JP2000169445A - Production of optically active 4-mercapto-2-pyrrolidinone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active 4-mercapto-2- pyrrolidinone derivative, capable of giving the subject compound having high purity through simple purification operations, by reacting an optically active sulfonyloxypyrrolidinone derivative with a thioacetic acid alkali salt in a specified solvent, then hydrolyzing the reaction product in the presence of a base. SOLUTION: This method for producing an optically active 4-mercapto-2- pyrrolidinone of formula IV comprises reacting a compound of formula I (R1 is a 1-6C alkyl or phenyl) having a R- or S-configuration with a compound of formula II (R2 is equal to R1; M is an alkali metal) in alcohols, sulfoxides or a mixed solvent of water with the alcohols or the sulfoxides to form a compound of formula III having the converted configuration, then hydrolyzing the formed compound of formula III in the presence of a base (preferably, ammonia, methylamine, etc.). The compound of formula IV is useful as an important intermediate compound for synthesizing a substance having excellent antibacterial activity. The method can provide an excellent industrial method by which an important intermediate compound for an antibiotic substance is synthesized in a low cost on a large scale.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active 4-mercapto-2-pyrrolidinone derivative useful as a synthetic intermediate of an antibacterial agent.

[0002]

2. Description of the Related Art Optically active (4R) -4-mercapto-
As a method for producing 2-pyrrolidinone, for example, (4S) -4-methanesulfonyloxy-2 in acetonitrile is used.
-Reacting pyrrolidinone with potassium thioacetate, (4
A method is known in which R) -4-acetylthio-2-pyrrolidinone is hydrolyzed to obtain the desired product (Japanese Patent Application Laid-Open No. Hei 7-165759). However, in this method, impurities that are not easily separated in the first-stage reaction are formed as by-products and are the target of the first-stage reaction (4R).
-4-acetylthio-2-pyrrolidinone by a complicated method,
For example, unless it is isolated and purified by silica gel chromatography or the like, high-purity optically active (4R) -4-mercapto-2-pyrrolidinone cannot be obtained, and the high-purity target compound can be economically synthesized in large quantities. To do so, this method is not always suitable.

[0003]

SUMMARY OF THE INVENTION The present inventors have conducted intensive studies to establish an industrial process for producing a high-purity optically active 4-mercapto-2-pyrrolidinone derivative. Reacting a 4-sulfonyloxy-2-pyrrolidinone derivative with an alkali thioacetate to produce an optically active 4-acylthio-2-pyrrolidinone derivative;
Further, they have found that a high-purity target compound can be obtained by hydrolyzing the obtained pyrrolidinone derivative in the presence of a base, using only a simple purification operation, and completed the present invention.

[0004]

The production method of the present invention has an R configuration or an S configuration, and has a general formula

[0005]

Embedded image [In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms or a phenyl group which may have a substituent (the substituent is an alkyl group having 1 to 6 carbon atoms, And 1 to 3 substituents selected from the group consisting of a halogenated alkoxy group and a halogen atom.) ]
And a compound represented by the general formula

[0006]

Embedded image (Wherein, R ² has the same meaning as R ¹ described above, and M represents an alkali metal).
Sulfoxides or a reaction mixture of the organic solvent and water in a mixed solvent, having an R- or S-coordination in which the coordination is reversed, a general formula

[0007]

Embedded image (Wherein R ² has the same meaning as described above), and is hydrolyzed in the presence of a base.

[0008]

Embedded image Is a method for producing optically active 4-mercapto-2-pyrrolidinone.

In the compounds represented by the general formulas (1), (2) and (3), the alkyl group having 1 to 6 carbon atoms of R ¹ and R ² is, for example, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1
-Ethylpropyl group, hexyl group, isohexyl group, 4
-Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2 -A linear or branched alkyl group having 1 to 6 carbon atoms such as a dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group or a 2-ethylbutyl group; It is an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and particularly preferably a methyl group.

