JPWO2016013225A1 - Process for producing diphenyl sulfide derivative and production intermediate - Google Patents

Abstract

Provided is a technique relating to a novel method for producing a diphenyl sulfide derivative. A method for producing a compound represented by the general formula (5) by asymmetric hydrolysis of a compound represented by the general formula (4) using porcine liver esterase or rabbit liver esterase. And a method for producing a compound comprising the asymmetric hydrolysis. [Selection figure] None

Description

  The present invention relates to a method for producing a diphenyl sulfide derivative and a technique relating to a compound that can be used as an intermediate for the production.

  The applicant discloses a diphenyl sulfide derivative represented by the following formula (A), which exhibits an excellent sphingosine-1-phosphate receptor 3 (S1P3) antagonistic action (for example, Patent Document 1).

In the formula (A), R ^a represents an alkoxy group having 1 to 6 carbon atoms, R ^b represents a propyl group or an allyl group, and Z represents a halogen atom.
The compound represented by the general formula (A) can be produced, for example, by the method described in Patent Document 1. One of a plurality of synthesis routes disclosed in Patent Document 1 is shown below.

In the above synthetic route, A ^b is a halogen atom, a methanesulfonyloxy group, shows a typical leaving group such as p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, A ^c is a halogen atom, a methanesulfonyloxy group, p A general leaving group such as toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, R ^c represents an alkyl group having 1 to 6 carbon atoms, R ^d represents a general protecting group for amino group, R ^e represents a hydrogen atom or a general protecting group for a phenolic hydroxyl group, and R ^a , R ^b and Z are the same as defined in formula (A).

  On the other hand, a method of constructing an amino acid having a quaternary asymmetric carbon by asymmetric hydrolysis of a symmetric diester derivative using an enzyme such as porcine liver esterase and subjecting the obtained product to a rearrangement reaction is known. (Non-Patent Document 1).

International Publication No. 2012/086184

Violeta Isub, et al. J. et al. Org. Chem. 2010, 75, 1612-1619.

  An object of this invention is to provide the technique regarding the novel manufacturing method of a diphenyl sulfide derivative.

  As a result of intensive studies on the above problems, the present inventors have conducted asymmetric hydrolysis of a specific symmetric diester derivative using porcine liver esterase or rabbit liver esterase, thereby obtaining a compound represented by the formula (A), etc. The present inventors have found that a compound represented by the general formula (5) can be obtained as a production intermediate in a method for producing a diphenyl sulfide derivative containing:

The gist of the present invention is as follows.
[1] General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. A method for producing a compound represented by:
General formula (4):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. ] The manufacturing method of the compound represented by the said General formula (5) including carrying out asymmetric hydrolysis using the pig liver esterase or rabbit liver esterase.

[2] The compound represented by the general formula (4) is asymmetrically hydrolyzed using the porcine liver esterase,
The method of [1], wherein the optical purity of the obtained compound represented by the general formula (5) is 99% ee or more.

[3] General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. A method for producing a compound represented by:
General formula (1):
[Wherein R ¹ , R ² and R ³ are the same as defined above. By converting the compound represented by the general formula (2):
[Wherein R ¹ , R ² and R ³ are the same as defined above. To obtain a compound represented by
The compound represented by the general formula (2) is represented by the general formula (3):
[Wherein, R ⁴ and R ⁵ are the same as defined above. And a compound represented by the general formula (4):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. To obtain a compound represented by
A method for producing a compound represented by the general formula (5), comprising asymmetric hydrolysis of the compound represented by the general formula (4) using porcine liver esterase or rabbit liver esterase.

[4] General formula (9):

[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms],
General formula (4):
[Wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms, and R ¹ , R ² , R ³ , and R ⁴ are the same as defined above. ] Is asymmetrically hydrolyzed using porcine liver esterase or rabbit liver esterase, and the general formula (5):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. To obtain a compound represented by
By subjecting the compound represented by the general formula (5) to a rearrangement reaction, the general formula (7):
[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above]. To obtain a compound represented by
The manufacturing method of the compound represented by the said General formula (9) including reducing the compound represented by the said General formula (7).

[5] The compound represented by the general formula (4) is asymmetrically hydrolyzed using the porcine liver esterase,
The method according to [4], wherein the obtained compound represented by the general formula (9) has an optical purity of 99.5% ee or more.

[6] General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. ] The compound represented by this.

[7] General formula (4):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. ] The compound represented by this.

  ADVANTAGE OF THE INVENTION According to this invention, the technique regarding the novel manufacturing method of a diphenyl sulfide derivative can be provided.

Hereinafter, one embodiment of the present invention will be described in detail.
In the following, the definition of the functional group of the general formula may be omitted with reference to the definition already described. It should be understood that the definitions cited refer to the definitions set forth in the description of the embodiments described below and do not refer to the definitions for the functional groups described in the description of the prior art. it can.

  In the present specification, the “alkyl group having 1 to 6 carbon atoms” is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and 1-ethylpropyl group. , 2-ethylpropyl group, hexyl group and the like.

  Moreover, when specifying, the C1-C6 alkyl group may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms. 1 to 5 substituents selected from the group consisting of

Preferred examples of the alkyl group having 1 to 6 carbon atoms represented by R ⁴ include an n-propyl group. The alkyl group having 1 to 6 carbon atoms represented by R ⁵ is preferably a methyl group, an ethyl group or a tert-butyl group, and particularly preferably a methyl group. Preferred examples of the alkyl group having 1 to 6 carbon atoms represented by R ⁶ include a tert-butyl group.
The “alkyl group having 1 to 6 carbon atoms which may have a substituent” is preferably a 2-methoxyethoxymethyl group (MEM group) or a methoxymethyl group (MOM group), more preferably a methoxymethyl group. Is mentioned.

Further, the “C1-C6 alkoxy group” is a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an isopropoxy group, a tert-butoxy group, and a hexyloxy group. The “C1-C6 alkoxy group” used as R ¹ is preferably an ethoxy group.
The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.

  Examples of the “aralkyl group” include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group. In addition, when specified, the aralkyl group may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms. 1 to 5 substituents selected from the group consisting of Examples of the “aralkyl group which may have a substituent” include a benzyl group and a p-methoxybenzyl group, preferably a benzyl group.

R ² is preferably an aralkyl group which may have a substituent from the viewpoint of improving crystallinity, and a benzyl group is particularly preferable.

