WO2001072681A1 - PROCESS FOR PRODUCING OPTICALLY ACTIVE α-HYDROXY-η-BUTYROLACTONE - Google Patents

Abstract

A process whereby both enantiomers of optically active α-hydroxy-η-butyrolactone, which are useful as medicinal intermediates, can be conveniently produced from inexpensive and easily available materials. Optically active α-hydroxy-η-butyrolactone is produced by reacting an optically active 4-amino-2-hydroxybutanoic acid derivative with nitrous acid and cyclizing under acidic conditions. Further, (S)-α-hydroxy-η-butyrolactone is reacted with sulfonyl chloride in the presence of a base to give (S)-α-sulfonyloxy-η-butyrolactone. It is further reacted with a carboxylic acid salt to give (R)-α-acyloxy-η-butyrolactone which is then deacylated by treating with an acid or a base in an alcoholic solvent to give (R)-α-hydroxy-η-butyrolactone.

Description

 Specification

 Method for producing optically active α-hydroxy-γ-butyrolactone

The present invention is a pharmaceutical intermediate, particularly antiasthmatics Intermediate (WO 9 7 24 3 6 5 ) usefulness optically active α- arsenide Dorokishi _ _gamma as - relates Puchiroraku ton production method. Background art

 Conventionally, the following methods have been known as methods for producing optically active α-hydroxy γ-petit mouth rataton.

By protecting 1) L-malic acid hydrate, manufactures a Jiokisoran compounds, then reduced with borane 'dimethyl Huy de complexes, by cyclization, (S) - Hiichihi Dorokishi one _y - A method for producing butyrolactone (Tetrahedron Lett. 1997, 36, 637 5).

 2) From racemic α-hydroxy-γ-butyral lactone (Organic Preparations and Procedures Int., 1985, 17 and 9 1.), optics using chiene brucine as a resolving agent Division method (J. Am. Chem. Soc. 1921, 2675.).

 3) A method of preparing a racemic mixture from racemic α-hydroxy-γ-butyrolactone and alkaloids and resolving it by fractional crystallization (J. Am. Chem. Soc.

8, 15 7 6.;).

4) Racemic _α- hydroxy- _{butyrolactone} was prepared using (Bu) acetate and lipase to produce (S) -α-hydroxy-butyrolactone and (R) _α-acetyloxy γ-butyrate ratatone. Separation of (S) -α-hydroxy-1-γ-butyrolactone by column chromatography and deacetylation of (R) -α-acetyloxy-y-petit mouth rataton with potassium carbonate in ethanol. And a method for producing (R) -α-hydroxy-1-γ-butyrolactone (Japanese Patent Application Laid-Open No. 3-228686).

5) Racemic α-hydroxy γ-butyrolactone is added selectively by microorganisms. (R) — 2,4-dihydroxybutyric acid is produced by water splitting, and unreacted phenhydroxy-1- _y -butyrolactone is extracted and removed, followed by deicing and cyclization in the presence of an acid catalyst. To produce (R) -hydroxy-γ-butyrolactone (JP-A-9-308479).

 However, prior art 1) uses an expensive reducing agent, borane-dimethyl sulfide complex, and conventional technology 2) uses expensive quinine-pursin as a resolving agent, and conventional technology 3). Since these methods are complicated in operation, it is difficult to carry out these methods industrially. In addition, in the prior arts 4) and 5), the optically active substance is separated from the expensive racemic rho-hydroxyl-y-butyrolactone, and the other optically active substance is not required. This is not an advantageous method.

Summary of the Invention

 In view of the above, an object of the present invention is to provide a method for easily producing an optically active γ-butyrolactone, which is useful as a pharmaceutical intermediate, from inexpensive and easily available raw materials.

The present inventors have conducted intensive studies in view of the above situation, and as a result, have found that optically active hydroxy-y-butyrolactone can be converted from optically active 4-amino-12-hydroxybutanoic acid derivative, which is a cheap and easily available raw material. In addition to developing a method that can be easily manufactured, the hydroxyl group of (S) -α-hydroxy-1- _γ -butyrolactone, which is manufactured from a less expensive (S)-4-amino-2-hydroxybutanoic acid derivative, can be efficiently sterically converted. The reversal led to the development of a method that could produce (R) -α-hydroxy-ptyloractone.

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

(In the formula, * represents an asymmetric carbon. R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.) An optically active 4-amino-2-hydroxybutanoic acid derivative represented by the following formula: By reacting with nitric acid, the following formula (2):

(Wherein * and R ¹ are the same as above. Q represents a hydroxyl group, a halogen or an alkoxy group having 1 to 5 carbon atoms.) An optically active 4-substituted 1-2-hydroxybutanoic acid derivative represented by the following formula: And further cyclizing it under acidic conditions, the following formula (3):

(In the formula, * is the same as above.) A method for producing optically active α-hydroxy_y-ptyloractone represented by the following formula:

 Further, the first invention provides an optically active compound represented by the above formula (2) by reacting an optically active 4-amino-2-hydroxybutanoic acid derivative represented by the above formula (1) with nitrous acid. It is also a method for producing 4-monosubstituted-2-hydroxybutanoic acid derivatives.

Furthermore, the first present invention is represented by the above formula (3) by cyclizing the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the above formula (2) under acidic conditions. It is also a method for producing optically active α-hydroxy γ-butyrolactone. Furthermore, a first aspect of the present invention is to react an optically active 4-amino-12-hydroxybutanoic acid derivative represented by the above formula (1), wherein R ¹ is a hydrogen atom, with nitrous acid. Thus, this is also a method for producing the optically active c-hydroxy y monobutyrolactone represented by the above formula (3).

 The second present invention provides the following formula (4):

で表される （S) — α—ヒ ドロキシ一γ—ブチロラタ トンと、 下記式 （5) ；

(S) -α-hydroxy-γ-butyrolataton represented by the following formula (5);

(In the formula, R ² is an alkyl group having 1 to 12 carbon atoms which may have a substituent, an aralkyl group having 7 to 12 carbon atoms which may have a substituent, or a substituent. Represents an aryl group having 6 to 12 carbon atoms by reacting a sulfonyl chloride represented by the following formula in the presence of a base to obtain the following formula (6);

(Wherein R ² is the same as above) to produce (S) —α-sulfonyloxy-γ-butyrolactone represented by the following formula (7):

(In the formula, R ³ represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be present, or an aryl group having 6 to 12 carbon atoms which may have a substituent, wherein Μ represents an alkali metal, an alkaline earth metal or Η represents an integer of 1 or 2.) is reacted with a carboxylate represented by the following formula:

(8);

(式中、 R ³は上記に同じ。 ） で表される （R) — α _ァシルォキシ一 γ—ブチ ロラク トンを製造し、 さらに、 アルコール溶媒中、 酸又は塩基を作用させ脱ァシ ル化する、 下記式 （9) ；

(Wherein, R ³ is the same as above). (R) — α_Acylosoxy-γ-butyrolactone is produced, and further deactylated by reacting with an acid or a base in an alcohol solvent. Equation (9) below;

で表される （R) — α—ヒ ドロキシ一 γ _プチロラク トンの製造法である。

This is a method for producing (R) -α-hydroxy-γ-ptyloractone represented by

 Further, the second present invention provides the above-mentioned (S) -heasulfonyloxy-1-y-butyrolactone represented by the above formula (6) by reacting with a carboxylate represented by the above formula (7). This is also a method for producing (R) -α-asyloxy_γ-butyrolactone represented by the formula (8).

 Hereinafter, the present invention will be described in detail. Detailed Disclosure of the Invention

 First, the compounds used in the present invention will be described.

 The optically active 4-amino-2-hydroxybutanoic acid derivative has the general formula (1)

で表される。 ここで、 *は不斉炭素を表し、 R ¹は、 水素原子又は炭素数 1〜 5 のアルキル基を表す。 アルキル基としては、 例えば、 メチル基、 ェチル基、 η _ プロピル基、 イソプロピル基、 η—ブチル基、 s e c一ブチル基、 又は t e r t —ブチル基等が挙げられる。 好ましくは、 メチル基又はェチル基である。

It is represented by Here, * represents an asymmetric carbon, and R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an η_propyl group, an isopropyl group, an η-butyl group, a sec-butyl group, and a tert-butyl group. Preferably, it is a methyl group or an ethyl group.

The optically active 4-amino-2-hydroxybutanoic acid in which R ¹ is a hydrogen atom can be easily produced from glutamic acid according to the method described in JP-A-50-409. An optically active 4-amino-2-hydroxybutanoic acid derivative in which R ¹ is an alkyl group having 1 to 5 carbon atoms is obtained from Org. Prep. Proce d. Int. It can be easily manufactured by referring to the methods described in 1998, 17 (2), 91-97. For example, optically active methyl 4-amino-2-hydroxybutanoate or optically active ethyl 4-amino-2-hydroxybutanoate wherein R ¹ is a methyl group or an ethyl group is optically active 4-amino-2-hydroxybutanoic acid. Can be easily produced by reacting the compound with sulfuric acid, hydrogen chloride or thionyl chloride in methanol or ethanol.

 (4) Monosubstituted 1-2-hydroxybutanoic acid derivatives are represented by the general formula (2)

で表される。 ここで、 *及び R ¹は上記に同じであり、 Qは、 水酸基、 ハロゲン 又は炭素数 1〜 5のァシルォキシ基を表す。 ハロゲンとしては、 例えば、 フッ素、 塩素、 臭素又はヨウ素が挙げられ、 好ましくは塩素又は臭素である。 また、 ァシ ルォキシ基としては、 例えばホルミルォキシ基、 ァセチルォキシ基、 プロピオ二 ルォキシ基、 n—プチリルォキシ基、 イソブチリルォキシ基又はビバロイルォキ シ基等が挙げられる。 好ましくは、 ァセチルォキシ基である。

It is represented by Here, * and R ¹ are the same as above, and Q represents a hydroxyl group, a halogen, or an alkoxy group having 1 to 5 carbon atoms. Examples of the halogen include fluorine, chlorine, bromine and iodine, and chlorine or bromine is preferable. Examples of the acyloxy group include, for example, a formyloxy group, an acetyloxy group, a propionyloxy group, an n-butyryloxy group, an isobutyryloxy group, and a bivaloyloxy group. Preferably, it is an acetyloxy group.

