JP2009019004A - Process for producing optically active aryloxycarboxylic acid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a process of simply producing an optically active aryloxycarboxylic acid derivative useful as an intermediate of drugs from an inexpensive raw material. <P>SOLUTION: The optically active aryloxycarboxylic acid derivative can be obtained by the acid hydrolysis of an optically active aryloxycarboxylic acid ester derivative represented by formula (3). The optically active aryloxycarboxylic acid ester derivative represented by formula (3) can be obtained by reacting an α-bromocarboxylic acid ester derivative represented by formula (1) with an aryloxy derivative represented by formula (2). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active aryloxycarboxylic acid derivative. An optically active aryloxycarboxylic acid derivative is an important intermediate in the production of pharmaceuticals, agricultural chemicals and the like.

  General formula (4)

（式中、Ｒ^１は炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｒ^２は炭素数１から１２の置換されていても良いアルキル基、炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ａｒは置換もしくは無置換アリール基を表す。＊は不斉炭素を表す。）で表される光学活性アリールオキシカルボン酸誘導体は、例えば、立体選択的なアリールオキシ化反応により、α−ハロエステルより合成することができる。その方法としては、例えば
ｉ） α−ブロモエステルのエステル基をパントラクトンとした後、アリールオキシ化反応を行う方法（特許文献１、非特許文献１）
ｉｉ） α−ブロモエステルのエステル基を乳酸誘導体とした後、アリールオキシ化反応を行う方法（特許文献１、２、非特許文献２）
が知られている。

(In the formula, R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms. R ² represents a substituted group having 1 to 12 carbon atoms. Represents an optionally substituted alkyl group, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl group having 7 to 15 carbon atoms, and Ar represents a substituted or unsubstituted aryl group. * Represents an asymmetric carbon.) Can be synthesized from an α-haloester by, for example, a stereoselective aryloxylation reaction. As the method, for example, i) a method in which an ester group of α-bromoester is changed to pantolactone and then an aryloxylation reaction is performed (Patent Document 1, Non-Patent Document 1)
ii) A method in which an ester group of an α-bromoester is converted to a lactic acid derivative and then an aryloxylation reaction is performed (Patent Documents 1 and 2, Non-Patent Document 2)
It has been known.

Moreover, as a manufacturing method of (alpha) -bromo ester used for said reaction, for example,
iii) Method of converting α-ketocarboxylic acid and lactic acid derivative to α-ketoester, then reducing with sodium borohydride and then brominating hydroxyl group (Patent Document 1)
iv) Method of esterifying α-bromocarboxylic acid and pantolactone with a condensing agent (Non-patent Document 1)
v) Method of making α-bromo acid chloride from chlorophenylacetic acid and then reacting with lactic acid derivative (Patent Document 2)
It has been known.

Special table 2000-501737 WO2007 / 038243 Journal of Organic Chemistry 1994, 59, p4683 Journal of Medicinal Chemistry 2005, 48, p4457

  However, in the method i), the stereoselectivity of the aryloxylation reaction is not sufficiently high, and in the method ii), hydrogen peroxide is used for conversion to the carboxylic acid after the aryloxylation reaction. There are many problems in producing on an industrial scale. In addition, regarding the method for producing an α-bromoester compound serving as a substrate for the aryloxylation reaction, the methods iii) and iv) have a long number of steps, and the method v) has chlorine ions in the reaction system. The α-chloroester form is partially mixed with the product α-bromoester form.

  In view of the problems of the conventional methods described above regarding the production of optically active aryloxycarboxylic acids, which are important intermediates in the pharmaceutical field, etc., the present inventors are easy to handle industrially and are inexpensively available. We have intensively studied methods that can be operated safely even on a large scale using only possible raw materials and reagents. As a result, a method for producing an optically active aryloxycarboxylic acid by acid hydrolysis of an optically active aryloxycarboxylic acid ester derivative has been developed. The optically active aryloxycarboxylic acid ester derivative can be obtained by performing an aryloxylation reaction stereoselectively from an α-bromocarboxylic acid ester derivative having an ester group as an optically active alcohol derivative.

  That is, the present invention relates to the general formula (3)

（式中、Ｒ^１は炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｒ^２は炭素数１から１２の置換されていても良いアルキル基、炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ａｒは置換もしくは無置換アリール基を表す。Ｙは炭素数１から１２の置換されていても良いアルキルオキシ基、炭素数１から１２の置換されていても良いモノアルキルアミノ基、炭素数１から１２の置換されていても良いジアルキルアミノ基を表す。＊は不斉炭素を表す。）で表される光学活性アリールオキシカルボン酸エステル誘導体を酸加水分解することを特徴とする一般式（４）；

(In the formula, R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms. R ² represents a substituted group having 1 to 12 carbon atoms. Represents an optionally substituted alkyl group, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl group having 7 to 15 carbon atoms, and Ar represents a substituted or unsubstituted aryl group. Y represents an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, and an optionally substituted dialkylamino group having 1 to 12 carbon atoms. (* Represents an asymmetric carbon.) General formula (4) characterized by acid hydrolysis of an optically active aryloxycarboxylic acid ester derivative represented by:

（式中、Ｒ^１，Ａｒは前記に同じ。＊は不斉炭素を表す。）で表される光学活性アリールオキシカルボン酸誘導体の製造方法に関する。

(Wherein R ¹ and Ar are the same as above. * Represents an asymmetric carbon.), And relates to a method for producing an optically active aryloxycarboxylic acid derivative.

  In the above invention, the optically active aryloxycarboxylic acid ester derivative represented by the general formula (3) is represented by the general formula (1);

（式中、Ｒ^１は炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｒ^２は炭素数１から１２の置換されていても良いアルキル基、炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｙは炭素数１から１２の置換されていても良いアルキルオキシ基、炭素数１から１２の置換されていても良いモノアルキルアミノ基、炭素数１から１２の置換されていても良いジアルキルアミノ基を表す。＊は不斉炭素を表す。）で表されるα−ブロモカルボン酸エステル誘導体を、一般式（２）；

(In the formula, R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms. R ² represents a substituted group having 1 to 12 carbon atoms. Represents an optionally substituted alkyl group, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl group having 7 to 15 carbon atoms, and Y represents a substituted group having 1 to 12 carbon atoms. An alkyloxy group which may be substituted, a monoalkylamino group which may be substituted having 1 to 12 carbon atoms, and a dialkylamino group which may be substituted having 1 to 12 carbon atoms, * represents an asymmetric carbon; An α-bromocarboxylic acid ester derivative represented by general formula (2);

（式中、Ａｒは置換もしくは無置換アリール基を表し、Ｍはアルカリ金属またはアルカリ土類金属を表す。）で表されるアリールオキシ誘導体で処理することにより得るのが好ましい。

(In the formula, Ar represents a substituted or unsubstituted aryl group, and M represents an alkali metal or an alkaline earth metal).