The number of substituents of the phenyl group which may have a substituent for R ¹ and R ² is preferably 1 to 2, and more preferably 1.

The alkyl group having 1 to 6 carbon atoms in the substitution of the phenyl group may be, for example, the same group as described above, and is preferably an alkyl group having 1 to 4 carbon atoms. Yes, more preferably a methyl group or an ethyl group, particularly preferably a methyl group.

The alkoxy group having 1 to 6 carbon atoms is a group in which the above “alkyl group having 1 to 6 carbon atoms” is bonded to an oxygen atom, and preferably has 1 to 4 carbon atoms.
And more preferably a methoxy group or an ethoxy group, and particularly preferably a methoxy group.

The halogen atom is a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, more preferably a chlorine or bromine atom, especially Preferably, it is a chlorine atom.

The phenyl group which may have a substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a fluorine atom, a chlorine atom and a bromine atom. A phenyl group optionally having one or two substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a chlorine atom and a bromine atom; A phenyl group optionally having one or two substituents selected from the group consisting of a methyl group, a methoxy group, a chlorine atom and a bromine atom; It is a phenyl group which may have a substituent, still more preferably a phenyl group, a 4-methylphenyl group or a 4-chlorophenyl group, and particularly preferably a phenyl group.

R ¹ and R ² are each preferably an alkyl group having 1 to 4 carbon atoms or a C ^{1 to} C 4 alkyl group.
An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a phenyl group optionally having 1 or 2 substituents selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom. And more preferably 1 to 3 carbon atoms.
An alkyl group or a methyl group, an ethyl group, a methoxy group, an ethoxy group, a phenyl group optionally having one or two substituents selected from the group consisting of a chlorine atom and a bromine atom, More preferably, it is a methyl group or a phenyl group which may have one substituent selected from the group consisting of a methyl group, a methoxy group, a chlorine atom and a bromine atom. A phenyl group, a 4-methylphenyl group or a 4-chlorophenyl group, and particularly preferably a methyl group or a phenyl group.

In the compound represented by the general formula (2),
The alkali metal of M is, for example, lithium, sodium,
Potassium or cesium, preferably sodium or potassium.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the first step, the amount of the compound (2) used is 1.0 to 3.
It is 0 equivalent.

The alcohols of the organic solvent used include, for example, methanol, ethanol, propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanole, 2-pentanole or 3 -An alcohol having 1 to 5 carbon atoms, such as pentanole,
It is preferably an alcohol having 1 to 4 carbon atoms, more preferably an alcohol having 2 to 4 carbon atoms, and particularly preferably ethanol or 2-butanol.

The sulfoxides of the organic solvent used include:
For example, alkyl sulfoxide having 1 to 4 carbon atoms such as dimethyl sulfoxide, diethyl sulfoxide, dipropyl sulfoxide or dibutyl sulfoxide, preferably dimethyl sulfoxide or diethyl sulfoxide, particularly preferably dimethyl sulfoxide It is a sulfoxide.

The solvent to be used is preferably an alcohol having 1 to 4 carbon atoms, dimethyl sulfoxide, diethyl sulfoxide or a mixed solvent of these organic solvents and water. Alcohol having 2 to 4 carbon atoms, dimethyl sulfoxide or a mixed solvent of these organic solvents and water, even more preferably alcohol having 2 to 4 carbon atoms, mixing of these alcohols with water Solvent or dimethyl sulfoxide, still more preferably alcohol or dimethyl sulfoxide having 2 to 4 hydrous carbon atoms, particularly preferably hydrous ethanol, hydrous 2-butanol or dimethyl sulfoxide.

The reaction temperature varies depending on the solvent used and the like, but is usually -10 to 120 ° C, preferably 50 to 100 ° C when the solvent used is an alcohol or hydroalcohol. In the case where the solvent used is a sulfoxide or a hydrous sulfoxide,
0-50 ° C. The reaction time varies depending on the reaction temperature, the amount of the compound (2) used, the solvent used and the like, but is usually 30 minutes to 30 hours, and preferably the solvent used is alcohols or hydrous alcohols. In some cases, it is 1 to 5 hours, and when the solvent used is a sulfoxide or a hydrous sulfoxide, it is 5 to 22 hours.