 Sulfonyl chloride has the general formula (5)

0

 2 II

 R—S—C1 (5)

It is represented by Here, R ² is an alkyl group having 1 to 12 carbon atoms which may have a substituent, an aralkyl group having 7 to 12 carbon atoms which may have a substituent, or having a substituent. Represents an aryl group having 6 to 12 carbon atoms, specifically, for example, a methyl group, an ethyl group, an isopropylinole group, a tert-butynole group, a chloromethinole group, a methyl group of a trifrenole, a benzinole group, Examples include a methoxybenzyl group, a phenyl group, a p-nitrophenyl group, an o-nitrophenyl group, a p-methylphenyl group, and the like, and preferably a methyl group, a phenyl group, and a p-methylphenyl group. Alkyl group of the R ^2, as the substituent in Ararukiru group and Ariru group, for example, include fluorine, chlorine, halogens such as bromine, nitro group, Shiano group, a carboxyl group, an alkoxy group of number 1-1 2 carbon And the number of substituents is 0 to 3.

 (S) — α-sulfonyloxyl-butyrolataton has the general formula (6)

で表される。 ここで、 R ²は上記に同じである。

It is represented by Where R ² is the same as above.

 The carboxylate is represented by the general formula (7)

で表される。 ここで、 R ³は、 水素原子、 置換基を有しても良い炭素数 1〜 1 2 のアルキル基、 置換基を有しても良い炭素数 2〜 1 2のアルケニル基、 置換基を 有しても良い炭素数 7〜 1 2のァラルキル基、 又は置換基を有しても良い炭素数 6〜 1 2のァリール基を表し、 具体的には、 例えば、 水素原子、 メチル基、 ェチ ノレ基、 n—プロピル基、 イソプロピル基、 n—ブチル基、 s e c—ブチル基、 t e r t —ブチル基、 クロロメチル基、 トリフルォロメチル基、 ビュル基、 シンナ ミル基、 ベンジル基、 p—メ トキシベンジル基、 フエネチル基、 フエニル基、 p —ニ ト ロフエ二ノレ基、 o—メチノレフエ二ノレ基、 m—メチノレフエ二ノレ基、 p—メチ ルフエ-ル基、 m—クロ口フエニル基等が挙げられ、 好ましくはメチル基、 ェチ ノレ基、 n—プロピル基、 イソプロピル基、 n—ブチル基、 s e c—ブチル基、 t e r t一ブチル基、 クロロメチル基、 フエニル基等が挙げられ、 更に好ましくは フエニル基が挙げられる。

It is represented by Here, R ³ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, or a substituent. Represents an aralkyl group having 7 to 12 carbon atoms which may be substituted or an aryl group having 6 to 12 carbon atoms which may have a substituent, and specifically, for example, a hydrogen atom, a methyl group, an ethyl group Nore, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, chloromethyl, trifluoromethyl, bur, cinnamyl, benzyl, p-methoxy Benzyl group, phenethyl group, phenyl group, p-nitrophenyl group, o-methinolephenyl group, m-methynolephenyl group, p-methylphenyl group, m-chlorophenyl group and the like. , Preferably a methyl group, an ethylene group, an n-propyl group Isopropyl, n- butyl group, sec- butyl group, tert one butyl group, chloromethyl group, phenyl group and the like, more preferably include phenyl groups.

Examples of the substituent in the alkyl group, alkenyl group, aralkyl group and aryl group of R ³ include halogen such as fluorine, chlorine and bromine, nitro group, cyano and the like. Groups, a carboxyl group, an alkoxy group having 1 to 12 carbon atoms, and the like, and the number of substituents is 0 to 3.

 M represents an alkali metal, an alkaline earth metal, or ammonium. Examples of the alkali metal include lithium, sodium, potassium, norevidium, and cesium, and preferably sodium or potassium. Examples of the alkaline earth metal include magnesium, calcium, barium and the like. Examples of the ammonium include ammonium, diisopropylammonium, triethylammonium, pyridinium, tetraethylammonium, tetrabutylammonium, triethylbenzylammonium and the like, and preferably triethylammonium. , Pyridinium, tetraethylammonium and tetrabutylammonium. N represents an integer of 1 or 2.

 (R) — ct-acylosoxy-γ-butyrolactone has the general formula (8)

で表される。 ここで、 R ³は上記に同じである ₍

It is represented by Where R ³ is the same as above ₍

 The carboxylic acid has the general formula (10)

R ^J , ヽ OH ( ¹⁰⁾ Where R ³ is the same as above. Next, a method for producing the optically active hydroxy γ-butyrolactone in the present invention will be described.

In the present invention, first, an optically active 4-monosubstituted compound represented by the above formula (2) is reacted with nitrous acid to cause the optically active 4-mono-2-hydroxybutanoic acid derivative represented by the above formula (1). 1. Produce 2-hydroxybutanoic acid derivatives. Here, the amount of nitrous acid used is preferably based on the 4-amino-12-hydroxybutanoic acid derivative. The molar amount is preferably 1 to 20 times, more preferably 1 to 5 times.

 Further, nitrous acid may be generated in the system by mixing an acid and a nitrite. In this case, examples of the acid include mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, perchloric acid, phosphoric acid, and boric acid; formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, vivalic acid, valeric acid, Carboxylic acids such as isovaleric acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, methoxyacetic acid, diethoxyacetic acid, hydroxyacetic acid, chloroacetic acid, dichloroacetic acid, triflenoacetic acid, oxalic acid, and malonic acid; Examples thereof include sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. Preferred are carboxylic acids, and more preferred are formic acid, acetic acid and propionic acid. The amount of the acid to be used is preferably 1 to 50 times, more preferably 2 to 20 times the molar amount of the 4-amino-2-hydroxybutanoic acid derivative.

 Examples of the nitrite include an alkali metal salt, an alkaline earth metal salt, an ammonium salt and the like, preferably an alkali metal salt, and more preferably a sodium salt or a potassium salt. The amount of nitrite used is preferably 1 to 10 times, more preferably 1 to 5 times the amount of 4-amino-2-hydroxybutanoic acid derivative, relative to the 4-amino-2-hydroxybutanoic acid derivative.

 The reaction solvent that can be used in this reaction is not particularly limited, and is preferably water or a carboxylic acid such as formic acid, acetic acid, or propionic acid. These may be used alone or in combination of two or more. The reaction temperature of this reaction is preferably 0 to 100 ° C, more preferably 0 to 40 ° C.

The order of addition of the reagents in this reaction is not limited. For example, nitrite or nitrite or an aqueous solution thereof may be added to an aqueous acid solution or a carboxylic acid solution of an optically active 4-amino-2-hydroxybutanoic acid derivative. It is added over 1 to 20 hours, preferably 1 to 10 hours, or an aqueous acid solution or a carboxylic acid solution of an optically active 4-amino-2-hydroxybutanoic acid derivative is added to an aqueous solution of nitrite or nitrite. It is advisable to add over 0.1 to 20 hours, preferably 1 to 10 hours. More preferably, an acid or acid aqueous solution is added to a solution of the optically active 4-amino-2-hydroxybutanoic acid derivative and nitrite for 0.1 to 20 hours, preferably 1 to 10 hours. \ Or acid Alternatively, a solution of an optically active 4-amino-2-hydroxybutanoic acid derivative and nitrite is added to an aqueous acid solution for 0.1 to 20 hours, preferably 1 to 10 hours. As a post-treatment of this reaction, for example, water or carboxylic acid is distilled off by an operation such as heating under reduced pressure to obtain the desired product, or a common extraction solvent such as ethyl acetate, dimethyl ether, methylene chloride, toluene The reaction solvent and the extraction solvent are distilled off from the extracted liquid by an operation such as heating under reduced pressure to obtain the desired product. In some cases, it can be used in the next step without isolation. In this step, the substituent Q of the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2) is determined by the acid used and the reaction solvent. For example, when hydrochloric acid or hydrobromic acid is used as the acid, if water is used as the reaction solvent, Q is a hydroxyl group and a halogen, and if a carboxylic acid such as formic acid, acetic acid or propionic acid is used as the reaction solvent, Q Is a hydroxyl group, a halogen and an acyloxy group. Mineral acids such as sulfuric acid, perchloric acid, phosphoric acid, and boric acid as the acid; when sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid are used, the reaction solvent is used. If water is used, Q is a hydroxyl group, and if a carboxylic acid such as formic acid, drunk acid or propionic acid is used as a reaction solvent, Q is an acyloxy group. As acids, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, vivalic acid, valeric acid, isovaleric acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, methoxyacetic acid, ethoxyacetic acid, hydroxyacetic acid, When carboxylic acids such as chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, oxalic acid, and malonic acid are used, if water is used as the reaction solvent, Q is a hydroxyl group or a hydroxyl group and an acyloxy group.

In this step, (S) -2,4-dihydroxybutanoic acid or (S) _4-acetyloxyl-2 is used as an optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2). -It is preferred to obtain hydroxybutanoic acid. Next, by treating the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the above formula (2) under acidic conditions, the optically active _α- hydroxyl represented by the above formula (3) is treated. — Convert to γ-ptyrolactone. As the above acidic conditions, compounds

It is more effective to select various conditions according to the substituent of (2). For example, when R ¹ is a hydrogen atom and Q is a hydroxyl group or a halogen, the treatment may be performed in an aqueous acid solution without isolation. Here, examples of the acid include mineral acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid and phosphoric acid, and preferably hydrochloric acid or sulfuric acid. The acid may be used in such an amount that the pH of the aqueous acid solution becomes 0 to 3, for example.