In the above invention, the compound represented by the general formula (1) is:
i) General formula (5);

（式中、Ｒ^１は炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。）で表されるカルボン酸誘導体と、ＰＢｒ_３および臭素とを反応させて、一般式（６）；

(Wherein R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms), and PBr ₃ and bromine to give a general formula (6);

（式中、Ｒ^１は前記に同じ。）で表されるα−ブロモ酸ブロミド誘導体とし、
ｉｉ）該一般式（６）で表されるα−ブロモ酸ブロミド誘導体と、一般式（７）；

(Wherein, R ¹ is the same as defined above) an α-bromo acid bromide derivative represented by:
ii) an α-bromo acid bromide derivative represented by the general formula (6); and the general formula (7);

（式中、Ｒ^２は炭素数１から１２の置換されていても良いアルキル基、炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｙは炭素数１から１２の置換されていても良いアルキルオキシ基、炭素数１から１２の置換されていても良いモノアルキルアミノ基、炭素数１から１２の置換されていても良いジアルキルアミノ基を表す。＊は不斉炭素を表す。）で表される光学活性アルコール誘導体とを反応させてなることが好ましい。

(In the formula, R ² is an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl having 7 to 15 carbon atoms. Y represents an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, or a substituted one having 12 to 12 carbon atoms. It represents a good dialkylamino group. * Represents an asymmetric carbon.) It is preferably formed by reacting with an optically active alcohol derivative represented by:

  Further, the present application relates to a) the general formula (5);

（式中、Ｒ^１は炭素数６から１４の置換されていても良いアリール基を表す。）で表されるカルボン酸誘導体に、ＰＢｒ_３および臭素を反応させて、一般式（６）；

(Wherein R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms) PBr ₃ and bromine are reacted with the carboxylic acid derivative represented by the general formula (6);

（式中、Ｒ^１は前記に同じ。）で表されるα−ブロモ酸ブロミド誘導体とし、ｂ）該一般式（６）で表されるα−ブロモ酸ブロミド誘導体と、一般式（７）；

(Wherein R ¹ is the same as above), and b) an α-bromo acid bromide derivative represented by the general formula (6); and a general formula (7);

（式中、Ｒ^２は炭素数１から１２の置換されていても良いアルキル基、炭素数６から１４の置換されていても良いアリール基、炭素数７から１５の置換されていても良いアラルキル基を表す。Ｙは炭素数１から１２の置換されていても良いアルキルオキシ基、炭素数１から１２の置換されていても良いモノアルキルアミノ基、炭素数１から１２の置換されていても良いジアルキルアミノ基を表す。＊は不斉炭素を表す。）で表される光学活性アルコール誘導体とを反応させてなる一般式（１）；

(In the formula, R ² is an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl having 7 to 15 carbon atoms. Y represents an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, or a substituted one having 12 to 12 carbon atoms. A good dialkylamino group (* represents an asymmetric carbon), and a general formula (1) obtained by reacting with an optically active alcohol derivative represented by formula (1);

（式中、Ｒ^１、Ｒ^２，Ｙは前記に同じ。＊は不斉炭素を表す。）で表されるα−ブロモカルボン酸エステル誘導体の製造方法にも関する。

(Wherein R ¹ , R ² and Y are the same as above, * represents an asymmetric carbon), and also relates to a method for producing an α-bromocarboxylic acid ester derivative represented by:

  According to the production method of the present invention, an optically active aryloxycarboxylic acid derivative useful as an intermediate for pharmaceuticals and the like can be produced from a raw material that is easily available at low cost by a simple and highly safe method.

  Hereinafter, the present invention will be described in detail.

  In the present invention, the optically active aryloxycarboxylic acid ester derivative represented by the general formula (3) is converted into the optically active aryloxycarboxylic acid derivative represented by the general formula (4). As the optically active aryloxycarboxylic acid derivative, for example, as shown in the following reaction formula, (a) a carboxylic acid derivative represented by the general formula (5) is represented by α-bromo represented by the general formula (1). A step of converting into a carboxylic acid ester derivative, (b) a step of converting the α-bromocarboxylic acid ester derivative into an optically active aryloxycarboxylic acid ester derivative represented by the general formula (3), and (c) the optically active aryl. It can be obtained through a step of converting an oxycarboxylic acid ester derivative into an optically active aryloxycarboxylic acid derivative represented by the general formula (4).

まず、本反応に用いられる化合物について以下に説明する。

First, the compound used for this reaction is demonstrated below.

In the present specification, R ¹ in the general formulas (1) and (3) to (6) represents an optionally substituted aryl group having 6 to 14 carbon atoms. Specifically, phenyl group, 4-chlorophenyl group, 3-chlorophenyl group, 2-chlorophenyl group, 4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group, 4-bromophenyl group, 3-bromo Phenyl group, 2-bromophenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 2-trifluoromethylphenyl group, 1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3 -Methylphenyl group, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4-nitro Represents a phenyl group, a 4-phenylphenyl group, etc., preferably a phenyl group, a 4-chlorophenyl group 3-chlorophenyl group, a 4-methoxyphenyl group, a 4-methylphenyl group, more preferably represents a 4-chlorophenyl group.

R ² in the general formulas (1), (3) and (7) is an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, and a carbon number. 7 to 15 optionally substituted aralkyl groups are represented. Specific examples include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a phenyl group, a 4-methylphenyl group, a naphthyl group, and a benzyl group, preferably a methyl group, an ethyl group, a phenyl group, and a benzyl group. Group, more preferably a methyl group.

  Y in the general formulas (1), (3), and (7) is an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, It represents a dialkylamino group having 1 to 12 carbon atoms which may be substituted, and specifically includes a methoxy group, an ethoxy group, a t-butoxy group, a pyrrolidinyl group, a piperidinyl group, a morpholyl group, a dimethylamino group, a diethylamino group, a diamino group, A benzylamino group, a benzylamino group, and a t-butylamino group, preferably a pyrrolidinyl group, a piperidinyl group, and a morpholinyl group, and more preferably a pyrrolidinyl group.

