WO2015076346A1

WO2015076346A1 - Method for producing optically active 2,6-dimethyltyrosine derivative

Info

Publication number: WO2015076346A1
Application number: PCT/JP2014/080811
Authority: WO
Inventors: 西山　章
Original assignee: 株式会社カネカ
Priority date: 2013-11-21
Filing date: 2014-11-20
Publication date: 2015-05-28
Also published as: JP2017014109A

Abstract

An optically active 2,6-dimethyltyrosine derivative represented by formula (1) (wherein R¹ represents a hydrogen atom or a protecting group for a phenol group; R² represents a protecting group for an amino group; and * represents an asymmetric carbon atom) and having improved optical purity can be produced by precipitating and removing a solid material having low optical purity from a solution comprising the optically active 2,6-dimethyltyrosine derivative and an organic solvent to improve the optical purity of the derivative in the mother liquor.

Description

Process for producing optically active 2,6-dimethyltyrosine derivative

The present invention relates to a method for producing an optically active 2,6-dimethyltyrosine derivative useful as a pharmaceutical intermediate.

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

Background art 1)
Using 4-iodo-3,5-dimethylphenyl acetate and a serine derivative as starting materials, methyl (Z) -2-acetamido-3- (4-acetoxy-2,6-dimethylphenyl) -2-propenoate was obtained. Produced at 65%. Next, this is hydrogenated in the presence of an asymmetric rhodium catalyst to produce 93% ee (S) -4-acetyl-N-acetyl-2,6-dimethyltyrosine methyl ester in a yield of 95%. . Subsequently, this was converted to Boc, and then (S) -N-Boc-2,6-dimethyltyrosine was produced by alkaline hydrolysis of the acetyl group and crystallized from a mixed solvent of ethyl acetate / heptane. (S) -N-Boc-2,6-dimethyltyrosine having a rate of 91% and 93% ee is obtained (Non-patent Document 1).

Background Art 2)
94.6% ee (S) -4-acetyl-N-acetyl-2,6-dimethyltyrosine methyl ester was prepared in the same manner as in Background Art 1), and then the ester was hydrolyzed using an aqueous alkaline solution. As a result, N-acetyl-2,6-dimethyltyrosine is produced. Subsequently, the acetyl group is asymmetrically hydrolyzed with acylase and then Boc converted to produce (S) -N-Boc-2,6-dimethyltyrosine, which is crystallized from an ethyl acetate / heptane mixed solvent. (S) -N-Boc-2,6-dimethyltyrosine having a yield of 54% and 99% ee is obtained (Non-patent Document 1).

Background Art 3)
Starting from O-benzyl-3,5-dimethyl-4-iodophenol and methyl 2-acetamidoacrylate, (Z) -2-acetamido-3- (4-benzyloxy-2,6-dimethylphenyl) -2 -Produce methyl propenoate in 70% yield. Next, this was hydrogenated in the presence of an asymmetric rhodium catalyst and then debenzylated by hydrogenation in the presence of a palladium catalyst, thereby yielding (S) -N-acetyl-2,6-dimethyl in a yield of 69%. Produces tyrosine methyl ester. Subsequently, (S) -4-acetyl-N-acetyl-2,6-dimethyltyrosine methyl ester is hydrolyzed with an aqueous hydrochloric acid solution and then Boc converted into (S) -N-Boc-2,6-dimethyl. Tyrosine is produced and crystallized from a mixed solvent of ethyl acetate / hexane to obtain 96% ee (S) -N-Boc-2,6-dimethyltyrosine with a yield of 83% (Patent Document 1).

U.S. Pat. No. 4,879,398

In the background art 1), an optically active 2,6-dimethyltyrosine derivative having 93% ee is produced by asymmetric hydrogenation, but the optical purity is not improved at all even if crystallization is performed thereafter, and 93% ee. The optically pure object cannot be obtained. Similarly, the background art 3) has not yet obtained an optically pure optically active 2,6-dimethyltyrosine derivative. In order to obtain an optically pure 2,6-dimethyltyrosine derivative, a complicated operation of asymmetric hydrolysis using an expensive acylase as in Background Art 2) is further required, and the yield is also reduced. There was a problem.
In crystallization of the 2,6-dimethyltyrosine derivative, the background technology 1) and the background technology 2) use an ethyl acetate / heptane mixed solvent, and the background technology 3) uses an ethyl acetate / hexane mixed solvent. These are common in that the optical purity of the precipitate is high, and is classified as a so-called preferential crystallization method.

As a result of intensive studies, the present inventor has found a method for easily producing a high optical purity target by efficiently improving the optical purity of the optically active 2,6-dimethyltyrosine derivative, thereby completing the present invention. It came.

