WO2009139438A1

WO2009139438A1 - Process for production of optically active carboxylic acid

Info

Publication number: WO2009139438A1
Application number: PCT/JP2009/058988
Authority: WO
Inventors: 和利菅原; 將太利川
Original assignee: 田辺三菱製薬株式会社
Priority date: 2008-05-15
Filing date: 2009-05-14
Publication date: 2009-11-19

Abstract

Disclosed is a process for producing an optically active carboxylic acid from a racemic carboxylic acid in a conventional production facility with high efficiency and at low cost. Specifically disclosed is a process for producing an optically active carboxylic acid represented by formula (1). The process comprises: dehydrating a carboxylic acid represented by formula (2) to produce a ketene compound; and reacting the ketene compound with D-(-)-pantolactone to hydrolyze the ketene compound. [In the formulae, R¹ represents an aryl which may be substituted, a heteroaryl which may be substituted, a cycloalkyl which may be substituted, or a heterocyclic group which may be substituted; R² represents an alkyl which may be substituted, a cycloalkyl which may be substituted, an aryl which may be substituted, a heteroaryl which may be substituted, -N(C_0-2-alkyl)(C_0-2-alkyl) or a cyclic amino; and R³ represents a hydrogen atom, a halogen atom or a trifluoromethyl.

Description

Process for producing optically active carboxylic acid

The present invention relates to a method for producing optically active carboxylic acid from racemic carboxylic acid.

A phenylacetamide derivative represented by the following formula is known as a compound having a glucokinase activating action and useful as a therapeutic agent for diabetes (Patent Documents 1 to 10).

[Wherein, R ¹ represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, or an optionally substituted heterocyclic group.
R ² is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —N (C _0-2 alkyl) (C _{0 -2} alkyl) or cyclic amino.
R ³ represents a hydrogen atom, a halogen atom or trifluoromethyl.
R ⁴ and R ⁵ independently represent a hydrogen atom, a halogen atom, OCF _n H _3-n , methoxy, CO ₂ R ⁶ , cyano, nitro, CHO, CONR ⁷ R ⁸ , CON (OCH ₃ ) CH ₃ Or C _1-2 alkyl, heteroaryl or C _3-7 cycloalkyl [these groups are halogen atoms, hydroxyl groups, cyano, methoxy, —NHCO ₂ CH ₃ and —N (C _0-2 alkyl) (C Or optionally substituted with 1 to 5 substituents independently selected from the group of _0-2 alkyl), or R ⁴ and R ⁵ are bonded together to form a carbonyl group Or after forming a 5- to 8-membered aromatic, heteroaromatic, carbocyclic or heterocyclic ring, it is condensed with the ring formed by T and -N = C-.
R ⁶ represents a hydrogen atom, or C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these Groups of: halogen atom, cyano, nitro, hydroxyl group, C _1-2 alkoxy, —N (C _0-2 alkyl) (C _0-2 alkyl), C _1-2 alkyl, C _3-7 cycloalkyl, 4 To 7-membered heterocyclic group, CF _n H _3-n , aryl, heteroaryl, CO ₂ H, —COC _1-2 alkyl, —CON (C _0-2 alkyl) (C _0-2 alkyl), SOCH ₃ , Optionally substituted with 1 to 6 substituents independently selected from the group of SO ₂ CH ₃ and —SO ₂ N (C _0-2 alkyl) (C _0-2 alkyl)] To express.
R ⁷ and R ⁸ independently represent a hydrogen atom, or C _1-4 alkyl, C _3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these groups are halogen Atom, cyano, nitro, hydroxyl group, C _1-2 alkoxy, —N (C _0-2 alkyl) (C _0-2 alkyl), C _1-2 alkyl, C _3-7 cycloalkyl, _4-7 membered heterocycle Groups, CF _n H _3-n , aryl, heteroaryl, COC _1-2 alkyl, —CON (C _0-2 alkyl) (C _0-2 alkyl), SOCH ₃ , SO ₂ CH ₃ and —SO ₂ N ( C _0-2 alkyl) (optionally substituted with 1 to 6 substituents independently selected from the group of C _0-2 alkyl), or R ⁷ and R ⁸ are 6-8 together with the N atom to which they are bonded Bicyclo nitrogen-containing heterocyclic group or a 4-8-membered nitrogen-containing Hajime Tamaki [these _{groups, C 1-2} _alkyl, independently from the group consisting of CH ₂ OCH _{3, COC 0-2} alkyl, hydroxyl and _SO 2 CH ₃ Optionally substituted with 1 to 2 substituents optionally selected].
n represents 1, 2 or 3.
T represents a heteroaromatic ring or a heterocyclic ring together with —N═C— to which it is bonded [only the N═C bond is an unsaturated site]. ]