In the present step, by using the compound (1) having the (R) coordinate, the coordination is inverted, and the compound (2) having the (S) coordinate is obtained. By using the compound (1), the coordination is inverted, and the compound (2) having the (R) configuration is obtained.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the target compound can be obtained by adding water or saline to the reaction mixture, neutralizing it as appropriate, extracting with an organic solvent such as dichloromethane or 2-butanol, and distilling off the solvent. Further, the residue obtained by distilling the solvent from the reaction mixture as it is or the extract of the target compound can be used in the next step. Further, if necessary, it can be further purified by a conventional method, for example, recrystallization, distillation and the like.

The hydrolysis step of the second step is preferably carried out in water or a water-containing solvent.

As the base used, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, barium hydroxide,
Hydroxides of alkaline earth metals such as calcium hydroxide, carbonates of alkali metals such as sodium carbonate and potassium carbonate, bicarbonates of alkali metals such as sodium bicarbonate and potassium bicarbonate, ammonia or methylamine And organic amines such as dimethylamine, propylamine and butylamine, preferably an alkali metal hydroxide, an alkali metal carbonate, ammonia or methylamine, and more preferably sodium hydroxide. , Potassium hydroxide or ammonia. In the case where alcohols or hydrous alcohols are used in the reaction of the first step, a suitable base used in the second step is an alkali metal hydroxide, an alkaline earth metal hydroxide, or an alkali metal hydroxide. When a sulfoxide or a hydrated sulfoxide is used in the reaction of the first step, a suitable base used in the second step is ammonia or bicarbonate of an alkali metal, ammonia or methylamine. Organic amines.

When the base is an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate or alkali metal bicarbonate, the amount of base used is:
It is 1.0 to 2.2 equivalents, preferably 1.0 to 2.0 equivalents, relative to compound (1). When the base is ammonia or organic amines, it is based on compound (1). 1 to 1
It is 2 equivalents, preferably 1.5 to 8 equivalents.

The solvent used is, for example, water or methanol, ethanol, propanol, 2-propanol,
Organic solvents such as alcohols such as 1-butanol and 2-butanol, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated carbons such as dichloromethane and chloroform, and nitriles such as acetonitrile or these. And a mixed solvent of water and water, preferably a water-containing alcohol or a water-containing dichloromethane.

The reaction temperature is usually from -30 to 50 ° C, preferably from -20 to 25 ° C.

The reaction time varies depending on the reaction temperature, the amount of the compound (2) to be used and the like, but is usually 30 minutes to 5 hours, preferably 1 to 5 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, if necessary, water or saline is added to the reaction mixture, neutralized, and extracted with an organic solvent such as dichloromethane or 2-butanol,
The target compound can be obtained by distilling off the solvent. Further, if necessary, it can be further purified by a conventional method, for example, recrystallization, distillation and the like.

The starting compounds (1) and (2) of the present invention are
It is a known compound or is easily produced by a known method. (For example, JP-A-7-165759, etc.) Optically active mercapto-2 obtained by the method of the present invention.
-Pyrrolidinone (4) can be converted to an excellent antibacterial active substance, for example, compound A shown below, using a known method (for example, the method described in JP-A-7-165759). (4) is useful as an important synthetic intermediate for an excellent antibacterial active substance.

[0032]

Embedded image Examples are shown below to describe the present invention more specifically.