That is, the present invention provides the following formula (1);

Wherein R ¹ is a hydrogen atom or a protecting group for a phenolic hydroxyl group, R ² is a protecting group for an amino group, and * represents an asymmetric carbon atom. A method for producing a dimethyltyrosine derivative, wherein a low optical purity 2,6-dimethyltyrosine derivative is precipitated as a solid from an organic solvent and removed from a solution comprising the 2,6-dimethyltyrosine derivative and an organic solvent, This is a method for producing an optically active 2,6-dimethyltyrosine derivative characterized in that the optical purity of the 2,6-dimethyltyrosine derivative in the mother liquor is improved.
The optical purity of the precipitate of the compound (1) is usually lower than the optical purity before the precipitation. The optical purity of the compound (1) before the precipitate formation is, for example, 91% ee or less. R ¹ is preferably a hydrogen atom or a benzyl group, and R ² is preferably a tert-butoxycarbonyl group. An auxiliary solvent may be further mixed with the organic solvent. The organic solvent is preferably at least one of isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, ethanol, isopropanol, acetone, methyl isobutyl ketone, or acetonitrile, and the auxiliary solvent is preferably hexane or heptane.
The compound (1) is, for example, the following formula (2);

(Wherein R ³ represents a hydrogen atom or a protecting group for a phenolic hydroxyl group; X represents a chlorine atom, a bromine atom or an iodine atom) and the following formula (3);

Wherein R ⁴ represents a hydrogen atom or an aryl group having 6 to 12 carbon atoms which may have a substituent, and R ⁵ represents an aryl group having 6 to 12 carbon atoms which may have a substituent. R ⁶ represents an alkyl group having 1 to 12 carbon atoms.) By reacting a glycine Schiff base represented by the following formula (4) with a base in the presence of an optically active phase transfer catalyst:

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , * are the same as above), and can be produced by further hydrolyzing and then protecting the amino group. It is. R ³ is preferably an ethoxycarbonyl group or a benzyl group, R ⁴ is preferably a hydrogen atom or a phenyl group, R ⁵ is preferably a phenyl group, R ⁶ is preferably an ethyl group or a tert-butyl group, and the absolute configuration is S is preferred. Examples of the base include potassium hydroxide, and examples of the optically active phase transfer catalyst include (11bR)-(−)-4,4-dibutyl-4,5-dihydro-2,6- Bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium 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 or N- (2-chlorobenzyl) cinconidinium bromide can be used.

According to the present invention, an optically active 2,6-dimethyltyrosine derivative having a 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.

The optically active 2,6-dimethyltyrosine derivative has the following formula (1):

It is represented by Here, R ¹ represents a hydrogen atom or a protecting group for a phenol hydroxyl group. Examples of the protecting group for the phenolic hydroxyl group include ether-type protecting groups such as aliphatic hydrocarbon groups (such as methyl, allyl and tert-butyl groups) and aralkyl groups (such as benzyl and p-nitrobenzyl groups); acyl Ester-type protecting groups such as groups (acetyl group, pivaloyl group, benzoyl group, trifluoroacetyl group, etc.); alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, etc.), allyl Carbonate-type protecting groups such as oxycarbonyl group and benzyloxycarbonyl group; silyl groups such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group; mesyl group, tosyl group, p-nitrobenzenesulfo group D Group, a sulfonyl group such as trifluoromethanesulfonyl group. A hydrogen atom, a methyl group, an allyl group, a tert-butyl group, a benzyl group, an acetyl group, a pivaloyl group, an ethoxycarbonyl group, a mesyl group, or a tert-butyldimethylsilyl group, more preferably a hydrogen atom or benzyl A group, particularly preferably a hydrogen atom.

R ² represents an amino-protecting group. Carbamate-type protecting groups such as alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group), allyloxycarbonyl group, benzyloxycarbonyl group, fluoren-9-ylmethoxycarbonyl group, etc. Acyl-type protecting groups such as formyl group, acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group and p-nitrobenzoyl group; sulfonyl-type protecting groups such as mesyl group, p-toluenesulfonyl group and p-nitrobenzenesulfonyl group And more preferably a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and particularly preferably a tert-butoxycarbonyl group.
* In the formula (1) represents an asymmetric carbon atom. The optically active 2,6-dimethyltyrosine derivative preferably has S in absolute configuration.

The optical purity of the 2,6-dimethyltyrosine derivative that can be used in the present invention is preferably 30% ee or more, more preferably 50% ee or more, and particularly preferably 70% ee or more. A 2,6-dimethyltyrosine derivative having a high optical purity that is acceptable as a pharmaceutical intermediate can be produced from such an optically pure starting material by the production method of the present invention.

In the present invention, the production method of the 2,6-dimethyltyrosine derivative is not particularly limited. For example, the asymmetric hydrogenation method described in Non-Patent Document 1 or Patent Document 1 (see the following formula (A)) Is mentioned.

Also, Tetrahedron Asymmetry, 2000, 11, 2917-2925. An optically active 2,6-dimethyltyrosine derivative may be produced using a chiral synthon as described in (see formula (B) below).

Preferably, an arylmethyl halide compound and a glycine Schiff base are reacted in the presence of a base and an optically active phase transfer catalyst, then the reaction product is hydrolyzed, and the amino group is protected. Yes (see formula (C) below).

