (b) or (c).
  • Lacosamide obtained by the production method of the present invention can be obtained by using usual dosage forms such as tablets, capsules, pills, granules, capsules, troches, syrups, solutions and injections (hereinafter referred to as “the present invention”). Can also be administered orally or parenterally.
  • the pharmaceutical preparation of the present invention can be prepared by a usual method using a pharmacologically acceptable carrier.
  • Examples of the above-mentioned “pharmacologically acceptable carrier” include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials. For example, excipients, lubricants, binders and disintegrants in solid preparations, or liquid preparations Solvents, solubilizers, suspending agents, isotonic agents, buffering agents, soothing agents and the like. Further, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, ⁇ -starch, corn starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous
  • excipients include silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
  • lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include ⁇ -starch, crystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose. And sodium carboxymethyl cellulose.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and the like.
  • solvent examples include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. It is done.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy
  • hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polysorbate, and polyoxyethylene hydrogenated castor oil.
  • isotonic agent examples include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the colorant include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos.
  • water-insoluble lake dyes eg, the above-mentioned water-soluble Edible tar pigment aluminum salts
  • natural pigments eg, ⁇ -carotene, chlorophyll, bengara
  • sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the content of lacosamide in the pharmaceutical preparation of the present invention varies depending on the dosage form, the dose of lacosamide, etc., and is, for example, about 1% to 100% by weight, preferably about 8% to 40% by weight of the whole pharmaceutical preparation. It is.
  • the dose of lacosamide varies depending on the administration subject, administration route, target disease, symptom, etc., but is usually about 0.1 mg / kg body weight to about 10 mg / kg body weight, preferably about 0 when administered orally to patients with epilepsy. .5 mg / kg body weight to about 10 mg / kg body weight, more preferably about 1 mg / kg body weight to about 4 mg / kg body weight, and the dosage thereof is about once to several times a day (eg, 1 Preferably 3 to 3 times).
  • R-PEA (265 g, 2.185 mol) was added at the same temperature over 15 minutes, and then the temperature was raised to 25 ° C. and stirred for 30 minutes.
  • CAA ⁇ MAA CAA (50.0 g, 401.4 mmol) was added dropwise to a 30% sodium methoxide methanol solution (237.4 mL, 1204.2 mmol) at 70 ° C. to 75 ° C. and stirred for 15 minutes.
  • the reaction solution was heated to 110 ° C. to 115 ° C. and stirred until the concentration of CAA was 0.5% or less.
  • the reaction solution is cooled to room temperature, methanol is removed by distillation under reduced pressure (temperature: 30 ° C to 85 ° C, pressure: 200 Torr to 205 Torr) and atmospheric distillation (temperature: 25 ° C to 110 ° C), and MAA as a colorless liquid Obtained (30.0 g, yield 55.18%).
  • MAA ⁇ PMAN A mixed solution of concentrated hydrochloric acid (14.2 mL) and water (126 mL) was cooled to 15 ° C. to 20 ° C., and MAA (10.0 g, 83.23 mmol) obtained in the above step was added dropwise over 10 minutes. The reaction was stirred at 25 ° C. for 5 hours. The reaction solution was cooled to 10 ° C. to 15 ° C., 20% aqueous sodium hydroxide solution was added to adjust the pH to 7.5, and the mixture was stirred at the same temperature for 15 minutes. To this reaction solution, R-PEA (10.6 g, 87.23 mmol) was added dropwise over 10 minutes.
  • the diastereomer ratio was measured by HPLC under the following conditions.
  • Buffer solution: acetonitrile / water 90/10
  • Mobile phase B: acetonitrile / water 90/10
  • the obtained mixture was extracted with toluene (550 mL), and the organic layer was washed with water (100 mL) and then concentrated under reduced pressure to obtain an aziridine derivative.
  • the obtained aziridine derivative was dissolved in methanol (100 mL), and a methanol solution (900 mL) of methanesulfonic acid (53.1 g, 0.55 mol) was added dropwise at 2 ° C. over 0.5 hours.
  • the reaction solution was heated to 40 ° C. over 0.5 hours and stirred at the same temperature for 6 hours.
  • the reaction solution was concentrated under reduced pressure to distill off methanol.
  • Toluene (500 mL) was added to the resulting mixture and neutralized by adding 2 mol / L sodium hydroxide solution at 5 ° C. The aqueous layer was extracted with toluene (300 mL), and the toluene layer was washed with water and concentrated under reduced pressure. 28% aqueous ammonia (1000 g) was added to the residue, and the mixture was stirred at 25 ° C. for 21 hours. The resulting mixture was concentrated under reduced pressure. Toluene was added to the residue and concentrated under reduced pressure to remove ammonia.
  • lacosamide having high optical purity can be industrially produced with high yield, inexpensively and safely.
  • an intermediate useful in the production of lacosamide can be provided.

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Abstract

La présente invention concerne un procédé pour la production industrielle, à haut rendement, peu coûteuse et sûre d'un lacosamide présentant une pureté optique élevée. La présente invention résout le problème grâce à un procédé pour la production industrielle, à haut rendement, peu coûteuse et sûre d'un lacosamide présentant une pureté optique élevée, suite à l'utilisation d'un corps intermédiaire spécifique. L'invention concerne également un corps intermédiaire utile dans la production de lacosamide.
PCT/JP2015/075653 2014-09-10 2015-09-09 Procédé de production d'un dérivé d'acide aminé WO2016039393A1 (fr)

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CN116262688A (zh) * 2021-12-14 2023-06-16 沈阳化工研究院有限公司 一种常压制备1,1,2-三甲氧基乙烷的方法

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US10975117B2 (en) 2015-11-13 2021-04-13 Api Corporation Method for producing lacosamide and intermediate thereof
US11623943B2 (en) 2015-11-13 2023-04-11 Api Corporation Method for producing lacosamide and intermediate thereof
CN116262688A (zh) * 2021-12-14 2023-06-16 沈阳化工研究院有限公司 一种常压制备1,1,2-三甲氧基乙烷的方法
CN116262688B (zh) * 2021-12-14 2024-05-14 沈阳化工研究院有限公司 一种常压制备1,1,2-三甲氧基乙烷的方法

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