WO2017043626A1

WO2017043626A1 - Method for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative

Info

Publication number: WO2017043626A1
Application number: PCT/JP2016/076605
Authority: WO
Inventors: 西山　章; 昇平山本
Original assignee: 株式会社カネカ
Priority date: 2015-09-11
Filing date: 2016-09-09
Publication date: 2017-03-16
Also published as: CN108026032B; CN108026032A; JPWO2017043626A1

Abstract

Provided is a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative, which is a compound useful as an intermediate for a medicine, in a simple manner and with high efficiency. 4-carbamoyl-2,6-dimethylbenzoic acid, a carbamoyl chloride and a base are reacted together to produce a corresponding acid anhydride mixture, and then the acid anhydride mixture is reduced to produce 4-carbamoyl-2,6-dimethylbenzyl alcohol. The use of this compound enables an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative to be produced in a simple manner and with high efficiency.

Description

Process for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative

The present invention relates to a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative useful as an intermediate of an opioid receptor agonist.

The following methods are known as methods for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivatives.

In the method described in Patent Document 1, a dimethyltyrosine derivative is used as a starting material, a phenol hydroxyl group is triflated, and then reacted with carbon monoxide gas in the presence of a palladium catalyst to produce a corresponding carboxylic acid. Subsequently, an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative is produced by condensing carboxylic acid with ammonia to convert to a corresponding amide, and further hydrolyzing the ester.

In the method described in Patent Document 2, 4-bromo-3,5-dimethylphenol is used as a starting material, a phenol hydroxyl group is triflated, and then reacted with carbon monoxide gas in the presence of a palladium catalyst to give a corresponding carboxylic acid. Manufacturing. Next, 4-bromo-3,5-dimethylbenzamide is produced by amidating the carboxylic acid and coupled with a dehydroamino acid derivative derived from serine in the presence of a palladium catalyst. The obtained dehydrophenylalanine derivative is asymmetrically hydrogenated in the presence of a rhodium catalyst, and then the ester is hydrolyzed to produce an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative.

In addition, in the method described in Patent Document 3, trihydroxylation of a phenol hydroxyl group using 4-bromo-3,5-dimethylphenol as a starting material, followed by coupling with dicyanozinc in the presence of a palladium catalyst and a copper catalyst. 4-Bromo-3,5-dimethylbenzonitrile is produced. Also, a corresponding zinc compound was prepared from N-Boc-β-iodo-L-alanine methyl ester derived from serine through multiple steps and zinc, and this and the previously prepared benzonitrile derivative were prepared in the presence of a palladium catalyst. Make a coupling. Subsequently, an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative is produced by simultaneously performing nitrile hydration and ester hydrolysis.

The method of Patent Document 1 or 2 described above is poor in economic efficiency in that an expensive palladium catalyst is used, and is difficult to implement on an industrial scale in terms of using highly toxic carbon monoxide gas. The method of Patent Document 3 is also economical in that it uses an expensive palladium catalyst, has a high environmental impact in that it uses highly toxic cyanide compounds and heavy metals, and is a suitable process from the viewpoint of industrial implementation. It's hard to say.

JP 2005-530749 gazette Special table 2007-529527 Japanese Patent Laying-Open No. 2015-013862

The problem to be solved by the present invention with respect to the above-described conventional techniques is that high-purity and high-optical purity optically active 4-carbamoyl-2,6-dimethylphenylalanine derivatives required for pharmaceutical intermediates can be easily and efficiently produced. There is to manufacture.

As a result of intensive studies, the present inventors have found a method for easily and efficiently producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative from readily available starting materials, and have completed the present invention.

That is, the present invention is as follows.

[I] [1] The following formula (1);

(In the formula, P represents a hydrogen atom or an amino-protecting group. R ⁵ represents a hydrogen atom, a C1-C12 alkyl group which may have a substituent, or a C6-C12 which may have a substituent. A C7 to C20 aralkyl group which may have a substituent, or a C3 to C12 cycloalkyl group which may have a substituent (* represents an asymmetric carbon atom). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative, comprising the following formula (2):

4-carbamoyl-2,6-dimethylbenzoic acid represented by the following formula (3);

(Wherein R ¹ and R ² are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3 to C12 cycloalkyl group which may have a substituent, and R ¹ and R ² may form a ring together.) By reacting a base, the following formula (4):

(Wherein R ¹ and R ² are the same as above), and by reducing the mixed acid anhydride, the following formula (5):

Of the optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the above formula (1), which comprises a step of producing 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula: Manufacturing method.
[2] The production method according to [1], wherein P is a hydrogen atom or a tert-butoxycarbonyl group, R ⁵ is a hydrogen atom, and the absolute configuration of * is S.
[3] The production method according to [1] or [2], wherein R ¹ is a methyl group or an ethyl group, and R ² is a methyl group or an ethyl group.
[4] The production method according to any one of [1] to [3], wherein the compound (4) is reduced with sodium borohydride in an alcohol solvent.
[5] The following formula (5) produced by the process according to any one of [1] to [4];

4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the following formula (6):

(Wherein X represents a leaving group) is converted into a 4-carbamoyl-2,6-dimethylbenzyl derivative represented by the following formula (7) in the presence of a base and an optically active phase transfer catalyst. ;

(Wherein R ³ represents a hydrogen atom or an optionally substituted C 6 to C 12 aryl group, and R ⁴ represents an optionally substituted C 6 to C 12 aryl group. R ⁶ Is a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, or a substituent. And a glycine Schiff base represented by the following formula (8):

(Wherein R ³ , R ⁴ , R ⁶ , and * are the same as those described above) are produced, and are further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis. The following formula (1):

(Wherein P, R ⁵ and * are the same as defined above). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
[6] X is a chlorine atom or bromine atom, R ³ is a phenyl group, R ⁴ is a phenyl group, and R ⁶ is a methyl group, an ethyl group, or a tert-butyl group. ] The manufacturing method of description.
[7] The base is potassium hydroxide, and the optically active phase transfer catalyst is (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4, [5] or [6], which is 5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium bromide.
[8] The following formula (5) produced by the process according to any one of [1] to [4];

4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the following formula (9):

Is converted to 4-carbamoyl-2,6-dimethylbenzaldehyde represented by the following formula, and then reacted with a glycine derivative to give the following formula (10):

(Wherein P is a hydrogen atom or an amino-protecting group. R ⁶ is a C1-C12 alkyl group which may have a substituent, or a C6-C12 aryl group which may have a substituent. Represents a C7 to C20 aralkyl group which may have a substituent, or a C3 to C12 cycloalkyl group which may have a substituent. The following formula (1), characterized by carrying out simultaneous hydrogenation;

(Wherein P, R ⁵ and * are the same as defined above). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
[9] The production method according to [8], wherein R ⁶ is a methyl group, an ethyl group, or a tert-butyl group.