The phenylacetamide derivative has an asymmetric carbon (marked with *), and among the optical isomers related to the asymmetric carbon, R ¹ —CH ₂ group (hereinafter, R ¹ -methyl group) is shown in the figure. It is known that β-coordinate isomers in the structural formula have high glucokinase activity.
A method for producing an optically active phenylacetamide derivative in which the R ¹ -methyl group is β-coordinated is described in, for example, Patent Documents 1, 5 and 9. In Patent Document 1, a racemic carboxylic acid of formula (2) is reacted with (R)-(+)-4-benzyl-2-oxazolidinone to form an imide of a diastereo mixture, which is separated by column chromatography and then hydrolyzed. Thus, an optically active carboxylic acid of the formula (1) is produced, and an optically active phenylacetamide derivative is produced by further amidation.

[Wherein, R ¹ , R ² and R ³ have the same meanings as described above. ]
In addition, a method is described in which the racemic carboxylic acid of the formula (2) is used as it is, and a racemic phenylacetamide derivative is introduced and separated by chiral HPLC. However, since these methods use column chromatography, they are not suitable for mass production, and only one optical isomer is extracted from the racemate, so that the yield does not exceed 50%.
In Patent Document 5, as described below, an asymmetric induction is attempted by alkylating and hydrolyzing an amide compound of a phenylacetate compound unsubstituted at the benzyl position and (1R, 2R)-(−)-pseudoephedrine. ing. However, the asymmetric yield is not described.

Patent Documents 8 and 10 also report similar reactions. However, none of the patent documents describes the degree of asymmetric induction.
In Patent Document 9, an optically active carboxylic acid is produced by hydrogenating an olefin compound in the presence of an asymmetric catalyst.

[Wherein, R ² has the same meaning as described above. ]
However, since a high hydrogen pressure of 50 bar is required, there is a problem that it cannot be produced by ordinary production equipment, and the catalyst and asymmetric ligand used are both expensive.

Non-Patent Documents 1 to 7 disclose that an optically active carboxylic acid is obtained by reacting a ketene compound derived from a racemic carboxylic acid represented by the following formula or the like with D-(-)-pantolactone or a lactic acid ester and hydrolyzing it. A method for producing an acid is described.
[Wherein, R is a hydrogen atom, methyl, isopropyl, phthaloylamino- (CH ₂ ) _m —, etc. (m is 0, 1 or 2). Phenyl is unsubstituted or phenyl substituted at the 4-position by methoxy, nitro, isobutyl or the like, or is replaced with methoxynaphthyl. ]
According to these non-patent documents, the chemical yield and asymmetric yield of this reaction may vary greatly depending on the compound and conditions. For example, with respect to phenyl, although the asymmetric yield did not decrease so much even when methoxy, nitro, or isobutyl was substituted at the 4-position in Non-Patent Document 1, diastereomeric excess was observed in the compound in which phenyl was changed to 6-methoxynaphthyl. The rate dropped to 80% de. Regarding R, in Non-Patent Documents 3 to 5, m is 0 in a reaction using a racemic carboxylic acid (m is 0, 1 or 2) in which R is phthaloylamino- (CH ₂ ) _m —. In the case (yield 88% / diastereomer excess 94% de), m is 1 (yield 75% / diastereomer excess 70% de), m is 2 (yield 78% / dia) Only when m is 1 at a stereomer excess of 94% de), the asymmetric yield was extremely reduced. That is, it is not easy for those skilled in the art to predict what chemical yield and asymmetric yield can be obtained with which compound in this reaction, and racemic compounds in which R is a cyclic group and sulfonyl is substituted phenyl. It was unclear if high asymmetric induction occurred with carboxylic acids.

WO 00/58293 WO 02/46173 WO 03/095438 WO 2004/050645 WO 2004/052869 WO 2004/072031 WO 2005/103021 WO 2006/016194 WO 2006/016178 WO 2007/051846

The problem to be solved by the present invention is to provide a method for producing optically active carboxylic acid from racemic carboxylic acid with a normal production facility at a good yield and at a low cost.

In order to solve the above-mentioned problems, the present inventors have conducted intensive research. As a result, the racemic carboxylic acid of the formula (2) is dehydrated into a ketene compound, reacted with D-(-)-pantolactone, and hydrolyzed. The present invention was completed by finding that the optically active carboxylic acid of the formula (1) was produced with high yield and asymmetric yield.