The arylmethyl halide compound has the following formula (2):

It is represented by Here, R ³ represents a hydrogen atom or a protecting group for a phenol hydroxyl group. Examples of protecting groups for phenolic hydroxyl groups include ether type protecting groups such as aliphatic hydrocarbon groups (such as methyl, allyl and tert-butyl groups) and aralkyl groups (such as benzyl and p-nitrobenzyl groups); acyl groups ( Ester-type protecting groups such as acetyl group, pivaloyl group, benzoyl group, trifluoroacetyl group, etc .; alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, etc.), allyloxycarbonyl Carbonate-type protecting groups such as benzyloxycarbonyl group; silyl groups such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group; mesyl group, tosyl group, p-nitrobenzenesulfonyl group, A sulfonyl group such as trifluoromethane sulfonyl group. A methyl group, an allyl group, a tert-butyl group, a benzyl group, an acetyl group, a pivaloyl group, an ethoxycarbonyl group, a mesyl group, or a tert-butyldimethylsilyl group, more preferably a benzyl group or an ethoxycarbonyl group It is. X represents a chlorine atom, a bromine atom, or an iodine atom. A bromine atom or an iodine atom is preferable. In addition, the synthesis method of 4-benzyloxy-2,6-dimethylbenzyl bromide is Tetrahedron Asymmetry, 2000, 11, 2917-2925. The method for synthesizing 4-iodomethyl-3,5-dimethylphenyl ethyl carbonate is described in Tetrahedron Asymmetry, 2009, 20, 1398-1401. It can be used as a reference.

The glycine Schiff base has the following formula (3):

It is represented by Here, R ⁴ represents a hydrogen atom or an aryl group having 6 to 12 carbon atoms which may have a substituent. A hydrogen atom, a phenyl group, and a p-chlorophenyl group are preferable, and a hydrogen atom or a phenyl group is more preferable. R ⁵ represents an aryl group having 6 to 12 carbon atoms which may have a substituent. A phenyl group, a p-methylphenyl group, a p-chlorophenyl group, a p-nitrophenyl group, and a p-methoxyphenyl group are preferable, and a phenyl group is more preferable. When both R ⁴ and R ⁵ are aryl groups, R ⁴ and R ⁵ may be the same as or different from each other. R ⁶ represents an alkyl group having 1 to 12 carbon atoms. A methyl group, an ethyl group, an isopropyl group, a tert-butyl group, or a benzyl group is preferable, and an ethyl group or a tert-butyl group is more preferable.

The amount of the glycine Schiff base (3) to be used is preferably 1 to 10 equivalents (fold molar amount), more preferably 1 to 3 equivalents, and particularly preferably the arylmethyl halide (2). 1.1 to 1.5 equivalents.

The reaction product (hereinafter sometimes referred to as tyrosine Schiff base) is represented by the following formula (4);

It is represented by Here, R ³ , R ⁴ , R ⁵ and R ⁶ are the same as described above. * Represents an asymmetric carbon atom, and S is preferably the absolute configuration.

Examples of the base include metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate. 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 (double molar amount), more preferably 1 to 10 equivalents, relative to the aryl methyl halide (2).

Examples of the optically active phase transfer catalyst include an optically active quaternary ammonium salt phase transfer catalyst and an optically active phase transfer catalyst complexed with metal atoms. Preferably, an optically active quaternary ammonium salt having a biphenyl skeleton and / or a binaphthyl skeleton, an optically active tartaric acid type quaternary ammonium salt, an optically active benzazepine type quaternary ammonium salt, or an optically active cinchona alkaloid type quaternary ammonium Examples thereof include a salt, or a nickel or copper catalyst complexed with an N, N′-bis (salicylidene) -1,2-cyclohexanediamine derivative (Jacobsen ligand). A particularly preferred catalyst is an optically active quaternary ammonium salt having a biphenyl skeleton and / or a binaphthyl skeleton, an optically active benzazepine-type quaternary ammonium salt, or an optically active cinchona alkaloid-type quaternary ammonium salt.
Specifically, (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 and other Maruoka catalysts (registered trademark); (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- , 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; Cenylquinidinium chloride; N-anthracenylquinium chloride; N- (2-chlorobenzyl) cinconidinium bromide; N- (2-chlorobenzyl) Cinconium 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-methyl) And benzyl) -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, (15bR) -14,14-dibutyl-5,6,7,8,14,15-hexahydro-1,12-bis (3,4,5-tri Fluorophenyl) -13H- [1,6] benzodioxetino [9.8,7-def] [2] benzazepinium bromide or N- (2-chlorobenzyl) cinchonidinium 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) to the arylmethyl halide (2), and more preferably. Is 0.5 equivalent, particularly preferably 0.1 equivalent. The lower limit is preferably 0.0001 equivalent, more preferably 0.001 equivalent, and particularly preferably 0.01 equivalent with respect to the arylmethyl halide (2).

The solvent for this reaction 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, 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, isopropyl acetate, etc. Ester solvents; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene and mesitylene; acetone and methyl Ketone solvents such as tilketone; 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, Amide solvents such as N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-methyl-ε-caprolactam, hexamethylphosphoramide; urea solvents such as dimethylpropylene urea; hexamethylphosphonic acid triamide, etc. A phosphonic acid triamide solvent or 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 ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether; hydrocarbon solvents such as pentane, hexane, heptane; benzene, toluene, xylene, ethylbenzene, mesitylene, etc. Aromatic hydrocarbon solvents; halogen solvents such as methylene chloride and 1,2-dichloroethane, more preferably tetrahydrofuran, methyl tert-butyl ether, hexane, heptane, toluene, xylene, ethylbenzene, mesitylene, methylene chloride, or 1 2-dichloroethane, particularly preferably toluene, xylene, ethylbenzene, or mesitylene.