The present invention includes the following inventions [II] to [V].

[II] The following formula (4);

A process for producing 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the following formula (1):

(Wherein P, R ⁵ and * are the same as defined above). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:

[III] The following formula (5);

[IV] Formula (5) below;

(Wherein P and R ⁶ are the same as defined above), wherein the dehydroamino acid derivative is produced, followed by asymmetric hydrogenation;

[V] Formula (4) below;

[VI] The present invention also provides the following formula (6):

(Wherein X represents a leaving group) and the 4-carbamoyl-2,6-dimethylbenzyl derivative. In particular, the present invention relates to a 4-carbamoyl-2,6-dimethylbenzyl derivative according to [VI], wherein X is a chlorine atom or a bromine atom.

[VII] The present invention also provides the following formula (4):

(Wherein R ¹ and R ² are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3-C12 cycloalkyl group which may have a substituent, and R ¹ and R ² may form a ring together.) Related to things. In particular, the present invention relates to the mixed acid anhydride according to [VII], wherein R ¹ is a methyl group or an ethyl group, and R ² is a methyl group or an ethyl group.

According to the present invention, an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative having high purity and high optical purity required for a pharmaceutical intermediate can be easily and efficiently produced.

Hereinafter, the method according to the present invention will be described in detail. First, the raw materials, intermediate products, and target products used in the present invention will be described.

In this specification, the C1-C12 alkyl group includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert-butyl group, an n- A pentyl group, n-hexyl group, n-decyl group, n-dodecyl group and the like can be mentioned.
Examples of the C6 to C12 aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
Examples of the aralkyl group of C7 to C20 (more preferably C7 to C12) include benzyl group, 1-phenethyl group, trityl group and the like.
Examples of the C3-12 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and an adamantyl group.
Substituents for C1-C12 alkyl groups, C6-C12 aryl groups, C7-C12 aralkyl groups and C3-12 cycloalkyl groups include, for example, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom Atom; hydroxyl group; alkoxy group such as methoxy group and ethoxy group; methylthio group; trifluoromethyl group; acetyl group; benzoyl group; cyano group; nitro group; carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group Is mentioned. The number of substitution groups and the substitution position are not particularly limited.

The optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative, which is the target product of the present invention, has the following formula (1);

(Hereafter, it may be called a compound (1).). Here, P represents a hydrogen atom or an amino-protecting group. Preferably hydrogen atom; carbamate-type protecting group such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, allyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, fluoren-9-ylmethoxycarbonyl group; formyl Acyl-type protecting groups such as acetyl, acetyl, trifluoroacetyl, pivaloyl, benzoyl and p-nitrobenzoyl groups; sulfonyl-type protecting groups such as mesyl, p-toluenesulfonyl and p-nitrobenzenesulfonyl More preferably a hydrogen atom, a tert-butoxycarbonyl group, or a benzyloxycarbonyl group, and particularly preferably a tert-butoxycarbonyl group.

Here, R ⁵ is a hydrogen atom, an optionally substituted C1 to C12 alkyl group, an optionally substituted C6 to C12 aryl group, or an optionally substituted C7 to C20. An aralkyl group or a C3-12 cycloalkyl group which may have a substituent. Preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-adamantyl group, a cyclohexyl group, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, a benzyl group, or a trityl group, A hydrogen atom, a methyl group, an ethyl group, or a tert-butyl group is more preferable, a hydrogen atom or a methyl group is still more preferable, and a hydrogen atom is particularly preferable.

Here, * represents an asymmetric carbon atom. The absolute configuration of compound (1) may be either R or S, and the preferred absolute configuration is S. The optical purity of the R-form or S-form compound (1) obtained by the production method according to the present invention is preferably 70% ee or more, more preferably 80% ee or more, and further preferably 90% ee or more.

The compound (1) is preferably a compound of the following formulas (1-1) to (1-12), more preferably (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- It is methyl (tert-butoxycarbonylamino) propanoic acid or (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoic acid.

4-Carbamoyl-2,6-dimethylbenzoic acid which is a starting material of the present invention has the following formula (2):

(Hereinafter, sometimes referred to as compound (2)).

This compound can be easily produced from 2,4,6-trimethylbenzoic acid, which is easily available at low cost, according to the method described in JP-A-63-253061. Specifically, 2,4,6-trimethylbenzoic acid is oxidized with potassium permanganate to produce 2,6-dimethylbenzene-1,4-dicarboxylic acid, and treated with methanol in the presence of a sulfuric acid catalyst. Thus, 4-methoxycarbonyl-2,6-dimethylbenzoic acid can be obtained, followed by treatment with ammonia gas, whereby the 4-carbamoyl-2,6-dimethylbenzoic acid can be produced.

The carbamoyl chloride used in the present invention has the following formula (3):

(Hereafter, it may be called a compound (3).). Here, R ¹ and R ² each independently have a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, or a substituent. Or a C7 to C12 aralkyl group or a C3 to C12 cycloalkyl group which may have a substituent. R ¹ and R ² may be different but are preferably the same. Specifically, R ¹ and R ² are methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl. Group, n-pentyl group, cyclohexyl group, allyl group, phenyl group, naphthyl group, benzyl group, 1-phenethyl group, phenyl group, 1-naphthyl group and the like. R ¹ and R ² may form a ring together. Examples of the group formed by combining R ¹ and R ² include a butylene group, a pentylene group, a diethyl ether-2,2′-diyl group, and the like. R ¹ and R ² are preferably a methyl group or an ethyl group, and more preferably an ethyl group.

Compound (3) is preferably a compound of the following formulas (3-1) to (3-9), more preferably dimethylcarbamoyl chloride or diethylcarbamoyl chloride, and still more preferably diethylcarbamoyl chloride.

The mixed acid anhydride which is an intermediate product of the present invention has the following formula (4):

(Hereinafter sometimes referred to as compound (4)), R ¹ and R ² are the same as described above. This compound is a novel compound not described in any literature.

The compound (4) is preferably a compound of the following formulas (4-1) to (4-9), more preferably 4-carbamoyl-2,6-dimethylbenzoic acid, N, N-dimethylcarbamic anhydride or 4-carbamoyl-2,6-dimethylbenzoic acid is N, N-diethylcarbamic anhydride, more preferably 4-carbamoyl-2,6-dimethylbenzoic acid is N, N-diethylcarbamic anhydride.

