WO2016039393A1

WO2016039393A1 - Production method for amino acid derivative

Info

Publication number: WO2016039393A1
Application number: PCT/JP2015/075653
Authority: WO
Inventors: 雅彦関
Original assignee: 株式会社エーピーアイコーポレーション
Priority date: 2014-09-10
Filing date: 2015-09-09
Publication date: 2016-03-17
Also published as: JPWO2016039393A1

Abstract

The purpose of the present invention is to provide a method for high-yield, inexpensive, and safe industrial production of a lacosamide having high optical purity. The present invention addresses said issue by providing a method for high-yield, inexpensive, and safe industrial production of a lacosamide having high optical purity, as a result of using a specific intermediate body. Also provided is an intermediate body useful in the production of lacosamide.

Description

Method for producing amino acid derivative

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. Furthermore, 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. However, these methods are not satisfactory in terms of yield and optical purity, and since a special separation device is necessary, a method that can be produced more efficiently and inexpensively is desired. .

US Reissue Patent RE38551 Specification U.S. Patent No. 6,048,899 International Publication No. 2006/037574 U.S. Patent No. 8,093,426 International Publication No. 2011/039781 International Publication No. 2010/052011 International Publication No. 2012/065891 International Publication No. 2011/092559

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.

As a result of intensive studies, the present inventor found an efficient and economical method for producing lacosamide through a specific intermediate, and completed the present invention.
That is, the present invention is as follows.
[1] General formula [I]:

Wherein, 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). ]
Or a salt thereof (hereinafter also referred to as compound [I]).
[2] General formula [III]:

Wherein, 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:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
[3] General formula [III]:

Wherein, 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). ]
Or a salt thereof represented by the general formula [IV]:

[Wherein, 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. ]
After reacting a compound represented by the formula (hereinafter also referred to as compound [IV]) with an acid, the resulting compound is represented by the general formula [V]:

Wherein, 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.
[4] General formula [IV]:

[Wherein, 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. ]
A compound represented by general formula [VI]:

[Wherein, R ¹ and R ² have the same meanings as described above. ]
The production method according to [3], which is obtained by reacting a compound represented by formula (hereinafter also referred to as compound [VI]) with sodium methoxide.
[5] General formula [IV]:

[Wherein, 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. ]
The compound represented by general formula [V]:

Wherein, 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). ]
Which comprises reacting with a compound represented by the formula or a salt thereof:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
[6] Formula [VII]:

After halogenating a compound represented by formula (hereinafter also referred to as compound [VII]) or a salt thereof, the obtained compound is represented by the general formula [V]:

Wherein, 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:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
[7] General formula [III]:

Wherein, 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). ]
Or a salt thereof is amidated to give a general formula [I]:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
Which comprises a step of producing a compound represented by the formula or a salt thereof: [XII]:

Or a salt thereof (hereinafter also referred to as compound [XII]).
[8] General formula [III]:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
The production method according to [7], which is obtained by reacting with a compound represented by the formula:
[9] Formula [VII]:

After halogenating the compound represented by the formula or a salt thereof, the obtained compound is represented by the general formula [V]:

Wherein, 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). ]
And a compound represented by the general formula [I]:

The manufacturing method of the compound represented by these, or its salt.
[10] General formula [I]:

Wherein, 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). ]
Is reduced to a compound represented by formula [II]:

A process for producing a compound represented by the formula (hereinafter also referred to as compound [II]) or a salt thereof:

The manufacturing method of the compound represented by these, or its salt.
[11] (1) Formula [II]:

The compound represented by the formula or a salt thereof is hydrolyzed to form the formula [X]

A process for producing a compound represented by formula (hereinafter also referred to as compound [X]) or a salt thereof,
(2) A compound represented by the formula [X] or a salt thereof is reacted with an acetylating agent to form a formula [XI]:

And a step of producing a compound represented by formula (hereinafter also referred to as compound [XI]) or a salt thereof, and (3) a step of benzylamidating the compound represented by formula [XI] or a salt thereof. The production method according to [10], which is characterized.
[12] (1 ′) Formula [II]:

Or a salt thereof is reacted with an acetylating agent to produce a compound of the formula [XIII]:

A step of producing a compound represented by formula (hereinafter also referred to as compound [XIII]) or a salt thereof, and (2 ′) a step of benzylamidating the compound represented by formula [XIII] or a salt thereof. [10] The production method according to [10].
[13] General formula [I]:

Wherein, 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]:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
Which comprises a step of producing a compound represented by the formula (hereinafter also referred to as compound [XIV]) or a salt thereof:

The manufacturing method of the compound represented by these, or its salt.
[14] General formula [XIV]:

Wherein, 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). ]
Or a salt thereof is benzylamidated to give a general formula [XV]:

[Wherein, R ³ and R ⁴ have the same meanings as described above. ]
The production method according to [13], further comprising a step of producing a compound represented by formula (hereinafter also referred to as compound [XV]) or a salt thereof.
[15] General formula [XV]:

Wherein, 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]:

The method according to [14], further comprising a step of producing a compound represented by formula (hereinafter also referred to as compound [XVI]) or a salt thereof.
[16] Formula [XII] obtained by the production method according to any one of [7] to [15]:

Or a salt thereof as an active ingredient.
[17] General formula [III]:

Wherein, 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). ]
Or a salt thereof.
[18] General formula [XIV]:

Wherein, 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). ]
Or a salt thereof.
[19] Formula [XIII]:

Or a salt thereof.