That is, the present invention is as follows.
[1] A process for producing an optically active carboxylic acid of the formula (1) by dehydrating the carboxylic acid of the formula (2) into a ketene compound, reacting with D-(−)-pantolactone and hydrolyzing it.

[Wherein, R ¹ , R ² and R ³ have the same meanings as described above. ]
[2] A process for producing an optically active carboxylic acid of the formula (1) by reacting a ketene compound of the formula (2a) with D-(−)-pantolactone and hydrolyzing it.

[Wherein, R ¹ , R ² and R ³ have the same meanings as described above. ]
[3] The carboxylic acid of formula (2) is dehydrated to form a ketene compound, reacted with D-(-)-pantolactone, and hydrolyzed to produce an optically active carboxylic acid of formula (1). A method for producing a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof by condensing with an amine of (3).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and T are as defined above]. ]
[4] A ketene compound of the formula (2a) and D-(−)-pantolactone are reacted and hydrolyzed to produce an optically active carboxylic acid of the formula (1), followed by an amine of the formula (3) and A process for producing a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof by condensation.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and T are as defined above]. ]
[5] The production method according to any one of [1] to [4], wherein R ¹ is 4-tetrahydropyranyl, R ² is cyclopropyl or cyclobutyl, and R ³ is a hydrogen atom.

“Alkyl” includes, for example, C _1-6 , preferably C _1-4 linear or branched alkyl, specifically methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, And hexyl. _Also, _{C 0-4} denotes an alkyl carbon number of 0, 1, 2, 3 or 4 in the _{C 0-4} alkyl etc., it means a hydrogen atom and alkyl 0 carbon atoms (alkenyl, alkynyl, The same meaning is also applied to cycloalkyl and the like).
“Cycloalkyl” includes, for example, C _3-8 , preferably C _3-6 cycloalkyl, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

Examples of “aryl” include phenyl and naphthyl, with phenyl being particularly preferred.
Examples of the “heterocyclic group” include a 4- to 8-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. May be oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, azetinyl, pyrrolidinyl, piperidinyl, azepanyl, dioxolanyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl and the like. Examples of the “4- to 8-membered nitrogen-containing heterocyclic group” include heterocyclic groups containing a 4- to 8-membered nitrogen atom among the above heterocyclic groups. Examples of the “6- to 8-membered bicyclo nitrogen-containing heterocyclic group” include cyclohexanothiazolyl, dihydrothiazolopyridinyl, thiazolopyridinyl and the like. In the heterocyclic group containing a sulfur atom, the sulfur atom may be oxidized with 1 or 2 oxygen atoms.
“Heteroaryl” includes 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from oxygen, sulfur and nitrogen atoms, specifically furyl, thienyl, Examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
“Cyclic amino” includes a “heterocyclic group” having a nitrogen atom and a group substituted with the nitrogen atom. Specific examples include pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl and the like.

As each substituent of “substituted aryl”, “substituted heteroaryl”, “substituted cycloalkyl” and “substituted heterocyclic group” in R ¹ , a hydroxyl group, a halogen atom, cyano, nitro, vinyl, ethynyl, methoxy, OCF _n H _3-n , —N (C _0-2 alkyl) (C _0-2 alkyl), CHO, C _1-2 alkyl [alkyl is a halogen atom, hydroxyl group, cyano, methoxy, —N (C _0-2 alkyl) ) (C _0-2 alkyl), optionally substituted with 1 to 5 substituents independently selected from the group of —SOCH ₃ and —SO ₂ CH ₃ ], and the like. One or two substituents may be substituted. In addition, when two such substituents are present, the two substituents may be bonded together to form a carbonyl group, or may be condensed with a bonded ring after forming a carbocyclic or heterocyclic ring. .
The substituents of “substituted alkyl”, “substituted cycloalkyl”, “substituted aryl” and “substituted heteroaryl” in R ² include a halogen atom, cyano, nitro, hydroxyl group, C _1-2 alkoxy, —N (C _0-2 alkyl) (C _0-2 alkyl), C _1-2 alkyl, CF _n H _3-n , aryl, heteroaryl, —COC _1-2 alkyl, —CON (C _0-2 alkyl) (C _{0 -2} alkyl), CH ₃ , SOCH ₃ , SO ₂ CH ₃ , —SO ₂ N (C _0-2 alkyl) (C _0-2 alkyl), etc., and the substituent is independently 1 to 6 May be substituted.