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 arylmethyl halide (2). Yes, particularly preferably 20 times the weight. The lower limit is preferably 0.1 times the weight, more preferably 0.5 times the weight, and particularly preferably 1 times the weight with respect to the arylmethyl halide (2).

Further water may be added for the purpose of accelerating the reaction rate of this reaction. The amount of water used is preferably 1 to 100 equivalents (fold moles), more preferably 3 to 30 equivalents, relative to the aryl methyl halide (2).

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 order of mixing the arylmethyl halide (2), glycine Schiff base (3), 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 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, an optically active 2,6-dimethyltyrosine is produced by hydrolyzing the protecting group of the tyrosine Schiff base (4), an ester, and optionally a phenol hydroxyl protecting group, and further protecting the amino group. An optically active 2,6-dimethyltyrosine derivative represented by the formula (1) can be produced.

The hydrolysis is preferably acid hydrolysis, and the acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid or the like. The amount of the acid used is preferably 1 to 100 equivalents, more preferably 3 to 30 equivalents, relative to the tyrosine Schiff base (4). The amount of water used is preferably 1 to 100 times the weight, more preferably 3 to 30 times the weight of the tyrosine Schiff base (4).

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 amino groups may be appropriately set according to the type of protecting group. Specifically, for example, when tert-butoxycarbonyl protection or benzyloxycarbonyl protection is performed, an aqueous solution of optically active 2,6-dimethyltyrosine obtained by the hydrolysis is added with sodium hydroxide, potassium hydroxide, sodium carbonate, After neutralization by adding a base such as potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, dibock (ie 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 optically active 2,6-dimethyltyrosine derivative (1) thus obtained has a sufficient purity that can be used in the subsequent steps. However, in order to increase the chemical purity, a general method such as column chromatography is used. The purity may be further increased by a purification method.

Any of the optically active 2,6-dimethyltyrosine derivatives (1) produced by the method described above preferably has an optical purity acceptable as a pharmaceutical intermediate such as 98% ee or more, more preferably 99% ee or more. There was a problem with no point. Therefore, as a result of intensive studies, the present inventor preferentially precipitated the 2,6-dimethyltyrosine derivative (1) having a low optical purity as a solid from an organic solvent, whereby the 2,6-dimethyltyrosine derivative ( 1) The optical purity of the optically active 2,6-dimethyltyrosine derivative (1) having high optical purity was successfully developed by improving the optical purity. Conventionally, the 2,6-dimethyltyrosine derivative is considered to cause preferential crystallization in which the crystallized product has higher optical purity than the mother liquor (or at least the optical purity of the crystallized product does not decrease) In Non-patent Document 1 and Patent Document 1 described above, 2,6-dimethyltyrosine derivatives were crystallized based on this idea. Contrary to these conventional ideas, specific 2,6-dimethyltyrosine derivatives (1) The present inventors have found that the optical purity of the crystallized product is poor and the optical purity of the mother liquor is increased.

Examples of the organic solvent include ester solvents such as ethyl acetate, isopropyl acetate, and methyl propionate; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and tert-butyl methyl ether; methanol, ethanol, isopropanol Alcohol solvents such as N-butanol and ethylene glycol; ketone solvents such as acetone, methyl ethyl ketone, acetophenone and methyl isobutyl ketone; nitrile solvents such as acetonitrile, propionitrile and benzonitrile; N, N-dimethylformamide, N , N-dimethylacetamide, N, N-diethylformamide, N, N-dipropylformamide, N, N-dibutylformamide, dimethyl sulfoxide, N-methylpyrrolidone, 1,3 Aprotic polar solvents such as dimethyl propylene urea and the like. Preferred are isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, ethanol, isopropanol, acetone, methyl isobutyl ketone, and acetonitrile, and more preferred is acetone. The said organic solvent may be used independently and may be used in mixture of 2 or more types. When mixing, the mixing ratio is not particularly limited. 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 or less, more preferably 50 times the weight of the 2,6-dimethyltyrosine derivative (1). Less than weight. The lower limit is preferably 1-fold weight or more, more preferably 3-fold weight or more with respect to the 2,6-dimethyltyrosine derivative (1).

Further, an auxiliary solvent may be added from the viewpoint of improving the recovery rate, improving the purity, and ensuring fluidity. Examples of the auxiliary solvent include water; aliphatic hydrocarbon solvents such as hexane and heptane; halogen solvents such as dichloromethane, 1,2-dichloroethane, chloroform and chlorobenzene; aromatic hydrocarbons such as toluene, xylene and mesitylene. And system solvents. Preferred are water, hexane, heptane, methylene chloride and toluene, and more preferred is hexane or heptane. The auxiliary solvent may be used alone or in combination of two or more. When mixing, the mixing ratio is not particularly limited. 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 or less, more preferably 50 times the weight of the 2,6-dimethyltyrosine derivative (1). Less than weight. The lower limit is preferably 1 or more times the weight, more preferably 3 or more times the weight of the compound (1).
When both an organic solvent and an auxiliary solvent are used, the ratio thereof can be appropriately set according to the type of the solvent. The amount of the organic solvent is, for example, 10 with respect to the total of the organic solvent and the auxiliary solvent. About 90% by weight, preferably about 20-80% by weight. When the organic solvent is the preferred solvent (especially acetone) and the auxiliary solvent is the preferred solvent (especially hexane or heptane), the amount of organic solvent is, for example, relative to the sum of the organic solvent and auxiliary solvent, It is about 10 to 80% by weight, preferably about 20 to 60% by weight, and more preferably about 25 to 45% by weight.

