JPH045031B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula () (In the formula, R represents a benzyl group.) This invention relates to an improved method for producing an optically active lactone represented by the following formula.

The optically active lactone represented by the general formula () is an important intermediate in the synthesis of (+)-biotin, its derivatives, and related compounds, and the object of the present invention is to make such an optically active lactone inexpensive and industrially available. The object of the present invention is to provide a manufacturing method that is economically advantageous.

Conventionally, the following method has been known as a method for synthesizing an optically active lactone represented by the general formula () (Japanese Patent Publication No. 32551/1983).

and (In the above formula, R is a benzyl group, and R ₃ is a cholesteryl or cyclohexyl group.) However, this method
Considering the poor solubility and fine crystallinity of 1,3-dibenzyl-hexahydro-1H-furo[3,4-d]imidazole-2,4,6-trione, this method cannot be said to be advantageous, and furthermore, the substituent R When ₃ is a cyclohexyl group, expensive ephedrine must be used as a resolving agent, and when R ₃ is a cholesteryl group, considering the cost, recovery method, handling, etc., it is by no means industrially satisfactory. do not have.

In view of this, the present inventors have investigated to eliminate the drawbacks of the above-mentioned conventional methods and produce optically active lactones represented by the general formula () in an industrially advantageous manner. We found that the use of an optically active amine having the structure specified in this application is very effective, and that the half ester mixture that is the raw material for it can be easily obtained by esterifying an easily synthesized dicarboxylic acid with alcohol. The invention was completed.

That is, the present invention is based on the general formula () (In the formula, R represents a benzyl group.) A dicarboxylic acid represented by the general formula () R′OH () (In the formula, R′ represents a lower alkyl group) is reacted with an alcohol represented by the general formula () R′OH () (wherein, R′ represents a lower alkyl group). General formulas () and () (In the formula, R and R' have the same meanings as above.) A mixture of half esters represented by (In the formula, R ₁ and R ₂ each represent a hydrogen atom, a halogen atom, or a lower alkyl group.) The optically active half ester represented by the above general formula () is separated by the action of an optically active amine represented by The general formula () is characterized in that only the carboxylic acid of the half ester is selectively reduced.
The present invention provides a method for producing an optically active lactone shown in the following.

In the present invention, the reaction between the dicarboxylic acid represented by the general formula () and the alcohol represented by the general formula () is usually carried out in the presence of an inert solvent.
This is carried out by heating in the presence or absence of a catalyst.

The dicarboxylic acid that is a raw material for this reaction can be produced using fumaric acid as a raw material, for example, as shown by the following formula.

In addition, examples of the alcohol that is the other raw material include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-propyl alcohol, and n-propyl alcohol.
-butyl alcohol, isobutyl alcohol, t
-butyl alcohol, n-pentyl alcohol,
Examples include isopentyl alcohol and n-hexyl alcohol.

The amount of alcohol used in this reaction is required to be 1 equivalent or more, preferably 2 equivalents or more relative to the dicarboxylic acid.

The solvent used in this reaction can be used without particular limitation as long as it is inert to the reaction, and examples thereof include toluene, benzene, xylene, chlorobenzene, dichlorobenzene, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, and the like.

Moreover, the above-mentioned raw material alcohol can also be used as a solvent.

There is no particular restriction on the amount of such solvent used.

Although it is not necessary to use a catalyst in this reaction, a catalyst may be used to improve the reaction rate. Such catalysts include, for example, formic acid,
Organic carboxylic acids such as acetic acid, propionic acid, valeric acid, phosphates, sulfates, chlorides, oxides, organic fatty acid salts, organic sulfonates, etc. of potassium, magnesium, zinc, iron, calcium, manganese, cobalt, etc. metal salts of, tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride,
Examples include surfactants such as organic quaternary ammonium salts such as dodecyltrimethylammonium chloride and caprylbenzyldimethylammonium chloride, higher fatty acid salts, polyoxyethylene alkyl phenol ether, and higher aliphatic alcohols. These may be used alone or as a mixture of two or more.

When a catalyst is used, the amount used is not particularly limited, but is usually in the range of 1/200 to the same weight as the dicarboxylic acid.

The reaction temperature is in the range of 50-200°C, preferably 70-180°C. When the reaction temperature is higher than the boiling point of the solvent, the reaction can be carried out using an autoclave.

There is no particular restriction on the reaction time.