In the present specification, “pig liver esterase” includes an esterase obtained using a genetic recombination technique, and is not limited to those derived from pigs. Examples of porcine liver esterase include PLE433 (DSM).
In the present specification, the “rabbit liver esterase” includes an esterase obtained by using a gene recombination technique, and is not limited to those derived from rabbits.
In this specification, the optical purity (% ee) refers to the ratio of a certain compound to the sum of the compound and its optical isomers. Specifically, the optical purity can be calculated based on the area percentage of a certain compound and its optical isomer in the HPLC measurement result.
The production method according to this embodiment is shown in the following scheme 1. Each step shown in Scheme 1 will be described in detail below.

In the reaction pathway, R ¹ represents an alkoxy group having 1 to 6 carbon atoms, and R ² may have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or a substituent. A good aralkyl group, R ³ represents a hydrogen atom or a halogen atom, R ⁴ represents an alkyl group having 1 to 6 carbon atoms, R ⁵ represents an alkyl group having 1 to ⁶ carbon atoms, and R ⁶ represents a carbon number 1-6 alkyl groups are shown.

(Process 1)
The compound represented by the general formula (2) can be obtained by converting the compound represented by the general formula (1) into a compound represented by the general formula (2).

In formula (1), R ¹ , R ² and R ³ are the same as defined above.

In formula (2), R ¹ , R ² and R ³ are the same as defined above.

The conversion can be performed based on, for example, a Wittig reaction, a Horner-Emmons reaction, a Peterson reaction, a TiCl ₄ —CH ₂ Cl ₂ —Zn reaction, or a Teve reaction. Among these, since the compound represented by the general formula (2) tends to decompose at a high temperature, it is preferable to perform the reaction based on the Peterson reaction in which the reaction proceeds at a relatively low temperature. The Peterson reaction was obtained, for example, by reacting a Peterson reagent such as trimethylsilylmethylmagnesium chloride, trimethylsilylmethylmagnesium bromide with the compound represented by the general formula (1) in a reaction solvent such as tetrahydrofuran. This can be done by treating the compound with an acid or base. The Peterson reagent such as trimethylsilylmethyl magnesium chloride is preferably used in an amount of, for example, 1 equivalent to 5 equivalents with respect to the compound represented by the general formula (1). More preferably, it is 1 equivalent or more and 2 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less. Moreover, it is preferable to use 1.2 equivalents or more of Peterson reagents such as trimethylsilylmethyl magnesium chloride with respect to the compound represented by the general formula (1) in terms of suppressing the formation of by-products. Accordingly, the amount of the Peterson reagent used is particularly preferably 1.2 equivalents or more and 1.5 equivalents or less with respect to the compound represented by the general formula (1).

  The reaction temperature is usually from −20 ° C. to the boiling point of the solvent, preferably from 0 ° C. to 70 ° C. Furthermore, the reaction temperature is more preferably 10 ° C. or more and 70 ° C. or less, even more preferably 15 ° C. or more and 50 ° C. or less, and particularly preferably 20 ° C. or more and 35 ° C. or less in that generation of by-products is suppressed. It is done.

Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, halogenated hydrocarbons such as dichloromethane, or the like. A mixture is mentioned, Preferably, ethers are mentioned, More preferably, tetrahydrofuran is mentioned. The reaction solvent is preferably used in an amount that is twice or more the amount of the compound represented by the general formula (1). The amount of the reaction solvent used is more preferably 2 to 7 times the amount of the compound represented by the general formula (1), particularly preferably the compound represented by the general formula (1). On the other hand, the amount is 3 times or more and 5 times or less.
The “double amount” shown in the present specification is a value obtained by dividing the volume (mL) of the solvent by the weight (g) of the compound.

  In addition, the compound represented by General formula (1) can be obtained based on the reaction pathway shown below, for example.

  Specifically, after a base such as sodium hydroxide is allowed to act on the compound represented by the general formula (p1) such as 5-alkoxy-1,3-benzoxiathiol-2-one, hydrogen peroxide solution, etc. Next, an alkyl halide such as benzyl bromide and a base such as potassium carbonate are allowed to act on the resulting product as necessary to obtain a compound represented by the general formula (p2). (Process P1). When the base and the oxidizing agent are sequentially allowed to act on the compound represented by the general formula (p1), the reaction solvent can be, for example, water, methanol, ethanol, or a mixture thereof, and the reaction temperature is, for example, 10 ° C. to 25 ° C. It can be set to ° C. In the reaction using an alkyl halide and a base, the reaction solvent can be N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, or a mixture thereof. It can be 20 degreeC-30 degreeC.

  Next, in the obtained compound represented by the general formula (p2), in the reaction solvent, in the presence of a reducing agent such as sodium borohydride or an acid such as hydrochloric acid or acetic acid, metal zinc, zinc amalgam, zinc- A compound represented by general formula (1) is obtained by allowing a copper alloy or the like to act and then reacting with a compound represented by general formula (p3) in a reaction solvent (step P2). In the reaction using metal zinc or the like, as the reaction solvent, for example, toluene, xylene, benzene, or a mixture thereof can be used, and the reaction temperature can be set at, for example, 50 ° C. to 60 ° C. In the reaction using the compound represented by the general formula (p3), the reaction solvent can be, for example, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or a mixture thereof. Moreover, reaction temperature can be 20 degreeC-60 degreeC, for example.

In the reaction pathway relating to Step P1 and Step P2, Xa represents a fluoro group, and R ¹ , R ² and R ³ are the same as defined above.

(Process 2)
The compound represented by the general formula (4) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (3).

In formula (4), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above.

In formula (3), R ⁴ and R ⁵ are the same as defined above.

  The reaction can be carried out, for example, by reacting the compound represented by the general formula (2) with the compound represented by the general formula (2) in the presence of a base in a reaction solvent. Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like. Halogenated hydrocarbons, methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and other alcohols, N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, etc. Amides, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , Butyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate or ethyl isovalerate, ketones such as acetone, or mixtures thereof. Preferably, sulfoxides are used, and dimethyl sulfoxide is more preferable. Regarding the order of addition of the reaction substrate, the solution of the compound represented by the general formula (2) may be added dropwise to the solution of the compound represented by the general formula (3) in terms of suppressing the formation of by-products. preferable. In both the solution of the compound represented by the general formula (3) and the solution of the compound represented by the general formula (2), the amount of the solvent is 2 times or more, more preferably 2 times or more and 7 times or less, More preferably, the amount is adjusted to be 3 times or more and 5 times or less.