The method for precipitating the optically active 2,6-dimethyltyrosine derivative of low optical purity as a solid is not particularly limited, and examples thereof include the following methods.
(A) A method in which an optically active 2,6-dimethyltyrosine derivative is dissolved in an organic solvent and then cooled to precipitate a solid.
(B) A method in which an optically active 2,6-dimethyltyrosine derivative is dissolved in an organic solvent and then concentrated to precipitate a solid.
(C) A method of precipitating a solid by dissolving an optically active 2,6-dimethyltyrosine derivative in an organic solvent and further adding an auxiliary solvent.
(D) A method of precipitating a solid by dissolving an optically active 2,6-dimethyltyrosine derivative in an organic solvent and then concentrating and substituting with an auxiliary solvent.

Further, solids may be precipitated by appropriately combining the methods (a) to (d). Further, when the solid is precipitated, a seed solid may be added. Examples of the solid used as a seed include low optical purity (for example, 50% ee or less, preferably 30% ee or less, more preferably 10% ee or less), particularly racemic 2, which is an equivalent mixture of S and R isomers. 6-dimethyltyrosine derivatives are preferred.
The implementation temperature in the method for depositing solids (a) to (d) is not particularly limited. Preferably, the temperature may be set below the temperature at which the optically active 2,6-dimethyltyrosine derivative is dissolved in the solvent species or mixed solvent species to be used, depending on the target precipitation amount and solid quality.
The optically active 2,6-dimethyltyrosine derivative of low optical purity deposited by the method of depositing the solids (a) to (d) is removed or separated by a method such as vacuum filtration, pressure filtration, or centrifugation. Can do. If the optical purity of the optically active 2,6-dimethyltyrosine derivative in the mother liquor is not sufficiently improved, the method of precipitating any of the solids (a) to (d) may be repeated again.

In the method of preferentially precipitating the low optical purity 2,6-dimethyltyrosine derivative (1) as a solid from an organic solvent, the optical purity of the 2,6-dimethyltyrosine derivative (1) before precipitation is, for example, It may be 91% ee or less, 90% ee or less, 85% ee or less, or 80% ee or less. Even from such low optical purity, the 2,6-dimethyltyrosine derivative (1) having high photochemical purity can be left in the mother liquor. The optical purity of the 2,6-dimethyltyrosine derivative (1) before precipitation is, for example, 30% ee or more, preferably 50% ee or more, and more preferably 70% ee or more.
The optical purity (E ₂ ) of the 2,6-dimethyltyrosine derivative (1) that precipitates may be lower than the optical purity (E ₁ ) before the precipitation. The optical purity (E ₃ ) of the 2,6-dimethyltyrosine derivative (1) in the mother liquor can be increased by making the optical purity (E ₂ ) of the precipitate lower than the optical purity before precipitation (E ₁ ). The difference (E ₁ -E ₂ ) between the optical purity (E ₁ ) before precipitation and the optical purity (E ₂ ) of the precipitate is, for example, 5% ee or more, preferably 20% ee or more, more preferably 40% ee. That's it. The larger this difference (E ₁ −E ₂ ) is, the more effective it is to increase the optical purity of the mother liquor. The upper limit of the difference (E ₁ −E ₂ ) is not particularly limited. For example, it is 95% ee or less, preferably 80% ee or less, and may be 60% ee or less.
The amount of precipitated 2,6-dimethyltyrosine derivative (1) (A ₂ ) is, for example, 1% by weight relative to the amount of 2,6-dimethyltyrosine derivative (1) before precipitation (A ₁ ). Above, preferably 5% by weight or more, more preferably 10% by weight or more. The greater the amount (A ₂ ) of the precipitate having low optical purity, the higher the optical purity of the mother liquor. The upper limit of the amount of precipitate (A ₂ ) is, for example, 60% by weight or less, preferably 40% by weight or less, relative to the amount (A ₁ ) of the 2,6-dimethyltyrosine derivative (1) before precipitation. More preferably, it is 20% by weight or less, particularly 15% by weight or less. The smaller the amount of precipitate (A ₂ ), the more optically pure 2,6-dimethyltyrosine derivative (1) in the mother liquor can be increased.
The optical purity (E ₃ ) of the 2,6-dimethyltyrosine derivative (1) in the mother liquor is, for example, 85% ee or more, preferably 90% ee or more, more preferably 95% ee or more, particularly preferably 98% ee. That's it. The amount (A ₃ ) of the 2,6-dimethyltyrosine derivative (1) in the mother liquor is, for example, 40% by weight or more with respect to the amount (A ₁ ) of the 2,6-dimethyltyrosine derivative (1) before precipitation. The amount is preferably 60% by weight or more, more preferably 80% by weight or more, and particularly preferably 8% by weight or more, for example, 99% by weight or less, 95% by weight or less, or 90% by weight or less.