According to the present invention, high optical purity lacosamide can be industrially produced in a high yield, inexpensively and safely. In addition, an intermediate useful in the production of lacosamide can be provided.

Definitions of symbols and terms used in the present invention will be described in detail below.
In the present specification, “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].
In the present specification, “MAD” means (R) -2-amino-3-methoxypropionic acid amide.
In the present specification, “PMAN” means (1′R) -2- (1′-methylbenzyl) amino-3-methoxypropionitrile. “PMAN” is an example of a compound represented by the general formula [III].
In the present specification, “MAA” means methoxyacetaldehyde dimethyl acetal. “MAA” is an example of a compound represented by the general formula [IV].
In the present specification, “CAA” means chloroacetaldehyde dimethyl acetal. “CAA” is an example of a compound represented by the general formula [VI].
In the present specification, “AME” means methyl acrylate.
In the present specification, “MCA” means (R) -2-amino-3-methoxypropionic acid.
In the present specification, “AMCA” means (R) -2-acetylamino-3-methoxypropionic acid.
In the present specification, “LACO” means (R) -2-acetamino-3-methoxy-N-benzylpropionic acid amide (lacosamide).
In the present specification, “AMAD” means (R) -2-acetylamino-3-methoxypropionamide.
In the present specification, “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].
In the present specification, “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].
In the present specification, “HMBA” means (R) —N-benzyl-2-amino-3-methoxypropionic acid amide.
In the present specification, “PEA” means α-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.
In the present specification, “DCM” means dichloromethane.
In the present specification, “DMF” means N, N′-dimethylformamide.
In the present specification, “DMA” means N, N-dimethylacetamide.
In the present specification, “DMSO” means dimethyl sulfoxide.
In the present specification, “NMP” means N-methyl-2-pyrrolidone.
In the present specification, “THF” means tetrahydrofuran.
In the present specification, “DCC” means N, N′-dicyclohexylcarbodiimide.
In the present specification, “EDC” means 1,2-dichloroethane.
In the present specification, “CDI” means 1,1-carbonyldiimidazole.
In the present specification, “Me” means a methyl group.
In the present specification, “Et” means an ethyl group.
In the present specification, “Ac” means an acetyl group.
In the present specification, “Bn” means a benzyl group.

In the present specification, unless otherwise specified, 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.
In the present specification, unless otherwise specified, examples of the “alkoxy group” include linear or branched alkoxy groups having 1 to 12 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group. Group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, etc. Is mentioned.
In the present specification, unless otherwise specified, 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.
In the present specification, unless otherwise specified, 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.
In the present specification, unless otherwise specified, 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.
In the present specification, unless otherwise specified, 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.
In the present specification, examples of the “acetylating agent” include acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like.

In the present specification, 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.
In the present specification, 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.
In the present specification, 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.

Next, the manufacturing method of this invention is demonstrated.
Step 1: Production of compound [II] or a salt thereof

[Wherein the symbols are as defined above. ]
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.
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.
As 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.
When hydrogen is used as a reducing agent, for example, 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.
When formic acid, ammonium formate, or triethylammonium formate is used as a reducing agent, 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. to 200 ° C., preferably 40 ° C. to 100 ° 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. When reducing in the presence 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. Preferred is hydrochloric acid, sulfuric acid or methanesulfonic acid, and 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)

[Wherein the symbols are as defined above. ]
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.
As the salt of compound [III], an acid salt is preferable. For example, hydrochloride, sulfate, p-toluenesulfonate, camphorsulfonate, tartrate, mandelate and the like can be used, preferably hydrochloric acid. Salt.
As 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.
As 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

[Wherein the symbols are as defined above. ]
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. Thus, 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. .
As 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.
When the acid is used, 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. Further, 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.

Step 4: Production of compound [IV]

[Wherein the symbols are as defined above. ]
Specifically, 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.

Compound [I] or a salt thereof can also be produced by the following method (Step 5).
Step 5: Production of Compound [I] or a Salt thereof (Part 2)

[Wherein the symbols are as defined above. ]
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. As the 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.
Next, 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.
Examples of 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.