  Ar in the general formulas (2) to (4) represents a substituted or unsubstituted aryl group, specifically a phenyl group, a 4-chlorophenyl group, a 3-chlorophenyl group, a 2-chlorophenyl group, a 4-fluorophenyl group, 3-fluorophenyl group, 2-fluorophenyl group, 4-bromophenyl group, 3-bromophenyl group, 2-bromophenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 2-trifluoro Methylphenyl group, 1-naphthyl group, 2-naphthyl group, 4-methylphenyl group, 3-methylphenyl group, 2-methylphenyl group, 4-ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4-nitrophenyl group, 4-phenylphenyl Nyl group, etc., preferably phenyl group, 4-chlorophenyl group, 3-chlorophenyl group, 4-methoxyphenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, more preferably 3 -Represents a trifluoromethylphenyl group.

  Next, these three steps (steps (a) to (c)) will be described in detail in the following order. In the present application, it is not necessary to perform all of these steps, and they can be performed independently.

1. Step (a)
In this step (a), the general formula (5)

で表されるカルボン酸誘導体に、ＰＢｒ_３および臭素を作用させ、一般式（６）

PBr ₃ and bromine are allowed to act on the carboxylic acid derivative represented by the general formula (6)

で表されるα−ブロモ酸ブロミド誘導体とした後、これに一般式（７）

And an α-bromoacid bromide derivative represented by the general formula (7)

で表される光学活性アルコール誘導体を作用させ、一般式（１）

And an optically active alcohol derivative represented by the general formula (1)

で表されるα−ブロモカルボン酸エステル誘導体を調製する。酸クロリドを経由する方法である参考例１ではα−クロロ体が副生するが、安価なＰＢｒ_３を使用するこの方法によれば、α−クロロ体の副生を回避することができる。

An α-bromocarboxylic acid ester derivative represented by the formula: In Reference Example 1, which is a method via acid chloride, an α-chloro compound is by-produced, but according to this method using inexpensive PBr ₃ , it is possible to avoid the by-production of the α-chloro compound.

The amount of PBr ₃ used in this step is 0.1 times mol to 2 mol per mol of the carboxylic acid derivative, preferably 0.3-fold molar amount to 1-fold molar amount.

  As the usage-amount of bromine, it is 1-10 molar equivalent with respect to a carboxylic acid derivative, Preferably it is 1-3 equivalent.

As a preparation method for the reaction, bromine may be added after reacting only PBr ₃ , or the reaction may be started in the presence of PBr ₃ and bromine from the beginning.

  The reaction temperature is preferably from 0 ° C to 160 ° C, more preferably from 40 ° C to 120 ° C, particularly preferably from 70 to 110 ° C.

  In this step, a reaction solvent is not particularly required, but an aprotic solvent can be used. Specifically, hydrocarbon solvents such as toluene, n-hexane and cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl t-butyl ether, dimethoxyethane and ethylene glycol dimethyl ether; methylene chloride, 1 , 2-dichloroethane, chlorobenzene, and other halogen-containing solvents; acetonitrile, acetamide, dimethylformamide, dimethylacetamide, and other nitrogen-containing solvents. A reaction without a solvent is preferred.

  After completion of the reaction, the optically active alcohol derivative represented by the general formula (7) can be reacted without isolation.

  The usage-amount of the compound represented by General formula (7) is 1-3 equivalent with respect to (alpha) -bromo acid bromide derivative, Preferably it is 1-1.5 equivalent.

  The reaction of the α-bromo acid bromide derivative and the compound represented by the general formula (7) proceeds without the presence of a base, but a base can also be used. The base to be used is not particularly limited. For example, amine bases such as triethylamine, N, N-diisopropylethylamine and pyridine, and inorganic bases such as potassium carbonate, sodium carbonate and lithium carbonate are preferable, and triethylamine is particularly preferable. Pyridine.

  Although there is no restriction | limiting in particular as the usage-amount of a base, 0.5-5 equivalent is preferable, Especially preferably, it is 1-1.5 equivalent.

  In the reaction between the α-bromo acid bromide derivative and the compound represented by the general formula (7), an aprotic solvent can be used as a solvent, but the solvent may not be used. Specifically, hydrocarbon solvents such as toluene, n-hexane and cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl t-butyl ether, dimethoxyethane and ethylene glycol dimethyl ether; methylene chloride, 1 , 2-dichloroethane, chlorobenzene, and other halogen-containing solvents; acetonitrile, acetamide, dimethylformamide, dimethylacetamide, and other nitrogen-containing solvents. Preferably, toluene and xylene can be used.

  The reaction temperature between the α-bromo acid bromide derivative and the general formula (7) is preferably 0 ° C to 160 ° C, more preferably 10 to 80 ° C.

  After completion of the reaction, the obtained reaction solution may be directly used in the next step, but a general post-treatment may be performed to isolate the product from the reaction solution. For example, after completion of the reaction, the pH of the reaction solution is adjusted as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. In addition, immediately after completion of the reaction, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and the same operation may be performed. After adding water as necessary, the reaction solvent may be distilled off.

2. Step (b)
In this step, the general formula (1)

で表されるα−ブロモカルボン酸エステル誘導体を一般式（２）

An α-bromocarboxylic acid ester derivative represented by the general formula (2)

で表されるアリールオキシ誘導体と反応させ、一般式（３）

Is reacted with an aryloxy derivative represented by the general formula (3)

で表される光学活性アリールオキシカルボン酸エステル誘導体に変換する。

Into an optically active aryloxycarboxylic acid ester derivative represented by

  The aryloxy derivative represented by the general formula (2) is prepared by allowing a base to act on a phenol derivative represented by ArOH.

  Examples of the base to be used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and barium hydroxide; lithium carbonate Alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrides such as lithium hydride and sodium hydride; lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide Metal alkoxides such as potassium t-butoxide and lithium t-butoxide; organolithiums such as n-butyllithium; organolithium amides such as lithium diisopropylamide; Grignards such as n-butylmagnesium chloride and t-butylmagnesium chloride Reagents; triethylamine, diisopropylethylamine, dicyclohexylamine, diisopropylamine, diethylamine, isopropylamine, n- butylamine, pyridine, and amines such as aniline. Preferred are alkali metal hydroxides, alkaline earth metal hydroxides and amines, and particularly preferred are t-butoxy lithium and lithium hydroxide.

  The method for preparing the aryloxy derivative represented by the general formula (2) is not particularly limited. For example, the aryloxy derivative may be prepared in an organic solvent and used for the reaction, or the α-bromoester derivative and ArOH may be mixed. A base may be added to the solution to generate in the reaction system.

  When a metal hydroxide or a hydrate thereof is used as a base when preparing the aryloxy derivative represented by the general formula (2), a corresponding amount of water is mixed in the system. In this case, after performing dehydration operations such as azeotropic dehydration and addition of a dehydrating agent, it may be reacted with the α-bromocarboxylic acid ester derivative represented by the general formula (1), or without performing the dehydration operation. The reaction may be performed in a water-containing state. That is, complicated operations such as azeotropic dehydration and addition of a dehydrating agent can be avoided, and the reaction can be performed simply. For example, lithium hydroxide monohydrate can be used as a base and subjected to the reaction without dehydration.