  The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used, and preferably 0 ° C. in that the yield of the compound represented by the general formula (4) can be improved. The temperature is 100 ° C. or less, more preferably 10 ° C. or more and 45 ° C. or less, and particularly preferably 20 ° C. or more and 40 ° C. or less.

  Examples of the base include inorganic bases such as cesium carbonate and potassium carbonate, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-. One or more of organic bases such as undecene and pyridine and alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide can be used, preferably inorganic bases, more preferably cesium carbonate. Can be mentioned. The usage-amount of a base can be used 1 equivalent or more with respect to the compound represented by General formula (2). Preferably they are 1 equivalent or more and 10 equivalents or less, More preferably, they are 1 equivalent or more and 5 equivalents or less, More preferably, they are 1.1 equivalents or more and 2.8 equivalents or less, Especially preferably, 1.2 equivalents or more and 1.8 equivalents or less are mentioned.

  It is preferable to use 1 equivalent or more and 10 equivalent or less of the compound represented by General formula (3) with respect to the compound represented by General formula (2). More preferably, 1.6 equivalents or more and 5 equivalents or less, more preferably 2 equivalents or more and 4 equivalents or less are used.

  When the crude product of Step 1 is used as it is in Step 2 without further purification, the compound represented by General Formula (1) is represented by General Formula (2) in a yield of 100%. The amount of the compound represented by the general formula (1) is regarded as the amount of the compound represented by the general formula (2).

(Process 3)
The compound represented by the general formula (5) can be obtained by reacting the compound represented by the general formula (4) with porcine liver esterase or rabbit liver esterase and performing hydrolysis (asymmetric hydrolysis). .
In the present specification, asymmetric hydrolysis refers to selective hydrolysis of one of the same two alkoxycarbonyl groups bonded to a quaternary carbon to convert it into a carboxy group. Means to preferentially produce one of the compounds having an optical isomer relationship.

In formula (5), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above.

  In this reaction, any porcine liver esterase or rabbit liver esterase can be used, and is not particularly limited. As described above, the porcine liver esterase may be a porcine liver esterase obtained by using a gene recombination technique. The rabbit liver esterase may also be a rabbit liver esterase obtained by using a gene recombination technique as described above.

When porcine liver esterase is used, a compound represented by general formula (5) with higher optical purity is obtained than when rabbit liver esterase is used, and the yield of the compound represented by general formula (5) is obtained. Will also improve. Therefore, the use of porcine liver esterase is preferred for the reaction.
The yield is a value obtained by dividing the amount of the target substance actually obtained by the amount of the target substance assumed to be theoretically obtained.

  Porcine liver esterase or rabbit liver esterase is preferably used in an amount of 50 wt% to 500 wt% with respect to the compound represented by the general formula (4). More preferable use amount is 60 wt% or more and 300 wt% or less, and more preferable use amount is 70 wt% or more and 150 wt% or less.

  The preferred pH for the reaction is 8.0 or less. From the viewpoint that the reaction rate can be further increased, the more preferable pH is 3.0 or more and 8.0 or less, further preferably 5.0 or more and 7.5 or less, and particularly preferably 6.0 or more and 7.0 or less. It is.

  The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used. However, when the reaction temperature is high, the enzyme is rapidly deactivated and the yield may decrease. Accordingly, a preferable reaction temperature is 50 ° C. or lower, more preferably 45 ° C. or lower, and still more preferably 38 ° C. or lower. The reaction temperature is preferably 20 ° C. or higher because the reaction rate decreases as the reaction temperature decreases. More preferably, 25 degreeC or more, Especially preferably, 30 degreeC or more is mentioned. Accordingly, the reaction temperature is preferably 20 ° C. or higher and 50 ° C. or lower, more preferably 25 ° C. or higher and 45 ° C. or lower, and particularly preferably 30 ° C. or higher and 38 ° C. or lower.

  The enzyme reaction can be performed using, for example, a solvent. Examples of the solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, and diglyme, aromatic compounds such as benzene, toluene, and xylene, nitriles such as acetonitrile and propionitrile, and halogenated carbonization such as dichloromethane. Hydrogens, methanol, ethanol, 2-propanol, tert-butyl alcohol, alcohols such as ethylene glycol and diethylene glycol, amides such as formamide, N-methylpyrrolidone and N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, Examples include sulfones such as sulfolane, ketones such as acetone, water, or a mixture thereof. When acetonitrile is used as a solvent, the reaction may not easily proceed. Preferable solvents include sulfoxides from the viewpoint of improving the yield, and more preferably dimethyl sulfoxide.

The amount of the solvent used is preferably 2 times or more and 30 times or less, more preferably 5 times or more and 20 times or less, still more preferably 7 times or more and 15 times the amount of the compound represented by the general formula (4). Double amount or less is mentioned.
Moreover, the compound represented by General formula (5) can be isolate | separated from the enzyme used for reaction according to a well-known method after completion | finish of reaction. Specifically, the compound represented by the general formula (5) may be obtained as a crude product by removing the enzyme by performing a treatment based on a filtration treatment or a solvent extraction method. Moreover, you may further refine | purify the crude product of the compound represented by General formula (5) by performing the process based on a crystallization process or HPLC method.

(Process 4)
The compound represented by the general formula (7) can be obtained by subjecting the compound represented by the general formula (5) to a rearrangement reaction.

In formula (7), R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above.

  The reaction can be performed based on the Curtius rearrangement, the Schmitt rearrangement, the Rossen rearrangement, the Hoffman rearrangement, etc., but is preferably performed based on the Curtius rearrangement. For example, in the presence of a base such as triethylamine, azidation of bis (4-methylphenyl) phosphoric azide, bis (4-chlorophenyl) phosphoric azide, diphenylphosphoric azide and the like into the compound represented by the general formula (5) React the reagent.

  The amount of the azidation reagent used can be, for example, 1 equivalent or more, preferably 1 equivalent or more and 5 equivalents or less with respect to the compound represented by the general formula (5). More preferably, it is 1 equivalent or more and 3 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less. When the crude product of Step 3 is used as it is in Step 4 without further purification, the compound represented by General Formula (4) is represented by General Formula (5) in 100% yield. The amount of the compound represented by the general formula (4) is regarded as the amount of the compound represented by the general formula (5).

  Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other inorganic bases, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7 -Organic bases, such as undecene, etc. are mentioned. Among these, it is preferable to use an organic base, and triethylamine is particularly preferable. The amount of the base used is preferably 1 equivalent or more and 3 equivalents or less with respect to the compound represented by the general formula (5). From the viewpoint of improving the yield, more preferably 1 equivalent to 2 equivalents, and particularly preferably 1 equivalent to 1.5 equivalents.