4-carbamoyl-2,6-dimethylbenzyl alcohol, which is an intermediate product of the present invention, has the following formula (5):

(Hereinafter, it may be referred to as a compound (5).)

The intermediate product of the present invention, 4-carbamoyl-2,6-dimethylbenzyl derivative, has the following formula (6):

(Hereinafter, it may be referred to as a compound (6).) Here, X represents a leaving group. Specifically, halogen atoms such as chlorine atom, bromine atom and iodine atom; methanesulfonyloxy group, ethanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, trifluoromethanesulfonyl Examples include sulfonyloxy groups such as oxy groups. Preferably they are halogen atoms, such as a chlorine atom, a bromine atom, and an iodine atom, More preferably, they are a chlorine atom or a bromine atom. This compound is a novel compound not described in any literature.

The glycine Schiff base used in the present invention has the following formula (7):

(Hereinafter, it may be referred to as a compound (7).) Here, R ³ represents a hydrogen atom or a C6 to C12 aryl group which may have a substituent. A hydrogen atom, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and a p-methoxyphenyl group are preferable, and a phenyl group is more preferable. R ⁴ represents a C6 to C12 aryl group which may have a substituent. R ³ and R ⁴ are each independently preferably a phenyl group, a p-methylphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, or a p-methoxyphenyl group, and more preferably a phenyl group. R ³ and R ⁴ may be the same as or different from each other, but are preferably the same.

R ⁶ is an optionally substituted C1-C12 alkyl group, an optionally substituted C6-C12 aryl group, an optionally substituted C7-C20 aralkyl group, or a substituted group. Represents a C3-12 cycloalkyl group which may have a group. Preferably, it is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-adamantyl group, a cyclohexyl group, a phenyl group, a p-chlorophenyl group, a p-nitrophenyl group, a benzyl group, or a trityl group, more preferably A methyl group, an ethyl group, or a tert-butyl group, more preferably a methyl group or a tert-butyl group, and particularly preferably a tert-butyl group.
R ⁶ may be the same as or different from R ⁵ depending on the synthesis route.

Compound (7) is preferably a compound of the following formulas (7-1) to (7-15), more preferably 2- (diphenylmethylidene) glycine tert-butyl ester.

The optically active amino acid derivative that is an intermediate product of the present invention has the following formula (8):

(Hereinafter, it may be referred to as compound (8).) Here, R ³ , R ⁴ , R ⁶ and * are the same as described above.

The compound (8) is preferably a compound of the following formulas (8-1) to (8-15), more preferably (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (Diphenylmethylideneamino) tert-butyl propanoate.

4-carbamoyl-2,6-dimethylbenzaldehyde, which is an intermediate product of the present invention, has the following formula (9);

(Hereinafter, it may be referred to as the compound (9).)

The dehydroamino acid derivative which is an intermediate product of the present invention has the following formula (10):

(Hereinafter, it may be referred to as compound (10).) Here, P and R ⁶ are the same as described above.

The compound (10) is preferably a compound of the following formulas (10-1) to (10-4), more preferably 3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxy Carbonylamino) methyl acrylate.

The present invention is illustrated as follows, and each step will be described step by step.

By reacting 4-carbamoyl-2,6-dimethylbenzoic acid represented by the formula (2), carbamoyl chloride represented by the formula (3) and a base, a mixture represented by the formula (4) The process for producing an acid anhydride will be described.

The amount of the carbamoyl chloride to be used is preferably 1 to 10 equivalents (times mol), more preferably 1 to 3 equivalents (times mol) based on the compound (2).

Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; trimethylamine And amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, and imidazole. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferably, amines such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, imidazole, etc. More preferably triethylamine or pyridine. The amount of the base used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (2).

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, etc. Ether solvents such as acetonitrile and nitrile solvents such as propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; benzene Aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as til sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε -Amide solvents such as caprolactam and hexamethylphosphoramide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide, and the like can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ether solvents, nitrile solvents, ketone solvents, or amide solvents, more preferred are tetrahydrofuran, acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, and particularly preferred is N. , N-dimethylformamide, or N, N-dimethylacetamide.

When the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore, the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (2). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (2), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the formation of by-products, the upper limit is preferably 150 ° C., more preferably 100 ° C., and particularly preferably 50 ° C. The lower limit is preferably −80 ° C., more preferably −30 ° C., and particularly preferably 0 ° C.

The reaction time in this reaction is not particularly limited and may be appropriately set. However, the upper limit is preferably 100 hours, more preferably 50 hours, and particularly preferably 25 hours. The lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.

There is no particular limitation on the mixing order of compound (2), compound (3), base and solvent in this step.

As a process after the reaction, a general process for obtaining a product from the reaction solution may be performed. For example, the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. Preferably, when water is added to the reaction solution, the target product precipitates as a solid, which may be filtered off. The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used. The purity may be further increased by a simple purification method.

Subsequently, a process for producing 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula (5) by reducing the mixed acid anhydride represented by the formula (4) will be described.

The reduction may be performed using a reducing agent. Reducing agents include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, triacetoxyaluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, hydrogenated Calcium boron, sodium cyanoborohydride, lithium triethylborohydride, lithium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride, borane, tributyltin hydride, silane, trichlorosilane, trimethoxy Examples thereof include silane and triethoxysilane. Preferred are lithium borohydride, sodium borohydride, and potassium borohydride, and more preferred is sodium borohydride. The amount of the reducing agent to be used is preferably 1 to 20 equivalents (times mole), more preferably 1 to 5 equivalents (times mole) based on the compound (4).

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used. Solvents: ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents: N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethyl Amide solvents such as phosphoramides; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. An alcohol solvent is preferable, methanol or ethanol is more preferable, and ethanol is particularly preferable.

If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (4). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (4), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

There is no particular limitation on the mixing order of compound (4), reducing agent, and solvent in this step.

As a process after the reaction, a general process for obtaining a product from the reaction solution may be performed. For example, the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. Preferably, the target product precipitated from the reaction solution is filtered off and washed with methanol or ethanol. The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used. The purity may be further increased by a simple purification method.

Next, using the 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula (5), the optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the formula (1) is obtained. A manufacturing method will be described.

There is no particular limitation as long as it is a method using Formula (5) as a starting material, but specifically, for example, the method shown in the following figure is preferable.

First, a method for converting 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula (5) into a 4-carbamoyl-2,6-dimethylbenzyl derivative represented by the formula (6) will be described. .

When X is a sulfonyloxy group, the compound (5) is sulfonylated to methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. Agents such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, imidazole It is good to let them. The amount of the sulfonylating agent to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (5). The amine is preferably used in an amount of 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) based on the compound (5).