  The amount of the aryloxy derivative represented by the general formula (2) is not particularly limited, but when an excess aryloxy anion is present in the reaction system, the optical activity represented by the general formula (3) that is a product. Since the base carbon of the aryloxy group of the aryloxycarboxylic acid ester derivative may isomerize, use of an excessive amount unnecessarily may cause a decrease in yield and purity. Therefore, it is 0.8-1.5 molar equivalent normally with respect to the (alpha) -bromo carboxylic acid ester derivative represented by General formula (1), Preferably it is 0.9-1.1 molar equivalent.

  There is no restriction | limiting in particular in the solvent used at this process, For example, hydrocarbon type solvents, such as toluene, n-hexane, a cyclohexane; Diethyl ether, tetrahydrofuran, 1, 4- dioxane, methyl t-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether, etc. Ether solvents; halogen solvents such as methylene chloride, 1,2-dichloroethane, chlorobenzene; nitrogen-containing solvents such as acetonitrile, acetamide, dimethylformamide, dimethylacetamide; alcohol solvents such as methanol, ethanol, isopropanol, and t-butanol Etc. can be used. These may be used alone or in combination of two or more. Preferably, it is a mixed solvent of THF and toluene.

  In this step, it is not necessary to use an additive, but it is preferable to perform the reaction in the presence of iodine ions using the additive. Examples of the additive include inorganic salts such as lithium iodide, sodium iodide, potassium iodide, magnesium iodide, and calcium iodide, and four salts such as tetrabutylammonium iodide, tetrapentylammonium iodide, and tetrahexylammonium iodide. A class ammonium salt etc. can be mentioned. Preferred are sodium iodide, potassium iodide and tetrabutylammonium iodide, and particularly preferred is sodium iodide.

  The reaction temperature is preferably −50 ° C. to 50 ° C., more preferably −10 ° C. to 30 ° C., and particularly preferably −5 to 10 ° C.

  In this step, the α-bromocarboxylic acid ester derivative obtained in the above step can be used as a substrate.

  After completion of the reaction, the obtained reaction solution may be directly used in the next step, or a general post-treatment may be performed to isolate the product from the reaction solution. For example, after completion of the reaction, the pH of the reaction solution is adjusted as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. In addition, immediately after completion of the reaction, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and the same operation may be performed. After adding water as necessary, the reaction solvent may be distilled off.

3. Step (c)
In this step, the general formula (3)

で表される光学活性アリールオキシカルボン酸エステル誘導体を酸加水分解して、一般式（４）

An optically active aryloxycarboxylic acid ester derivative represented by the formula (4)

で表される光学活性アリールオキシカルボン酸誘導体に変換する。このように酸を用いることにより、参考例２に示される従来の過酸化水素水を用いた条件で問題となる、ラセミ化を抑制することが可能である。また、工業的規模の生産で問題となる過酸化水素の使用を回避できる。

Into an optically active aryloxycarboxylic acid derivative represented by By using an acid in this way, it is possible to suppress racemization, which is a problem under the conditions using the conventional hydrogen peroxide solution shown in Reference Example 2. In addition, the use of hydrogen peroxide, which is a problem in industrial scale production, can be avoided.

  The acid used in this step is not particularly limited, and examples include mineral acid, hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid and the like. be able to. In particular, methanesulfonic acid, sulfuric acid, hydrochloric acid, hydrochloric acid and acetic acid are preferably used.

  Although there is no restriction | limiting in particular as an equivalent of the acid to be used, 0.1 mol equivalent-100 mol equivalent are preferable with respect to an optically active aryloxycarboxylic acid ester derivative, More preferably, it is 1-20 mol equivalent.

  The reaction temperature is preferably 0 ° C to 150 ° C, more preferably 10 ° C to 80 ° C, and particularly preferably 20 to 80 ° C.

  In this step, it is not necessary to use a solvent, but it is also possible to use a solvent. Specifically, hydrocarbon solvents such as toluene, n-hexane and cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methyl t-butyl ether, dimethoxyethane, ethylene glycol dimethyl ether; methylene chloride, 1 Halogen-based solvents such as 1,2-dichloroethane and chlorobenzene; nitrogen-containing solvents such as acetonitrile, acetamide, dimethylformamide and dimethylacetamide; carboxylic acid solvents such as acetic acid and propionic acid can be used. Preferred are hydrophilic solvents such as acetonitrile, THF, acetone and acetic acid. These may be used alone or in combination of two or more.

  After completion of the reaction, the obtained reaction solution may be subjected to the next step, but in order to obtain a product from the reaction solution, a general post-treatment may be performed. For example, after completion of the reaction, the pH of the reaction solution is adjusted as necessary, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. In addition, immediately after completion of the reaction, the reaction solvent may be distilled off by an operation such as heating under reduced pressure, and the same operation may be performed. After adding water as necessary, the reaction solvent may be distilled off. Alternatively, after completion of the reaction, the pH of the reaction solution may be adjusted at a desired temperature, and the precipitated crystals may be filtered.

  The target product thus obtained is almost pure, but purification may be carried out by a general technique such as crystallization purification, fractional distillation, column chromatography, etc. to further increase the purity. The obtained object may be dried using a dryer or the like.

  The solvent used for crystallization is appropriately changed depending on the target compound. Examples of the solvent include pentane, hexane, heptane, octane, water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, benzene, toluene, xylene, trimethylbenzene, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, dimethyl ether, t-butyl methyl ether, acetonitrile, pro Examples include pionitrile, butyronitrile, acetone, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, and a mixed solvent of two or more of these.

  In addition, in this application, the compound represented by General formula (1) and the compound represented by General formula (3) do not necessarily need to be obtained by the process (a) or the process (b). Needless to say, those obtained by other methods can be used.