[0033]

Example 1 (4R) -4-Mercapto-2-pyrrolidinone In a nitrogen stream, 21940 g of (4S) -4-methanesulfonyloxy-2-pyrrolidinone obtained in Reference Example 1 in 1940 mL of ethanol and water Add 165 g of potassium thioacetate to the 216 mL solution, and then add
For 3 hours. Next, cool to 35-40 ° C and add water 2
After adding 16 mL, the mixture was cooled to 0 to 10 ° C., and 480 g of a 10% aqueous sodium hydroxide solution was added dropwise. Thereafter, the reaction solution was kept at 0 to 5 ° C. for 1 to 1.5 hours, and further cooled to 10 ° C. or lower to adjust the pH of the reaction solution to 6 with 4N hydrochloric acid. The reaction mixture was concentrated, and the obtained concentrate was extracted five times with dichloromethane. The combined extract was concentrated again, cooled, and ethylcyclohexane was added dropwise to precipitate crystals. The solution containing the crystals thus obtained was concentrated, cooled and stirred to complete crystal precipitation. The precipitated crystals were collected by filtration, washed with cooled ethylcyclohexane, and dried to obtain 122.1 g of crude crystals. Activated carbon was added to the ethyl acetate solution of the crude crystals, and the mixture was stirred. The activated carbon was removed by filtration, and the activated carbon was washed with ethyl acetate. The solution obtained by combining the filtrate and the washing solution was concentrated, and ethylcyclohexane was added dropwise. After cooling and stirring the solution containing the crystals thus obtained, the crystals were collected by filtration. The crystals were washed with a cooled mixed solvent of ethylcyclohexane-ethyl acetate (9: 3) and then dried to obtain 100 g of the desired compound (yield: 70.7% from the compound of Reference Example 1). Retention time of high performance liquid chromatography: 5.5 minutes Content by internal standard method using high performance liquid chromatography: 98% The above retention time and content were measured under the following conditions. Column: L-column ODS (4.6 mmφx250
mm) (manufactured by the Chemical Inspection Association) Moving bed: water-methanol-acetic acid (850: 150: 0.
5) Flow rate: 1.0 ml / min Column temperature: 35 ° C Optical purity: 99.8ee The above optical purity was obtained by reacting (4R) -4-mercapto-2-pyrrolidinone with phenyl isocyanate (4R). -4-phenylaminocarbonylthio-2-
The optical purity of pyrrolidinone was measured using high performance liquid chromatography under the following conditions. Column: Chiral cell OB-H (4.6mmφx250mm)
(Manufactured by Daicel Chemical Industries, Ltd.) Moving bed: n-hexane-isopropanol-ethanol (50: 7: 3) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Retention time: 25 minutes Infrared absorption spectrum ν _max ^KBr cm ^-1 : 2539,1699,1683 Example 2 (4R) -4-mercapto-2-pyrrolidinone 75.26 g of (4S) -4-methanesulfonyloxy-2-pyrrolidinone obtained in Reference Example 2 under a nitrogen stream.