  The reaction can be performed, for example, in a reaction solvent. Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, and diglyme, aromatic compounds such as benzene, toluene, and xylene, nitriles such as acetonitrile and propionitrile, and halogenation such as dichloromethane. Hydrocarbons, formamide, N-methylpyrrolidone, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate , Isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, ethyl isovalerate, etc., ketones such as acetone, The mixtures thereof, preferably, benzene, toluene, can be used an aromatic hydrocarbon solvent such as xylene, more preferably toluene. From the viewpoint of improving the yield, when the compound represented by the general formula (5) is reacted with an azide reagent to produce an acyl azide, the amount of the solvent is preferably small. The solvent is preferably used in an amount of 20 times or less with respect to the compound represented by the general formula (5). More preferably, the amount is 15 times or less, more preferably 10 times or less. After the acyl azide is formed, the rearrangement reaction is preferably allowed to proceed with heating to generate isocyanate. At this time, the reaction rate can be adjusted by adding the acyl azide solution to a separately heated solvent.

  The reaction temperature is, for example, suitably 0 ° C. or more and 60 ° C. or less, preferably 20 ° C. or more and 55 ° C. or less, more preferably 30 ° C. or more and 50 ° C. or less when acylazide is produced. The reaction temperature is suitably 60 ° C. or more and 150 ° C. or less, for example, in the production of isocyanate, preferably 70 ° C. or more and 100 ° C. or less, more preferably 75 ° C. or more and 100 ° C. or less.

  Next, the alkali metal alkoxide represented by the general formula (13) is allowed to act on the obtained product.

In formula (13), M represents a sodium atom or a potassium atom, and R ⁶ has the same definition as above. As the compound represented by the general formula (13), a commercially available compound can be used. For example, it can be prepared in a reaction solution by reacting a compound such as sodium hydride or metal sodium with an alcohol. It may be used.

  Alkali metal alkoxides such as sodium alkoxide are preferably used in an amount of 1 to 5 equivalents relative to the compound represented by the general formula (5). From the viewpoint of improving the yield, more preferably 1.3 equivalents or more and 3 equivalents or less, and particularly preferably 1.4 equivalents or more and 1.8 equivalents or less.

  The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used, but preferably ranges from −10 ° C. to the boiling point of the solvent used, particularly preferably 0 to 30 ° C., more preferably The range of 10-30 degreeC is mentioned.

(Process 5)
The compound represented by the general formula (9) can be obtained by reducing the compound represented by the general formula (7).

In formula (9), R ¹ , R ² , R ³ , R ⁴ and R ⁶ are the same as defined above.

  In the reduction treatment, for example, the compound represented by the general formula (7) is dissolved in a reaction solvent such as tetrahydrofuran, the obtained solution is added to a reducing agent, and an alcohol such as ethanol or methanol is further added to react. Can be done.

  The reducing agent is aluminum hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, trimethoxy lithium aluminum hydride, aluminum hydride, diisobutyl aluminum hydride, lithium triethylborohydride, hydrogen One or more of boron hydrides such as sodium borohydride, potassium borohydride, lithium borohydride, lithium tri (sec-butyl) borohydride, potassium trihydride (sec-butyl) borohydride are used. be able to. More preferred is a boron hydride reducing agent, still more preferred is lithium borohydride. It is preferable that a reducing agent is 1 equivalent or more and 10 equivalent or less with respect to the compound represented by General formula (7), for example. More preferably, they are 2 equivalents or more and 8 equivalents or less, More preferably, 4 equivalents or more and 7 equivalents or less are mentioned.

  The reducing agent may be prepared and used in combination with a lithium salt such as lithium chloride, lithium bromide or lithium iodide and a boron hydride reducing agent such as sodium borohydride or potassium borohydride. Preferably, a method using a boron hydride reducing agent in the presence of lithium chloride is used. More preferred is a method using potassium borohydride in the presence of lithium chloride.

  When a reducing agent is prepared by combining a lithium salt and a boron hydride-based reducing agent, the preferred usage amount of the lithium salt and the boron hydride-based reducing agent is 1 for each compound represented by the general formula (7). Equivalent to 10 equivalents. More preferably, all are 2 equivalents or more and 8 equivalents or less, More preferably, all are 4 equivalents or more and 7 equivalents or less.

  The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used. From the viewpoint of improving the yield, it is preferably 0 ° C. or higher and 55 ° C. or lower, more preferably 25 ° C. or higher and 55 ° C. or lower. .

  The reaction can be performed, for example, in a reaction solvent. Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, diglyme, aromatic compounds such as benzene, toluene, xylene, hydrocarbons such as hexane, heptane, cyclohexane, or the like. A mixture is mentioned. Preferably, ethers are used, and more preferably, tetrahydrofuran is used.

  The preferable use amount of the alcohol is, for example, 0.5 to 10 times the compound represented by the general formula (7). From the viewpoint of improving the yield, more preferably 0.7 times or more and 2 times or less, still more preferably 0.8 times or more and 1.2 times or less.

  The resulting compound represented by the general formula (9) can be purified by recrystallization to remove impurities that are difficult to purify and improve the chemical purity. Furthermore, the optical purity can be further increased by the recrystallization. As the solvent used for recrystallization, it is preferable to use toluene and heptane in that crystals excellent in fluidity and filterability can be obtained with high yield. Particularly preferred is a mixed solvent of toluene: heptane = 1: 2 to 1: 5.

(Step 6)
The compound represented by the general formula (11) is converted to a phosphate ester of the hydroxyl group of the compound represented by the general formula (9) using the method described in Patent Document 1, and then R ⁶ and R ² . It can be obtained by deprotection and dealkylation of the phosphate group.

  As described above, in the present embodiment, the compound represented by the general formula (5) can be produced using porcine liver esterase or rabbit liver esterase. The compound represented by the general formula (5) can be used as a production intermediate in a method for producing a diphenyl sulfide derivative including, for example, the compound represented by the above formula (A). Therefore, according to this embodiment, a novel method for producing a diphenyl sulfide derivative can be provided. In particular, by using porcine liver esterase, a compound represented by the general formula (5) having high optical purity can be obtained. Therefore, it is possible to produce the final product diphenyl sulfide derivative with high optical purity.

  EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide

  5-Ethoxy-1,3-benzoxiathiol-2-one (20.00 g, 102 mmol) was added to a mixture of ethanol (20 mL) and water (50 mL). A solution of sodium hydroxide (12.23 g, 306 mmol) in water (50 mL) was added to the mixture at an internal temperature of 15 to 25 ° C., and the mixture was stirred at an internal temperature of 40 to 47 ° C. for 1 hour. The reaction solution was cooled, 35% aqueous hydrogen peroxide (4.95 g, 50.9 mmol) was added at an internal temperature of 12 to 20 ° C., and the mixture was stirred at an internal temperature of 20 to 24 ° C. for 1 hour. The reaction solution was cooled, 30 mL of concentrated hydrochloric acid was added at an internal temperature of 4 to 13 ° C., and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed successively with a mixture of sodium bisulfite (20.00 g) and water (200 mL) and saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a yellow oil (15.5 g).

  The obtained yellow oil (15.5 g) was dissolved in N, N-dimethylformamide (100 mL), potassium carbonate (16.90 g, 122 mmol) at an internal temperature of 21 ° C., and benzyl bromide (21 to 27 ° C.). 17.43 g (102 mmol) was added, and the mixture was stirred at an internal temperature of 24-27 ° C. for 2.5 hours. Water (160 mL) was added to the reaction solution at an internal temperature of 24-33 ° C., and the mixture was stirred at an internal temperature of 25-30 ° C. for 30 minutes. The precipitated crystals were collected by filtration and washed with water (60 mL) and diisopropyl ether (60 mL). The precipitated crystals were dried at 40 ° C. under reduced pressure to obtain 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide (18.19 g, 69% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.29 (6H, t, J = 6.9 Hz), 3.87 (4H, q, J = 6.9 Hz), 5.11 (4H, s), 6. 81 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 3.1 Hz), 7.30-7.33 (2H, m), 7.37-7.40 (4H , M), 7.48-7.50 (4H, m)

Reference Example 2 Synthesis of 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde

1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide (16.0 g, 30.8 mmol) was added to a mixed solution of toluene (80 mL) and concentrated hydrochloric acid (32 mL), and dissolved by heating. Zinc powder (5.04 g, 77.1 mmol) was added to the mixture at an internal temperature of 50 to 57 ° C., and the mixture was stirred at an internal temperature of 54 to 57 ° C. for 1.5 hours. The reaction solution was cooled, water (48 mL) was added at an internal temperature of 20 to 25 ° C., and liquid separation was performed. The organic layer was washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a yellow oil (16.6 g).
The obtained yellow oil (8.09 g) was dissolved in N, N-dimethylformamide (39 mL), and 2-chloro-4-fluorobenzaldehyde (4.76 g, 30.0 mmol), Potassium carbonate (6.22 g, 45.0 mmol) was added at a temperature of 25-30 ° C. The mixture was heated and stirred at an internal temperature of 50 to 56 ° C. for 1 hour, and water (39 mL) was added at an internal temperature of 54 to 58 ° C. The reaction solution was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration and washed with water (39 mL). The precipitated crystals were dried under reduced pressure at 50 ° C. to obtain a brown powder (11.3 g). Ethanol (57 mL) was added and suspended by heating at an internal temperature of 50 to 55 ° C. for 0.5 hour. The mixture was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration and washed with ethanol (34 mL). The precipitated crystals were dried at 50 ° C. under reduced pressure to obtain 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde (10.5 g, 88% yield).
MS (FI +): m / z 398 [M] ⁺

Example 1 Synthesis of 2-benzyloxy-5-ethoxyphenyl 3-chloro-4-vinylphenyl sulfide (Step 1)

  Tetrahydrofuran (200 mL) of 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde (50 g, 125 mmol) in 1.0 mol / L trimethylsilylmethylmagnesium chloride tetrahydrofuran solution (163 mL, 163 mmol) under nitrogen atmosphere The solution was added with stirring at an internal temperature of 27 to 28 ° C. over 32 minutes. The mixture was stirred at an internal temperature of 25 to 27 ° C. for 1 hour, then cooled, and concentrated hydrochloric acid (40 mL) was added at an internal temperature of 2 to 11 ° C. over 10 minutes. The reaction solution was stirred at an internal temperature of 8 to 21 ° C. for 1 hour and 20 minutes, and then water (100 mL), isopropyl acetate (500 mL), and water (400 mL) were sequentially added at an internal temperature of 21 to 26 ° C. The organic layer was separated, and the organic layer was mixed with water (500 mL), sodium bicarbonate (25.0 g) and water (500 mL), sodium chloride (50.0 g) and water (500 mL), sodium chloride (50.0 g). And sequentially washed with a mixture of water and water (500 mL). The organic layer was dried using anhydrous sodium sulfate (125 g), and anhydrous sodium sulfate was removed by filtration. 4-tert-Butylpyrocatechol (500 mg) was added to the filtrate, and after confirming dissolution, the filtrate was concentrated under reduced pressure at an external temperature of 39 ° C. Isopropyl acetate (100 mL) was added, and the mixture was concentrated under reduced pressure at an external temperature of 39 ° C. to obtain a brown oil (53.9 g). The obtained brown oil was used for the next reaction without further purification.

Example 2 Synthesis of dimethyl 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -propylmalonate (Step 2)

Dimethyl sulfoxide (200 mL) was added to the brown oil (53.9 g) obtained in Example 1 and dissolved.
Under a nitrogen atmosphere, dimethyl 2-propylmalonate (48.0 g, 276 mmol) was dissolved in dimethyl sulfoxide (200 mL), and cesium carbonate (61.3 g, 188 mmol) was added at 29 to 32 ° C. with stirring. A dimethyl sulfoxide (200 mL) solution of the brown oil (53.9 g) obtained in Example 1 described above was added to the mixture at an internal temperature of 31 ° C. over 1 hour and 4 minutes, and the internal temperature was 29 to 31 ° C. The mixture was stirred for 6 hours and then allowed to stand overnight. The reaction solution was cooled, and toluene (1.00 L) and water (1.00 L) were added at an internal temperature of 14 to 16 ° C. The organic layer was separated, washed with a mixed solution of sodium chloride (100 g) and water (1.00 L), and dried using anhydrous sodium sulfate (100 g). After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a brown oil (96.7 g).
Diisopropyl ether (150 mL) was added to the brown oil obtained at an internal temperature of 25 ° C. to obtain a mixed solution. The mixture was heated, diisopropyl ether (100 mL) was further added, and the mixture was stirred at an internal temperature of 50 to 53 ° C. for 10 minutes. The mixture was filtered and washed with diisopropyl ether (25.0 mL). The filtrate and washings were combined and concentrated under reduced pressure. Methanol (250 mL) was added to the resulting concentrated residue, heated, and stirred at 50 to 51 ° C. for 30 minutes, then cooled, and stirred at an internal temperature of 25 to 30 ° C. for 30 minutes. The precipitate was collected by filtration and washed with methanol (50.0 mL). Dried under reduced pressure at 40 ° C., dimethyl 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate (57.0 g, 80% yield) )
MS (ESI +): m / z 571 [M + H] ⁺