In the present invention, compound [XII] (lacosamide) or 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). be able to.
<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.
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. 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. For the 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.
As the 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.
As 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. As the solvent, water, THF, toluene, ethyl acetate or the like can be used. When a solvent is 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. Can also be obtained as

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.
As 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. These may be used as a mixture.
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.
As the base, N-methylmorpholine, triethylamine, N-methylimidazole and the like can be used, and these may be used in combination.
When a base is used, 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.
After reacting with an activator, it is further reacted with benzylamine.
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.

<Method B: Step 9 → 10>
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.
As the 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.
As 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. As the solvent, water, THF, toluene, ethyl acetate or the like can be used. When a solvent is 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. to 80 ° C., preferably 0 ° C. to 40 ° 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.
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.

In the present invention, 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: Step 11 → 12 → 13 → 14>

Step 11: Production of compound [XIV] or a salt thereof

[Wherein the symbols are as defined above. ]
Compound [XIV] or a salt thereof can be produced by reacting compound [I] or a salt thereof with an acid.
As the 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

[Wherein the symbols are as defined above. ]
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.
As the 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.
As 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.
In addition to the condensing agent, it is preferable to use additives such as 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

[Wherein the symbols are as defined above. ]
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.
As 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 0.0001 mmol to 1 mmol, preferably 0.0005 mmol to 0.05 mmol, relative to 1 mmol of compound [XV] or a salt thereof.

As 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.
When hydrogen is used as a reducing agent, for example, 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.
When formic acid, ammonium formate, or triethylammonium formate is used as a reducing agent, 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. For example, it can be produced by the method described in WO2006 / 037574 and US Pat. No. 6048899.
As the acetylating agent, acetic anhydride, acetyl chloride, N-acetylimidazole, acetic acid and the like can be used.
When 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.
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.

In order to improve the purity of the compound [XII] or a salt thereof, the obtained compound [XII] (lacosamide) or a salt thereof can be recrystallized after completion of the reaction.
Examples of 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. Preferable examples of 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. Preferable examples of 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. Preferable examples of the salt with organic acid 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. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.

Compounds [I], [II], [III], [V], [VII], [VIII], [IX], [X], [XI], [XII], [XIII], [XIV] of the present invention ], [XV] or [XVI] or salts thereof include solvates. Examples of solvates include hydrates and alcohol solvates (eg, methanol solvates and ethanol solvates).

In the present invention, 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. In this case, 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.

Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, α-starch, corn starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous Examples thereof include silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include α-starch, crystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose. And sodium carboxymethyl cellulose.
Examples of the disintegrant 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.
Examples of the solvent 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.
Examples of the solubilizer 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.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polysorbate, and polyoxyethylene hydrogenated castor oil.
Examples of the isotonic agent 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, α-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. 1 and 2), water-insoluble lake dyes (eg, the above-mentioned water-soluble Edible tar pigment aluminum salts), natural pigments (eg, β-carotene, chlorophyll, bengara) and the like.
Examples of the 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).

The present invention will be described more specifically with reference to examples below, but the present invention is not limited thereto.
In the following examples, “%” in concentration and content represents “% by weight” unless otherwise specified. The ratio shown in the mixed solvent indicates “volume ratio” unless otherwise specified.

Example 1 (Manufacture of PMAN)

A mixture of concentrated hydrochloric acid (106.32 g, 2.914 mol) and water (3.167 L) was cooled to 15 ° C. to 20 ° C., and commercially available MAA (250.0 g, 2.081 mol) was added over 15 minutes, then at 25 ° C. Stir for 5 hours. The reaction solution was cooled to 10 ° C. to 15 ° C., and a 49% aqueous sodium hydroxide solution was added to adjust the pH to 7.5. To this reaction solution, 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. Sodium cyanide (102 g, 2.081 mol) and water (250 mL) were added to the reaction solution, and the mixture was stirred at 25 ° C. for 60 hours. The reaction solution was extracted with methylene chloride (500 mL × 1 time, 250 mL × 4 times). The organic layers were combined and washed with water (250 mL × 2). The organic layer was concentrated under reduced pressure at 40 ° C. to obtain the desired product as a brown liquid (396 g, yield 93.2%, HPLC purity 88.54%, diastereomer ratio (PMAN: diastereomer) = 37.6: 57.6).
¹ H NMR (CDCl ₃ ): δ 7.38-7.24 (m, 5H), 3.96-3.86 (m, 1H), 3.5-3.45 (m, 2H), 3.39-3.28 (m, 4H), 3.07-2.86 (m , 1H), 1.35-1.18 (m, 3H)
Mass [M + H] ⁺ : 205 amu;
HRMS: [M + Na] Calculated 227.1160, observed 227.117