From the mother liquor obtained by such solid precipitation / solid-liquid separation treatment, the organic solvent and auxiliary solvent are distilled off by an operation such as heating under reduced pressure to thereby improve optical purity of optically active 2,6-dimethyl. A tyrosine derivative can be obtained. Furthermore, by recrystallization from methylene chloride, toluene, ethyl acetate, hexane, or the like, a target product having a high optical purity of 99% ee or more can be obtained as a solid. In particular, as the optical purity of the 2,6-dimethyltyrosine derivative of the mother liquor is increased by the solid precipitation / solid-liquid separation treatment, the first solid precipitation / solid-liquid separation treatment (recrystallization) is performed in the next solid precipitation / solid-liquid separation treatment (recrystallization). Contrary to the liquid separation treatment, the precipitated solid tends to have higher optical purity than the mother liquor. The extent to which the optical purity on the mother liquor side can be increased by solid precipitation / solid-liquid separation treatment will increase the optical purity of the precipitated solid by the next solid precipitation / solid-liquid separation treatment. Can be easily set experimentally. According to the method of the present invention, the optical purity of the 2,6-dimethyltyrosine derivative on the mother liquor side is increased in the first solid precipitation / solid-liquid separation treatment, and the optical purity on the precipitate side in the next solid precipitation / solid-liquid separation treatment. It is possible to make the equipment common or shared in the first and subsequent solid precipitation / solid-liquid separation processes. Therefore, the equipment burden can be reduced. In addition, the target having high optical purity can be finally recovered as a solid separated from the liquid (mother liquid), and impurities other than the optical isomer can be easily removed.

This application claims the benefit of priority based on Japanese Patent Application No. 2013-240537 filed on Nov. 21, 2013. The entire contents of the specification of Japanese Patent Application No. 2013-240537 filed on November 21, 2013 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.

In this example, the yield and optical purity of each compound were analyzed using high performance liquid chromatography under the conditions described below.
<Chemical purity analysis system>
Column: Nakarai Cosmo Seal 5C18-AR-II 250 × 4.6 mm, 5 μm
Eluent: acetonitrile / phosphate buffer aqueous solution (pH 2.5) = 1/1 (v / v)
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Detection wavelength: 210 nm
Retention time: N-Boc-2,6-dimethyltyrosine = 4.2 minutes O-benzyl-N-Boc-2,6-dimethyltyrosine = 24.0 minutes <Optical purity analysis system>
Column: Daicel Chiral Pack QN-AX 150x4.6mm, 5μm
Eluent: methanol / acetic acid / ammonium acetate = 98/2 / 0.5 (v / v / w)
Flow rate: 1.0 mL / min
Column temperature: 30 ° C
Detection wavelength: 254 nm
Retention time: (R) -N-Boc-2,6-dimethyltyrosine = 4.0 minutes (S) -N-Boc-2,6-dimethyltyrosine = 4.6 minutes (R) -O-benzyl-N -Boc-2,6-dimethyltyrosine = 4.4 minutes (S) -O-benzyl-N-Boc-2,6-dimethyltyrosine = 4.8 minutes

Example 1 Synthesis of (S) —N-Boc-2,6-dimethyltyrosine N- (diphenylmethylene) glycine tert-butyl ester (10.74 g, 36 mmol), Maruoka Catalyst ((11bR)-(−) -4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ', 2'-e] azepi Nitrobromide) (21.0 mg, 0.1 mol%), 85 wt% potassium hydroxide (9.23 g, 140 mmol), water (6.55 g), toluene (70 mL), 4-iodomethyl-3, A toluene solution (70 mL) of 5-dimethylphenyl ethyl carbonate (76.4 wt%, 12.23 g, 28 mmol) was added at 20 ° C., and the mixture was stirred for 17 hours. 70 mL of water was added for washing, and water (56 mL) and concentrated hydrochloric acid (29.17 g, 280 mmol) were added to the organic layer, followed by stirring at 90 ° C. for 5 hours. After cooling to room temperature, the organic layer was separated and the aqueous layer was washed with toluene (35 mL). Tetrahydrofuran (35 mL), potassium carbonate (30.96 g, 224 mmol), and ditert-butyl dicarbonate (9.17 g, 42 mmol) were sequentially added, and the mixture was stirred at 40 ° C. for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (140 mL). The organic layer was washed twice with water (35 mL) and concentrated under reduced pressure to give the title compound as a brown oil (15.17 g) (55.6 wt%, yield: 90%, optical purity: 88. 9% ee).