Examples of the “aromatic ring” include benzene and naphthalene, and benzene is particularly preferable.
Examples of the “heteroaromatic ring” include a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom. Thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.
Examples of the “carbocycle” include C _3-8 , preferably C _3-6 cycloalkane, and specifically include cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.
Examples of the “heterocycle” include a 4- to 8-membered non-aromatic heterocycle containing 1 or 2 heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom, specifically, an oxetane , Tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, azetidine, pyrrolidine, piperidine, azepane, dioxolane, piperazine, homopiperazine, morpholine, thiomorpholine and the like. In the heterocyclic ring containing a sulfur atom, the sulfur atom may be oxidized with 1 or 2 oxygen atoms.

Preferable examples of “heteroaromatic ring or heterocyclic ring formed with —N═C— to which T is bonded” include 2-pyrazinyl, 2-thiazolyl and 3-pyrazolyl. When the ring is 2-pyrazinyl or 2-thiazolyl, each of R ⁴ and R ⁵ is preferably independently a hydrogen atom, methyl or fluoro. When the ring is 3-pyrazolyl, each of R ⁴ and R ⁵ is preferably independently hydrogen or C _1-2 alkyl. Particularly preferred examples of the ring substituted with R ⁴ and R ⁵ include 2-pyrazinyl, 5-fluoro-2-thiazolyl, 1-methyl-1H-pyrazol-3-yl.
Preferred examples of R ¹ include cycloalkyl, hydroxycycloalkyl, oxocycloalkyl, tetrahydropyranyl and the like.
Preferable examples of R ² include methyl, cyclopropyl, cyclobutyl and the like.

Preferred examples of the optically active phenylacetamide derivative of the formula (4) include (2R) -2- (4-cyclobutanesulfonylphenyl) -N-pyrazin-2-yl-3- (tetrahydropyran-4-yl). Propionamide, (2R) -2- (4-cyclobutanesulfonylphenyl) -N- (1-methyl-1H-pyrazol-3-yl) -3- (tetrahydropyran-4-yl) propionamide, (2R)- 2- (4-Cyclobutanesulfonylphenyl) -N- (5-fluorothiazol-2-yl) -3- (tetrahydropyran-4-yl) propionamide, (2R) -2- (4-cyclopropanesulfonylphenyl) -N- (5-fluorothiazol-2-yl) -3- (tetrahydropyran-4-yl) propionamide, ( R) -2- (4-cyclopropanesulfonylphenyl phenyl) -N- pyrazin-2-yl-3- (tetrahydropyran-4-yl) propionamide, and the like.

Examples of the “pharmaceutically acceptable salt” include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, or acetate, fumarate, oxalate, citrate, methane Organic acid salts such as sulfonate, benzenesulfonate, tosylate or maleate are listed. Moreover, when it has a substituent such as carboxyl, examples of the salt include salts with bases such as alkali metal salts such as sodium salt or potassium salt or alkaline earth metal salts such as calcium salt. Pharmacologically acceptable salts also include internal salts and can be in the form of solvates such as hydrates thereof.

The optically active carboxylic acid of the formula (1) is produced by dehydrating the carboxylic acid of the formula (2) to form a ketene compound, reacting with D-(-)-pantolactone and hydrolyzing.

[Wherein, R ¹ , R ² and R ³ have the same meanings as described above. ]
Various known methods can be applied to dehydrate the racemic carboxylic acid of formula (2) to form a ketene compound. For example, the carboxylic acid can be converted into an acid chloride and subsequently treated with a base. Can be implemented. An acid chloride can be obtained by, for example, reacting a chlorinating agent in a reaction solvent at a temperature from 0 ° C. to the boiling point of the reaction solvent, preferably from room temperature to 50 ° C. Examples of the chlorinating agent include phosphorus oxychloride, thionyl chloride, oxalyl chloride and the like. The amount used is, for example, 1 to 2 equivalents based on the racemic carboxylic acid, or the reaction is carried out using a large excess in combination with a solvent. However, it is preferably 1 to 1.2 equivalents. When an excess chlorinating agent is used, it may be distilled off after completion of the reaction and replaced with the solvent used in the next step, but when a small excess amount that does not adversely affect the next step is used, It can be used for the next reaction without distilling off the solvent. When oxalyl chloride is used as the chlorinating agent, it is desirable to add a small amount of dimethylformamide (DMF). Any reaction solvent can be used as long as it can dissolve raw materials, reagents and the like and does not adversely affect the reaction. For example, hydrocarbon solvents (hexane, heptane, benzene, toluene, chlorobenzene, etc.) ), Halogen solvents (methylene chloride, chloroform, 1,2-dichloroethane, etc.), ether solvents (diethyl ether, tetrahydrofuran (THF), dioxane, etc.) and the like. Preferable solvents include methylene chloride, toluene, THF and the like. The subsequent treatment with a base can be carried out by adding the base as it is to the reaction solution of the above reaction. Examples of the base include tertiary amines (triethylamine, trimethylamine, dimethylethylamine, N-methylmorpholine, tetramethylethylenediamine, 1,4-diazabicyclo [2.2.2.] Octane, etc.) and the like. The amount of the base used is, for example, 2 to 5 equivalents, preferably 2.1 to 3 equivalents with respect to the racemic carboxylic acid. An example of a reaction temperature is −50 to 30 ° C., preferably −20 to 15 ° C.