Further, by adding an organic solvent and extracting and recovering the target substance in the organic layer, the conversion rate can be further improved. In this case, examples of the organic solvent include ester solvents such as ethyl acetate, butyl acetate, and methyl propionate; acetyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethyloxetane, and diethylene glycol dimethyl ether. Ether solvents; hydrocarbon solvents such as toluene, benzene, and xylene; and halogen solvents such as dichloromethane, 1,2-dichloroethane, and chloroform. Preferably, an organic solvent having low compatibility with water is used, and specific examples thereof include ethyl acetate, toluene, tetrahydrofuran, methynole tert-butyl ether, and the like. The reaction temperature of this reaction is preferably from 0 to 100 ° C, more preferably from 30 to 70 ° C. As another cyclization condition, for example, when R ¹ is an alkyl group having 1 to 5 carbon atoms and Q is a hydroxyl group, the acid is contained in the organic solvent of the optically active 4-substituted 12-hydroxybutanoic acid derivative. The cyclization can be carried out by adding Here, examples of the organic solvent include ester solvents such as ethyl acetate, butyl acetate, and methyl propionate; getinoleatenole, tetrahydrofuran, methinole tert-butylinoleatenole, 1,4-dioxane, dimethoxetane, diethylene glycol dimethyl ether Ether solvents such as acetonitrile, propionitrile and the like; nitrile solvents such as acetonitrile and propionitrile; ketone solvents such as acetone, methyl ethyl ketone, 3-pentanone, cyclopentanone and cyclohexanone; toluene, benzene, Hydrocarbon solvents such as xylene; and halogen solvents such as dichloromethane, 1,2-dichloroethane and chlorophonolem. Preferably, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, acetone, acetonitrile and the like are mentioned.

Examples of the acid include mineral acids such as sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric acid, and phosphoric acid, or methanesulfonic acid, benzenesnolefonic acid, and p-toluenesnole Organic acids such as sulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid are exemplified. Preferred are sulfuric acid, hydrogen chloride and methanesulfonic acid. The acid is used in an amount of 0.01 to 10 times, preferably 0.1 to 2 times, the molar amount of the optically active 4-amino-12-hydroxybutanoic acid derivative. The reaction temperature of this reaction is preferably 0 to 100 ° C, more preferably 30 to 70 ° C.

As another cyclization condition, for example, when R ¹ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and Q is an acyloxy group having 1 to 5 carbon atoms, the dehydration is performed in an alcohol in the presence of an acid. It is advisable to carry out cyclization together with acylation. Here, as the acid, sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric acid, mineral acid such as phosphoric acid, or methansnolephonic acid, benzenesnolephonic acid, p_tonoreensnorehon Acids, organic acids such as trisulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Preferred are sulfuric acid, hydrogen chloride and methanesulfonic acid, and more preferred is sulfuric acid. The acid is used in an amount of 0.01 to 10 moles, preferably 0.01 to 2 moles, per mole of the optically active 4-amino-12-hydroxybutanoic acid derivative.

Examples of the alcohols include methanol, ethanol, n- propanol one Honoré, Isopuronoヽ⁰ Nonore, n- Butanonore ethyleneglycidyl Konore, diethylene recall etc., include alcohols of from 1 to 5 carbon atoms, preferably methanol or Ethanol is mentioned. The reaction temperature of this reaction is preferably from 0 to 100 ° C, more preferably from 40 to 90 ° C. In this reaction, the cyclization yield can be further increased by distilling off the alcohol by an operation such as heating under reduced pressure.

 General post-treatment may be performed as post-treatment of this reaction. For example, the target product can be obtained by distilling off the reaction solvent and the extraction solvent from the reaction solution or the extract by an operation such as heating under reduced pressure. Furthermore, the target substance can be purified by a general method such as column chromatography or fractional distillation to increase the purity.

t In this step, as the optically active 4-monosubstituted 1-2-hydroxybutanoic acid derivative represented by the formula (2), (S) -2,4-dihydroxybutanoic acid or (S) -4-acetyloxy1-2- It is preferable to use hydroxybutanoic acid to obtain (S) -hydroxy-1- _y -ptyrolactone as the optically active α-hydroxy-γ-butyrolataton represented by the formula (3). In the above formula (1), when R ¹ is a hydrogen atom, and optically active 4-amino-2-hydroxybutanoic acid is reacted with nitrous acid, in the above formula (2), R ¹ is a hydrogen atom Optically active 4-hydroxy-2-hydroxybutanoic acid does not pass through the carboxyl group in the molecule, so that the optically active hydroxy-l-buta-ratone represented by the above formula (3) is involved. Can also be manufactured directly. However, since the product is often a mixture with the optically active 4-substituted-2-hydroxybutanoic acid, the treatment is preferably carried out under acidic conditions to further increase the yield.

In the above formula (1), 4-amino-2-hydroxybutanoic acid in which R ¹ is a hydrogen atom can be produced using glutamic acid as a raw material as described above, but natural L-glutamic acid is used as a raw material. (S) —4-Amino-12-hydroxybutanoic acid is available at a lower cost than (R) —4-amino-12-hydroxybutanoic acid starting from D-glutamic acid. . Therefore, the above reaction is a more effective method for producing (S) -α-hydroxy- _y -butyrolactone.

Next, the stereochemistry of (S) -α-hydroxy-1-γ-butyrolactone, which can be produced at low cost by the above reaction, is inverted, and the (R) _α-hydroxy_y—petite represented by the above formula (9) is inverted. A method of manufacturing the mouth rata will be described.

That is, in this reaction, first, (S) -hydroxy-γ-butyrolataton represented by the above formula (4) is reacted with a sulfoyluclide represented by the above formula (5) in the presence of a base. By this, (S) -α-sulfonyloxy- _γ -butyrolactone represented by the above formula (6) is produced.

Here, as the sulfonyl chloride, for example, methanesulfonyl chloride, ethanesnorefonyl chloride, isopropylsulfonyl chloride, η-butansnorefoninochloride, tert-butansnorefoninochloride , Methanesolephoninolek mouth light, pheninolemethanesnorefoninolek mouth light, p-methoxyphenolenomethanesnorefoninolecride light, benzenesnorefoninolek mouth light, p — tonorenence / Refoninochloride, p-nitrobenzenetin renochloride, o_nitrobenzenesnorefoninolechloride, p-chloroben Examples thereof include zensulfonyl chloride and the like, preferably, methanesulfonyl chloride, benzenesnorefoninolechloride, and p-tonolenesnorefoninochloride. The amount of sulfoyurc mouth ride used is preferably 1 to 10 times, more preferably 1 to 3 times the molar amount of (S) -hydroxy-1-γ-butyrolactone.

 Examples of the base include ammonia; primary amines such as methylamine, ethylamine, benzylamine, and aniline; secondary amines such as getylamine, diisopropylamine, dibenzylamine, and diphenylamine; trimethylamine, triethylamine, and tributylamine. , Triphenylamine, diisopropylethylamine, Ν-methylmorpholine, Ν-methylbiperidine, imidazole, pyridine, ρ-cyclomouth pyridine, 2_picoline, 3-picoline, 4-hydroxy, Ν-dimethylaminopyridine, Tertiary amines such as 1,7-diazabicyclo [5,4,0] -pand — 7-ene; lithium hydroxide, sodium hydroxide, hydroxide hydroxide, magnesium hydroxide, sodium carbonate, carbonate Potassium, magnesium carbonate, hydrogen carbonate Toriumu, bicarbonate force Riumu, lithium hydride, inorganic base such as hydrogenation Natoriumu. Preferably, tertiary amines are used, and more preferably, triethylamine or pyridine. As the amount of base used,

The amount is preferably 1 to 20 times, more preferably 1 to 5 times, the amount of (S) -α-hydroxy-γ-butyrolataton.

 The reaction temperature of this reaction is preferably from 120 to 80 ° C, more preferably from 0 to 50 ° C.

Examples of the organic solvent that can be used in this reaction include non-protonic solvents. Non-protonic solvents include, for example, ester solvents such as ethyl acetate, butyl acetate, methyl alcohol propionate and propyl formate; ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone and cyclohexanone; acetonitrile, propio! Nitrile solvents such as nitrile; ether solvents such as getyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethoxetane, diethylene glycol dimethyl ether; pentane, hexane, toluene, benzene, xylene Hydrocarbon solvents such as dichloromethane; 1,2-dichloromethane Halogen-based solvents such as roethane, chloroform, carbon tetrachloride, and cyclobenzene; dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylpropylene perrea, dimethylsulfoxide, and hexamethylphosphoric triamide And non-protonic polar solvents such as The above solvents may be used alone or in combination of two or more. Preferred among the above solvents are ethynol ethers such as getyl ether, tetrahydrofuran, methynole tert-butynoleatenole, 1,4-dioxane, dimethoxetane, and diethylene glycol dimethyl ether; pentane, hexane, toluene, Hydrocarbon solvents such as benzene and xylene. As the post-treatment of this reaction, general post-treatment for obtaining a product from the reaction solution may be performed. For example, water is added to the reaction solution after completion of the reaction, and an extraction operation is performed using a common extraction solvent, for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and 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. The target product thus obtained may be purified by a general method such as crystallization purification, fractional distillation, or column chromatography, and the purity may be further increased.

In the (S) -α-sulfonyloxy-γ-butyrolataton produced by this reaction, R ² is a phenyl group, and (S) -α-phenylsulfonyloxy-γ-butyrolataton and R ² Is a ρ-methylphenyl group, and (S) -α- (ρ_methylphenyl) sulfonyloxy_γ-butyrolactone is a novel compound not described in the literature. Next, by reacting (S) -α-sulfonyloxy-γ-butyrolataton represented by the above formula (6) with a carboxylate represented by the above formula (7), (R) -α-Axyloxy-γ-ptyloractone represented by (8) is produced.

Here, examples of the carboxylate include sodium formate, potassium formate, lithium acetate, magnesium formate, sodium acetate, potassium acetate, rubidium acetate, cesium acetate, magnesium acetate, calcium acetate, barium acetate, ammonium acetate, Tetrabutylammonium acetate, triethylammonium acetate, Sodium onate, Sodium butyrate, Sodium isobutyrate, Sodium valerate, Sodium bivalate, Sodium acetoacetate, Potassium dichloroacetate, Sodium trichloroacetate, Sodium trifluoroacetate, Sodium oxalate, Dipotassium malonate, Maleic acid Disodium, sodium acrylate, sodium methacrylate, sodium cinnamate, sodium pyruvate, sodium phenylacetate, potassium p-chlorophenylacetate, sodium benzoate, potassium benzoate, cesium benzoate, magnesium benzoate , Ammonium benzoate, tetrabutyl ammonium benzoate, sodium o-methyl benzoate, sodium m-methyl benzoate, sodium p-methyl benzoate, nato p-methyl benzoate Um, sodium p- two Toro acid, o- main butoxy potassium benzoate, potassium salicyl acid, disodium phthalate and the like. The above carboxylate is preferably sodium formate, sodium acetate, potassium acetate, cesium acetate, sodium butyrate, sodium isobutyrate, sodium vivalate, sodium benzoate, potassium benzoate, cesium benzoate, o-methyl Examples thereof include sodium benzoate, sodium m-methylbenzoate, and sodium p-methylbenzoate, and more preferably sodium benzoate or benzoic acid rim. The amount of the carboxylate used is preferably 1 to 10 times, and more preferably 1 to 5 times the molar amount of the optically active polysulfonyloxy-y-butyrolactone.