Example 3 Synthesis of (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid (Step 3)

(PLE433)
1 mol / L phosphoric acid (40 g) was added to a mixed solution of Batch CFE (1600 g, 60 V% CFE, containing PLE (Porcine Liver Esterase) 433, provided by DSM) and Kpi buffer (500 mL) to pH 6.5. To the mixture, dimethyl 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate (26.7 g, A solution of 45.8 mmol) in dimethyl sulfoxide (450 mL) was added in 15 minutes and washed with dimethyl sulfoxide (50 mL). The mixture was stirred at 35 ° C. for 47 hours. 1 mol / L phosphoric acid (350 mL) was added to the reaction solution to adjust the pH to 3.4, and isopropyl acetate (1.0 L) was added. The reaction solution was filtered using Dicalite (5 wt%), and the insoluble matter collected by filtration was washed with isopropyl acetate. The insoluble matter collected by filtration and isopropyl acetate were mixed and then filtered, and the insoluble matter was washed with isopropyl acetate and water. All filtrates and washings were combined and separated. The organic layer was washed 4 times with water (500 mL) and then concentrated under reduced pressure to obtain a reddish brown oil (29 g). After adding isopropyl acetate (6 g) and heptane (30 g) to the obtained reddish brown oily substance and confirming crystallization, heptane (300 g) was added over 1 hour. After stirring at room temperature for 1 hour, the precipitate was collected by filtration and washed with heptane. After drying under reduced pressure, (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid (22.1 g, 85% yield) was obtained. Rate, 99.6% ee).

(PLE)
2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate dimethyl (400 mg) was dissolved in dimethyl sulfoxide (4.0 mL) An acid buffer (pH 7.0, 40 mL) and PLE (Porcine Liver Esterase, 400 mg, SIGMA-ALDRICH) were added at room temperature, followed by stirring at an external temperature setting of 40 ° C. for 6 days. The reaction mixture was filtered through celite (4.00 g) and washed with ethyl acetate (8.0 mL). 1.0 mol / L hydrochloric acid (20 mL) and ethyl acetate (20 mL) were added to the filtrate, and the organic layer was separated. The organic layer was washed successively with a mixture of water (20 mL), sodium chloride (2.0 g) and water (20 mL). The organic layer was dried using anhydrous sodium sulfate, anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product (421.2 mg) was subjected to silica gel column chromatography (Si60N, spherical, 40-100 μm, 8.0 g: elution solvent, hexane: ethyl acetate = 4: 1 → ethyl acetate), and (2R ) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid (221 mg,> 99% ee) was obtained.

  In Example 3, the optical purity of the obtained product was calculated based on the following formula (e1) from the areas of the R-form and S-form obtained in the measurement under HPLC condition A shown below.

Optical purity (% ee) = (R-formation amount−S-formation amount) / (R-formation amount + S-formation amount) × 100 (e1)

  Here, the R form means (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid. The S form means (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid.

HPLC condition A
Column: Kromasil 3-Amycoat (4.6 mm × 150 mm, 3 μm)
Mobile phase: ethanol / 2-propanol / trifluoroacetic acid = 90/10 / 0.05
Flow rate: 1.5 mL / min.
Temperature: 20 ° C
Detection wavelength: 305 nm
Retention time: (R) isomer; 2.61 minutes, (S) isomer; 4.67 minutes

Example 4 (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino) pentane Synthesis of methyl acid (step 4)

(2R) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-methoxycarbonylpentanoic acid (10.0 g, 18.0 mmol) was added to toluene ( 100 mL) was added and dissolved, and then triethylamine (2.75 mL, 19.7 mmol) was added followed by diphenylphosphoric acid azide (4.24 mL, 19.7 mmol). The mixture was stirred at an internal temperature of 40 ° C. for 1.5 hours, then further heated and stirred at an internal temperature of 85 ° C. for 2 hours. The reaction liquid was cooled to room temperature, 0.5 mol / L hydrochloric acid (100 mL) was added, and liquid separation was performed. The organic layer was washed successively with water (100 mL), saturated sodium hydrogen carbonate solution (100 mL), and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil (11.2 g).
To a mixture of tert-butanol (18.0 mL) and toluene (60.0 mL) was added tert-butoxy sodium (2.59 g, 27.0 mmol). To the mixture, a toluene (26.0 mL) solution of the previously synthesized brown oil (11.2 g) was added dropwise at room temperature over 5 minutes. After the dropwise addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, saturated ammonium chloride solution (100 mL) and water (20 mL) were added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL) and dried using anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Heptane (14.0 mL) and ethyl acetate (7 mL) were added to the residue and dissolved, and short column chromatography (silica gel Si60N, 63-210 μm, 10 g) was performed to obtain a pale yellow oil (11.0 g). . The resulting pale yellow oil was used in the next reaction without further purification.

Example 5 (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino) pen Synthesis of tanol (process 5)

Tetrahydrofuran (60 mL) was added to potassium borohydride (4.85 g, 90.0 mmol), lithium chloride (3.82 g, 90.0 mmol) was added at room temperature, and the resulting mixture was heated at an internal temperature of 40 ° C. for 22 hours. Stir. A solution of the pale yellow oil (11.0 g) synthesized in Example 4 in tetrahydrofuran (30 mL) was added dropwise to the mixture over 5 minutes, followed by ethanol (10 mL) over 1 hour. The mixture was stirred for 1 hour, then ice-cooled, and 1 mol / L hydrochloric acid (90 mL) was added dropwise over 10 minutes. The reaction solution was extracted with ethyl acetate (100 mL), and the organic layer was washed successively with 1 mol / L potassium hydroxide (100 mL) twice and saturated brine (50 mL). The organic layer was dried using anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Toluene (30 mL) was added to the residue, heated, and stirred at 55 ° C. for 15 minutes. After hot filtration, the filtrate was stirred at 55 ° C. for 15 minutes, and then heptane (240 mL) was added. The filtrate to which heptane was added was cooled, stirred at 38 ° C. for 5 minutes, and then stirred at room temperature for 30 minutes. The precipitate was collected by filtration to obtain a white powder (7.79 g). Toluene (46.7 mL) was added to dissolve the white powder, and then the solution was heated. The solution was stirred at 55 ° C. for 30 minutes and then heptane (18.7 mL) was added dropwise. The mixture was stirred for 30 minutes, then cooled and stirred at 38 ° C. for 30 minutes. The precipitate was collected by filtration and (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino). ) Pentanol (6.90 g, 64% yield,> 99.9% ee) was obtained.
Optical rotation: [α] _D ²⁴ -6.81 (c 0.98, CHCl ₃ )

  In Example 5, by recrystallizing with toluene and heptane, crystals excellent in fluidity and filterability can be obtained with high yield. By this operation, (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1) having improved optical purity and chemical purity was obtained. -Dimethylethoxycarbonylamino) pentanol can be obtained.