HPLC purity and diastereomer ratio were measured by HPLC under the following conditions.
Column: Unisole C18 (150mm × 4.6mm, 3μm)
Buffer solution: acetonitrile / water = 90/10
Mobile phase A: 0.7708 g NH ₄ OAc in 1000 mL H ₂ O
Mobile phase B: 90% aq. CH ₃ CN
Gradient program: 0 minutes (A liquid / B liquid = 97/3), 25 minutes (A liquid / B liquid = 5/95), 37 minutes to 10 minutes (A liquid / B liquid = 97/3)
Flow rate: 0.8mL / min Injection volume: 5μL
Detection wavelength: 215nm
Column temperature: 40 ° C

Example 2 (Production of PMAN)

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. To this was added sodium cyanide (4.10 g, 83.23 mmol), and the mixture was stirred at 10 ° C. to 15 ° C. for 15 minutes, and concentrated hydrochloric acid (10.12 mL) was added dropwise while maintaining the temperature at 20 ° C. or lower. The reaction was stirred at 25 ° C. for 48 hours. After completion of the reaction, the reaction solution was extracted with methylene chloride (25 mL × 4 times). The organic layers were combined, washed with water (2 × 20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give PMAN as a brown liquid (11.8 g, 69.41% yield, diastereomer ratio (PMAN: dia). Stereomer) = 34.9: 64.2).
¹ H NMR (CDCl ₃ ): δ 7.38-7.24 (m, 5H), 3.96-3.86 (m, 1H), 3.5-3.45 (m, 2H), 3.39-3.28 (m, 4H), 3.07-2.86 ( m, 1H), 1.35-1.18 (m, 3H)
Mass [M + H] ⁺ : 205 amu
HRMS: [M + Na] Calculated 227.1160, observed 227.117

The diastereomer ratio was measured by HPLC under the following conditions.
Column: Unisole C18 (150mm × 4.6mm, 3μm)
Buffer solution: acetonitrile / water = 90/10
Mobile phase A: 10 mmol / L ammonium acetate Mobile phase B: acetonitrile / water = 90/10
Gradient program: 0 minutes (A liquid / B liquid = 3/0), 5 minutes (A liquid / B liquid = 3/5), 10 minutes (A liquid / B liquid = 95/25), 15 minutes (A liquid) / B liquid = 95/35), 20 minutes (A liquid / B liquid = 3/37), 25 minutes (A liquid / B liquid = 3/42)
Flow rate: 0.8mL / min Injection volume: 5μL
Detection wavelength: 215nm
Column temperature: 40 ° C

Example 3 (Production of PMAD hydrochloride)

PMAN → PMAD
To a mixture of PMAN (394 g, 1.938 mol), potassium carbonate (37.51 g, 0.2714 mol) and DMSO (594 mL), 25% aqueous hydrogen peroxide (538 mL, 3.876 mol) was added over 3 hours at 20-25 ° C. And stirred at the same temperature for 2 hours. After confirming the completion of the reaction with TLC (thin-layer chromatography, eluent: hexane / ethyl acetate = 8/2), water (594 mL) was added dropwise over 20 minutes at 20 ° C to 25 ° C, and 2 hours at 25 ° C. Stir. Methylene chloride (594 mL) was added to the reaction solution, and the aqueous layer was extracted with methylene chloride (394 mL × 2 times). The organic layers were combined, washed with water (394 mL x 3 times), and concentrated under reduced pressure to obtain PMAD as a white solid (455.0 g, yield 105.5%, HPLC purity 77.78%, diastereomer ratio (PMAD: diastereomer) = 57.99: 39.06).
¹ H NMR (CDCl ₃ ) (mixture of diastereomers): δ 7.41-7.21 (m, 7.3H), 5.76 (s, 0.7H, exchangable), 3.80-3.70 (m, 1H), 3.56-3.50 (m, 1H ), 3.40-3.35 (m, 1.3H), 3.22-3.10 (m, 3.7H), 1.45-1.35 (m, 3H)
Mass [M + H] ⁺ : 223

PMAD → PMAD hydrochloride Isopropanol (4.55 L) was added to PMAD obtained in the above step and cooled to 15 ° C. to 20 ° C. Concentrated hydrochloric acid (364 mL) was added dropwise over 60 minutes, and then 30 ° C. at 25 ° C. Stir for minutes. After confirming the completion of the reaction with TLC (developing solvent: ethyl acetate), the reaction solution was heated to 70 ° C. to 75 ° C. over 30 minutes and then cooled to 25 ° C. over 45 minutes. The reaction mixture was cooled to 0 ° C.-5 ° C. over 1 hour, then filtered and washed with isopropanol (455 mL) to give PMAD hydrochloride as a white solid (246.5 g, 46.5% yield, HPLC purity 97.83%). , Diastereomeric ratio (PMAD hydrochloride: diastereomer) = 97.41: 2.16).
Melting point: 227 ℃
¹ H NMR (DMSO): δ 9.46 (bs, 1H), 9.20 (bs, 1H), 7.8 (s, 1H), 7.71 (s, 1H), 7.47-7.42 (m, 5H), 4.3 (bs, 1H ), 3.61-3.43 (m, 2H), 3.38 (s, 1H), 3.24 (s, 3H), 1.61 (d, J = 8Hz, 3H)
¹³ C NMR (DMSO): δ 166.9, 136.5, 129.0, 128.9, 128.1, 70.0, 58.4, 57.3, 57.0, 20.1
Mass [M + H] ⁺ : 223