Further, the carboxylate may be generated in the system from the carboxylic acid represented by the above formula (10) and a base. In this case, examples of the carboxylic acid include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, vivalic acid, cyclohexanecarboxylic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, and oxalic acid , Malonic acid, maleic acid, fumaric acid, acrylic acid, methacrylic acid, cinnamic acid, vivalic acid, phenylacetic acid, p-clophenylphenylacetic acid, diphenylacetic acid, benzoic acid, o-methylbenzoic acid, m-methylbenzoic acid , P-methylbenzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, o-methoxybenzoic acid, salicylic acid, phthalic acid, nicotinic acid and the like. Preferred are formic acid, diacid, propionic acid, butyric acid, isobutyric acid, vivalic acid, benzoic acid and the like, and more preferred is benzoic acid. Above force The amount of rubonic acid to be used is preferably 1 to 10 times, more preferably 1 to 5 times the molar amount of optically active α-sulfonyloxy-γ-butyrolactone. Examples of the base include lithium hydroxide, sodium hydroxide, rhodium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium fluoride, and the like. Inorganic bases; metal alkoxides such as sodium methoxide, sodium ethoxide and lithium tert-butoxide; metal hydrides such as lithium hydride, sodium hydride and lithium hydride; ammonia, butyramine, aniline, diisopropyla Min, cyclohexylamine, diphenylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, diisopropylethylamine, N-methylmorpholine, N-methylbiperidine, imidazole, pyridine, Amines such as p-chloropyridine, 2-picoline, 3-picoline, 4-N, N-dimethylaminoviridine, 1,7-diazabicyclo [5,4,0] -ndecou-7-ene and the like. Preferably, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine and the like are mentioned. The amount of the base to be used is preferably 0.5 to 10 times, more preferably 0.5 to 5 times, the molar amount of the optically active monosulfonyloxy_γ-butyrolataton.

 The reaction temperature of this reaction is preferably 0 to 120 ° C, more preferably 20 to 80 ° C.

Organic solvents that can be used in this reaction include, for example, nonprotonic solvents. Non-protonic solvents include, for example, ester solvents such as ethyl acetate, butyl acetate, methyl propionate, and propyl formate; ketone solvents such as acetone, methyl ethyl ketone, cyclopentanone, and cyclohexanone; acetonitrile, N-tolyl solvents such as propio-tolyl; etc .; Ethanol solvents such as getyl ether, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, dimethoxetane, diethylene glycol resin methinolate ethereol; pentane , Hexane, tonolen, benzene, xylene, etc .; hydrocarbon solvents; dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, cyclobenzene, etc .; Non-protonic polar solvents such as norformamide, dimethinoreacetamide, N-methinolepyrrolidone, dimethinolepropylene perylene, dimethylsulfoxide, and hexamethylphosphoric triamide. The above solvents may be used alone or in combination of two or more. In the above-mentioned solvents, preferably, ether solvents such as getyl ether, tetrahydrofuran, methinole tert-butyl ether, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide, dimethinoreacetamide, N— Non-protonic polar solvents such as methylpyrrolidone, dimethylpropylenediarea, dimethylsulfoxide and hexamethylphosphoric triamide, and the like, more preferably dimethylformamide, dimethylacetamide, N-methylpyrrolidone, Non-protonic polar solvents such as dimethyl sulfoxide.

In this reaction, the (R) -α-acyloxy-γ-butyrolact represented by the above formula (8) can be obtained at an unexpectedly high optical yield by suitably selecting the reaction reagent and reaction conditions. Tons can be produced. For example, (S) -c-sulfonyloxy_γ-butyrolactone represented by the above formula (6) wherein R ² is a ρ-methylphenyl group and the above formula (7) wherein R ³ is a phenyl group The carboxylate represented by is reacted in, for example, dimethylformamide to produce (R) -hydroxy-γ-butyrolactone which is completely stereoinverted and R ³ is a phenyl group. You can do this.

 As the post-treatment of this reaction, general post-treatment for obtaining a product from the reaction solution may be performed. For example, water is added to the reaction solution after completion of the reaction, and an extraction operation is performed using a common extraction solvent, for example, ethyl acetate, getyl ether, methylene chloride, toluene, hexane and 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. The target product thus obtained may be purified by a general method such as crystallization purification, fractional distillation, or column chromatography to further increase the purity.

In the above formula (8), R ³ is a hydrogen atom, an η-propyl group, an isopropyl group, an η-butyl group, a sec-butyl group, a tert-butynole group, a chloromethyl group, or a phenyl group (R ) — Γ-butyrolactone is referred to in the literature. Are new compounds not described in the above. Next, an acid or a base is allowed to act on the optically active α-acylsoxy-γ-petit mouth lactone represented by the above formula (8) in an alcohol solvent to deacylate the compound, whereby the above formula (9) (R) -α-hydroxy γ-petit ratatone represented by

 Here, examples of the alcohol include alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propanol, isopropanol, η-butanol, and ethylene glycol, and preferably methanol or ethanol. Examples of the acid include mineral acids such as sulfuric acid, nitric acid, hydrogen chloride, hydrogen bromide, perchloric acid, and phosphoric acid; and organic acids such as ρ-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. Acids, preferably sulfuric acid or hydrogen chloride.

 Examples of the base include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate and the like; sodium methoxide Metal alkoxides such as sodium, sodium ethoxide, magnesium ethoxide, sodium isopropoxide, lithium tert-butoxide; ammonia, methylamine, diisopropylamine, trimethinoleamine, triethylamine, tributylamine, triphenylenoleamine, diisopropylamine Tinoleamine, N-methylmorpholine, N-methylbiperidine, imidazole, pyridine, p-cyclopyridine, 3-picoline, 2-picoline, 4-N, N-dimethylaminopyridine, 1,7- Amines such as azabicyclo [5,4,0] -index-17-ene; and the like, preferably sodium carbonate, carbonated sodium, sodium hydroxide, hydroxylated sodium, sodium methoxide; Sodium ethoxide and the like can be mentioned.

The amount of the acid or base to be used is 0.01 to 10 times, more preferably 0.01 to 1 times the molar amount of the optically active α-acyloxy-γ-butyrolactone. Regarding the reaction temperature in the case of an acid, the reaction is preferably performed at 0 to 120 ° C, more preferably at 40 to 100 ° C. In the case of a base, preferably 20 to 7 The temperature is preferably 0 ° C, more preferably 0 to 40 ° C.

 As the post-treatment of this reaction, general post-treatment for obtaining a product from the reaction solution may be performed. For example, the target product can be obtained by distilling off the reaction solvent from the reaction solution after the reaction by heating under reduced pressure or the like. In addition, the excess acid or base may be removed by filtration after neutralization, and purified by a general method such as column chromatography and fractional distillation to further increase the purity.

Above, using the method of the present invention, an inexpensive optically active from starting materials _alpha - both Enanchioma arsenide Dorokishi _ _gamma _ Petit port rata tons, respectively efficiently produced to can Rukoto. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Synthesis Example 1 (R) — Production of 4-amino-2-hydroxybutanoic acid

D Monoglutamic acid 7.35 g (50 mmo 1), water 15 g, acetic acid 12.0 g (20 Ommo 1) slurry solution, sodium nitrite 5.175 g (75 m An aqueous solution (20 mL) of mo 1) was added dropwise at 15 ° C. for 3 hours. After stirring at room temperature for 24 hours, acetic acid and water were distilled off under reduced pressure to obtain a yellow oil. Here, 30.36 g (50 Ommo 1) of 28 wt% ammonia water was added, and the mixture was stirred at 15 ° C. for 20 hours. Ammonia was distilled off by concentration under reduced pressure, and a 10 wt% aqueous solution of caustic soda was added to adjust the pH to l = 1, and then the remaining ammonia was distilled off under reduced pressure. To this, 20.0 g (150 mm o 1) of a 33 wt% aqueous solution of caustic soda was added, and the mixture was cooled in an ice bath, and a 12 wt% aqueous solution of sodium hypochlorite 46.56 g (75 m mo 1) was added, and the mixture was stirred for 10 minutes, and then heated and stirred at 70 ° C. for 30 minutes. After cooling to room temperature, the pH was adjusted to 7 with concentrated sulfuric acid, and the mixture was charged into an ion exchange resin (Amberlite IR-120B, dry weight: 200 g). After developing 150 OmL of water, developing with 150 OmL of 1N ammonia water, collecting and concentrating a fraction with ninhydrin coloring yielded 1.1.401 g of a tan solution. . Here, add 3 OmL of ethanol. As a result, white crystals were precipitated, which was filtered and dried under vacuum to obtain 2.79 g of (R) -4-amino-12-hydroxybutanoic acid (isolation yield: 45%). '' Example 1 Production of (R) -α-hydroxy-petit mouth ratatone

 To 1.06 g (8.39 mmo 1) of (R) -4-amino-2-hydroxybutanoic acid prepared in Synthesis Example 1, 3 mL of water and 2.52 g (42. Ommo 1) of acetic acid were added. 8.68 g (12.6 mmo 1) of a 10 wt% sodium nitrite aqueous solution was added dropwise at 15 ° C. for 2 hours. After performing the reaction at 15 ° C for 2 hours, water and acetic acid were distilled off by concentration under reduced pressure, 5 mL of water was added, and the pH was adjusted to 1 with concentrated sulfuric acid. 20 mL of ethyl acetate was added thereto, and the mixture was stirred at 50 ° C for 30 minutes, and then the organic layer was separated. Further, the same extraction was performed by adding 2 OmL of ethyl acetate to the aqueous layer, and this operation was repeated three times. The extracts were combined, dried over anhydrous magnesium sulfate, and concentrated to give 764 mg of a yellow oil. Purification by Kugelrohr distillation (decompression degree: 1 mmHg, 110 ° C to 120 ° C) yielded 476 mg of (R) -α-hydroxy-gamma-petit-mouth lactone (isolated yield). (37%) as a colorless oil.