  In Example 5, the optical purity of the obtained product was calculated based on the following formula (e2) from the areas of R and S isomers obtained in the measurement under HPLC condition B shown below.

  Optical purity (% ee) = (S-formation amount−R-formation amount) / (S-formation amount + R-formation amount) × 100 (e2)

  Here, the R form means (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonyl). Means amino) pentanol. The S form is (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino) pen Means Tanol.

HPLC condition B
Column: CHIRALPAK ID (4.6 mm × 250 mm, 5 μm)
Mobile phase: acetonitrile / diluted phosphoric acid solution (1 → 1000) = 65/35
Flow rate: 1.0 mL / min.
Temperature: 40 ° C
Detection wavelength: 210 nm
Retention time: (R) isomer; 18.9 minutes, (S) isomer; 20.2 minutes

Reference Example 3 Synthesis of 5-ethoxy-2-methoxymethoxybenzenethiol

5-Ethoxy-1,3-benzoxiathiol-2-one (10.00 g, 51.0 mmol) was added to a mixture of ethanol (10 mL) and water (50 mL). Sodium hydroxide (6.12 g, 153 mmol) was added to the mixture at an internal temperature of 12 to 28 ° C. The mixture was stirred at an internal temperature of 40 to 48 ° C. for 1.5 hours. The reaction solution was cooled, 35% aqueous hydrogen peroxide (2.25 mL, 25.5 mmol) was added at an internal temperature of 10 to 28 ° C., and the mixture was stirred at an internal temperature of 20 to 28 ° C. for 2 hours. The reaction mixture was cooled, 15 mL of concentrated hydrochloric acid was added at an internal temperature of 10 to 18 ° C., and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed sequentially with 10% sodium bisulfite (100 mL) and saturated brine (100 mL). The organic layer was dried using anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a brown oil (8.18 g).
The obtained brown oil (8.18 g) was dissolved in tetrahydrofuran (30 mL). N, N-diisopropylethylamine (16.5 g, 127 mmol) was added to the mixture at an internal temperature of 25 ° C., and chloromethyl methyl ether (7.7 mL, 101 mmol) was added at an internal temperature of 25 to 37 ° C. The mixture was stirred at an internal temperature of 55-62 ° C. for 4 hours. A saturated ammonium chloride solution (75 mL) and water (25 mL) were added to the reaction solution at an internal temperature of 11 to 26 ° C. The reaction solution was extracted with ethyl acetate (100 mL) and ethyl acetate (50 mL). The organic layers were combined, washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a brown oil (9.74 g).
Ethanol (54.0 mL) was added to the obtained brown oil (5.27 g), and sodium borohydride (2.61 g, 69.0 mmol) was added at an internal temperature of 30 to 40 ° C. The mixture was stirred at an internal temperature of 30 to 40 ° C. for 1 hour. The reaction solution was cooled, and water (53 mL) was added at an internal temperature of 15 to 25 ° C., and a mixed solution of ammonium chloride (10.5 g) and water (53 mL) was added at an internal temperature of 20 to 25 ° C. Extracted twice with diisopropyl ether (53 mL). The organic layers were combined and extracted with a mixture of sodium hydroxide (2.64 g) and water (54 mL), a mixture of sodium hydroxide (1.32 g) and water (27 mL). The aqueous layers were combined, and concentrated hydrochloric acid (8.4 mL) was added at an internal temperature of 15 to 20 ° C. The mixture was extracted with diisopropyl ether (53 mL), and the obtained extract was washed with saturated brine (26 mL) and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 5-ethoxy-2-methoxymethoxybenzenethiol (4.82 g, 69% yield).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 6.8 Hz), 3.51 (3H, s), 3.83 (1H, s), 3.96 (2H, q, J = 6.8 Hz), 5.16 (2H, s), 6.60-6.62 (1 H, m), 6.82 (1 H, d, J = 3.1 Hz), 7.00 (1 H, d, J = 8.7 Hz)

Reference Example 4 Synthesis of 4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorobenzaldehyde

2-Chloro-4-fluorobenzaldehyde (10.0 g, 63.1 mmol) was dissolved in N, N-dimethylformamide (50 mL), and potassium carbonate (13.1 g, 94.6 mmol) was added. The mixture was heated, and a solution of 5-ethoxy-2-methoxymethoxybenzenethiol (14.2 g, 66.2 mmol) in N, N-dimethylformamide (20 mL) was added dropwise at an internal temperature of 50 to 63 ° C. The mixture was stirred at an internal temperature of 50 to 56 ° C. for 1 hour, then cooled, and water (70 mL) was added at an internal temperature of 30 to 35 ° C. The reaction solution was stirred at an internal temperature of 20 to 30 ° C. for 0.5 hour, further cooled, and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour. The precipitate was collected by filtration and washed with water (80 mL). This was dried under reduced pressure at a preset temperature of 40 ° C. to obtain 4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorobenzaldehyde (22.2 g, 100% yield).
¹ H NMR (500 MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 6.9 Hz), 3.38 (3H, s), 3.99 (2H, q, J = 6.9 Hz), 5. 10 (2H, s), 6.96-6.99 (1H, m), 7.05-7.10 (3H, m), 7.19 (1H, d, J = 9.2 Hz), 7. 76 (1H, d, J = 8.4 Hz), 10.35 (1H, s)

Example 6 Synthesis of dimethyl 2- {2- [4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate

Synthesis was performed in the same manner as in Examples 1 and 2, using 4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorobenzaldehyde.
¹ H NMR (500 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.3 Hz), 1.23-1.28 (2H, m), 1.35 (3H, t, J = 7.3 Hz) ), 1.94-1.98 (2H, m), 2.04-2.15 (2H, m), 2.56-2.60 (2H, m), 3.44 (3H, s), 3.73 (6H, s), 3.91 (2H, J = 7.3 Hz), 5.11 (2H, s), 6.71 (1H, d, J = 3.1 Hz), 6.75- 6.78 (1H, m), 7.06 (1H, d, J = 9.2 Hz), 7.12-7.17 (2H, m), 7.31 (1H, d, J = 1.5 Hz) )

(Study on enzyme: Process 3)
In Table 1, various enzymes were used for the hydrolysis reaction of dimethyl 2- {2- [4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate. The comparison result is shown.