52.76 g of potassium thioacetate was added to a solution of 527 mL of 2-butanol (in terms of dry weight) and 75 mL of water.
Was added, and the mixture was heated and stirred at 70 to 75 ° C. for 4 hours. Next, return to room temperature, 30 mL of water, and then 15 m of saturated saline.
L was added, stirred and separated. 226 mL of 2-butanol and 7.5 mL of saturated saline were added to the obtained aqueous layer, and the mixture was stirred again and separated. The organic layer was removed, combined with the previous organic layer, cooled to −10 ° C. to −5 ° C., and a mixture of 59.5 g of a 48% aqueous sodium hydroxide solution and 75 mL of water was added dropwise. Thereafter, the mixture was kept at -10 to -5 ° C for 1.5 hours, and the pH of the reaction solution was adjusted to 4 with concentrated hydrochloric acid. Water 29
After adding 4 mL, the mixture was concentrated and extracted four times with dichloromethane. Ethyl acetate was added to the combined extracts and concentrated again. 5.36 g (weight in terms of dry product) of secondary crystals of (4R) -4-mercapto-2-pyrrolidinone obtained in the previous synthesis, ethyl acetate and activated carbon were added to the concentrated solution, and the mixture was stirred. The activated carbon was removed by filtration and washed with ethyl acetate. The combined solution of the filtrate and the washings was concentrated and cooled to complete the crystallization. The crystals obtained by filtration were washed with ethyl acetate and dried to obtain 35.68 g (yield 7 from the compound of Reference Example 2).
2.5%) of the desired compound. Retention time of high performance liquid chromatography: 5.5 minutes Content by internal standard method using high performance liquid chromatography: 98.5% The above retention time and content were measured under the following conditions. Column: L-column ODS (4.6 mmφx250
mm) (manufactured by the Chemical Inspection Association) Moving bed: water-methanol-acetic acid (850: 150: 0.
5) Flow rate: 1.0 ml / min Column temperature: 35 ° C Optical purity: 99.8ee The above optical purity was obtained by reacting (4R) -4-mercapto-2-pyrrolidinone with phenyl isocyanate (4R). -4-phenylaminocarbonylthio-2-
The optical purity of pyrrolidinone was measured using high performance liquid chromatography under the following conditions. Column: Chiral cell OB-H (4.6mmφx250mm)
(Manufactured by Daicel Chemical Industries, Ltd.) Moving bed: n-hexane-isopropanol-ethanol (50: 7: 3) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Retention time: 25 minutes Infrared absorption spectrum ν _max ^KBr cm ^-1 : 2539,1699,1683 The solution obtained by combining the washing solution and the filtrate at the time of obtaining the primary crystal was concentrated and cooled to precipitate a crystal. The crystals were collected by filtration and washed with ethyl acetate to obtain 5.66 g of (4R) -4-mercapto-2-pyrrolidinone secondary crystal (dry weight). The secondary crystals obtained here were used in the next synthesis of (4R) -4-mercapto-2-pyrrolidinone.