_{^ -NMR (CD C 1 3,} 40 OMH z / p pm); 2. 28 (l H, m), 2. 6 1 (l H, m), 3. 70 (1 H, bs) N 4. 2 5 (lH, m), 4.44 (1H, dd), 4.53 (1H, dd)

The optical purity was determined by derivatizing tert-butyldiphenylsilyl ether. That is, to the above (R) -α-hydroxy-1-γ-butyrolataton 100 mg, add tert-butynolefiefenii / resilinorecole mouth 4.12 mg, imidazo-monole 204 mg, dimethylformamide 3 mL, and add 40 mL The mixture was stirred for 16 hours. 7 mL of water and 10 mL of hexane were added, the aqueous layer was removed, washed with 1 OmL of water, and concentrated to obtain 505 mg of a pale yellow oil. HPLC (Analysis conditions; Column: Daicel Chiral Cell OD—H 4.6 x 250 mm, Eluent: Isopropanol Z hexane = 5Z95, Flow rate: 0.5 mL / min. Column temperature: 30 ° C, Detector: The optical purity measured by UV at 220 nm was 97.2% ee. Example 2 Production of (S) -α-hydroxyv_-butyrolactone To a commercially available (Aldrich No. 46 735-9) (S) —4-amino-12-hydroxybutanoic acid (119 g, lmol), 300 mL of water and 360 g of acetic acid (5 mol) were added. 207 g of an aqueous solution of 138 g (2mo 1) of sodium nitrate was added dropwise at 15 ° C for 6 hours. After performing the reaction at 15 ° (:, 16 hours later), 565 g of a yellow solution was obtained by concentration under reduced pressure.The pH was adjusted to 1 by adding concentrated sulfuric acid (about 52 mL), and 1 L of ethyl acetate was added. And stirred for 30 minutes at 50 ° C. After separating the organic layer, 1 L of ethyl acetate was further added to the aqueous layer, and the same extraction operation was performed, and this operation was repeated three times. After drying over anhydrous magnesium sulfate and concentrating, 88.86 g of a yellow oil was obtained, which was purified by vacuum distillation (degree of vacuum: lmmHg, 100 to 110 ° C) to obtain (S ) — Α-hydroxy-1-γ-butyrolatatone 59.65 g (isolation yield 55%) was obtained as a colorless oil, and the optical purity was measured by the method described in Example 1. Example 3 Production of (S) -α-hydroxy-τ-ptyloractone

(S) — 4-Amino-2-hydroxybutanoic acid 1.19 g (1 Ommo 1) from the commercial product (Aldrich No. 46 735-9), 1 OmL of water, 4.6 g of formic acid (10 Ommo 1) was added, and a water solution (10 mL) of 1.38 g (2 Ommo 1) of sodium nitrite was added at 15 ° C for 1 hour. After performing the reaction at 15 ° C for 16 hours, the mixture was concentrated until the total amount became 6.6 g, and the pH was adjusted to 1 by adding concentrated sulfuric acid. To this, 2 OmL of ethyl acetate was added, and after stirring at 50 ° C. for 30 minutes, the organic layer was separated. The same extraction operation was further repeated for the aqueous layer three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 1.517 g of a pale yellow oil. GC (analysis conditions: glass column, silicon OV—210 (10%) on Uniport HP (80 / l 00mesh) 4 mX 3 mm i.d .; column temperature 130 ° C; injection temperature 200 ° C; detector temperature 200 ° C; helium 3 OmL / min; detector FID), the reaction yield of (S) -α-hydroxy-1-γ-petit mouth ratatone was calculated to be 45%. Met. Example 4 Production of (S) -α-hydroxy_γ-butyrolactone 6.0 g (100 mm o 1) of acetic acid was added to 1.19 g (1 Omm o 1) of (S) —4-amino-2-hydroxybutanoic acid (Aldrich No. 46735-9) commercially available. 1.38 g (20 mm o 1) of sodium nitrite was added at 15 ° C for 1 hour. After performing the reaction at 15 ° C. for 3 hours, a methanol solution (20 mL) of concentrated sulfuric acid (1.225 g (12.5 mmo 1)) was added, and the mixture was heated and stirred at 70 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, 3 OmL of acetonitrile was added, and the mixture was further concentrated. To this was added 3 OmL of acetonitrile, 1.012 g (10 mmo 1) of triethylamine was added, and the precipitated solid was filtered off.The mother liquor was concentrated to give an orange oil 1.18 g was gotten. According to the method described in Example 3, the reaction yield of (S) -hydroxy-γ-butyrolactone was calculated to be 39%. Example 5 Production of (S) -α-hydroxy V-butyrolatatone

 (S) — 4-amino-1-hydroxybutanoic acid 1.19 g (1 Ommo 1), 1.38 g of sodium nitrite (2 Ommo 1) from commercial sales (Aldrich No. 46 735— 9) Aqueous solution (5 mL) of 3.6 g (60 mmol) of acetic acid was added to an aqueous solution (15 mL) of this at 15 ° C for 30 minutes. After a reaction was carried out at 15 ° C for 16 hours, the mixture was concentrated until the total amount reached 6.0 g, and the pH was adjusted to 1 by adding concentrated sulfuric acid. To this, 2 OmL of ethyl acetate was added, and after stirring at 50 ° C for 30 minutes, the organic layer was separated. The same extraction operation was further repeated three times for the aqueous layer. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain 2.210 g of a pale yellow oil. The reaction yield of (S) -α-hydroxy_γ-butyrolataton calculated by the method described in Example 3 was 85%. Example 6 Production of (S) -α-hydroxy-y-petit mouth ratatone

To an aqueous solution (5 mL) of acetic acid 3.6 g (6 Ommo 1) was marketed (A 1 drich No. 4673 5-9). (S) —4-amino-1-hydroxybutanoic acid 1.19 g (1 Ommo 1) and 1.38 g (20 mmo 1) of sodium nitrite in water (15 mL) were added at 15 ° C. for 1.5 hours. After a reaction was carried out at 15 ° C. for 16 hours, the mixture was concentrated until the total amount became 6.Og, and adjusted to pH = 1 by adding concentrated sulfuric acid. To this was added 2 O mL of ethyl sulphate, and after stirring at 50 ° C for 30 minutes, the organic layer was separated. The same extraction operation was further repeated three times for the aqueous layer. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to obtain 2.2741 g of a pale yellow oil. According to the method described in Example 3, the reaction yield of (S) -hydroxy_γ-petit mouth ratatone was calculated to be 88%. Example 7 Production of (S) -α-hydroxy_γ-butyrolactone

 To an aqueous solution (5 mL) of 1.38 g (2 Ommo1) of sodium nitrite was added 3.6 g (60 mmo1) of acetic acid and a commercially available solution (Aldrich No. 46773-5-9 ) Of (S) —4-amino-2-hydroxybutanoic acid (1.19 g, 1 Ommo 1) in water (15 mL) was added at 15 ° C. for 1.5 hours. After the reaction was carried out at 15 ° C for 16 hours, the mixture was concentrated until the total amount became 6. Og, and the pH was adjusted to 1 by adding concentrated sulfuric acid. 2 OmL of ethyl acetate was added thereto, and the mixture was stirred at 50 ° C. for 30 minutes, and then the organic layer was separated. The same extraction operation was further repeated for the aqueous layer three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to obtain 1.7581 g of a pale yellow oil. According to the method described in Example 3, the reaction yield of (S) -hi-hydroxy-γ-butyrolactone was calculated to be 89%. Synthesis Example 2 Preparation of (S) -methyl 4-amino-2-hydroxybutanoate

 Add (20 mL) of methanol to (O) (83.9 mmo1) of (S) —4-amino-2-hydroxybutanoic acid (10.Og (83.9 mmo1)) commercially available (Aldrich No. 4673 35-9). Calorie, 60 g of a 10 wt% methanolic hydrochloric acid solution was added at 5 ° C. To this was added 11.1 Og (92.3 mmo 1) of thionyl chloride, and the mixture was stirred at 15 ° C for 3 hours. This solution was concentrated under reduced pressure to obtain 17.22 g of methyl (S) -4-amino-12-hydroxybutanoate.

— NMR (CD ₃ OD, 40 OMHz / ppm); 1.90—1.97 (1 H, m), 2.07-2.13 (1 H, m), 3.2 4—3.25 (2H, m), 3.70 (3H, s), 4.28—4.30 (1H, m) Example 8 Production of (S) -α-hydroxy-Y-butyrolactone

 To 1.33 g (6.5 mmo 1) of methyl (S) _4-amino-2-hydroxybutanoate prepared in Synthesis Example 2, 1 OmL of water and 6.0 g (10 Omm o 1) was added, and an aqueous solution (1 OmL) of 1.38 g (2 Omm o 1) of sodium nitrite was added at 15 ° C. for 1 hour. After the reaction was carried out at 15 ° C for 16 hours, the mixture was concentrated until the total amount became 6.6 g, and the pH was adjusted to 1 by adding concentrated sulfuric acid. 20 mL of ethyl acetate was added thereto, and the mixture was stirred at 50 ° C. for 30 minutes, and then the organic layer was separated. The same extraction operation was further repeated for the aqueous layer three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated to obtain 1.0932 g of a pale yellow oil. According to the method described in Example 3, the reaction yield of (S) -a-hydroxy γ-butyrolactone was calculated to be 71%. Example 9 Production of (S) -a- (p-methylphenyl) sulfonyloxy-V-butyrate ratatone

(S) —Philo-droxy _y— petitolactone prepared in Example 2 was added to 5.0 g (46.3 mmo 1), 50 mL of tetrahydrofuran, 9.38 g of triethylamine (9 2. 6 mm o 1) was added, and ρ-tonolene snorefonino rechloride 10.60 g (55.6 mm o 1) was added thereto. After stirring at 5 ° C for 2 hours, the temperature was raised to 15 ° C, and the mixture was further stirred for 3 hours. Here, 2.65 g (13.9 mmo1) of p-toluenesulfonyl chloride was added, and after 13 hours at 15 ° C, the reaction was carried out. And concentrated under reduced pressure to 13 volumes. Ethyl acetate (3 OmL) was added for extraction, the aqueous layer was separated, and the organic layer was washed with 3 N hydrochloric acid (1 OmL) and water (2 OmL) sequentially, and then concentrated to give a reddish brown solid. 29 g were obtained. The solid was added with 1 OmL of ethyl acetate and 2 OmL of hexane, washed with stirring, filtered, and dried in vacuo to give (S) -a- (p-methylphenyl) sulfonyloxy- _γ -butyrolactone 1 0.41 g (88% isolated yield) was obtained as gray crystals.