The reaction of the produced ketene compound and D-(-)-pantolactone can be carried out, for example, by adding D-(-)-pantolactone as it is to the reaction solution of the above reaction. The amount of D-(−)-pantolactone used is, for example, 1.1 to 2 equivalents, preferably 1.2 to 1.5 equivalents, relative to the racemic carboxylic acid. Examples of the reaction temperature include −100 to 30 ° C., but it is preferable to start the reaction at a temperature of −78 to 0 ° C. and gradually raise the temperature. Subsequently, isolation and purification can be performed by conventional methods. At this stage, unnecessary isomers produced as a by-product can be separated and removed by operations such as recrystallization, but can also be separated and removed by recrystallization after the subsequent hydrolysis.
D-(-)-pantolactone is represented by the following structural formula and is also called (R) -pantolactone.

The optically active carboxylic acid of the formula (1) can be produced by hydrolyzing and purifying the resulting D-(−)-pantolactone ester. Hydrolysis is preferably performed under conditions that do not cause isomerization at the asymmetric carbon site as much as possible. Examples of the hydrolysis method include, for example, an alkali hydroxide (lithium hydroxide, lithium hydroxide) in a mixed solvent of alcohol solvent (methanol, ethanol, etc.) or ether solvent (THF, dioxane, etc.) and water in the presence of hydrogen peroxide. And a method of treating with sodium hydroxide, potassium hydroxide, etc.). The amount of hydrogen peroxide to be used is 0.1 to 5 equivalents, preferably 1 to 3 equivalents, relative to D-(-)-pantolactone ester. The amount of alkali hydroxide used is, for example, 1 to 3 equivalents, preferably 1 to 1.5 equivalents. Examples of the reaction temperature include −5 ° C. to 30 ° C. Subsequently, isolation and purification can be performed by conventional methods. Further, by performing recrystallization, unnecessary isomers by-produced can be separated and removed.
In addition, the pantolactone ester can be hydrolyzed without racemization by a method of treating with various acids in the presence of water. Examples of the acid used include acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, and mixtures thereof. Examples of the reaction temperature include 0 ° C. to 100 ° C.

The optically active carboxylic acid of formula (1) is subsequently condensed with an amine of formula (3) to produce a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and T are as defined above]. ]
Regarding the production of the compound of the formula (3) used in this reaction, the reaction of the optically active carboxylic acid of the formula (1) with the compound of the formula (3), and the production of a pharmaceutically acceptable salt, Patent Document 1 mentioned above. 10 to 10 are described in detail together with many examples, and can be easily produced by referring to these descriptions.

Hereinafter, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is not limited to these examples.

Reference example 1
(4-Cyclopropylsulfanylphenyl) -hydroxyacetic acid ethyl ester

To a suspension of aluminum chloride (127.7 g) in chlorobenzene (480 mL), with stirring, a solution of ethyl glyoxalate (108.7 g) in chlorobenzene (160 mL) was added dropwise at 30 ° C. over 15 minutes, followed by cyclopropylphenyl sulfide. A solution of (80.0 g) in chlorobenzene (160 mL) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 4 hours. Ice water (400 mL) was added to the reaction solution, and 10% aqueous sodium hydrogen sulfite solution (400 mL) was further added. The organic layer was separated, and the aqueous layer was extracted twice with toluene (200 mL). The organic layers were combined, washed with a 10% aqueous sodium carbonate solution (160 mL), dried (magnesium sulfate), and the solvent was distilled off under reduced pressure. The residue was recrystallized from toluene (160 mL) -normal heptane (480 mL) to obtain the title compound (98.5 g).
¹ H-NMR (400 MHz) δ: 7.36 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 5.11 (d, J = 4.6 Hz, 1H), 4.32-4.12 ( m, 2H), 3.43 (t, J = 5.1 Hz, 1H), 2.21-2.14 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.11-1.04 (m, 2H), 0.72-0.66 (m, 2H).