Example 3 (4R) -4-Mercapto-2-pyrrolidinone 82.43 g of (4S) -4-methanesulfonyloxy-2-pyrrolidinone obtained in Reference Example 2 under a nitrogen stream.
57.79 g of potassium thioacetate was added to a solution of 577 mL of 2-butanol and 82 mL of water (in terms of dry weight).
Was added, and the mixture was heated and stirred at 70 to 75 ° C. for 4 hours. Next, the temperature of the reaction mixture was returned to 35 to 40 ° C., 17 mL of saturated saline was added, and the mixture was stirred and separated. 2- in the obtained aqueous layer
247 mL of butanol and 8 mL of saturated saline were added, and the mixture was stirred again and separated. The organic layer was taken, combined with the previous organic layer, cooled to −10 to −5 ° C., and a mixture of 65.17 g of a 48% aqueous sodium hydroxide solution and 82 mL of water was added dropwise. Thereafter, the reaction solution was maintained at -10 to -5 ° C for 1.5 hours, adjusted to pH 4 with concentrated hydrochloric acid, and separated. The aqueous layer was removed and extracted twice with 2-butanol. The organic layer and the extract were combined and concentrated. Ethyl acetate was further added, and the mixture was concentrated again under reduced pressure. To the concentrated solution, 6.52 g (weight in terms of dry product) of secondary crystals of (4R) -4-mercapto-2-pyrrolidinone obtained in the previous synthesis, ethyl acetate and activated carbon were added and stirred. The activated carbon was removed by filtration and washed with ethyl acetate. The combined solution of the filtrate and the washing was concentrated and cooled to precipitate crystals. The crystals obtained by filtration were washed with ethyl acetate, dried and dried to obtain 39.35 g (yield from the compound of Reference Example 2: 73.35 g).
(0%) of the desired compound. Retention time of high performance liquid chromatography: 5.5 minutes Content by internal standard method using high performance liquid chromatography: 94.3% The above retention time and content were measured under the following conditions. Column: L-column ODS (4.6 mmφx250
mm) (manufactured by the Chemical Inspection Association) Moving bed: water-methanol-acetic acid (850: 150: 0.
5) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Optical purity: 100% ee The above optical purity was obtained by reacting (4R) -4-mercapto-2-pyrrolidinone with phenyl isocyanate (4R). -4-phenylaminocarbonylthio-2-
The optical purity of pyrrolidinone was measured using high performance liquid chromatography under the following conditions. Column: Chiral cell OB-H (4.6mmφx250mm)
(Manufactured by Daicel Chemical Industries, Ltd.) Moving bed: n-hexane-isopropanol-ethanol (50: 7: 3) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Retention time: 25 minutes Infrared absorption spectrum ν _max ^KBr cm ^-1 : 2539,1699,1683 The washing solution and the filtrate at the time of obtaining the primary crystal were combined, concentrated, and cooled to precipitate a crystal. The crystals were collected by filtration and washed with ethyl acetate to obtain (4R) -4-mercapto-2-pyrrolidinone secondary crystals (6.41 g, weight in terms of dry product). The secondary crystals obtained here were used in the next synthesis of (4R) -4-mercapto-2-pyrrolidinone.