^{X H-NMR (CD C 1} 3, 4 0 OMH z / ppm); 2. 4 5 (3 H, s), 2. 4 8- 2. 5 4 (1 H, m), 2. 6 8- 2.73 (1H, m), 4.26 (1 H, m), 4.45 (1H, m), 5.07 (1H, dd), 7.37 (2H, d), 7.86 (2H, d) 1 0 (S) One a-methylsulfonyloxy _ One butyrolactone

 To 5.10 g (47.3 mmo 1) of (S) _a-hydroxy one rat mouth produced in Example 2 was added 20 mL of tetrahydrofuran and 10.2 g of triethylamine. (94.6 mmo 1) was added thereto, and 6.87 g (56.8 mmo 1) of methanesnorefonino rechloride was added thereto. After stirring at 15 ° C for 16 hours, 20 mL of water and 5 OmL of ethyl acetate were added, the aqueous layer was separated, and the organic layer was sequentially washed with 20 mL of 1.5 N hydrochloric acid and 20 mL of water. After washing, the filtrate was concentrated to obtain 4.88 g of a reddish brown oily substance. Purification by silica gel force chromatography (Merck's Kiese 1ge 1600, hexane / ethyl acetate = 3/1 to 2/1) gave (S) -a-methylsulfonyloxy-γ — Butyrolactone 4.17 g (isolation yield 47%) was obtained as a pale yellow solid.

^{: H-NMR (CD C 1} 3, 4 0 OMH z / ppm); 2. 5 2- 2. 5 8 (1 H, m), 2. 7 4 - 2. 7 8 (1 H, m), 3.27 (3H, s), 4.34 (1H, m), 4.50 (1H, m), 5.33 (1H, dd) Example 11 (S) --(o-Nitrofueninole) Production of snorefoninoleoxy v-butyrolactone

To 1.08 g (10.Ommol) of (S) -hydroxy-γ-butyrolactone prepared in Example 2, 5 mL of tetrahydrofuran and 2.02 g of triethylamine (20. Ommol) was added, and 2.95 g (12. Ommol) of o-nitrobenzenesnorefoninolechloride was added thereto. After stirring at 5 ° C for 3 hours, the temperature was raised to 15 ° C, and the mixture was further stirred for 2 hours. 15 mL of water and 20 mL of ethyl acetate were added, the aqueous layer was separated, and the organic layer was washed successively with 15 mL of 3N hydrochloric acid and 15 mL of water, and then concentrated to give a reddish-brown oil. 55 g were obtained. Silica gel column chromatography (Kieselgel 60 manufactured by Merck, methanol ethyl acetate = 1/5) to give (S) -a- (o-nitrophenyl) sulfonyloxy γ-butyrolactone (1.12 g, isolated yield 39%) as a pale yellow oil .

'H-NMR (CD C 1 3, 4 0 OMH z / ppm); 2. 6 1 - 2. 6 7 (1 H, m), 2. 7 6- 2. 8 6 (1 H, m), 4.31-4.39 (1H, m), 4.46-4.56 (1H, m), 5.41 (1H, dd), 7.81-7. 8 9 (3 H, m), 8.26 (1 H, d) Example 12 Production of 2 (R) _a-benzoyloxy-γ-butyrolactone

ノ111 1 ₁1. カ ラム温度： 3 0°C、 検出器： UV 2 2 0 nm) にて光学純度を測定すると、 1 0 0 % e e . であった。 (S) -a- (p-methylphenyl) sulfonyloxy-γ-butyrate ratatone prepared in Example 9 50.0 g (184 mmo 1), sodium benzoate 53.1 g ( A solution of 368 mmO 1) and 35 OmL of dimethylformamide was stirred at 60 ° C. for 3 hours. 700 mL of water and 70 OmL of ethyl ethyl perate were added, the aqueous layer was removed, and the aqueous layer was further extracted with 70 mL of ethyl acetate, and the organic layers were combined. The organic layer was further washed 5 times with 30 O mL of water, dried over anhydrous magnesium sulfate, and concentrated to precipitate a solid. Here, 30 mL of ethyl acetate and 15 OmL of hexane were added, and the crystals were stirred and washed, filtered and dried in vacuo to give (R) -a_benzoyloxy-γ-butyrolactone 36.91 g ( Isolation yield: 97%) was obtained as white crystals. HPLC (Analysis conditions; column: Daicel Chiral Cell OJ 4.6 X 25 Omm, eluent: isopropanol hexane

111 111 1 ₁ 1. The optical purity was measured at a column temperature of 30 ° C. and a detector of UV 220 nm) and found to be 100% ee.

^{1 H-NMR (CD C 1} 3 4 0 OMH z / ppm); 2. 3 9- 2. 4 9 (1 H, m), 2. 8 0 - 2. 8 8 (1 H, m), 4 3 4—4.4 1 (1H, m), 4.52-4.57 (1H, m), 5.63 (1H, dd), 7.45 (2H, m) dd), 7.61 (1H, dd), 8.08 (2H, d) Example 13 Production of 13 (R) -a-benzoyloxy-γ-butyrolactone

(S) -a-methylsulfonyloxy-γ-butyrol prepared in Example 10 A solution of 360 mg (2 mmo1) of croton, 864 mg (6 mmo1) of sodium benzoate, and 1 OmL of dimethylformamide was stirred at 60 ° C for 16 hours. . HPLC (Column: YMC OD S—AA—30 34.6 X 25 Omm, Eluent: Acetonitrile Z distilled water = 15/8, 5, Flow rate: 1. OmLZmin. Column temperature: 40 ° C, detector: (R) -α-benzoyloxy at UV 220 nm)

— The reaction yield of γ-butyrolactone was determined to be 100%. The optical purity measured by the method described in Example 12 was 97.4% e e. Example 14 Production of 4 (R) -α-benzoyloxy-γ-butyrolatatone

 (S) -α-methylsulfonyloxy-γ-butyrolactone prepared in Example 10 360 mg (2 mmo 1), potassium benzoate 961 mg (6 mmo 1), dimethyl A solution of 1 OmL of formamide was stirred at 60 ° C for 16 hours. According to the method described in Example 10, the reaction yield of (R)-(1-benzoyloxy) -γ-butyrolatatone was determined to be 96%. The optical purity measured by the method described in Example 12 was 97.2% e e. Example 15 Production of 5 (R) -α-benzoyloxy-γ-butyrolactone

 (S) -α-methylsulfonyloxy γ_butyrolataton prepared in Example 10 360 mg (2 mmol), lithium benzoate 768 mg (6 mmo 1), dimethylformamide 5 The mL solution was stirred at 60 ° C. for 16 hours. According to the method described in Example 13, the reaction yield of (R)-(1-benzoyloxy) -γ-butyrolataton was determined to be 76%. The optical purity measured by the method described in Example 12 was 86.8% e e. Example 16 Production of 6 (R) -α-benzoyloxy-γ-butyrolatatone

(S) -α-methylsulfonyloxy-γ-butyrolataton prepared in Example 10 360 mg (2 mmo 1), cesium benzoate 152 4 mg (6 mmo 1), dimethyl A solution of 5 mL of formamide was stirred at 60 ° C for 16 hours. According to the method described in Example 13, (R) -hydroxybenzoyl γ-butyrolactate The reaction yield of the compound was 100%. The optical purity measured by the method described in Example 12 was 98.0% ee. Example 1 Production of 7 (R) -α-benzoyloxy-ptyloractone

 (S) -α-methylsulfonyloxy-γ-butyrolactone prepared in Example 10 360 mg (2 mmo 1), ammonium chloride, and 732 mg (6 mmo 1) A solution of cesium fluoride 911 mg (6 mmo 1) and dimethylformamide 5 mL was stirred at 60 ° C. for 16 hours. According to the method described in Example 13, the reaction yield of (R) -phenylbenzoyl γ-butyrolactone was found to be 93%. The optical purity measured by the method described in Example 12 was 95.6% e e. Example 18 Production of 8 (R) -α-benzoyloxy-γ-butyrolatatone

 (S) -a- (o--trophenyl) sulfonyloxy-γ-butyrate ratatone prepared in Example 11 1 256 mg (1 mmo 1), sodium benzoate 288 mg (2 mmo 1) and 3 mL of dimethylformamide were stirred at 60 ° C for 16 hours. According to the method described in Example 13, the reaction yield of (R) -hi-benzoyloxy-γ-butyrolactone was found to be 80%. The optical purity measured by the method described in Example 12 was 73.6% e e. Example 19 Production of 9 (R) -α-benzoyloxy-γ-butyrolatatone

(S) -a- (p-methylphenyl) sulfonyloxy-gamma-butyrolactone prepared in Example 9 256 mg (1 mmo1), sodium benzoate 288 mg (2 mmo1), dimethyl A solution of 3 mL of sulfoxide was stirred at 50 ° C for 16 hours. According to the method described in Example 13, the reaction yield of (R) -hi-benzoyloxy-gamma-butyrolactone was found to be 94%. The optical purity measured by the method described in Example 12 was 99.6% ee. Example 20 Production of 0 (R) -α-benzoyloxy-γ-butyrolatatone (S) -a- (p-methylphenyl) sulfonyloxy-γ-butyrolactone prepared in Example 9 256 mg (1 mm o 1), sodium benzoate 288 mg (2 mm o 1), A solution of 3 mL of tetrahydrofuran was stirred at 50 ° C for 16 hours. According to the method described in Example 13, the reaction yield of (R)-(1-benzoyloxy) -γ-butyrolatatone was determined to be 31%. The optical purity measured by the method described in Example 12 was 100% ee. Example 2 Production of 1 (R) -α-benzoyloxy-γ-butyrolactone

 (S) -a- (p-methylphenyl) sulfonyloxy-γ-butyrolactone prepared in Example 9 256 mg (1 mm o 1), sodium benzoate 288 mg (2 mm o 1), A solution of 3 mL of ethyl acetate was stirred at 50 ° C. for 16 hours. The reaction yield of (R) -α-benzoyloxy_γ-butyrolactone as determined by the method described in Example 13 was 15%. The optical purity measured by the method described in Example 12 was 100% e e. Example 2 Preparation of 2 (R) -H-benzoyloxy γ-petit mouth rataton