  The “conversion rate” described in Table 1 is a value calculated based on the following formula (e3) from the area percentage (%) of the obtained raw material and target product after measuring the reaction solution under the HPCL condition C shown below. It is. Here, the target product includes both the compound (R form) represented by the formula (15) and the enantiomer (S form) of the compound represented by the formula (15).

Conversion rate (%) = (HPLC area percentage of target product) / (HPLC percentage of remaining raw material + HPLC area percentage of target product) × 100 (%) (e3)

  “Optical purity” described in Table 1 is a value calculated based on the following formula (e4) from the areas of the R-form and S-form obtained by measuring the reaction solution under the HPLC condition D shown below. .

Optical purity (% ee) = (R-formation amount−S-formation amount) / (R-formation amount + S-formation amount) × 100 (%) (e4)

HPLC condition C (reaction monitor)
Precolumn: Inertsil ODS-3 (4.0 mm ID × 10 mm)
This column: Inertsil ODS-3 (4.6 mm ID × 150 mm, 3 μm)
Mobile phase: acetonitrile / diluted phosphoric acid (1 → 1000) = 70/30 → 95/5 (0 to 25 min.)
Temperature: 40 ° C
Flow rate: 1.0 mL / min
Measurement wavelength: 210 nm
Retention time: target product; 11.84 minutes, raw material; 19.55 minutes

HPLC condition D (optical purity)
Precolumn: Inertsil ODS-3 (4.0 mm ID × 10 mm)
This column: CHIRALPAK AD-3R (4.6 mm ID × 150 mm)
Mobile phase: acetonitrile / diluted phosphoric acid (1 → 1000) = 55/45
Temperature: 40 ° C
Flow rate: 1.0 mL / min
Detection wavelength: 210 nm
Retention time: (R) isomer; 11.82 minutes, (S) isomer; 16.08 minutes

(Example 7)
2- {2- [4- (2-methoxymethoxy-5-ethoxyphenylthio) -2-chlorophenyl was added to a mixed solution of Esterase from Porcine Liver (10.0 mg) and phosphate buffer (pH 7.0, 1.0 mL). A solution of dimethyl sulfoxide (100 μL) in dimethyl ethyl} -2-propylmalonate (10.0 mg) was added. The mixture was stirred at a set temperature of 40 ° C. for 24 hours. When the reaction solution was measured under HPLC condition D, the optical purity of the compound represented by the formula (15) was 99.5% ee.

(Example 8)
The conditions were the same as in Example 7 except that the ester from Rabbit river was used. When measured under HPLC condition D, the optical purity of the compound represented by formula (15) was 69.7% ee.

(Comparative Examples 1-26)
The same operation as in Example 7 was performed except that the enzymes shown in Table 1 were used. In Comparative Examples 1 to 26, the hydrolysis reaction did not proceed.

  As can be understood from the results shown in Table 1, when the esterase porcine liver, a porcine liver esterase, or the esterase rabbit antibody, a rabbit liver esterase, the hydrolysis reaction proceeds, but other enzymes are not used. When used, the reaction does not proceed at all. In particular, when Esterase from Porcine Liver was used, the compound represented by Formula (15) was obtained with higher optical purity.

  According to this embodiment, the novel manufacturing method of the diphenyl sulfide derivative containing the compound disclosed in patent document 1 can be provided. The production method of the present embodiment is inexpensive and a compound with high optical purity can be obtained. Therefore, according to the present embodiment, the diphenyl sulfide derivative can be advantageously produced industrially, and a high-quality pharmaceutical product can be provided.

Claims (7)

General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. A method for producing a compound represented by:
General formula (4):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. ] The manufacturing method of the compound represented by the said General formula (5) including carrying out asymmetric hydrolysis using the pig liver esterase or rabbit liver esterase. The compound represented by the general formula (4) is asymmetrically hydrolyzed using the porcine liver esterase,
The method of Claim 1 that the optical purity of the compound represented by the said General formula (5) obtained is 99% ee or more. General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. A method for producing a compound represented by:
General formula (1):
[Wherein R ¹ , R ² and R ³ are the same as defined above. By converting the compound represented by the general formula (2):
[Wherein R ¹ , R ² and R ³ are the same as defined above. To obtain a compound represented by
The compound represented by the general formula (2) is represented by the general formula (3):
[Wherein, R ⁴ and R ⁵ are the same as defined above. And a compound represented by the general formula (4):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. To obtain a compound represented by
A method for producing a compound represented by the general formula (5), comprising asymmetric hydrolysis of the compound represented by the general formula (4) using porcine liver esterase or rabbit liver esterase. General formula (9):

[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁶ represents an alkyl group having 1 to 6 carbon atoms].
General formula (4):
[Wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms, and R ¹ , R ² , R ³ and R ⁴ are the same as defined above. ] Is asymmetrically hydrolyzed using porcine liver esterase or rabbit liver esterase, and the general formula (5):
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above. To obtain a compound represented by
By subjecting the compound represented by the general formula (5) to a rearrangement reaction, the general formula (7):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as defined above]. To obtain a compound represented by
The manufacturing method of the compound represented by the said General formula (9) including reducing the compound represented by the said General formula (7). The compound represented by the general formula (4) is asymmetrically hydrolyzed using the porcine liver esterase,
The method of Claim 4 that the optical purity of the compound represented by the said General formula (9) obtained is 99.5% ee or more. General formula (5):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. ] The compound represented by this. General formula (4):
[Wherein R ¹ represents an alkoxy group having 1 to 6 carbon atoms;
R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R ³ represents a hydrogen atom or a halogen atom;
R ⁴ represents an alkyl group having 1 to 6 carbon atoms;
R ⁵ represents an alkyl group having 1 to 6 carbon atoms. ] The compound represented by this.