Example 4 (4R) -4-Mercapto-2-pyrrolidinone In a nitrogen stream, 10 g of (4S) -4-methanesulfonyloxy-2-pyrrolidinone obtained in Reference Example 1 was added to a solution of 10 g of dimethylsulfoxide in 6 mL of thioacetic acid. potassium
9.53 g was added, and the mixture was stirred at 20 to 25 ° C for 17 hours.
Then, 40 mL of water was added, and dichloromethane 100
The aqueous layer was extracted twice more with 100 mL of dichloromethane. Of the three obtained dichloromethane extracts, the first dichloromethane extract was washed twice with 40 mL of 25% saline to obtain dichloromethane solution-1. Washing liquid-1 of the two obtained washing liquids (first washing liquid: washing liquid-1; later washing liquid: washing liquid-2) was extracted with a second dichloromethane extract. Washing liquid-2 was extracted from the organic layer thus obtained to obtain dichloromethane solution-2. The aqueous layer obtained by the above operation was collected, extracted with a third dichloromethane extract, and extracted with dichloromethane solution-3.
I got The solution obtained by collecting the dichloromethane solutions 1 to 3 was cooled to −5 to 0 ° C. under a nitrogen stream, and 10 mL of water and 14 mL of 28% aqueous ammonia were added.
Stirred for hours. The organic layer obtained by liquid separation was subjected to 25% saline.
Extracted twice with 10 mL and combined with the previously obtained aqueous layer.
The pH of the aqueous solution thus obtained was adjusted to pH 4 by adding concentrated hydrochloric acid, and extracted three times with 100 mL of dichloromethane. The extracts were combined and concentrated. Ethylcyclohexane was added to the concentrated solution, followed by cooling to precipitate crystals. The crystals obtained by filtration were washed with a dichloromethane-ethylcyclohexane mixed solvent and dried to obtain 4.87 g (yield: 72% from the compound of Reference Example 1) of the target compound. Retention time of high performance liquid chromatography: 5.5 minutes Content by internal standard method using high performance liquid chromatography: 96.6% The above retention time and content were measured under the following conditions. Column: L-column ODS (4.6 mmφx250
mm) (manufactured by the Chemical Inspection Association) Moving bed: water-methanol-acetic acid (850: 150: 0.
5) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Optical purity: 100% ee The above optical purity was obtained by reacting (4R) -4-mercapto-2-pyrrolidinone with phenyl isocyanate (4R). -4-phenylaminocarbonylthio-2-
The optical purity of pyrrolidinone was measured using high performance liquid chromatography under the following conditions. Column: Chiral cell OB-H (4.6mmφx250mm)
(Manufactured by Daicel Chemical Industries, Ltd.) Moving bed: n-hexane-isopropanol-ethanol (50: 7: 3) Flow rate: 1.0 ml / min Column temperature: 35 ° C. Retention time: 25 minutes Infrared absorption spectrum ν _max ^KBr cm ^-1 : 2539,1699,1683 Reference Example 1 (4S) -4-methanesulfonyloxy-2-pyrrolidinone (4S) -4-hydroxy-2-pyrrolidinone 13
0.5 g of 653 mL of acetonitrile solution was cooled to 0 to 5 ° C., 137.8 g of N-methylimidazole was added, and the temperature was further lowered to 10 ° C. or lower, and 162.6 g of methanesulfonyl chloride was added dropwise. After dropping, raise the internal temperature to 34-36.
C. for 1 hour, then 1-butanol was added and concentrated. Thereafter, the concentrate was cooled, and the precipitated crystals were collected by filtration.
The crystals were washed with cooled 1-butanol, dried (4
215.6 g (yield 93.2%) of S) -4-methanesulfonyloxy-2-pyrrolidinone was obtained. Retention time of high performance liquid chromatography: 5.1 minutes Content by internal standard method using high performance liquid chromatography: 99.3% The above retention time and content were measured under the following conditions. Column: TSK-gel ODS-8OTM (4.6 mmφ
x250mm) (manufactured by Tosoh Corporation) Moving layer: acetonitrile-0.01M aqueous solution of ammonium acetate (10:90) Flow rate: 1.0 ml / min Column temperature: 35 ° C Infrared absorption spectrum ν _max ^KBr cm ^-1 : 1719,1697,1659,
1305,1177,1171,1159,963 Reference Example 2 (4S) -4-methanesulfonyloxy-2-pyrrolidinone (4S) -4-hydroxy-2-pyrrolidinone 18
2.00 g of 910 mL of acetonitrile solution was
C. and cooled to 184.75 g of N-methylimidazole
And further reduce the temperature to 10 ° C or lower
226.81 g of chloride were added dropwise. After dropping, 3
The mixture was kept at 0 to 35 ° C. for 1 hour, and then 2-butanol was added, followed by further concentration. Thereafter, the concentrated liquid was cooled, the precipitated crystals were collected by filtration, and the crystals were washed with 2-butanol (yield 91.
5%, value as a dry product). The obtained (4S) -4-methanesulfonyloxy-2-pyrrolidinone crystal was used in the next step without drying. Retention time of high performance liquid chromatography: 5.1 minutes Content by internal standard method using high performance liquid chromatography: 98.1% (in terms of dry product) The above retention time and content were measured under the following conditions. Column: TSK-gel ODS-8OTM (4.6 mmφ
x250mm) (manufactured by Tosoh Corporation) Moving layer: acetonitrile-0.01M aqueous solution of ammonium acetate (10:90) Flow rate: 1.0 ml / min Column temperature: 35 ° C Infrared absorption spectrum ν _max ^KBr cm ^-1 : 1719,1697,1659,
1305,1177,1171,1159,963