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

Example 1 (S) -N, N-tetramethylene lactamide

０℃に冷却した（Ｓ）−乳酸メチル（１３３ｇ、１．２８ｍｏｌ）にピロリジン（１００ｇ、１．４１ｍｏｌ）を添加し、室温で１３６時間撹拌した。その後、減圧濃縮を行ない、蒸留精製（１ｍｍＨｇ、１０４℃）により、（Ｓ）−Ｎ，Ｎ−テトラメチレン乳酸アミドを得た。（１５３ｇ、１．０７ｍｏｌ、８３％収率）
１Ｈ ＮＭＲ（ＣＤＣｌ_３）δ１．３４（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），１．８２−２．０３（ｍ，４Ｈ），３．３０−３．６１（ｍ，４Ｈ），４．３０（ｑ，Ｊ＝６．６Ｈｚ，１Ｈ）．

Pyrrolidine (100 g, 1.41 mol) was added to (S) -methyl lactate (133 g, 1.28 mol) cooled to 0 ° C. and stirred at room temperature for 136 hours. Thereafter, concentration under reduced pressure was performed, and (S) -N, N-tetramethylenelactic acid amide was obtained by distillation purification (1 mmHg, 104 ° C.). (153 g, 1.07 mol, 83% yield)
1H NMR (CDCl ₃ ) δ 1.34 (d, J = 6.6 Hz, 3H), 1.82-2.03 (m, 4H), 3.30-3.61 (m, 4H), 4.30 (Q, J = 6.6 Hz, 1H).

Example 2 1-Methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl-2-bromo-2- (4-chlorophenyl) acetate

４−クロロフェニル酢酸（１０．０ｇ、５８．６ｍｍｏｌ）に三臭化リン（６．４ｇ、２３．４ｍｍｏｌ）を添加し、１００℃まで昇温した。この溶液に臭素（１１．２ｇ、７０．３ｍｍｏｌ）を１時間かけて滴下し、１００℃で１４時間撹拌した。さらに臭素（３．０ｇ、１８．８ｍｍｏｌ）を添加し１００℃で３時間撹拌後、再び臭素（３．０ｇ、１８．８ｍｍｏｌ）を添加し１００℃で２．５時間撹拌した。室温まで冷却後、トルエン（２０ｍＬ）を添加し、続けて（Ｓ）−Ｎ，Ｎ−テトラメチレン乳酸アミド（９．２ｇ、６４．５ｍｍｏｌ）のトルエン溶液（２０ｍＬ）を添加した。さらにピリジン（６．０ｇ、７６．２ｍｍｏｌ）を滴下し、室温で１．５時間撹拌した。次に反応混合物を水（２０ｇ）で希釈し、有機層を取得した。水（２０ｇ）で有機層を洗浄後、無水硫酸マグネシウムを用いて乾燥した。減圧下で溶媒を留去することにより、２４．５ｇの油状物を得た（９６％収率、５６．１ｍｍｏｌ）。
１Ｈ ＮＭＲ（ＣＤＣｌ_３）δ１．４４（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．４８（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），１．８０−２．０２（ｍ，８Ｈ），３．３２−３．５８（ｍ，８Ｈ），５．２１−５．２７（ｍ，２Ｈ），５．４１（ｓ，１Ｈ），５．４２（ｓ，１Ｈ），７．３１−７．３５（ｍ，４Ｈ），７．４８−７．５３（ｍ，４Ｈ）．

Phosphorous tribromide (6.4 g, 23.4 mmol) was added to 4-chlorophenylacetic acid (10.0 g, 58.6 mmol), and the temperature was raised to 100 ° C. Bromine (11.2 g, 70.3 mmol) was added dropwise to this solution over 1 hour, followed by stirring at 100 ° C. for 14 hours. Further, bromine (3.0 g, 18.8 mmol) was added and stirred at 100 ° C. for 3 hours, bromine (3.0 g, 18.8 mmol) was added again, and the mixture was stirred at 100 ° C. for 2.5 hours. After cooling to room temperature, toluene (20 mL) was added, followed by the addition of a toluene solution (20 mL) of (S) -N, N-tetramethylene lactamide (9.2 g, 64.5 mmol). Further, pyridine (6.0 g, 76.2 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with water (20 g) to obtain an organic layer. The organic layer was washed with water (20 g) and then dried using anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure gave 24.5 g of an oil (96% yield, 56.1 mmol).
1H NMR (CDCl ₃ ) δ 1.44 (d, J = 6.8 Hz, 3H), 1.48 (d, J = 6.6 Hz, 3H), 1.80-2.02 (m, 8H), 3 .32-3.58 (m, 8H), 5.21-5.27 (m, 2H), 5.41 (s, 1H), 5.42 (s, 1H), 7.31-7.35 (M, 4H), 7.48-7.53 (m, 4H).

Example 3 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromo-2- (4-chlorophenyl) acetate 4-chlorophenylacetic acid (100.0 g, 586 mmol) with three odors Phosphorus bromide (64 g, 234 mmol) was added and the temperature was raised to 100 ° C. Bromine (141 g, 703 mmol) was added dropwise to this solution over 2 hours, and the mixture was stirred at 100 ° C. for 3.5 hours. Further bromine (9.4 g, 59 mmol) was added and stirred at 100 ° C. for 4 hours. After cooling to room temperature, toluene (200 g) was added, followed by addition of a solution of (S) -N, N-tetramethylenelactic acid amide (92 g, 645 mmol) in toluene (200 g) with water cooling. Then, pyridine (60 g, 762 mmol) was added dropwise and stirred at room temperature for 12 hours. Further, pyridine (4.6 g, 58 mmol) was added and stirred at room temperature for 2 hours, and then the reaction mixture was diluted with water (300 g) to obtain an organic layer. The organic layer was washed with water (200 g) and dried using anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 232.9 g of an oil (82% yield, 480 mmol).

Example 4 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid

ｔ−ブトキシリチウム（１．９ｇ、２３．８ｍｍｏｌ）のＴＨＦ溶液（４０ｍＬ）に３−（トリフルオロメチル）フェノール（４．２ｇ、２５．９ｍｍｏｌ）のトルエン溶液（４０ｍＬ）を添加し、室温で３０分間撹拌した。この溶液を、−１℃まで冷却した実施例２で得られた化合物（未精製品、８．１ｇ、２１．６ｍｍｏｌ）のトルエン溶液（３０ｍＬ）に９時間かけて滴下した。実施例２で得られた化合物より目的物への変換率は９４％であり、目的物のジアステレオ比は９８：２であった。この溶液に４規定塩酸０．２ｍＬを加えた後に２１ｇまで減圧濃縮を行なった。トルエン２６ｇを加え減圧濃縮を行ない、再びトルエン３５ｇを加え１８ｇまで減圧濃縮を行なった。その後、酢酸（１６．０ｇ）と３５％塩酸（４０ｇ）を添加し、６０℃で１１時間撹拌した。次に反応混合物にトルエン（４４ｇ）加え、抽出操作を行なった。得られた抽出液を水（３０ｇ）で３回洗浄し、無水硫酸マグネシウムを用いて乾燥した。減圧下で溶媒を留去することにより、９．１ｇの油状物を得た（１８．６ｍｍｏｌ、８６％収率、９２．２％ｅｅ）。
１Ｈ ＮＭＲ（ＣＤＣｌ_３）δ５．６４（ｓ，１Ｈ），７．０５（ｄｄ，Ｊ＝８．２，２．５Ｈｚ，１Ｈ），７．２０（ｓ，１Ｈ），７．２６（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３６−７．４０（ｍ，３Ｈ），７．５１（ｄｔ，Ｊ＝８．５，２．２Ｈｚ，２Ｈ）．