Reference example 2
(4-Cyclopropylsulfanylphenyl) -acetic acid ethyl ester

Boron trifluoride diethyl ether was added to a solution of (4-cyclopropylsulfanylphenyl) -hydroxyacetic acid ethyl ester (6.9 g) and triethylsilane (5.2 mL) prepared in Reference Example 1 in methylene chloride (100 mL) under ice-cooling. (3.8 mL) was added, and the mixture was stirred at room temperature for 17 hours. Triethylsilane (5.2 mL) and boron trifluoride diethyl ether (3.8 mL) were sequentially added, and the mixture was further stirred at room temperature for 26 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution (50 mL), and after liquid separation, the organic layer was washed successively with water (25 mL) and saturated brine (25 mL), and dried (magnesium sulfate). The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane (1: 4 to 1: 1)) to obtain the title compound (5.3 g).
MS (m / z) APCI: 237 (M + H) ⁺

Reference example 3
(4-Cyclopropylsulfanylphenyl) -acetic acid ethyl ester The ester of Reference Example 2 can also be produced by the following method.

To a solution of (4-cyclopropylsulfanylphenyl) -oxoacetic acid ethyl ester (Patent Document 9; 0.99 g) and triethylsilane (1.9 mL) in methylene chloride (15 mL) under ice-cooling, boron trifluoride diethyl ether (1.5 mL) ) And stirred at room temperature for 23 hours. The reaction mixture is added to a 7% aqueous sodium hydrogen carbonate solution (15 mL), and the layers are separated. The organic layer is washed with water and saturated brine (15 mL), dried (magnesium sulfate), and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane (1: 4 to 1: 1)) to obtain the compound of Reference Example 2 (0.51 g).
MS (m / z) APCI: 237 (M + H) ⁺

Reference example 4
2- (4-Cyclopropylsulfanylphenyl) -3- (4-tetrahydropyranyl) -propionic acid ethyl ester

To a solution of (4-cyclopropylsulfanylphenyl) -acetic acid ethyl ester (2.4 g) prepared in Reference Example 2 in THF (50 mL) was added 1M lithium hexamethyldisilazide THF solution (10.9 mL) at −13 ° C. The mixture was stirred at the same temperature for 1 hour. A solution of 4-tetrahydropyranylmethyl iodide (Patent Document 6; 2.9 g) in toluene (10 mL) and N, N′-dimethylpropyleneurea (1.8 mL) were added, and the mixture was warmed to room temperature and stirred for 2 hours. . Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried (magnesium sulfate), and the solvent was evaporated under reduced pressure to give a residue. The residue was obtained by silica gel column chromatography (ethyl acetate-hexane (1 : 20 to 1: 1)) to give the title compound (2.1 g).
MS (m / z) APCI: 335 (M + H) ⁺

Reference Example 5
2- (4-Cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid

To a solution of 2- (4-cyclopropylsulfanylphenyl) -3- (4-tetrahydropyranyl) -propionic acid ethyl ester (835 mg) prepared in Reference Example 4 in methylene chloride (16 mL) was added m -Chloroperbenzoic acid (75%, 1.4 g) was added, the temperature was raised to room temperature, and the mixture was stirred at the same temperature for 5 hours. A 10% aqueous sodium sulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium carbonate solution (10 mL) was added, and the mixture was extracted with methylene chloride (30 mL). The organic layer was washed successively with water (10 mL) and saturated brine (10 mL), dried (magnesium sulfate), and the residue obtained by evaporating the solvent under reduced pressure was directly used in the next reaction.
The residue was dissolved in ethanol (18 mL), 2M aqueous sodium hydroxide solution (2.5 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 14 hr. Add 6M hydrochloric acid (1 mL), extract with methylene chloride (40 mL), wash the organic layer sequentially with water (10 mL) and saturated brine (10 mL), dry (magnesium sulfate), and remove the solvent under reduced pressure. Distilled off. The residue was recrystallized from isobutyl acetate (20 mL) -normal heptane (10 mL) to obtain the title compound (591 mg).
MS (m / z) APCI: 339 (M + H) ⁺

Reference Example 6
2- (4-Cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid The racemic carboxylic acid of Reference Example 5 can also be produced by the following method.