When X is a halogen atom, the compound (5) includes sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride, sulfonyl bromide, phosphorus tribromide, iodine / triphenylphosphine, boron tribromide, thionyl chloride and the like. A halogenating agent may be allowed to act. Preferred is sulfonyl chloride, phosphorus tribromide, or thionyl chloride, and more preferred is phosphorus tribromide. The amount of the halogenating agent to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (5). When these halogenating agents are allowed to act, if necessary, trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7- Amines such as ene, pyridine, quinoline and imidazole may be used. The amount of the amine to be used is preferably 0.01 to 1 mol, more preferably 0.05 to 0.5 mol, per 1 mol of the compound (5).

Further, after preparing the compound (6) in which X is a sulfonyloxy group, sodium chloride, potassium chloride, tetrabutylammonium chloride, sodium bromide, potassium bromide, tetrabutylammonium bromide, sodium iodide, iodine X may be converted to the compound (6) wherein a halogen atom such as a chlorine atom, a bromine atom or an iodine atom is allowed to act on a halide such as potassium iodide or tetrabutylammonium iodide.

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, etc. Ether solvents such as acetonitrile and nitrile solvents such as propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; benzene Aromatic hydrocarbon solvents such as toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; Sulfoxide solvents such as til sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε -Amide solvents such as caprolactam and hexamethylphosphoramide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide, and the like can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ether solvents, nitrile solvents, ester solvents, halogen solvents, or amide solvents, and more preferred are tetrahydrofuran, acetonitrile, ethyl acetate, methylene chloride, N, N-dimethylformamide, or N, N—. Dimethylacetamide, particularly preferably tetrahydrofuran, acetonitrile, ethyl acetate, or methylene chloride.

If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore, the upper limit is preferably 100 times weight, more preferably 50 times weight, relative to the compound (5). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (5), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 100 ° C., more preferably 70 ° C., and particularly preferably 40 ° C. The lower limit is preferably −80 ° C., more preferably −50 ° C., and particularly preferably −20 ° C.

The mixing order of compound (5) in this step, solvent, sulfonylating agent, amine, or compound (5) in this step, solvent, and halogenating agent is not particularly limited.

As a process after the reaction, a general process for obtaining a product from the reaction solution may be performed. For example, the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained. Preferably, the target product precipitated from the reaction solution is filtered off and washed with water, ethyl acetate, methylene chloride, hexane, heptane or the like. The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used. The purity may be further increased by a simple purification method.

Next, the 4-carbamoyl-2,6-dimethylbenzyl derivative represented by the formula (6) is reacted with the glycine Schiff base represented by the formula (7) in the presence of a base and an optically active phase transfer catalyst. Thus, a method for producing the optically active amino acid derivative represented by the formula (8) will be described.

Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like. Sodium hydroxide or potassium hydroxide is preferable, and potassium hydroxide is more preferable. The amount of the base used is preferably 0.5 to 50 equivalents (fold moles), more preferably 1 to 10 equivalents (fold moles) relative to the compound (6).

Examples of the optically active phase transfer catalyst include an optically active quaternary ammonium salt phase transfer catalyst, an optically active quaternary phosphonium salt phase transfer catalyst having a biphenyl skeleton and / or a binaphthyl skeleton, and a complex with an optically active metal atom. Examples include the formed phase transfer catalyst. Preferably, optically active quaternary ammonium salt having biphenyl skeleton and / or binaphthyl skeleton, optically active tartaric acid type quaternary ammonium salt, or optically active cinchona alkaloid type quaternary ammonium salt, biphenyl skeleton and / or binaphthyl skeleton Optically active quaternary phosphonium salt phase transfer catalyst, nickel complexed with N, N′-bis (salicylidene) -1,2-cyclohexanediamine derivative (Jacobsen ligand), or copper catalyst . More preferably, (11bS)-(+)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c : 1 ′, 2′-e] azepinium bromide, (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ', 2'-e] azepinium bromide, (S, S) -3,4,5-trifluorophenyl-NAS bromide, (R, R) -3 , 4,5-trifluorophenyl-NAS bromide, (S, S) -β-naphthyl-NAS bromide, (R, R) -β-naphthyl-NAS bromide, (15bR) -14,14-dibutyl-5 6,7,8,14,15-hexahydro-1,12-bis (3 , 4,5-trifluorophenyl) -13H- [1,6] benzodioxetino [9.8,7-def] [2] benzazepinium bromide, (15bS) -14,14-dibutyl-5, 6,7,8,14,15-Hexahydro-1,12-bis (3,4,5-trifluorophenyl) -13H- [1,6] benzodioxetino [9.8,7-def] [ 2) Benzazepinium bromide; N-benzyl cinchonidinium chloride; N-benzyl cinchonium chloride; N-anthracenyl cinchonidinium chloride; N-anthracenyl cinchonium chloride; N-anthracenyl quinidinium chloride; N-anthracenylquinium chloride; N- (2-chlorobenzyl) cincodinium bromide; 6,10-dibenzyl-N, N′-dimethyl-N N, N ′, N′-tetrakis (4-methylbenzyl) -1,4-dioxaspiro [4.5] decane- (2R, 3R) -diylbis (methylammonium) tetrafluoroborate ((R, R) — TaDiAS); 6,10-dibenzyl-N, N′-dimethyl-N, N, N ′, N′-tetrakis (4-methylbenzyl) -1,4-dioxaspiro [4.5] decane- (2S, 3S ) -Diylbis (methylammonium) tetrafluoroborate ((S, S) -TaDiAS). Particularly preferably, (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium bromide.

As the amount of the optically active phase transfer catalyst used is too large, it is not preferable in terms of cost. Therefore, the upper limit is preferably 1 equivalent (times mol), more preferably 0, relative to the compound (6). 0.5 equivalent (fold mole), particularly preferably 0.1 equivalent (fold mole). The lower limit is preferably 0.0001 equivalent (times mol), more preferably 0.001 equivalent (times mol), and particularly preferably 0.01 equivalent (times mol) relative to the compound (6). It is.

The amount of the compound (7) to be used is preferably 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) with respect to the compound (6).

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used. Solvents: ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethyl Amide solvents such as acetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide; ureas such as dimethylpropylene urea Solvents such as phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ether solvents, hydrocarbon solvents, aromatic hydrocarbon solvents, or halogen solvents, more preferably tetrahydrofuran, methyl tert-butyl ether, hexane, heptane, toluene, xylene, ethylbenzene, mesitylene, methylene chloride, Or 1,2-dichloroethane, particularly preferably methyl tert-butyl ether, toluene, xylene, ethylbenzene, or mesitylene.