(S)--(p-methylphenyl) sulfonyloxy-V-butyrolactone prepared in Example 9 256 mg (1 mmo1), sodium benzoate 288 mg (2 mmo1) A solution of 1 mL of ethyl acetate and 1 mL of dimethylformamide was stirred at 50 ° C. for 16 hours. According to the method described in Example 13, the reaction yield of (R) —c—benzoyloxy-γ-butyrolactone was found to be 74%. The optical purity measured by the method described in Example 12 was 100 ° / ₀ ee. Example 2 Preparation of 3 (R) -H-benzoyloxy-y_butyrolatatone

(S) -a- (p-methylphenyl) sulfonyloxy-y-butyrolactone prepared in Example 9 256 mg (1 mmo 1), sodium benzoate 288 mg (2 mm o 1) A 3 mL solution was stirred at 50 ° C. for 16 hours. According to the method described in Example 13, (R) _-α -benzoyloxy-γ-petit mouth lacto The reaction yield of the compound was determined to be 16%. The optical purity measured by the method described in Example 12 was 100% ee. Example 24 Production of 4 (R) -α-benzoyloxy-γ-butyrolactone

(S) -a- (p-methylphenyl) sulfonyloxy-γ-butyrolactone prepared in Example 9 256 mg (1 mmo 1), benzoic acid 244 mg (2 mmo 1), sodium carbonate A solution of 106 mg (1 mmo 1) and 3 mL of dimethylformamide was stirred at 60 ° C. for 4 hours. The reaction yield of (R) -a-benzoyloxy-γ-butyrolactone was determined by the method described in Example 13 to be 96%. The optical purity measured by the method described in Example 12 was 99.8% ee. Example 2 Preparation of 5 (R) _a_benzoyloxy- _y -butyrolactone

 (S) -a- (p-methylphenyl) sulfonyloxy-γ-butyral lactone prepared in Example 9 256 mg (1 mm o 1), benzoic acid 244 mg (2 mm o 1), A solution of magnesium ethoxide 114 mg (1 mmo 1) and dimethylformamide 5 mL was stirred at 60 ° C. for 3 hours. According to the method described in Example 13, the reaction yield of (R) 1-benzoyloxy-1-γ-butyrolactone was found to be 53%. The optical purity measured by the method described in Example 12 was 89.2% e e. Example 2 Production of 6 (R) -α-benzoyloxy-Y-petit mouth ratataton

(S) —Hi-I (ρ_methylphenyl) sulfonyloxy-γ-butyrolactone prepared in Example 9 256 mg (1 mmo 1), benzoic acid 244 mg (2 mmo 1), triethylamine 202 mg ( 2 mmo 1) and 5 mL of dimethinoleformamide were stirred at 60 ° (:, 3 hours. According to the method described in Example 13, (R) -α-benzoyloxy-γ-butyrolata The reaction yield was calculated to be 92%, and the optical purity measured by the method described in Example 12 was 99.4% ee. Example 2 Production of 7 (R) -α-acetyloxy-v-butyrolactone- (S) -a- (p-methylphenyl) sulfonyloxy-gamma-butyrolactone prepared in Example 9 5.0 g (1 9.5 mm o 1), a solution of sodium acetate 3.20 g (3 9. O mm o 1), dimethylformamide 50 mL, 60. C, and stirred for 7 hours. 70 mL of water and 7 OmL of ethyl acetate were added, the aqueous layer was removed, and the aqueous layer was further extracted with 70 mL of ethyl acetate, and the organic layers were combined. The organic layer was further washed 5 times with 30 mL of water, dried over anhydrous magnesium sulfate, and concentrated to give (R) -a-I-cetyloxy-1 "/-butyrolactone as a brown oil (1.94 g, purity 7 5 wt% and a reaction yield of 52%).

^{1 H-NMR (CD C 1} 3, 4 0 OMH z / ppm); 2. 1 7 (3 H, s), 2. 2 8 - 2. 3 3 (1 H, m), 2. 6 8 - 2.76 (1H, m), 4.28-4.35 (1H, m), 4.46-4.51 (1H, m), 5.44 (1H , dd) Example 28 Preparation of 8 (R) -a-chloroacetyloxy-gamma-butyrolactone (S) -Hi-ichi (ρ-methylphenyl) sulfonyloxy-γ-butyrolactone 2 prepared in Example 9 0.07 g (7.48 mmo 1); a solution of 1.74 g (15.Ommo 1) of sodium acetate and 2 OmL of dimethylformamide at 50 ° C for 16 hours Stirred. 3 O mL of water and 30 mL of ethyl acetate were added, the aqueous layer was removed, and the aqueous layer was further extracted with 3 O mL of ethyl ethyl acetate, and the organic layers were combined. The organic layer was further washed five times with 2 O mL of water, dried over anhydrous magnesium sulfate and concentrated to obtain 1.55 g of a pale yellow oil. Purification by silica gel column chromatography (Iese 1ge 160, manufactured by Merck, hexane Z ethyl acetate = 1/1) gave (R)-(1-chloroacetyloxy-γ-butyrolactone 9). 51 mg (isolation yield: 71%) was obtained as a colorless oil.

^{1 H-NMR (CD C 1} 3, 4 0 OMH z / pm); 2. 3 3 - 2. 4 1 (1 H, m), 2. 7 2 - 2. 7 9 (1 H, m), 4.2 4—4.37 (1H, m), 4.47-4.53 (1H, m), 4.82 (2H, s), 5.52 (1H , dd) Example 29 Production of (R) _-α -bivaloyloxy- _y -butyrolactone

(S) -a- (p-methylphenyl) sulfonyloxy-γ-butyrate ratatone prepared in Example 9 2.67 g (10. Ommo 1), pivalic acid 2.04 g (20.0 mmo1), 1.68 g (20 mmo1) of sodium hydrogen carbonate and 2 OmL of dimethylformamide were stirred at 50 ° C for 16 hours. 70 mL of water and 100 mL of ethyl acetate were added, the aqueous layer was removed, and the aqueous layer was further extracted with 5 mL of ethyl acetate, and the organic layers were combined. The organic layer was further washed three times with 5 OmL of water, dried over anhydrous magnesium sulfate, and concentrated to obtain 2.411 g of a pale yellow oil. Purification by silica gel column chromatography (Keeese 1 ge 160 from Merck, hexane Z ethyl acetate = 31) yielded (R) -a-bivaloylox-Y-petit mouth ratatotone 1 33 g (isolation yield 52%) were obtained as a colorless oil. _{^{1 H-NMR (CDC 1 3}} , 40 OMH z / ppm); 1. 25 (9H, s), 2. 25 - 2. 3 3 (1 H, m), 2. 66- 2. 72 (l H , m), 4.28—4.34 (1H, m), 4.45—4.50 (1H, m), 5.41 (1H, dd) Example 30 (R) —a —Hydroxy y-Production of ptyloractone

A 28 wt% sodium methoxide solution was prepared by adding a solution of (R)-(1-benzoyloxy-γ-butyrolactone) (12.91 g (62.7 mmol)) prepared in Example 12 to methanol (6 OmL). · 209 g (6.3 mmo 1) was added at 15 ° C and stirred for 7 hours. To this, an operation of adding 615 mg (6.3 mmo 1) of concentrated sulfuric acid, distilling off methanol by vacuum concentration, further adding 6 OmL of acetonitrile, and reconcentrating was repeated twice. To the obtained yellow oil, 5 OmL of ethyl acetate and 1.27 g (12.5 mmo 1) of triethylamine were added, and the precipitated solid was separated by filtration. The resulting yellow oil was purified by distillation (vacuum degree: lmmHg, 95-98 ° C). As a result, (R) _a-hydroxy-1-γ-butyrolactone (4.81 g, isolated yield) 75%) as a colorless oil. The optical purity measured by the method described in Example 1 was 99.6% ee. Example 3 Production of 1 (R) -Hydroxy-butyrolactone A solution of 1.333 g (6.94 mmo 1) of (R) -α-acetyloxy-γ-butyrolactone prepared in Example 27 in methanol (1 OmL) was added with a 28 wt% sodium methoxide solution 13 Omg ( 0.67 mm o 1) was kneaded at 15 ° C and stirred for 1 hour. To this, 68 mg (0.69 mmo 1) of concentrated sulfuric acid was added, methanol was distilled off by concentration under reduced pressure, 10 ml of acetonitrile was further added, and the operation of reconcentration was repeated twice. To the obtained yellow oil was added 1 OmL of acetonitrile, 140 mg (1.38 mmol) of triethylamine, and the precipitated solid was separated by filtration to obtain 1.051 g of a yellow oil. The reaction yield of (R) -α-hydroxy- _γ -butyrolactone calculated by the method described in Example 3 was 77%. The optical purity measured by the method described in Example 1 was 98.6% ee. Example 3 Production of 2 (R) -α-hydroxy-γ-butyrolactone

To a solution of (R)-(1-chloroacetyloxy) -γ-butyrolactone 83.0 mg (4.65 mmo 1) produced in Example 28 in methanol (10 mL) was added 28 wt. 68 mg (0.35 mmo 1) of a 15% sodium methoxide solution was added at 15 ° C., and the mixture was stirred for 16 hours. To this, 52 mg (0.53 mmo 1) of concentrated sulfuric acid was added, methanol was distilled off by concentration under reduced pressure, 5 ml of acetonitrile was further added, and the operation of reconcentration was repeated twice. To the obtained yellow oil, 5 mL of acetonitrile and 71 mg (0.7 Ommo 1) of triethylamine were added, and the precipitated solid was separated by filtration to obtain 706 mg of a yellow oil. By the method described in Example 3, (R) _- α - calculating the reaction yield of human Dorokishi γ- butyrate port rata tons, it was 85%. The optical purity measured by the method described in Example 1 was 91.4% ee. Example 3 Production of 3 (R) -α-hydroxybutyrolataton

Prepared in Example 2 9 (R) - methanol (1 OML) solution of Fei one Bibariruokishi one γ- Buchirorata tons 1. 3 7 g (7. 3 7mmo 1), 28 wt 0 I isocyanatomethyl Riumume Tokishido solution 142m g (0.74mm o 1) at 15 ° C While stirring. An operation of adding 72 mg (0.74 mmo 1) of concentrated sulfuric acid, distilling off methanol by vacuum concentration, further adding 3 OmL of acetonitrile, and performing reconcentration was repeated twice. To the obtained yellow oil, 3 OmL of ethyl acetate and 149 mg (1.47 mmo 1) of triethylamine were added, and the precipitated solid was separated by filtration to obtain 799 mg of a yellow oil. According to the method described in Example 3, the reaction yield of (R) -hi-hydroxy- _γ -butyrolactone was calculated to be 67%. The optical purity measured by the method described in Example 1 was 90.4% ee. Industrial applicability

 The present invention has the above-mentioned constitution, and can easily produce optically active α-hydroxy-ptyrolactone, which is useful as a pharmaceutical intermediate, from inexpensive and easily available raw materials.