(Example 2) Synthesis of (S) -N-Boc-2,6-dimethyltyrosine N- (diphenylmethylene) glycine tert-butyl ester (384 mg, 1.3 mmol), N- (2-chlorobenzyl) cinchodi To a solution of nitrobromide (46 mg, 10 mol%), 85 wt% potassium hydroxide (330 mg, 5 mmol), water (234 mg), toluene (10 mL), 4-iodomethyl-3,5-dimethylphenyl ethyl carbonate (73. A toluene solution (1.5 mL) of 4 wt%, 455 mg, 1 mmol) was added at 5 ° C. and stirred for 20 hours. Water (10 mL) was added for washing, and water (10 mL) and concentrated hydrochloric acid (1 mL) were added to the organic layer, followed by stirring at 90 ° C. for 5 hours. After cooling to room temperature, the organic layer was separated and the aqueous layer was washed with toluene (3 mL). Tetrahydrofuran (5 mL), potassium carbonate (1105 mg, 8 mmol), and ditert-butyl dicarbonate (327 mg, 1.5 mmol) were sequentially added, and the mixture was stirred at 25 ° C. for 16 hours. After adjusting to pH = 2 with concentrated hydrochloric acid, ethyl acetate (20 mL) was added for extraction. The organic layer was washed twice with water (5 mL) and concentrated under reduced pressure to give the title compound as a brown oil (yield: 59%, optical purity: 74.6% ee).

Example 3 Synthesis of (S) -N-Boc-2,6-dimethyltyrosine N- (benzylidene) glycine ethyl ester / toluene solution (45 wt%, 1104 mg, 2.6 mmol), Maruoka catalyst ((11bR) -(-)-4,4-dibutyl-4,5-dihydro-2,6-bis (3,4,5-trifluorophenyl) -3H-dinaphtho [2,1-c: 1 ', 2'- e] Azepinium bromide) (3 mg, 0.2 mol%), 85 wt% potassium hydroxide powder (660 mg, 10 mmol), and 4-iodomethyl-3,5-dimethylphenyl ethyl carbonate in a solution of toluene (10 mL). A toluene solution (10 mL) of (73.0 wt%, 915 mg, 2 mmol) was added at 5 ° C. and stirred for 3 hours. Water (10 mL) was added for washing, and water (8 mL) and concentrated hydrochloric acid (2083 mg, 20 mmol) were added to the organic layer, followed by stirring at 90 ° C. for 16 hours. After cooling to room temperature, the organic layer was separated and the aqueous layer was washed with toluene (5 mL). Tetrahydrofuran (5 mL), potassium carbonate (2211 mg, 16 mmol) and ditert-butyl dicarbonate (654 mg, 3 mmol) were sequentially added, and the mixture was stirred at 40 ° C. for 3 hours. After cooling to room temperature, the pH was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed twice with water (5 mL) and concentrated under reduced pressure to give the title compound as a brown oil (yield: 88%, optical purity: 82.6% ee).

Example 4 Synthesis of (S) -N-Boc-2,6-dimethyltyrosine N- (diphenylmethylene) glycine tert-butyl ester (768 mg, 2.6 mmol), Maruoka Catalyst ((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) (3 mg, 0.2 mol%), 85 wt% potassium hydroxide (660 mg, 10 mmol), water (468 mg), toluene (10 mL) in a solution of 4-iodomethyl. A toluene solution (10 mL) of −3,5-dimethylphenyl ethyl carbonate (73.0 wt%, 915 mg, 2 mmol) was added at 20 ° C., and 2 And the mixture was stirred time. Water (10 mL) was added for washing, and water (8 mL) and concentrated hydrochloric acid (2083 mg, 20 mmol) were added to the organic layer, followed by stirring at 90 ° C. for 5 hours. After cooling to room temperature, the organic layer was separated and the aqueous layer was washed with toluene (5 mL). Tetrahydrofuran (5 mL), potassium carbonate (2211 mg, 16 mmol) and dibok (654 mg, 3 mmol) were sequentially added, and the mixture was stirred at 25 ° C. for 16 hours. After adjusting to pH = 2 with concentrated hydrochloric acid, ethyl acetate (20 mL) was added for extraction. The organic layer was washed twice with water (5 mL) and concentrated under reduced pressure to give the title compound as a brown oil (yield: 71%, optical purity: 87.8% ee).

Examples 5-12 Purification of (S) -N-Boc-2,6-dimethyltyrosine 73.3% ee (S) -N-Boc-2,6-dimethyltyrosine (90.3% by weight, 342 mg, 1 mmol) was added with an organic solvent and dissolved by heating, and then cooled and crystallized. If necessary, an auxiliary solvent was added. If no solid was precipitated, racemic seed crystals were added. After the solid precipitated, the mixture was stirred at 25 ° C. for 30 minutes, and then the solid was filtered off under reduced pressure. The results analyzed for the optical purity of the title compound in the solid and mother liquor are shown below.

In Table 1, AcO ⁱ Pr: isopropyl acetate, MTBE: methyl tert-butyl ether, THF: tetrahydrofuran, IPA: isopropanol, EtOH: ethanol, MIBK: methyl isobutyl ketone, AN: acetonitrile.

Example 13 Purification of (S) -N-Boc-2,6-dimethyltyrosine 73.3% ee (S) -N-Boc-2,6-dimethyltyrosine (90.3% by weight, 342 mg, 1 mmol) was added with acetone (6 mL) and dissolved, and then hexane (6 mL) was added to precipitate a solid. The following table shows the results of adding 1 mL each of hexane and examining the transition of the optical purity of the title compound in the mother liquor.