To a solution of (4-cyclopropylsulfanylphenyl) -acetic acid ethyl ester (1.7 g) prepared in Reference Example 2 in acetone (26 mL), a solution of Oxone (registered trademark: 6.0 g) in water (17 mL) at room temperature. Was dripped. After stirring at the same temperature for 3 hours, the precipitated inorganic salt was filtered, and 20% aqueous sodium thiosulfate solution (2 mL) and 7% aqueous sodium hydrogen carbonate solution (20 mL) were sequentially added to the filtrate, and ethyl acetate (50 mL) was added. After liquid separation, the aqueous layer was extracted twice with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, dried (magnesium sulfate), evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate-hexane (1: 6 to 1: 1)). To obtain compound (A) (1.4 g).
MS (m / z) APCI: 269 (M + H) ⁺
To a THF (15 mL) solution of the obtained compound (A) (1.0 g), 1M lithium hexamethyldisilazide THF solution (4.1 mL) was added at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. A solution of 4-tetrahydropyranylmethyl iodide (1.1 g) in toluene (5 mL) and N, N′-dimethylpropyleneurea (0.68 mL) were added, and the mixture was warmed to room temperature and stirred for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried (magnesium sulfate), and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane (1: 4 to 1: 1)). Purification gave compound (B) (1.1 g).
MS (m / z) APCI: 367 (M + H) ⁺
To a solution of the obtained compound (B) (730 mg) in methanol (4 mL) was added 2M aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was concentrated until distillation of water was observed under reduced pressure, water (7 mL) t-butyl methyl ether (7 mL) was added, and the aqueous layer was separated. 5M hydrochloric acid (1.5 mL) was added to the aqueous layer, followed by extraction three times with t-butyl methyl ether (7 mL). The organic layer was dried (magnesium sulfate) and the solvent was distilled off under reduced pressure to give Reference Example 5 Compound (670 mg) was obtained.
MS (m / z) APCI: 339 (M + H) ⁺

Example 1
(R) -2- (4-Cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid

To a solution of 2- (4-cyclopropylsulfonylphenyl) -3- (4-tetrahydropyranyl) -propionic acid (5.0 g) and DMF (32 mg) prepared in Reference Example 5 in methylene chloride (100 mL), 20 Oxalyl chloride (1.5 mL) was added at ° C and stirred at the same temperature for 2 hours. The reaction mixture was cooled to −15 ° C., dimethylethylamine (5.3 mL) was added, and the mixture was stirred for 30 min. The reaction solution was cooled to −78 ° C., and a solution of D-(−)-pantolactone (2.5 g) in methylene chloride (30 mL) was added dropwise over 20 minutes, and the same temperature was maintained for 30 minutes and at −60 ° C. for 2 hours. The mixture was stirred at −40 ° C. for 17 hours and further at 20 ° C. for 2 hours. Water (50 mL) was added to the reaction mixture, the organic layer was separated, washed with saturated brine (30 mL), dried (magnesium sulfate), evaporated under reduced pressure, and the resulting residue was used as is. Used for the reaction. At this time, the diastereomeric excess of the obtained crude pantolactone ester was 82% de (the diastereomeric excess was measured by chiral HPLC: CHIRALPAK-IB, normal hexane-isopropanol = 70: 30).
The above residue was dissolved in methanol (100 mL), 30% aqueous hydrogen peroxide solution (4.5 mL) and 4M aqueous lithium hydroxide solution (4.4 mL) were successively added under ice-cooling, and the mixture was stirred at the same temperature for 3 hr. A 10% aqueous sodium sulfite solution (90 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water (60 mL) and toluene (80 mL) were added, and the aqueous layer was separated. To the aqueous layer was added 6M hydrochloric acid (6 mL), and the mixture was extracted with chloroform (80 mL). The organic layer was washed successively with water (20 mL) and saturated brine (20 mL), dried (magnesium sulfate), and reduced in pressure. The bottom solvent was distilled off. The residue was recrystallized from isobutyl acetate (30 mL) -n-heptane (3 mL) to obtain the title compound (3.4 g). The optical purity of the carboxylic acid obtained at this time was 99.3% ee (optical purity was measured by chiral HPLC: CHIRALCEL-OJ-RH, 0.1% phosphate buffer-acetonitrile = 4: 1).
MS (m / z) APCI: 339 (M + H) ⁺

According to the present invention, optically active carboxylic acid can be produced from racemic carboxylic acid with ordinary production equipment at a good yield and at low cost.