Example 4 (Production of PMAD hydrochloride)

Bromine (88.0 g, 0.55 mol) was added dropwise over 2 hours to a commercially available solution of AME (50 g, 0.58 mol) in methanol (150 mL). After stirring the reaction solution for 13 hours, R-PEA (66.8 g, 0.55 mol) was added dropwise at 5 ° C. over 1 hour. Further, a solution of triethylamine (111 g, 1.1 mol) in methanol (110 mL) was added dropwise at 5 ° C. over 1 hour, followed by stirring at 25 ° C. for 2 hours. Water (150 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to distill off methanol. 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. Concentrated hydrochloric acid (97.8 g) and isopropanol (1223 mL) were added to the residue, and the mixture was heated up to 70 ° C to 75 ° C over 30 minutes to dissolve, then cooled to 25 ° C over 45 minutes, and further over 1 hour And cooled to 0 ° C to 5 ° C. The precipitated crystals were collected by filtration and washed with isopropanol (50 mL) to obtain PMAD hydrochloride (56.9 g, yield 40%).
Melting point: 227 ° C
¹ H NMR (DMSO): δ 9.46 (bs, 1H), 9.20 (bs, 1H), 7.8 (s, 1H), 7.71 (s, 1H), 7.47-7.42 (m, 5H), 4.3 (bs, 1H ), 3.61-3.43 (m, 2H), 3.38 (s, 1H), 3.24 (s, 3H), 1.61 (d, J = 8Hz, 3H)
¹³ C NMR (DMSO): δ 166.9, 136.5, 129.0, 128.9, 128.1, 70.0, 58.4, 57.3, 57.0, 20.1
Mass [M + H] ⁺ : 223.

Example 5 (Production of MAD hydrochloride)

10% palladium on carbon (0.0058 g, 0.00385 mmol) was added to a methanol (100.0 mL) solution of PMAD hydrochloride (10.0 g, 38.64 mmol) obtained in Example 3 and charged in an autoclave, under hydrogen pressure (10 Kg / cm ² to 11 kg / cm ² ) and stirred at 75 ° C. for 30 hours. The reaction was cooled to 25 ° C. and filtered through celite. The filtration residue was washed with methanol (15.0 mL × 2 times). The filtrate and washings were combined and concentrated under reduced pressure to obtain MAD hydrochloride as a white solid (5.6 g, yield 94.6%).
Melting point: 200.9 ℃
IR (KBr): ν _max = 1695.6cm ^-1 (C = O of amide)
¹ H NMR (DMSO): δ 8.31 (s, 3H), 8.08 (d, J = 12Hz, 1H), 7.56 (s, 1H), 3.93 (t, J = 8Hz, 1H), 3.71 (dd, J = 4Hz, 2H), 3.29 (s, 3H)
¹³ C NMR (DMSO): δ 168.0, 70.3, 58.4, 52.1
Mass [M + H] ⁺ : 119

Example 6 (Production of MCA)

MAD hydrochloride (4.0 g, 25.86 mmol) obtained in Example 5 and 0.7 mol / L hydrochloric acid (20 mL) were charged into a shield tube and stirred at 100 ° C. for 24 hours. After confirming the completion of the reaction with TLC (developing solvent: 5% methanol / methylene chloride), the reaction solution was concentrated under reduced pressure to obtain a crude MCA hydrochloride (mixture with ammonium chloride) as a sticky yellow solid. (6.3g).
¹ H NMR (CD ₃ OD): δ 3.39 (s, 3H), 3.65-3.84 (m, 3H)
Mass [M-HCl + H] ⁺ : 120

Charge the crude product of MCA hydrochloride (0.5 g) obtained in the above step to an ion exchange resin (Dowex 50X4, strongly acidic), flush with water until the eluate is neutral (pH 7), then target product 0.5% aqueous ammonia was allowed to flow until (MCA) was completely eluted. Fractions containing the desired product were collected and concentrated to obtain MCA (0.27 g).
IR (KBr): ν _max = 3434, 1635, 1509, 1100
¹ H NMR (DMSO-d ₆ ): δ7.61-7.48 (bs, 3H), 3.67 (dd, J = 10.4, 3.6Hz, 1H), 3.61-3.57 (m, 1H), 3.45 (dd, J = 7.2, 3.6Hz, 1H), 3.27 (s, 3H)
Mass [M + H] ⁺ = 120

Example 7 (Manufacture of AMCA)