To a solution of t-butoxylithium (1.9 g, 23.8 mmol) in THF (40 mL) was added a toluene solution (40 mL) of 3- (trifluoromethyl) phenol (4.2 g, 25.9 mmol), and the mixture was stirred at room temperature for 30 minutes. Stir for minutes. This solution was added dropwise over 9 hours to a toluene solution (30 mL) of the compound obtained in Example 2 (unrefined product, 8.1 g, 21.6 mmol) cooled to −1 ° C. The conversion rate from the compound obtained in Example 2 to the target product was 94%, and the diastereo ratio of the target product was 98: 2. To this solution was added 0.2 mL of 4N hydrochloric acid, and the mixture was concentrated under reduced pressure to 21 g. 26 g of toluene was added and concentrated under reduced pressure, 35 g of toluene was added again, and the mixture was concentrated under reduced pressure to 18 g. Thereafter, acetic acid (16.0 g) and 35% hydrochloric acid (40 g) were added, and the mixture was stirred at 60 ° C. for 11 hours. Next, toluene (44 g) was added to the reaction mixture, and an extraction operation was performed. The obtained extract was washed three times with water (30 g) and dried using anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure gave 9.1 g of an oil (18.6 mmol, 86% yield, 92.2% ee).
1H NMR (CDCl ₃ ) δ 5.64 (s, 1H), 7.05 (dd, J = 8.2, 2.5 Hz, 1H), 7.20 (s, 1H), 7.26 (d, J = 7.8 Hz, 1 H), 7.36-7.40 (m, 3 H), 7.51 (dt, J = 8.5, 2.2 Hz, 2 H).

Example 5 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] t-butoxylithium acetate (42.0 g, 525 mmol) in THF solution (890 mL) was added 3- A toluene solution (910 mL) of (trifluoromethyl) phenol (92.9 g, 573 mmol) was added, and the mixture was stirred at room temperature for 1 hour. This solution was added dropwise to a toluene solution (660 mL) of the compound obtained in Example 2 (unrefined product, 178.9 g, 477 mmol) cooled to −1 ° C. over 12 hours. The conversion rate from the compound obtained in Example 2 to the target product was 94%, and the diastereo ratio of the target product was 97: 3. To this solution was added 4.0 mL of 4N hydrochloric acid, and the mixture was concentrated under reduced pressure to 356 g. Toluene 900 g was added and concentrated under reduced pressure, and toluene 900 g was added again and concentrated under reduced pressure to 395 g. Thereafter, acetic acid (357 g) and 35% hydrochloric acid (894 g) were added, and the mixture was stirred at 60 ° C. for 15 hours. Next, toluene (900 g) was added to the reaction mixture, and an extraction operation was performed. The obtained extract was washed 3 times with water (720 g) and dried using anhydrous magnesium sulfate. Distilling off the solvent under reduced pressure gave 210 g of an oil (434 mmol, 92% yield, 91.3% ee).

Example 6 1-Methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate

ｔ−ブトキシリチウム（４７２ｍｇ、５．９ｍｍｏｌ）のＴＨＦ溶液（８ｍＬ）に３−（トリフルオロメチル）フェノール（１．０４ｇ、６．４ｍｍｏｌ）のトルエン溶液（８ｍＬ）を添加し、室温で３０分間撹拌した。この溶液を、−１℃まで冷却した実施例２で得られた化合物（未精製品、２．０ｇ、５．３ｍｍｏｌ）とヨウ化ナトリウム（８０ｍｇ、０．５３ｍｍｏｌ）のトルエン溶液（６ｍＬ）に５時間かけて滴下し、３０分撹拌した。実施例２で得られた化合物より目的物への変換率は９９％であり、目的物のジアステレオ比は９９：１であった。

To a solution of t-butoxylithium (472 mg, 5.9 mmol) in THF (8 mL) was added a toluene solution (8 mL) of 3- (trifluoromethyl) phenol (1.04 g, 6.4 mmol) and stirred at room temperature for 30 minutes. did. This solution was cooled to −1 ° C. in a toluene solution (6 mL) of the compound obtained in Example 2 (unrefined product, 2.0 g, 5.3 mmol) and sodium iodide (80 mg, 0.53 mmol). The solution was added dropwise over time and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 99%, and the diastereo ratio of the target product was 99: 1.

Example 7 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate lithium hydroxide monohydrate A toluene solution (6 mL) of 3- (trifluoromethyl) phenol (1.32 g, 8.2 mmol) was added to a THF solution (4 mL) of the Japanese product (313 mg, 7.5 mmol), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, 8 mL of THF and 8 mL of toluene were added. This solution was cooled to −1 ° C. in a toluene solution (6 mL) of the compound obtained in Example 2 (unrefined product, 2.0 g, 5.3 mmol) and sodium iodide (80 mg, 0.53 mmol). The solution was added dropwise over time and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 94%, and the diastereo ratio of the target product was 99: 1.

Example 8 1-Methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate t- butoxylithium ( A toluene solution (8 mL) of 3- (trifluoromethyl) phenol (1.04 g, 6.4 mmol) was added to a THF solution (8 mL) of 472 mg, 5.9 mmol), and the mixture was stirred at room temperature for 30 minutes. This solution was cooled to −1 ° C. in toluene solution (6 mL) of the compound obtained in Example 2 (unrefined product, 2.0 g, 5.3 mmol) and tetrabutylammonium iodide (197 mg, 0.53 mmol). Over 3 hours, and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 97%, and the diastereo ratio of the target product was 99: 1.

Example 9 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate t- butoxylithium ( A toluene solution (8 mL) of 3- (trifluoromethyl) phenol (1.04 g, 6.4 mmol) was added to a THF solution (8 mL) of 472 mg, 5.9 mmol), and the mixture was stirred at room temperature for 30 minutes. This solution was cooled to −1 ° C. in a toluene solution (6 mL) of the compound obtained in Example 2 (unpurified product, 2.0 g, 5.3 mmol) and tetrabutylammonium bromide (172 mg, 0.53 mmol). The solution was added dropwise over 6 hours and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 95%, and the diastereo ratio of the target product was 98: 2.