(Example 14) Purification of (S) -N-Boc-2,6-dimethyltyrosine Crude (S) -N-Boc-2,6-dimethyltyrosine (55.6 wt%, prepared in Example 1) Acetone (10 mL) and hexane (15 mL) were added to 3.0 g (5.4 mmol) of optical purity: 88.9% ee). When a racemic seed crystal was added thereto, a solid was precipitated. After stirring at 25 ° C. for 1 hour, the solid was filtered under reduced pressure (yield: 7%, solid optical purity: 9.2% ee, mother liquid optical purity: 98.0% ee). The mother liquor was concentrated under reduced pressure to obtain a yellow oily substance, and dichloromethane (10 mL) was added thereto to precipitate crystals. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure, washed with dichloromethane / hexane = 1/1 (10 mL), and dried in vacuo to give the title compound as a white solid (1032 mg, yield: 62%, 98.5% ee).

Example 15 Purification of (S) -N-Boc-2,6-dimethyltyrosine Crude (S) -N-Boc-2,6-dimethyltyrosine (55.6% by weight, prepared in Example 1) Acetone (10 mL) and hexane (25 mL) were added to 3.0 g (5.4 mmol) of optical purity: 88.9% ee). When a racemic seed crystal was added thereto, a solid was precipitated. After stirring at 25 ° C. for 1 hour, the solid was filtered under reduced pressure (yield: 8%, optical purity of solid: 11.0% ee, optical purity of mother liquor: 99.0% ee). The mother liquor was concentrated under reduced pressure to obtain a yellow oily substance, and when methyl isobutyl ketone (5 mL) and hexane (5 mL) were added thereto, crystals were precipitated. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure, washed with methyl isobutyl ketone / hexane = 1/2 (15 mL), and dried in vacuo to give the title compound as a white solid (768 mg, yield). Rate: 46%, 100% ee).

(Example 16) Purification of (S) -O-benzyl-N-Boc-2,6-dimethyltyrosine 69.4% ee (S) -O-benzyl-N-Boc-2,6-dimethyltyrosine 300 When acetone (1 mL) and hexane (3 mL) were added to 0.5 mg (0.75 mmol), a solid was precipitated. After stirring at 25 ° C. for 3 hours, the solid was filtered off under reduced pressure (yield: 9%, optical purity of solid: 33.4% ee). The mother liquor was concentrated under reduced pressure to obtain a colorless oily substance. When ethyl acetate (2 mL) and hexane (6 mL) were added thereto, crystals were precipitated. After cooling to 5 ° C. and stirring for 30 minutes, the crystals were filtered off under reduced pressure, washed with hexane (5 mL) and dried in vacuo to give the title compound as a white solid (105.2 mg, yield: 35%, 96 .4% ee).

The present invention can be used for the production of an optically active 2,6-dimethyltyrosine derivative useful as a pharmaceutical intermediate.

Claims

Following formula (1);

Wherein R 1 is a hydrogen atom or a protecting group for a phenolic hydroxyl group, R 2 is a protecting group for an amino group, and * represents an asymmetric carbon atom. A method for producing a dimethyltyrosine derivative, characterized in that the optical purity in a mother liquor is improved by precipitating and removing a low optical purity solid from a solution comprising a 2,6-dimethyltyrosine derivative and an organic solvent. A process for producing an optically active 2,6-dimethyltyrosine derivative.
The manufacturing method of Claim 1 with which the optical purity of the deposit of the said compound (1) is lower than the optical purity before precipitation.
The production method according to claim 1 or 2, wherein the optical purity of the compound (1) before the formation of the precipitate is 91% ee or less.
The production method according to any one of claims 1 to 3, wherein R 1 is a hydrogen atom or a benzyl group, and R 2 is a tert-butoxycarbonyl group.
The production method according to any one of claims 1 to 4, wherein an auxiliary solvent is further mixed with the organic solvent.
6. The organic solvent is at least one of isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, ethanol, isopropanol, acetone, methyl isobutyl ketone, or acetonitrile, and the auxiliary solvent is hexane or heptane. Manufacturing method.
The compound (1) is represented by the following formula (2):

(Wherein R 3 represents a hydrogen atom or a protecting group for a phenolic hydroxyl group; X represents a chlorine atom, a bromine atom or an iodine atom) and the following formula (3);

Wherein R 4 represents a hydrogen atom or an aryl group having 6 to 12 carbon atoms which may have a substituent, and R 5 represents an aryl group having 6 to 12 carbon atoms which may have a substituent. R 6 represents an alkyl group having 1 to 12 carbon atoms.) By reacting a glycine Schiff base represented by the following formula (4) with a base in the presence of an optically active phase transfer catalyst:

(Wherein R 3 , R 4 , R 5 , R 6 , and * are the same as above), and the amino group is protected after further hydrolysis to produce the compound. The production method according to any one of claims 1 to 6, wherein:
R 3 is an ethoxycarbonyl group or a benzyl group, R 4 is a hydrogen atom or a phenyl group, R 5 is a phenyl group, R 6 is an ethyl group or a tert-butyl group, The manufacturing method according to claim 7, wherein the arrangement is S.
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 Fluorophenyl) -3H-dinaphtho [2,1-c: 1 ′, 2′-e] azepinium 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, or N- ( The production method according to claim 7 or 8, which is 2-chlorobenzyl) cinconidinium bromide.