If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore, the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (6). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (6), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

Further water may be added for the purpose of accelerating the reaction rate of this reaction. The amount of water used is preferably 0.1 to 100 equivalents (times mole), more preferably 1 to 30 equivalents (times mole), relative to the compound (6).

The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 120 ° C., more preferably 50 ° C., and particularly preferably 30 ° C. The lower limit is preferably −80 ° C., more preferably −50 ° C., and particularly preferably −20 ° C.

The reaction time in this reaction is not particularly limited and may be appropriately set. However, the upper limit is preferably 120 hours, more preferably 100 hours, and particularly preferably 80 hours. The lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.

There is no particular limitation on the mixing order of compound (6), compound (7), optically active phase transfer catalyst, base, water and solvent in this step.

As a process after the reaction, a general process for obtaining a product from the reaction solution may be performed. For example, the reaction solution after completion of the reaction is subjected to an extraction operation using water, a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.

The optical purity of the R-form or S-form compound (8) obtained by this step is preferably 80% ee (where% ee represents the enantiomeric excess), more preferably 85% ee or more, and still more preferably 88 % Ee or higher.

The target product thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to further increase the purity, crystallization, fractional distillation, solution washing, column chromatography, etc. are generally used. The purity may be further increased by a simple purification method.

Subsequently, the optically active amino acid derivative represented by the formula (8) is produced and further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis, whereby the optical activity represented by the formula (1). A process for producing a 4-carbamoyl-2,6-dimethylphenylalanine derivative will be described.

The acid used for the acid hydrolysis is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, more preferably sulfuric acid or methane. Sulfonic acid. The amount of the acid used is preferably 0.5 to 100 equivalents (fold moles), more preferably 1 to 20 equivalents (fold moles) relative to the compound (8). The amount of water used is preferably 0.1 to 100 times the weight of the compound (8), more preferably 1 to 30 weights.

The reaction temperature in this hydrolysis is not particularly limited and may be appropriately set. However, in order to reduce the formation of by-products, the upper limit is preferably 120 ° C., and more preferably 100 ° C. Preferably it is 0 degreeC as a minimum, More preferably, it is 20 degreeC.

Protecting conditions for the amino group may be appropriately set according to the type of protecting group (P). Specifically, for example, when tert-butoxycarbonyl protection or benzyloxycarbonyl protection is performed, an aqueous solution of optically active 4-carbamoyl-2,6-dimethylphenylalanine obtained by the hydrolysis is added with sodium hydroxide, potassium hydroxide. After neutralization with a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., di-tert-butyl dicarbonate or benzyloxycarbonyl chloride may be added. For the purpose of accelerating the reaction, the base may be further added to control the pH during the reaction to 7 or more.

The optical purity of the R-form or S-form compound (1) obtained in this step is the same as that of the raw material compound (8) or lower than that of the raw material compound (8), or the compound (8). Higher optical purity. The optical purity of the R-form or S-form compound (1) is preferably 85% ee, more preferably 88% ee or more, and even more preferably 89% ee or more.

The compound (1) thus obtained has a sufficient purity that can be used in the subsequent steps. However, for the purpose of increasing the chemical purity, the compound (1) can be further purified by a general purification method such as column chromatography. May be raised. Preferably, the compound (1) having high chemical purity and high optical purity can be obtained by crystallization from methanol or a mixed solvent of methanol / water. The optical purity of the R-form or S-form compound (1) after purification is preferably 90% ee or more, more preferably 95% ee or more, and further preferably 98% ee or more.

Another method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the formula (1) using the 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula (5) This method will also be described.

First, a method for converting 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula (5) into 4-carbamoyl-2,6-dimethylbenzaldehyde represented by the formula (9) will be described.

As a method for converting alcohol to aldehyde, a generally well-known oxidation reaction may be used. Specifically, for example, Jones oxidation reaction using chromic acid or pyridinium chlorochromate; oxidation reaction using sulfur trioxide / pyridine complex, etc .; Swan using dimethyl sulfoxide / trifluoroacetic anhydride, dimethyl sulfoxide / oxalyl chloride, etc. Oxidation reaction; sodium hypochlorite / 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamido-2 , 2,6,6-tetramethylpiperidine-1-oxyl and other oxyl radicals, etc. A tempo oxidation reaction is preferred. The amount of the sodium hypochlorite to be used is preferably 1 to 10 equivalents (times mole), more preferably 1 to 3 equivalents (times mole) based on the compound (5). The amount of the oxyl radical used is preferably 0.001 to 1 equivalent (times mole), more preferably 0.01 to 0.5 equivalent (times mole) with respect to the compound (5). is there.

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, water; tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol Ether solvents such as dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ester solvents such as ethyl acetate, n-propyl acetate and isopropyl acetate; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane Aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene and mesitylene; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane Sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε -Amide solvents such as caprolactam and hexamethylphosphoramide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide, and the like can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferably, water, ether solvent, ester solvent, aromatic hydrocarbon solvent, or halogen solvent, more preferably water, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene , Xylene, ethylbenzene, mesitylene, methylene chloride, or 1,2-dichloroethane, particularly preferably water, methyl tert-butyl ether, ethyl acetate, or toluene.

The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 100 ° C., more preferably 50 ° C., and particularly preferably 20 ° C. The lower limit is preferably −80 ° C., more preferably −50 ° C., and particularly preferably −20 ° C.

In the case of employing the compound (5) of this step, the solvent, and the tempo oxidation reaction, there is no particular limitation on the mixing order of sodium hypochlorite and oxy radical.

Next, a method for converting into a dehydroamino acid derivative represented by the above formula (10) by reacting 4-carbamoyl-2,6-dimethylbenzaldehyde represented by the above formula (9) with a glycine derivative will be described. .

Examples of the glycine derivative include phosphonoglycine derivatives. The phosphonoglycine derivative is preferably N- (tert-butoxycarbonyl) -phosphonoglycine trimethyl ester, N- (tert-butoxycarbonyl) -phosphonoglycine triethyl ester, N- (benzyloxycarbonyl) -phosphonoglycine. And trimethyl ester, N- (benzyloxycarbonyl) -phosphonoglycine triethyl ester, and the like. The amount of the phosphonoglycine derivative to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (9).

Further, when reacting the phosphonoglycine derivative, it is better to use a base. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate. Inorganic bases such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert Alkoxides such as butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide; metal hydrides such as sodium hydride, potassium hydride, calcium hydride; Ethylamine, triethylamine, tributylamine, diisopropylethylamine, N- methylpyrrolidine, N- methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, quinoline, include amines such as imidazole. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferably, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium hydride, potassium hydride, 1,8 -Diazabicyclo [5,4,0] undec-7-ene, more preferably sodium tert-butoxide, potassium tert-butoxide, sodium hydride, 1,8-diazabicyclo [5,4,0] undec-7 -En. The amount of the base to be used is preferably 1 to 10 equivalents (fold moles), more preferably 1 to 3 equivalents (fold moles) relative to the compound (9).