Example 10 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate LiOH.H ₂ O A toluene solution (6 mL) of 3- (trifluoromethyl) phenol (1.32 g, 8.2 mmol) was added to a THF solution (4 mL) of (314 mg, 7.5 mmol), and stirred at room temperature for 1 hour. After concentration under reduced pressure, 8 mL of THF and 8 mL of toluene were added. This solution was cooled to −1 ° C. in a toluene solution (6 mL) of the compound obtained in Example 2 (unrefined product, 2.0 g, 5.3 mmol) and sodium iodide (80 mg, 0.53 mmol). The solution was added dropwise over time and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 94%, and the diastereo ratio of the target product was 99: 1.

Example 11 1-Methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate LiOH.H ₂ O A toluene solution (4 mL) of 3- (trifluoromethyl) phenol (1.13 g, 6.9 mmol) was added to a THF solution (4 mL) of (269 mg, 6.4 mmol), and the mixture was stirred at room temperature for 1 hour. This solution was cooled to −1 ° C. in a toluene solution (6 mL) of the compound obtained in Example 2 (unrefined product, 2.0 g, 5.3 mmol) and sodium iodide (80 mg, 0.53 mmol). The solution was added dropwise over time and stirred for 30 minutes. The conversion rate from the compound obtained in Example 2 to the target product was 96%, and the diastereo ratio of the target product was 98: 2.

Example 12 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid

１−メチル−２−オキソ−２−テトラヒドロ−１−Ｈ−１−ピロリルエチル ２−［３−（トリフルオロメチル）フェノキシ］−２−（４−クロロフェニル）アセテート（６０．８ｍｇ、０．１３ｍｍｏｌ、ジアステレオ比９７：３）にアセトニトリル１ｍＬと３５％塩酸０．５ｍＬを加えて室温で１００時間撹拌することにより、変換率１００％で、光学純度９３％ｅｅの（Ｒ）−２−（４−クロロフェニル）−２−［３−（トリフルオロメチル）フェノキシ］酢酸を得た。

1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (60.8 mg, 0.13 mmol, dia By adding 1 mL of acetonitrile and 0.5 mL of 35% hydrochloric acid to stereo ratio 97: 3) and stirring at room temperature for 100 hours, (R) -2- (4-chlorophenyl) having a conversion rate of 100% and an optical purity of 93% ee ) -2- [3- (trifluoromethyl) phenoxy] acetic acid was obtained.

Example 13 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2 -[3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (60.8 mg, 0.13 mmol, diastereo ratio 97: 3) was added 1 mL of acetone and 0.5 mL of 35% hydrochloric acid at room temperature. (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid having a conversion rate of 95% and an optical purity of 92% ee was obtained.

Example 14 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2 -To [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (60.8 mg, 0.13 mmol, diastereo ratio 97: 3), 1 mL of acetic acid and 0.5 mL of 50% sulfuric acid were added at room temperature. (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid having a conversion rate of 97% and an optical purity of 93% ee was obtained.

Example 15 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2 -[3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (60.8 mg, 0.13 mmol, diastereo ratio 97: 3) with 1 mL acetic acid, 0.5 mL water, and methanesulfonic acid 0 (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] having an optical conversion rate of 97% and an optical purity of 94% by adding 5 mL and stirring at room temperature for 22 hours Acetic acid was obtained.

Example 16 (R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2 -To [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (60.8 mg, 0.13 mmol, diastereo ratio 97: 3), 1 mL of acetic acid and 0.5 mL of 35% hydrochloric acid were added to add 40 By stirring at ° C for 20 hours, (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid having a conversion rate of 100% and an optical purity of 92% ee was obtained.

Example 17 Crystallization of (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid

（Ｒ）−２−（４−クロロフェニル）−２−［３−（トリフルオロメチル）フェノキシ］酢酸（２．９ｇ、８．９ｍｍｏｌ、９２．３％ｅｅ）の５０％トルエン溶液にヘキサン（３ｇ）を滴下し、室温で１時間撹拌した。その後、ヘキサン（９ｇ）を添加し、さらに室温で１時間撹拌した。析出した結晶を濾取し、ヘキサン／トルエン＝１０／１溶液で洗浄後、減圧下で乾燥することにより白色固体を得た（２．２ｇ、６．７ｍｍｏｌ、７５％収率、９９．３％ｅｅ）

(R) -2- (4-Chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid (2.9 g, 8.9 mmol, 92.3% ee) in 50% toluene solution with hexane (3 g) Was added dropwise and stirred at room temperature for 1 hour. Thereafter, hexane (9 g) was added, and the mixture was further stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with a hexane / toluene = 10/1 solution, and dried under reduced pressure to obtain a white solid (2.2 g, 6.7 mmol, 75% yield, 99.3%). ee)

Example 18 Crystallization of (R) -2- (4 -chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid (R) -2- (4-chlorophenyl) -2- [3- (Trifluoromethyl) phenoxy] hexane (12 g) was added dropwise to a 50% toluene solution of acetic acid (3.0 g, 9.1 mmol, 92.3% ee), stirred at room temperature for 1 hour, and then at -2 ° C for 1 hour. Stir. The precipitated crystals were collected by filtration, washed with a hexane / toluene = 10/1 solution, and dried under reduced pressure to obtain a white solid (2.5 g, 7.6 mmol, 84% yield, 99.4%). ee)

Example 19 Crystallization of (R) -2- (4 -chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid (R) -2- (4-chlorophenyl) -2- [3- Hexane (64 g) was added dropwise to a (trifluoromethyl) phenoxy] acetic acid (128 g, 387 mmol, 91.3% ee) 50% toluene solution and stirred at room temperature for 4 hours. Thereafter, hexane (128 g) was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with a hexane / toluene = 10/1 solution, and dried under reduced pressure to obtain a white solid (75.0 g, 228 mmol, 59% yield, 99.3% ee).

(Reference Example 1)
1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromo-2- (4-chlorophenyl) acetate 4-chlorophenylacetic acid (10.0 g, 58.6 mmol) to 1,2-dichloroethane 29 mL, DMF 0.02 mL, and thionyl chloride (9.1 g, 76 mmol) were added, and the mixture was stirred at 70 ° C. for 2 hours. Thereafter, bromine (14.5 g, 90.8 mmol) was added dropwise, and the mixture was stirred at 85 ° C. for 17 hours. After cooling to room temperature, 43 mL of 1,2-dichloroethane was added, and the mixture was concentrated under reduced pressure to about 40 mL. This acid chloride solution was added dropwise at 0 ° C. to a 1,2-dichloroethane solution (43 mL) of (S) —N, N-tetramethylenelactic acid amide (8.6 g, 60 mmol) and triethylamine (6.3 g, 62 mmol). After heating up to room temperature over 1 hour, it stirred at the same temperature for further 4 hours. The reaction mixture was diluted with 50 mL of water to obtain an organic layer. Further, the organic layer was washed with 50 mL of 10% Na ₂ S ₂ O ₃ aqueous solution and 50 mL of saturated NaHCO ₃ solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-methyl-2-oxo-2-tetrahydro -1-H-1-pyrrolylethyl 2-bromo-2- (4-chlorophenyl) acetate was obtained (61% yield. 17 mol% of 1-methyl-2-oxo-2-tetrahydro-1-H-1- Pyrrolylethyl 2-chloro-2- (4-chlorophenyl) acetate was contaminated).