A mixture of MCA (15.0 g, 125.8 mmol), THF (90.0 mL) and water (10.0 mL) obtained in the same manner as in Example 6 was cooled to 15 ° C. to 20 ° C., and then acetic anhydride (15.42 mL, 151.06 mmol). ) Was added dropwise over 15 minutes. The reaction temperature was raised to 25 ° C. and stirred for 6 hours. The reaction solution was cooled to 15 ° C. to 20 ° C. and acetic anhydride (6.42 g, 62.94 mmol) was added dropwise over 10 minutes, followed by stirring at 25 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (75.0 mL) was added to the residue and stirred for 10 minutes. The product was collected by filtration and washed with ethyl acetate (30.0 mL) to obtain AMCA (20.3 g, yield). Rate 100%, HPLC purity 97.08%, optical purity = 99.0% ee).
¹ H NMR (DMSO-d ₆ ): δ 12.69 (s, 1H, exchangeable), 8.19 (d, J = 8.0Hz, 1H, exchangeable), 4.44-4.40 (m, 1H), 3.65-3.61 (m, 1H ), 3.51-3.48 (m, 1H), 3.25 (s, 3H), 1.86 (s, 3H)
Mass [M + H] ⁺ : 162

HPLC purity was measured by HPLC under the following conditions.
Column: Unisole C18 (150mm × 4.6mm, 3μm)
Buffer solution: acetonitrile / water = 90/10
Mobile phase A: 10 mmol / L ammonium acetate Mobile phase B: acetonitrile / water = 90/10
Gradient program: 0 minutes (A liquid / B liquid = 3/0), 5 minutes (A liquid / B liquid = 3/5), 10 minutes (A liquid / B liquid = 95/25), 15 minutes (A liquid) / B liquid = 95/35), 20 minutes (A liquid / B liquid = 3/37), 25 minutes (A liquid / B liquid = 3/42)
Flow rate: 0.8mL / min Injection volume: 5μL
Detection wavelength: 215nm
Column temperature: 40 ° C

The optical purity was measured by HPLC under the following conditions.
Column: ChiralPak AD-H (250mm × 4.6mm, 5μm)
Mobile phase A: n-hexane Mobile phase B: ethanol A: B = 90: 10
Flow rate: 1.0mL / min Injection volume: 5μL
Detection wavelength: 210nm
Column temperature: 40 ° C

Example 8 (Production of LACO)

AMCA (12.0 g, 74.46 mmol) obtained in Example 7 was dissolved in methanol (240.0 mL), cooled to −75 ° C., and N-methylmorpholine (8.61 g, 9.4 mL, 81.91 mmol) was added for 15 minutes. It was dripped over. After stirring the reaction solution at the same temperature for 15 minutes, isobutyl chloroformate (11.19 g, 10.7 mL, 81.91 mmol) was added dropwise over 30 minutes while maintaining -75 ° C., and the mixture was stirred at the same temperature for 45 minutes. Benzylamine (8.78 g, 9.0 mL, 81.91 mmol) was added dropwise to the reaction mixture over 45 minutes, and the mixture was stirred at −75 ° C. for 18 hours. The reaction solution was heated to 0 ° C. to 5 ° C. and 1 mol / L hydrochloric acid (48.0 mL) was added. The aqueous layer was extracted with ethyl acetate (36.0 mL × 3 times). The organic layers were combined, washed with saturated brine (48.0 mL), and concentrated under reduced pressure to obtain crude LACO (16.8 g, yield 90.32%, HPLC purity 96.66%, optical purity 98.1%). [α] _D ²⁵ +15.05 ^o (c 1.0, MeOH)

The optical purity was measured by HPLC under the following conditions.
Column: Chiral cel OD-H (250mm × 4.6mm, 5μm)
Mobile phase A: n-hexane Mobile phase B: isopropanol A: B = 75: 25
Flow rate: 0.7mL / min Injection volume: 5μL
Detection wavelength: 210nm
Column temperature: 30 ° C

Example 9 (Production of PMCA hydrochloride)

A mixture of PMAD hydrochloride (30.0 g, 115.90 mmol) obtained in the same manner as in Example 3 and 0.7 mol / L hydrochloric acid (300 mL) was stirred at 100 to 105 ° C. for 24 hours. After the reaction solution was cooled to 25 ° C., the pH was adjusted to 5.7, and the precipitated solid was filtered to obtain PMCA hydrochloride (15.0 g, yield 57.96%).
IR (KBr): ν _max = 3031, 2986, 2871, 1631, 1574, 1357, 1119, 701 cm ^-1
¹ H NMR (MeOH-d ₄ ): δ7.45-7.42 (m, 5H), 4.59 (q, J = 6.8Hz, 1H), 3.69-3.57 (m, 2H), 3.34-3.30 (m, 1H) , 3.27 (s, 3H), 1.70 (d, J = 6.8Hz, 3H)
¹³ C-NMR (DMSO-d ₆ ): δ 171.6, 142.8, 128.4, 127.4, 127.0, 72.8, 59.0, 58.2, 56.1, 23.5
HRMS: [M + H] calcd for C ₁₂ H ₁₇ NO ₃ Na 246.1106, found 246.1101
LC-MS [M + H] ⁺ : 224