[0036]

Industrial Applicability The present invention is a process for producing optically active mercapto-2-pyrrolidinone, which is an important synthetic intermediate for antibiotics, with high purity by using only a simple purification procedure. It is an industrially superior method because it can be synthesized in large quantities in large quantities.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Ayako Tanabe 173 Nakahara Kamijuku, Hiratsuka City, Kanagawa Prefecture In-house (72) Inventor Shun Kojima 173 Nakahara Kamijuku, Hiratsuka City, Kanagawa Prefecture In-house Sankyo Stock Company (72) Invention Person Tadashi Soejima 11-15-303 Sadabacho, Hiratsuka-shi, Kanagawa Prefecture (72) Inventor Josuke Yoda 4255 Yokouchi, Hiratsuka-shi, Kanagawa Prefecture Sankyo Kasei Fujimi Dormitory F-term (reference) 4C069 AB15 BC12 BC14 BC16 CC20

Claims (16)

[Claims] (1) The compound has an R configuration or an S configuration, and has a general formula: [In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms or a phenyl group which may have a substituent (the substituent is an alkyl group having 1 to 6 carbon atoms, And 1 to 3 substituents selected from the group consisting of a halogenated alkoxy group and a halogen atom.) ]
And a compound represented by the general formula: (Wherein, R ² has the same meaning as R ¹ described above, and M represents an alkali metal).
Reacting in a mixed solvent of sulfoxides or the organic solvent and water, having an R-coordination or S-coordination in which the coordination is inverted, and having the general formula: (Wherein, R ² has the same meaning as described above.) 2. The compound having an R configuration or an S configuration, and having the general formula: In the formula, R ¹ is an alkyl group having 1 to 6 carbon atoms or a phenyl group which may have a substituent (the substituent is an alkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms) And 1 to 3 substituents selected from the group consisting of an alkoxy group having the formula (1) and a halogen atom. And a compound represented by the general formula: (Wherein, R ² has the same meaning as R ¹ described above, and M represents an alkali metal).
Reaction with sulfoxides or a mixed solvent of the organic solvent and water, the compound having an R- or S-coordination in which the coordination is inverted, and having the general formula: (Wherein, R ² has the same meaning as described above), and is hydrolyzed in the presence of a base. A method for producing optically active 4-mercapto-2-pyrrolidinone represented by the formula: 3. The method according to claim 1, wherein R ¹ and R ² are the same or different and each have an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, A method for producing a phenyl group which may have 1 to 2 substituents selected from the group consisting of an alkoxy group having 1 to 4 atoms, a fluorine atom, a chlorine atom and a bromine atom. 4. The method according to claim 1, wherein R ¹ and R ² are the same or different and each have an alkyl group having 1 to 3 carbon atoms, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a chlorine group. A method for producing a phenyl group which may have one or two substituents selected from the group consisting of an atom and a bromine atom. 5. The method according to claim 1, wherein R ¹ and R ² are the same or different and each is one selected from the group consisting of a methyl group or a methyl group, a methoxy group, a chlorine atom and a bromine atom. A method for producing a phenyl group which may have a substituent. 6. The method according to claim 1, wherein R ¹ and R ² are the same or different and each is a methyl group, a phenyl group, a 4-methylphenyl group or a 4-chlorophenyl group. 7. The method according to claim 1, wherein R ¹ and R ² are the same or different and each is a methyl group or a phenyl group. 8. The method according to claim 1, wherein M is potassium or sodium. 9. The method according to claim 1, wherein the solvent used for the reaction between the compound (1) and the compound (2) has a carbon number of
A production method, which is an alcohol having 1 to 4 alcohols, dimethyl sulfoxide, diethyl sulfoxide or a mixed solvent of these organic solvents and water. 10. The method according to claim 1, wherein the solvent used in the reaction between the compound (1) and the compound (2) is alcohol having 2 to 4 carbon atoms, dimethyl sulfoxide, or an organic solvent thereof. A production method that is a mixed solvent with water. 11. The method according to claim 1, wherein the solvent used in the reaction between the compound (1) and the compound (2) is an alcohol having 2 to 4 carbon atoms, or a mixture of these alcohols and water. A production method which is a solvent or dimethyl sulfoxide. 12. The process according to claim 1, wherein the solvent used in the reaction between the compound (1) and the compound (2) is alcohol or dimethyl sulfoxide having 2 to 4 carbon atoms. . 13. The production method according to claim 1, wherein the solvent used in the reaction between the compound (1) and the compound (2) is aqueous ethanol, aqueous 2-butanol, or dimethyl sulfoxide. 14. The compound according to claim 2, wherein the solvent used for the reaction between the compound (1) and the compound (2) is an alcohol or a mixed solvent of an alcohol and water, and is used for hydrolysis of the compound (3). The production method wherein the base to be used is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, ammonia or methylamine. 15. The compound according to claim 2, wherein the solvent used for the reaction between the compound (1) and the compound (2) is a sulfoxide or a mixed solvent of a sulfoxide and water, and is used for hydrolyzing the compound (3). The production process wherein the base to be used is ammonia or organic amines. 16. The method according to claim 15, wherein the base is ammonia or methylamine.