The solvent in this step is not particularly limited as long as it does not affect the reaction. Specifically, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and ethylene glycol are used. Solvents: ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; nitrile solvents such as acetonitrile and propionitrile; ethyl acetate, n-propyl acetate, Ester solvents such as isopropyl acetate; Aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; Aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, and mesitylene Solvents; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogen solvents such as methylene chloride and 1,2-dichloroethane; sulfoxide solvents such as dimethyl sulfoxide; N, N-dimethylformamide, N, N-dimethyl Amide solvents such as acetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide; ureas such as dimethylpropylene urea Solvents such as phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide can be used. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ether solvents, ester solvents, aromatic hydrocarbon solvents, or halogen solvents, more preferably tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, toluene, xylene, ethylbenzene. , Mesitylene, methylene chloride, or 1,2-dichloroethane, particularly preferably tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, toluene, or methylene chloride.

When the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore, the upper limit is preferably 100 times weight, more preferably 50 times weight with respect to the compound (9). Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (9), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

The reaction temperature in this reaction is not particularly limited and may be set as appropriate. However, in order to reduce the production of by-products, the upper limit is preferably 120 ° C., more preferably 80 ° C., and particularly preferably 50 ° C. The lower limit is preferably −80 ° C., more preferably −30 ° C., and particularly preferably 0 ° C.

There is no particular limitation on the mixing order of compound (9), glycine derivative, solvent, and base added as necessary in this step.

Next, a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the formula (1) by asymmetric hydrogenation of the dehydroamino acid derivative represented by the formula (10) As for, there is no particular limitation as long as the desired configuration can be obtained. Examples thereof include a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst, or a method of reducing by a microorganism such as yeast. Among them, a method of reducing by hydrogenation using an optically active transition metal complex as a catalyst is preferable.

The optically active transition metal catalyst is preferably an optically active phosphorus-containing ligand, more preferably an optically active bisphosphine, and particularly preferably (R, R) -1,2-ethanediylbis [(2 -Methoxyphenyl) phenylphosphine] ((R, R) -DIPAMP). The transition metal catalyst is preferably palladium, rhodium, platinum, or iridium, preferably rhodium. Here, the usage amount of the catalyst, the reaction temperature, the reaction solvent, the hydrogen pressure, and the like may be in accordance with the conditions described in Patent Document 2.

The optical purity of the R-form or S-form compound (1) obtained by this step is preferably 85% ee, more preferably 88% ee or more, and still more preferably 89% ee or more.

This application claims the benefit of priority based on Japanese Patent Application No. 2015-180200 filed on September 11, 2015. The entire contents of the specification of Japanese Patent Application No. 2015-180200 filed on September 11, 2015 are incorporated herein by reference.

Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention in any way.

Reference Example 1 Preparation of 4-carbamoyl-2,6-dimethylbenzoic acid A solution consisting of 2,4,6-trimethylbenzoic acid (500 g, 3.05 mol) and water (6500 mL) was cooled to 5-10 ° C. To this was added sodium hydroxide (793 g, 19.83 mol). Subsequently, potassium permanganate (1300 g, 8.23 mol) was added in portions over 12 hours. After stirring at 5-8 ° C. for 16 hours, sodium sulfite (20 g) was added to the reaction mixture, and the mixture was stirred at 15-20 ° C. for 1 hour. The precipitated manganese dioxide was filtered off and washed with a 5% aqueous sodium hydroxide solution (1000 mL). Concentrated hydrochloric acid (about 600 mL) was added to the filtrate and acidified to precipitate a solid, which was stirred at 10 ° C. for 5 hours. The solid was filtered off under reduced pressure, washed with water (3000 mL), and the wet crystals were transferred to another container. Methanol (2500 mL) and water (2500 mL) were added thereto, and the mixture was refluxed for 3 hours. The mixture was cooled to 20 to 25 ° C., and the precipitated solid was filtered off under reduced pressure. The solid was washed with water (2000 mL) and dried under reduced pressure to give 2,6-dimethylbenzene-1,4-dicarboxylic acid as a white solid (285 g, yield: 48%).

Thionyl chloride (53 g, 0.441 mol) was dropped into a methanol solution (1425 mL) of 2,6-dimethylbenzene-1,4-dicarboxylic acid (285 g, 1.47 mol) while maintaining the temperature at 10 ° C. to 20 ° C. did. After completion of the dropwise addition, the reaction temperature was set to 50 ° C. to 55 ° C. and stirred for 8 hours. After concentration under reduced pressure to remove methanol, 22% aqueous ammonia (4 L) was added to the resulting residue, and the mixture was stirred at 15 to 20 ° C. for 24 hours. Thereafter, concentration was performed under reduced pressure, and the reaction solution was concentrated to about 1500 to 2000 mL, and then concentrated hydrochloric acid (250 mL) was added dropwise and stirred at 0 to 5 ° C. for 5 hours. The precipitated solid was collected by filtration, and the crystals were washed with water (1000 mL) to obtain 255 g of the title compound (yield: 89%).
¹ H NMR (DMSO-d ₆ ): δ 13.32 (brs, 1H), 7.96 (s, 1H), 7.59 (s, 2H), 7.38 (s, 1H), 2.31 ( s, 6H)

Example 1 4-Carbamoyl-2,6-dimethylbenzoic acid Production of N, N-diethylcarbamic anhydride An N, N-dimethylformamide solution of the compound obtained in Reference Example 1 (255 g, 1.32 mol) To (1275 mL), diethylcarbamoyl chloride (270 g, 1.98 mol), triethylamine (213 g, 2.11 mol), and pyridine (104 g, 1.32 mol) were sequentially added while maintaining the reaction temperature at 28 to 32 ° C. After stirring for 16 hours, the reaction solution was cooled to 0 to 10 ° C., and water (3825 mL) was added dropwise while maintaining the temperature. The resulting slurry solution was stirred for 2 to 3 hours while maintaining the temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with water (500 mL) and dried under reduced pressure to obtain 339 g of the title compound (yield: 97%).