Example 10 (Production of PMBA)

A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.55 g, 2.89 mmol) and methylene chloride (2.5 mL) was cooled to 0 ° C. to 5 ° C., and N-methylmorpholine ( 0.29 g, 2.89 mmol) was added over 5 minutes. In a separate container, PMCA hydrochloride obtained in Example 9 (0.5 g, 1.92 mmol), methylene chloride (10 mL), 1-hydroxybenzotriazole (0.39 g, 2.89 mmol) and benzylamine (1.24 g, 11.55 mmol). ) Was added and cooled to 0 ° C., and the previously prepared mixture was added to this mixture at the same temperature. The reaction solution was slowly warmed to 25 ° C. and then stirred for 20 hours. The reaction was cooled to 0-5 ° C. and water (15 mL) was added. The aqueous layer was extracted with methylene chloride (2 × 5 mL). The organic layers were combined, washed with water (2 × 10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.1% methanol / methylene chloride solution) to obtain yellow oily PMBA (0.27 g, yield 45.0%).
IR (KBr): ν _max = 3327, 2925, 1652, 1518, 1453, 1111, 761, 699 cm ^-1
¹ H NMR (DMSO-d ₆ ): δ 8.44 (t, J = 6.0Hz, 1H exchangeable), 7.35-7.29 (m, 6H), 7.26-7.19 (m, 4H), 4.32 (dd, J = 6.0, 2.4Hz, 2H), 3.63 (q, J = 6.4Hz, 1H), 3.45-3.38 (m, 1H), 3.33-3.31 (m, 1H), 3.16 (s, 3H), 3.00 (m, 1H), 2.42 (bs, 1H exchangeable), 1.23 (d, J = 6.4Hz, 3H)
¹³ C-NMR (DMSO-d ₆ ): δ 172.1, 145.5, 139.6, 128.2, 128.1, 126.9, 126.7, 126.6, 126.5, 73.8, 59.5, 58.1, 55.9, 42.0, 24.9
HRMS: [M + H] ⁺ calcd for C ₁₉ H ₂₄ N ₂ O ₂ H 313.1916, found 313.1916
Mass [M + H] ⁺ : 313

Reference Example 1 (Manufacture of HMBA)

A mixture of PMBA (12.0 g, 38.4 mmol), methanol (100 mL) and 10% palladium carbon (0.41 g, 0.19 mmol) at 70 ° C. to 75 ° C. under hydrogen pressure (10 kg / cm ² to 11 kg / cm ² ) For 22 hours. The reaction solution was cooled to 25 ° C. and then filtered through celite. Celite was washed with methanol (48 mL). The filtrate and washings were combined and concentrated under reduced pressure to 100 ml, 10% palladium on carbon (0.41 g, 0.19 mmol) was added, and hydrogen was applied at 70 ° C. to 75 ° C. (10 kg / cm ² to 11 kg / cm ^2). ) For 10 hours. The reaction solution was cooled to 25 ° C. and then filtered through celite. Celite was washed with methanol (48 mL). The filtrate and washings were combined and concentrated under reduced pressure to obtain oily HMBA (6.9 g, yield 86%).
¹ H NMR (DMSO-d ₆ ): δ 8.44 (t, 1H exchangeable), 7.35-7.29 (m, 5H), 4.32 (d, 2H), 3.50-3.20 (m, 8H)
Mass m / z: 209 [M + H] ⁺

Reference Example 2 (LACO production)

A mixture of HMBA (1.54 g, 7.39 mmol), THF (9.3 mL), water (1.54 mL) and triethylamine (0.82 g, 8.13 mmol) is stirred for 5 minutes and acetic anhydride (0.83 g, 8.13 mmol) is added at 25 ° C. In addition, the mixture was stirred at the same temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water (10.0 mL) was added to the residue, and a 6 mol / L aqueous hydrochloric acid solution was added to adjust the pH to 1-2. This mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed successively with water (2 × 10.0 mL) and saturated brine (10.0 mL), and concentrated under reduced pressure to obtain crude LACO (2.2 g, quantitative). The obtained crude LACO was recrystallized from ethyl acetate to obtain LACO as a white solid (1.48 g, yield 80%, optical purity 100% ee).
[α] _D ²⁵ +16.4 ^o (c 1.0, MeOH)
¹ H NMR (CDCl ₃ ): δ7.24-7.40 (m, 5H), 6.78 (br s, 1H), 6.48 (br s, 1H), 4.51-4.60 (m, 1H), 4.48 (d, J = 5.7 Hz, 2H), 3.81 (dd, J = 9.5, 4.2 Hz, 1H), 3.40-3.48 (m, 1H), 3.38 (s, 3H), 2.03 (s, 3H)
Mass: m / z 251 [M + H] ⁺
The optical purity was measured by HPLC under the following conditions.
Column: Chiralcel OD-H (250mm × 4.6mm, 5μm)
Mobile phase A: n-hexane Mobile phase B: isopropanol A: B = 75: 25
Flow rate: 0.7mL / min Injection volume: 5μL
Detection wavelength: 210nm
Column temperature: 30 ° C