Claims

Claims The following formula (1);

(In the formula, * represents an asymmetric carbon. R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.) An optically active 4-amino-2-hydroxybutanoic acid derivative represented by the following formula: The following formula (2):

(In the formula, * and R ¹ are the same as above. Q represents a hydroxyl group, halogen or an alkoxy group having 1 to 5 carbon atoms.) Production of an optically active 4-monosubstituted -2-hydroxybutanoic acid derivative Law. 2. The process according to claim 1, wherein nitrous acid is generated in the system from nitrite and acid. 3. The production method according to claim 2, wherein the nitrite is sodium nitrite or potassium nitrite. 4. The production method according to claim 2, wherein the acid is a carboxylic acid. 5. The method according to claim 4, wherein the carboxylic acid is formic acid, acetic acid or propionic acid. 6. The production method according to any one of claims 1 to 5, wherein water, formic acid, acetic acid, or propionic acid is used as a reaction solvent. - 7. The production method according to claim 6, wherein water is used as a reaction solvent. 8. The production method according to any one of claims 1 to 7, wherein R ¹ is a hydrogen atom. 9. The production method according to any one of claims 1 to 8, wherein Q is a hydroxyl group or an acetyloxy group. 10. Any one of claims 1 to 9, wherein the optically active 4-amino-2-hydroxybutanoic acid derivative represented by the formula (1) is (S) -4-amino-12-hydroxybutanoic acid. The production method according to item 1. 1 1. Optically active 4-monosubstituted 2-hydroxybutanoic acid derivative represented by the formula (2): Power (S) -2,4-dihydroxybutanoic acid or (S) -4-acetyloxy The production method according to any one of claims 1 to 10, wherein the production method is 2-hydroxybutanoic acid. 1 2. The following formula (2) produced by the method according to any one of claims 1 to 11;

(In the formula, * represents an asymmetric carbon. R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Q represents a hydroxyl group, a halogen, or an acyloxy group having 1 to 5 carbon atoms.) Optically active 4-mono-substituted 1-2-hydroxybutanoic acid derivatives Characterized by the following formula (3): 0)

(In the formula, * is the same as above.) A method for producing an optically active α-hydroxy-1-γ-butyrolactone represented by the formula: 13. The process according to claim 12, wherein the cyclization is carried out in an aqueous sulfuric acid solution or an aqueous hydrochloric acid solution. 14. The production method according to claim 12, wherein the cyclization is carried out in the presence of an organic solvent having low compatibility with water. 15. The production method according to claim 14, wherein the organic solvent is ethyl acetate, toluene, tetrahydrofuran, or methyl monobutyl ether. 1 6. The production method according to claim 12, wherein the cyclization is carried out in an organic solvent in the presence of an acid. 17. The process according to claim 16, wherein the organic solvent is ethyl acetate, toluene, tetrahydrofuran, methyl tert_butyl ether, acetone or acetonitrile. 1 8. The process according to claim 12, wherein the cyclization is carried out in an alcohol in the presence of an acid. 19. The method according to claim 18, wherein the alcohol is methanol or ethanol. 20. The method according to any one of claims 16 to 19, wherein the acid is sulfuric acid, hydrogen chloride or methanesulfonic acid. 2 1. The optically active 4-substituted 12-hydroxybutanoic acid derivative represented by the formula (2) is (S) —2,4-dihydroxybutanoic acid or (S) —4-acetyloxy1-2-hydroxybutanoic acid. 21. The optically active hydroxy-γ-butyrolactone represented by the formula (3) is (S) -α-hydroxy-1-γ-butyrolactone. The production method according to item 1. 22. The following equation (1):

(Wherein, * represents an asymmetric carbon.) By reacting an optically active 4-amino-2-hydroxybutanoic acid derivative represented by the formula (1) wherein R ¹ is a hydrogen atom with nitrous acid, The following formula (3): (3)

(In the formula, * is the same as above.) A method for producing an optically active α-hydroxy-1-γ-butyrolactone represented by the formula: 23. The method according to claim 22, wherein nitrous acid is generated in the system from nitrite and acid. 24. The claim according to claim 1, wherein the nitrite is sodium nitrite or potassium nitrite. The production method according to paragraph 23. 25. The production method according to claim 23 or 24, wherein the acid is a carboxylic acid. 26. The method according to claim 25, wherein the carboxylic acid is formic acid, acetic acid or propionic acid. 27. The production method according to any one of claims 22 to 26, wherein water, formic acid, acetic acid, or propionic acid is used as a reaction solvent. 28. The production method according to any one of claims 22 to 27, wherein water is used as a reaction solvent. 29. The optically active 4-amino-2-hydroxybutanoic acid derivative represented by the formula (1) is (S) -4-amino-2-hydroxybutanoic acid, and the optically active 4-amino-2-hydroxybutanoic acid represented by the formula (3) Ichihi Dorokishi one _gamma - Buchirorata tons (S) _- α - process according to any one of claims first 22-28 wherein a heat Dorokishi one γ- butyrolactone tons. 30 Following formula (4)

(S) —Phenoxydroxy-1-γ-butyrolactone represented by the following formula (5); 0 R ² — i— C1 (5)  ΰ (Wherein, R ² represents an alkyl group having 1 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be possessed, or an aralkyl group having 6 to 12 carbon atoms which may have a substituent. ) Is reacted in the presence of a base to give the following formula (6):

(Wherein R ² is the same as above) to produce (S) —α_sulfonyloxy-γ-monopetit ratatatone represented by the following formula (7):

(In the formula, R ³ represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be present, or an aryl group having 6 to 12 carbon atoms which may have a substituent, wherein Μ represents an alkali metal, an alkaline earth metal or Η represents an integer of 1 or 2.) and reacted with a carboxylate represented by the following formula (8):

(Wherein, R ³ is the same as above). (R) — α-Acylosoxy-γ-butyrolactone is produced, and further reacted with an acid or a base in an alcohol solvent to deacylate it. The following equation (9): (9)

A method for producing (R) -α-hydroxy-γ-butyrolactone represented by 3 1. The method according to claim 1, wherein the (S) -hydroxy-1-γ-butyrolactone represented by the formula (4) is produced by the method according to any one of claims 11 to 29. The production method according to paragraph 30. 3 2. In the reaction of (S) -O-hydroxy-γ-butyrolactone represented by the formula (4) with the sulfonyl chloride represented by the formula (5), the base is a tertiary amine. 30. The production method according to claim 30 or 31, wherein 33. The production method according to claim 32, wherein the tertiary amine is triethylamine or pyridine. 34. The method according to any one of claims 30 to 33, wherein the alcohol solvent used for deacylation is methanol or ethanol. 35. The method according to any one of claims 30 to 34, wherein the acid used for deacylation is sulfuric acid or hydrogen chloride. 36. The method according to any one of claims 30 to 34, wherein the base used for deacylation is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide. The manufacturing method described. 3 7. The following formula (6); (6)

(Wherein, R ² represents an alkyl group having 1 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be possessed, or an aralkyl group having 6 to 12 carbon atoms which may have a substituent. (S) -Hysulfonyloxy-γ-butyrolactone represented by the following formula (7):

(In the formula, R ³ represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkenyl group having 2 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may be present, or an aryl group having 6 to 12 carbon atoms which may have a substituent, wherein Μ represents an alkali metal, an alkaline earth metal or Represents an ammonia, η represents an integer of 1 or 2, and is reacted with a carboxylate represented by the following formula (8):

(Wherein, R ³ is the same as described above.) A method for producing (R) _α-acyloxy-γ-butyrolactone represented by: . 3 8 R ² is methyl group, phenyl group, or ρ- Mechirufue - A process according to any one of claims 3 0-3 7 wherein a Le group. 39. In the reaction between (S) -α-sulfonyloxy-γ-butyrolataton represented by the formula (6) and the carboxylate represented by the formula (7), the reaction solvent is a non-protonic polar solvent The production method according to any one of claims 30 to 38, wherein 40. The production method according to any one of claims 30 to 39, wherein Μ is an aluminum alloy. 41. The method according to claim 40, wherein the alkali metal is sodium or steel. 42. The carboxylate represented by the formula (7) is converted to the following formula (10);

(In the formula, R ³ is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may have a substituent, an alkyl group having 2 to 12 carbon atoms which may have a substituent, Represents an aralkyl group having 7 to 12 carbon atoms which may have a group, or an aryl group having 6 to 12 carbon atoms which may have a substituent. The process according to any one of claims 30 to 41, wherein the process is prepared in a system from 43. The process according to claim 42, wherein the base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or pyridine. 44. R ³ is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a chloromethyl group, or a phenyl group The production method according to any one of claims 30 to 43. 4 5. Process according to the fourth item 4 claims wherein R ³ is phenyl group. 4 6. The following formula (6): R ² S0 ₂ 0 ,, „ In the above, R ² is a phenyl group or a p-methylphenyl group. (S) -Hysulphoninoleoxy-l-y-butyrolactone. ' 47. In the formula (6), R ² represents a p-methylphenyl group, and is (S) -α- (ρ_methylphenyl) sulfonyloxy-1 "-petit mouth ratatone. A compound as described. 48 The following formula (8);

In the above, R ³ is a hydrogen atom, an η-propyl group, an isopropyl group, an η-butyl group, a sec-butynole group, a tert-butynole group, a chloromethynole group, or a feninole group (R) -α-acyloxy _ y—Butyrolata ton. 49. The compound according to claim 48, wherein in the formula (8), R ³ represents a tert-butyl group, a chloromethyl group, or a fuunyl group. 50. In the formula (8), R ³ represents a phenyl group, and (R) _—α —ba 50. The compound according to claim 49, which is an ox-γ-petit mouth rataton.