Example 2 Preparation of 4-carbamoyl-2,6-dimethylbenzyl alcohol The solid (339 g, 1.28 mol) obtained in Example 1 was added to ethanol (6780 mL), water (339 mL), and sodium borohydride ( 154 g, 4.06 mol) was added continuously at 10-20 ° C. The reaction temperature was raised to 30 to 35 ° C. and the mixture was stirred for 8 hours. The precipitated solid was filtered off and washed with ethanol (200 mL). The obtained filtrate was concentrated under reduced pressure to obtain 239 g of the title compound (yield: 100%).
¹ H NMR (CDCl ₃ ): δ 7.48 (s, 2H), 4.78 (d, J = 5.5 Hz, 2H), 2.49 (s, 6H)

Example 3 Production of 4-carbamoyl-2,6-dimethylbenzyl bromide To the solid obtained in Example 2 (239 g, 1.28 mol) was added methylene chloride (2390 mL) and cooled to 0-10 ° C. . To this solution, phosphorus tribromide (376 g, 1.39 mol) was added dropwise and stirred for 6 hours. Thereafter, water (2400 mL) was added over 1 hour while maintaining the temperature at 0 to 5 ° C., and the mixture was further stirred for 5 hours. The precipitated solid was collected by filtration, washed with cold water (500 mL), and dried under reduced pressure. Ethyl acetate (800 mL) was added to the obtained solid, and the mixture was stirred at 65 to 70 ° C. for 2 hr, heptane (800 mL) was added, and the mixture was further stirred for 2 hr. After cooling to 25-30 ° C., the precipitated solid was collected by filtration and washed with heptane (500 mL). The title compound 204g was obtained by drying under reduced pressure (yield: 66%).
¹ H NMR (CDCl ₃ ): δ 7.48 (s, 2H), 6.16 (brs, 1H), 5.86 (brs, 1H), 4.55 (s, 2H), 2.46 (s, 6H)

Example 4 Production of tert-butyl (Sb) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (diphenylmethylideneamino) propanoate (11bR)-(−)-4,4 Dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium bromide (9 .3 mg, 0.012 mmol), 4-carbamoyl-2,6-dimethylbenzyl bromide (10 g, 41 mmol), 2- (diphenylmethylidene) glycine tert-butyl ester (13 g, 45 mmol) and methyl tert-butyl ether (207 mL) Was added and cooled to 2 ° C. While stirring the reaction solution, 50% aqueous potassium hydroxide solution (32 g) was added dropwise, and the mixture was stirred for 23 hours while maintaining 2 to 10 ° C. Extraction was performed by adding water (100 mL), and the obtained organic layer was further washed with water (100 mL) and used in the next step (yield: 100%, optical purity: 90% ee). The optical purity was determined by the following analysis.

(Optical purity analysis)
Column: Daicel AD-H column Mobile phase: Hex / IPA = 95/5
Flow rate 0.5mL / min
Wavelength: 254nm
Column temperature: 30 ° C

Example 5 Production of (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoic acid Solution obtained in Example 4 (88 g, 20 mmol) Was heated to 60 ° C., methanesulfonic acid (19 g, 200 mmol) was added and stirred for 2 hours. The reaction solution was ice-cooled, water (60 mL) was added, and the mixture was stirred at room temperature for 30 min. Extraction was performed, and the pH of the obtained aqueous layer was adjusted to 11 with a 30% aqueous sodium hydroxide solution, ditert-butyl dicarbonate (5.2 g, 24 mmol) was added, and the pH was maintained at 40 ° C. while maintaining pH. Stir for hours. Isopropanol (10 mL) was added to the reaction solution, and after ice cooling, the pH was adjusted to 3 with concentrated hydrochloric acid while stirring. After stirring at the same temperature for 1 hour, the precipitated solid was collected by filtration and washed with a mixed solution of water / methanol = 2/1. Drying under reduced pressure yielded 6.41 g of the title compound (yield: 95%, optical purity: 92% ee). The optical purity was determined by the following analysis.

(Optical purity analysis)
Column: SUMICHIRAL OA-5000
Mobile phase: 2 mM copper sulfate aqueous solution / IPA = 95/5
Flow rate 1.0mL / min
Wavelength: 254nm
Column temperature: 40 ° C

(Example 6) Production of (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoic acid The solid (1.8 g, (5.4 mmol) was added with methanol (18 mL) and stirred at 60 ° C. for 30 minutes. While maintaining the temperature, water (4 mL) was added, followed by cooling to room temperature and further stirring for 30 minutes. The precipitated solid was collected by filtration, washed with a mixed solution of water / methanol = 2/1, and dried under reduced pressure to obtain 1.4 g of a solid (yield: 78%, optical purity: 99% ee). The optical purity was determined by the following analysis.

(Optical purity analysis)
Column: SUMICHIRAL OA-5000
Mobile phase: 2 mM copper sulfate aqueous solution / IPA = 95/5
Flow rate 1.0mL / min
Wavelength: 254nm
Column temperature: 40 ° C
¹ H NMR (DMSO): δ 7.80 (s, 1H), 7.48 (s, 2H), 7.2 (m, 2H), 4.1 (m, 2H), 3.10 (d, 2H) ), 2.95 (dd, 1H), 2.32 (s, 6H), 1.30 (s, 9H)

Example 7 Preparation of 4-carbamoyl-2,6-dimethylbenzyl chloride To the solid obtained in Example 2 (179 mg, 1 mmol) was added methylene chloride (5 mL) and pyridine (7.8 mg, 0.1 mmol). And cooled to 5 ° C. To this solution was added thionyl chloride (376 g, 1.39 mol), and the mixture was stirred for 1 hour, heated to 25 ° C., and stirred for 3 hours. The precipitated solid was collected by filtration, washed with dichloromethane / hexane = 1/1 (6 mL), and dried under reduced pressure to obtain 198 mg of the title compound (yield: 100%).
¹ H NMR (DMSO): δ 8.1 (brs, 1H), 7.57 (s, 2H), 7.32 (brs, 1H), 4.80 (s, 2H), 2.40 (s, 6H) )

(Example 8) Preparation of 4-carbamoyl-2,6-dimethylbenzaldehyde To the solid (179 mg, 1 mmol) obtained in Example 2, water (2 mL), sodium hydrogen carbonate (252 mg, 3 mmol), 2, 2, 6,6-Tetramethylpiperidine-1-oxyl (7.8 mg, 0.05 mmol) and ethyl acetate (2 mL) were added and cooled to 5 ° C. A solution consisting of sodium hypochlorite pentahydrate (296 mg, 1.8 mmol) and water (4 mL) was added dropwise over 10 minutes. After stirring at 5 ° C. for 1 hour, ethyl acetate (20 mL) and water (5 mL) were added for extraction, and the organic layer was further washed with saturated brine (5 mL) and dried over anhydrous magnesium sulfate. A white slurry (2 mL) was obtained by concentrating the organic layer under reduced pressure, 2 mL of hexane was added, and the mixture was stirred at 25 ° C. for 30 minutes. The solid was filtered off under reduced pressure, washed with hexane (10 mL), and dried under reduced pressure to give the title compound as a white solid (77 mg, yield: 42%).