(Reference Example 2)
To a solution of LiOH · 1H ₂ O 110 mg in water 2.6 mL, 30% hydrogen peroxide 0.5 mL was added at 0 ° C. and stirred for 1 hour. This solution was dissolved in 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2- [3- (trifluoromethyl) phenoxy] -2- (4-chlorophenyl) acetate (506.8 mg, 1. 05 mmol, diastereo ratio 97: 3) was slowly added dropwise to a THF 2 mL solution, and the mixture was further reacted for 2 hours. The reaction was stopped with 1 mL of saturated aqueous sodium hydrogen sulfite solution, and the pH of the aqueous layer was adjusted to 2 with 1N hydrochloric acid. When 10 mL of toluene was added for extraction, (R) -2- (4-chlorophenyl) -2- [3- (trifluoromethyl) phenoxy] acetic acid was obtained with a conversion rate of 99% and an optical purity of 89% ee.

Claims (18)

General formula (3)

(In the formula, R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms. R ² represents a substituted group having 1 to 12 carbon atoms. Represents an optionally substituted alkyl group, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl group having 7 to 15 carbon atoms, and Ar represents a substituted or unsubstituted aryl group. Y represents an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, and an optionally substituted dialkylamino group having 1 to 12 carbon atoms. (* Represents an asymmetric carbon.) General formula (4) characterized by acid hydrolysis of an optically active aryloxycarboxylic acid ester derivative represented by:

(Wherein R ¹ and Ar are the same as above. * Represents an asymmetric carbon.) A process for producing an optically active aryloxycarboxylic acid derivative represented by: The production method according to claim 1, wherein R ² is a methyl group. The production method according to claim 1 or 2, wherein Y is a pyrrolidinyl group. The production method according to claim 1, wherein R ¹ is a 4-chlorophenyl group. Ar is a 3-trifluoromethyl-phenyl group, The manufacturing method in any one of Claims 1-4. The production method according to claim 1, wherein the acid hydrolysis is performed using any one or more of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid. The manufacturing method of Claim 6 which uses hydrochloric acid for acid hydrolysis. The optically active aryloxycarboxylic acid ester derivative represented by the general formula (3) is represented by the general formula (1);

(In the formula, R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms. R ² represents a substituted group having 1 to 12 carbon atoms. Represents an optionally substituted alkyl group, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl group having 7 to 15 carbon atoms, and Y represents a substituted group having 1 to 12 carbon atoms. An alkyloxy group which may be substituted, a monoalkylamino group which may be substituted having 1 to 12 carbon atoms, and a dialkylamino group which may be substituted having 1 to 12 carbon atoms, * represents an asymmetric carbon; An α-bromocarboxylic acid ester derivative represented by general formula (2);

(Wherein Ar represents a substituted or unsubstituted aryl group, and M represents an alkali metal or an alkaline earth metal). The manufacturing method of the optically active aryloxycarboxylic acid derivative represented by General formula (4) in any one of these. The production method according to claim 8, wherein the reaction of the compound represented by the general formula (1) and the aryloxy derivative represented by the general formula (2) is performed in a solvent containing toluene. The production method according to claim 8 or 9, wherein the reaction of the compound represented by the general formula (1) and the aryloxy derivative represented by the general formula (2) is performed in the presence of iodine ions. M of the aryloxy derivative represented by General formula (2) is lithium, The manufacturing method in any one of Claims 8-10. The production method according to any one of claims 8 to 11, wherein any of t-butoxy lithium, lithium hydroxide, and lithium carbonate is used for the preparation of the aryloxy derivative represented by the general formula (2). The production method according to any one of claims 8 to 12, wherein the reaction of the compound represented by the general formula (1) and the aryloxy derivative represented by the general formula (2) is performed in the presence of water. The compound represented by the general formula (1)
i) General formula (5);

(Wherein R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms), and PBr ₃ and bromine to give a general formula (6);

(Wherein, R ¹ is the same as defined above) an α-bromo acid bromide derivative represented by:
ii) an α-bromo acid bromide derivative represented by the general formula (6); and the general formula (7);

(In the formula, R ² is an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl having 7 to 15 carbon atoms. Y represents an optionally substituted alkyloxy group having 1 to 12 carbon atoms, an optionally substituted monoalkylamino group having 1 to 12 carbon atoms, or a substituted one having 12 to 12 carbon atoms. 14 represents a good dialkylamino group, * represents an asymmetric carbon), and is reacted with an optically active alcohol derivative represented by the general formula (4) according to any one of claims 8 to 13; The manufacturing method of the optically active aryloxycarboxylic acid derivative represented by this. i) General formula (5);

(Wherein R ¹ represents an optionally substituted aryl group having 6 to 14 carbon atoms and an optionally substituted aralkyl group having 7 to 15 carbon atoms) and PBr ₃ and bromine are reacted to give a general formula (6);

(Wherein, R ¹ is the same as defined above)
ii) an α-bromo acid bromide derivative represented by the general formula (6); and the general formula (7);

(In the formula, R ² is an optionally substituted alkyl group having 1 to 12 carbon atoms, an optionally substituted aryl group having 6 to 14 carbon atoms, and an optionally substituted aralkyl having 7 to 15 carbon atoms. Y represents an alkyloxy group having 1 to 12 carbon atoms which may be substituted, a monoalkylamino group having 1 to 12 carbon atoms which may be substituted, or a substituent having 1 to 12 carbon atoms It represents a good dialkylamino group. * Represents an asymmetric carbon.), Which is reacted with an optically active alcohol derivative represented by the general formula (1)

(Wherein R ¹ , R ² and Y are the same as above. * Represents an asymmetric carbon.) A method for producing an α-bromocarboxylic acid ester derivative represented by: The production method according to claim 15, wherein R ² is a methyl group. The production method according to claim 15 or 16, wherein Y is a pyrrolidinyl group. The production method according to claim 15, wherein R ¹ is a 4-chlorophenyl group.