Claims

A process for producing an optically active carboxylic acid of formula (1) by dehydrating a carboxylic acid of formula (2) to form a ketene compound, reacting with D-(-)-pantolactone, and hydrolyzing it.

[Wherein, R 1 represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, or an optionally substituted heterocyclic group.
R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —N (C 0-2 alkyl) (C 0 -2 alkyl) or cyclic amino.
R 3 represents a hydrogen atom, a halogen atom or trifluoromethyl. ]
A process for producing an optically active carboxylic acid of formula (1) by reacting a ketene compound of formula (2a) with D-(-)-pantolactone and hydrolyzing it.

[Wherein, R 1 , R 2 and R 3 have the same meaning as in claim 1. ]
The carboxylic acid of formula (2) is dehydrated to form a ketene compound, reacted with D-(-)-pantolactone and hydrolyzed to produce an optically active carboxylic acid of formula (1), followed by formula (3) A method for producing a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof by condensing with an amine of:

[Wherein, R 1 represents an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, or an optionally substituted heterocyclic group.
R 2 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —N (C 0-2 alkyl) (C 0 -2 alkyl) or cyclic amino.
R 3 represents a hydrogen atom, a halogen atom or trifluoromethyl.
R 4 and R 5 independently represent a hydrogen atom, a halogen atom, OCF n H 3-n , methoxy, CO 2 R 6 , cyano, nitro, CHO, CONR 7 R 8 , CON (OCH 3 ) CH 3 Or C 1-2 alkyl, heteroaryl or C 3-7 cycloalkyl [these groups are halogen atoms, hydroxyl groups, cyano, methoxy, —NHCO 2 CH 3 and —N (C 0-2 alkyl) (C Or optionally substituted with 1 to 5 substituents independently selected from the group of 0-2 alkyl), or R 4 and R 5 are bonded together to form a carbonyl group Or after forming a 5- to 8-membered aromatic, heteroaromatic, carbocyclic or heterocyclic ring, it is condensed with the ring formed by T and -N = C-.
R 6 represents a hydrogen atom, or C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these Groups of: halogen atom, cyano, nitro, hydroxyl group, C 1-2 alkoxy, —N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4 To 7-membered heterocyclic group, CF n H 3-n , aryl, heteroaryl, CO 2 H, —COC 1-2 alkyl, —CON (C 0-2 alkyl) (C 0-2 alkyl), SOCH 3 , Optionally substituted with 1 to 6 substituents independently selected from the group of SO 2 CH 3 and —SO 2 N (C 0-2 alkyl) (C 0-2 alkyl)] To express.
R 7 and R 8 independently represent a hydrogen atom, or C 1-4 alkyl, C 3-7 cycloalkyl, aryl, heteroaryl or a 4- to 7-membered heterocyclic group [these groups are halogen Atom, cyano, nitro, hydroxyl group, C 1-2 alkoxy, —N (C 0-2 alkyl) (C 0-2 alkyl), C 1-2 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycle Groups, CF n H 3-n , aryl, heteroaryl, COC 1-2 alkyl, —CON (C 0-2 alkyl) (C 0-2 alkyl), SOCH 3 , SO 2 CH 3 and —SO 2 N ( C 0-2 alkyl) (which may be substituted with 1 to 6 substituents independently selected from the group of (C 0-2 alkyl)), or R 7 and R 8 are 6-8 together with the N atom to which they are bonded Bicyclo nitrogen-containing heterocyclic group or a 4-8-membered nitrogen-containing Hajime Tamaki [these groups, C 1-2 alkyl, independently from the group consisting of CH 2 OCH 3, COC 0-2 alkyl, hydroxyl and SO 2 CH 3 Optionally substituted with 1 to 2 substituents optionally selected].
n represents 1, 2 or 3.
T represents a heteroaromatic ring or a heterocyclic ring together with —N═C— to which it is bonded [only the N═C bond is an unsaturated site]. ]
Reacting a ketene compound of formula (2a) with D-(-)-pantolactone and hydrolyzing to produce an optically active carboxylic acid of formula (1), followed by condensation with an amine of formula (3) To produce a phenylacetamide derivative of formula (4) or a pharmaceutically acceptable salt thereof.

[Wherein, R 1 , R 2 , R 3 , R 4 , R 5 and T have the same meaning as defined in claim 3. ]
The production method according to any one of claims 1 to 4, wherein R 1 is 4-tetrahydropyranyl, R 2 is cyclopropyl or cyclobutyl, and R 3 is a hydrogen atom.