(Example 9) Preparation of methyl 3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) acrylate The solid (177 mg, 1 mmol) obtained in Example 8 was mixed with N -(Tert-butoxycarbonyl) -phosphonoglycine trimethyl ester (357 mg, 1.2 mmol), methylene chloride (10 mL), 1.8-diazabicyclo [5,4,0] undec-7-ene (198 mg, 1.3 mmol) ) And stirred at 25 ° C. for 4 days. Methylene chloride was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (3 mL), water (3 mL) and concentrated hydrochloric acid (1.5 mL), and the organic layer was further washed twice with water (5 mL). The extract was concentrated under reduced pressure, and ethyl acetate (3 mL) and hexane (3 mL) were added to the residue to precipitate a solid. After stirring at 25 ° C. for 15 minutes, the solid was filtered off under reduced pressure, washed with hexane (10 mL), and dried under reduced pressure to give the title compound as a white solid (268 mg, yield: 69%).
¹ H NMR (CD ₃ OD): δ 7.56 (s, 2H), 7.10 (s, 1H), 3.87 (s, 3H), 2.25 (s, 3H), 1.38 (s) , 9H)

Example 10 Preparation of methyl (S) -3- (4-carbamoyl-2,6-dimethylphenyl) -2- (tert-butoxycarbonylamino) propanoate The solid obtained in Example 9 (174 mg, 0 0.5 mmol), methanol (20 mL), tetrafluoroboric acid (R, R)-(−)-1,2-bis [(o-methoxyphenyl) (phenyl) phosphino] ethane (1,5-cyclooctadiene) A solution consisting of rhodium (I) (3.8 mg, 1 mol%) was put in an autoclave and reacted at 60 ° C. for 7 days in a hydrogen atmosphere of 80 atm. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a white solid (100 mg, yield: 57%).
¹ H NMR (CDCl ₃ ): δ 7.46 (s, 2H), 6.09 (brs, 1H), 5.65 (brs, 1H), 5.12 (d, 1H), 4.5 (m, 1H), 3.65 (s, 3H), 3.11 (d, 2H), 2.39 (s, 6H), 1.36 (s, 9H)

Claims

Following formula (1);

(In the formula, P represents a hydrogen atom or an amino-protecting group. R 5 represents a hydrogen atom, a C1-C12 alkyl group which may have a substituent, or a C6-C12 which may have a substituent. A C7 to C20 aralkyl group which may have a substituent, or a C3 to C12 cycloalkyl group which may have a substituent (* represents an asymmetric carbon atom). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative, comprising the following formula (2):

4-carbamoyl-2,6-dimethylbenzoic acid represented by the following formula (3);

(Wherein R 1 and R 2 are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3 to C12 cycloalkyl group which may have a substituent, and R 1 and R 2 may form a ring together.) By reacting a base, the following formula (4):

(Wherein R 1 and R 2 are the same as above), and by reducing the mixed acid anhydride, the following formula (5):

Of the optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by the above formula (1), which comprises a step of producing 4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the formula: Manufacturing method.
The production method according to claim 1, wherein P is a hydrogen atom or a tert-butoxycarbonyl group, R 5 is a hydrogen atom, and the absolute configuration of * is S.
The production method according to claim 1, wherein R 1 is a methyl group or an ethyl group, and R 2 is a methyl group or an ethyl group.
The production method according to any one of claims 1 to 3, wherein the compound (4) is reduced with sodium borohydride in an alcohol solvent.
The following formula (5) produced by the process according to any one of claims 1 to 4;

4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the following formula (6):

(Wherein X represents a leaving group) is converted into a 4-carbamoyl-2,6-dimethylbenzyl derivative represented by the following formula (7) in the presence of a base and an optically active phase transfer catalyst. ;

(Wherein R 3 represents a hydrogen atom or an optionally substituted C 6 to C 12 aryl group, and R 4 represents an optionally substituted C 6 to C 12 aryl group. R 6 Is a C1-C12 alkyl group which may have a substituent, a C6-C12 aryl group which may have a substituent, a C7-C20 aralkyl group which may have a substituent, or a substituent. And a glycine Schiff base represented by the following formula (8):

(Wherein R 3 , R 4 , R 6 , and * are the same as those described above) are produced, and are further subjected to acid hydrolysis, or the amino group is protected after acid hydrolysis. The following formula (1):

(Wherein P, R 5 and * are the same as defined above). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
The X is a chlorine atom or a bromine atom, R 3 is a phenyl group, R 4 is a phenyl group, and R 6 is a methyl group, an ethyl group, or a tert-butyl group. Manufacturing method.
The base is potassium hydroxide, and the optically active phase transfer catalyst is (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-tri The process according to claim 5 or 6, which is fluorophenyl) -3H-dinaphtho [2,1-c: 1 ', 2'-e] azepinium bromide.
The following formula (5) produced by the process according to any one of claims 1 to 4;

4-carbamoyl-2,6-dimethylbenzyl alcohol represented by the following formula (9):

Is converted to 4-carbamoyl-2,6-dimethylbenzaldehyde represented by the following formula, and then reacted with a glycine derivative to give the following formula (10):

(Wherein P is a hydrogen atom or an amino-protecting group. R 6 is a C1-C12 alkyl group which may have a substituent, or a C6-C12 aryl group which may have a substituent. Represents a C7 to C20 aralkyl group which may have a substituent, or a C3 to C12 cycloalkyl group which may have a substituent. The following formula (1), characterized by carrying out simultaneous hydrogenation;

(Wherein P, R 5 and * are the same as defined above). A method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative represented by:
The production method according to claim 8, wherein R 6 is a methyl group, an ethyl group, or a tert-butyl group.
Following formula (6);

A 4-carbamoyl-2,6-dimethylbenzyl derivative represented by the formula (wherein X represents a leaving group).
The 4-carbamoyl-2,6-dimethylbenzyl derivative according to claim 10, wherein X is a chlorine atom or a bromine atom.
Following formula (4);

(Wherein R 1 and R 2 are C1-C12 alkyl groups which may have a substituent, C6-C12 aryl groups which may have a substituent, C7- A C12 aralkyl group, a C3-C12 cycloalkyl group which may have a substituent, and R 1 and R 2 may form a ring together.) object.
The mixed acid anhydride according to claim 12, wherein R 1 is a methyl group or an ethyl group, and R 2 is a methyl group or an ethyl group.