INDUSTRIAL APPLICABILITY According to the present invention, lacosamide having high optical purity can be industrially produced with high yield, inexpensively and safely. In addition, an intermediate useful in the production of lacosamide can be provided.
This application is based on Japanese Patent Application No. 2014-184568 (filing date: September 10, 2014) filed in Japan, the contents of which are incorporated in full herein.

Claims

General formula [I]:

Wherein, 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). ]
Or a salt thereof.
General formula [III]:

Wherein, 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). ]
Comprising a step of amidating a compound represented by the formula:
:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
General formula [III]:

Wherein, 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). ]
Or a salt thereof represented by the general formula [IV]:

[Wherein, 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. ]
The compound represented by general formula [V]:

Wherein, 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 claim 2, which is obtained by reacting with a compound represented by the formula:
General formula [IV]:

[Wherein, 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. ]
A compound represented by general formula [VI]:

[Wherein, R 1 and R 2 have the same meanings as described above. ]
The production method according to claim 3, wherein the compound is obtained by reacting a compound represented by formula (II) with sodium methoxide.
Formula [IV]:

[Wherein, 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. ]
The compound represented by general formula [V]:

Wherein, 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). ]
Comprising a step of reacting with a compound represented by the formula or a salt thereof:
:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
Formula [VII]:

After halogenating the compound represented by the formula or a salt thereof, the obtained compound is represented by the general formula [V]:

Wherein, 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:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
The manufacturing method of the compound represented by these, or its salt.
General formula [III]:

Wherein, 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). ]
Or a salt thereof is amidated to give a general formula [I]:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
Which comprises a step of producing a compound represented by the formula or a salt thereof: [XII]:

The manufacturing method of the compound represented by these, or its salt.
General formula [III]:

Wherein, 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). ]
Or a salt thereof represented by the general formula [IV]:

[Wherein, 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. ]
The compound represented by general formula [V]:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
It is obtained by making it react with the compound or its salt represented by these, The manufacturing method of Claim 7 characterized by the above-mentioned.
Formula [VII]:

After halogenating the compound represented by the formula or a salt thereof, the obtained compound is represented by the general formula [V]:

Wherein, 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). ]
And a compound represented by the general formula [I]:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
Which comprises a step of producing a compound represented by the formula or a salt thereof: [XII]:

The manufacturing method of the compound represented by these, or its salt.
General formula [I]:

Wherein, 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). ]
Is reduced to a compound represented by formula [II]:

Which comprises a step of producing a compound represented by the formula or a salt thereof: [XII]:

The manufacturing method of the compound represented by these, or its salt.
(1) Formula [II]:

The compound represented by the formula or a salt thereof is hydrolyzed to form the formula [X]:

A process for producing a compound represented by the formula:
(2) A compound represented by the formula [X] or a salt thereof is reacted with an acetylating agent to form a formula [XI]:

11. The method according to claim 10, further comprising a step of producing a compound represented by the formula: or a salt thereof; and (3) a step of benzylamidating the compound represented by formula [XI] or a salt thereof: Production method.
(1 ′) Formula [II]:

Or a salt thereof is reacted with an acetylating agent to produce a compound of the formula [XIII]:

11. The method according to claim 10, further comprising the step of producing a compound represented by the formula: or a salt thereof; and (2 ′) benzylamidating the compound represented by the formula [XIII] or a salt thereof. Manufacturing method.
General formula [I]:

Wherein, 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]:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
Which comprises a step of producing a compound represented by the formula or a salt thereof: [XII]:

The manufacturing method of the compound represented by these, or its salt.
General formula [XIV]:

Wherein, 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). ]
Or a salt thereof is benzylamidated to give a general formula [XV]:

[Wherein, R 3 and R 4 have the same meanings as described above. ]
The production method according to claim 13, further comprising a step of producing a compound represented by the formula:
General formula [XV]:

Wherein, 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]:

The production method according to claim 14, further comprising a step of producing a compound represented by the formula:
Formula [XII] obtained by the production method according to any one of claims 7 to 15:

Or a salt thereof as an active ingredient.
General formula [III]:

Wherein, 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). ]
Or a salt thereof.
General formula [XIV]:

Wherein, 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). ]
Or a salt thereof.
Formula [XIII]:

Or a salt thereof.