Through such a reaction, mixtures of half esters represented by the general formulas () and () can be easily obtained from dicarboxylic acids and alcohols in good yields, and these can be separated by conventional separation means such as concentration, crystallization, etc. It is then easily isolated as a mixture from the reaction solution and subjected to the next division process. Further, in some cases, the reaction solution containing a mixture of these may be used as is for the next division treatment.

Thus, for example, when using methanol as alcohol, (4S,5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolysin-2-one and (4S,5R)-
A mixture of 1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one was obtained, which is similarly represented by the general formulas () and () corresponding to the alcohols used (4S, 5R). )-1,3-dibenzyl-4-carboxy-5-alkoxycarbonylimidazolidine-
A mixture of 2-one and (4S,5R)-1,3-dibenzyl-5-carboxy-4-alkoxycarbonylimidazolidin-2-one is obtained.

Here, the alkoxy group is ethoxy, n-
Propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy,
Examples include cyclopentyloxy and cyclohexyloxy.

By allowing an optically active amine represented by general formula () to act as a resolving agent on a mixture of such half esters represented by general formula () and (), optically active half esters represented by general formula () are obtained. Esters can be separated.

More specifically, a mixture of the above half esters is treated with an optically active amine represented by the general formula () to precipitate a diastereomeric salt of the optically active half ester and the optically active amine represented by the general formula (). The optically active half ester represented by the general formula () can be obtained by obtaining the crystal as a crystal and decomposing it with an acid.

Alternatively, a diastereomer salt of an optically active half ester represented by the general formula () and an optically active amine represented by the general formula () is separated as precipitated crystals, and an acid is added to the liquid to perform acid decomposition treatment to form a general compound. An optically active half ester represented by the general formula () can be obtained by obtaining a half ester mixture containing an excess of the optically active half ester represented by the formula () and preferentially crystallizing the mixture.

The optically active amine represented by the general formula () used as a resolving agent is, for example, α-
Phenyl-β-phenylethylamine, α-phenyl-β-(P-tolyl)ethylamine, α-(P
-tolyl)-β-phenylethylamine, α-phenyl-β-(P-chlorophenyl)ethylamine, α-(P-chlorophenyl)-β-phenylethylamine, α-(P-tolyl)-β-(P- tolyl)-ethylamine, α-(P-chlorophenyl)
Optically active substances such as -β-(P-chlorophenyl)-β-ethylamine are exemplified.

The amount of the resolving agent used is about 0.7 to 1.2 moles, preferably 0.8 to 1.1 moles, relative to the mixture of half esters represented by general formulas () and ().

A solvent is usually used in this separation process, and examples include a mixed solvent of water and a water-soluble organic solvent such as methanol, ethanol, isopropyl alcohol, and acetone, or benzene, toluene, chloroform, ethyl acetate, and methyl isobutyl ketone. , hexane, petroleum ether, etc. alone or in combination.

The amount of solvent used is an amount suitable for fractional crystallization of the diastereomeric salt produced from its solution.

The reaction temperature is arbitrary within the range of -20°C to the boiling point of the solvent used, but is preferably at least the temperature at which the produced salt precipitates.

In this way, a diastereomeric salt of an optically active half ester and an optically active amine is formed, and if necessary, a previously prepared general formula () is formed.
A crystal of a diastereomer salt of an optically active half ester represented by the formula () and an optically active amine represented by the general formula () is inoculated as a seed crystal, and the diastereomer salts () to () are precipitated by means such as cooling. After separating this, it is decomposed using an acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, and the liberated optically active half ester represented by the general formula ( Alternatively, it can be isolated by extraction treatment with a mixed solvent of these.

Alternatively, the ()-() diastereomer salt was obtained as precipitated crystals from the diastereomer salt of the optically active half ester represented by the general formula () and () and the optically active amine represented by the general formula (). After concentrating the solution if necessary, add the above-mentioned acid to the concentrated residue for decomposition treatment, extract the decomposed solution with a solvent, and further concentrate to remove excess optically active half ester represented by the general formula (). By obtaining a half ester mixture of and crystallizing it using a suitable solvent, the general formula () is obtained.
The optically active half ester represented by can be preferentially crystallized and isolated.

Here, examples of solvents suitable for the above preferential crystallization include ethanol, n-butanol, ethyl ether, benzene, toluene, xylene, methyl isobutyl ketone, chloroform, acetonitrile, ethyl acetate, etc. alone or in mixtures thereof; Alternatively, a mixed solvent of the above solvents and hexane, petroleum ether, or petroleum benzyl may be used, and the amount used is not particularly limited, but it is usually 2 times to 30 times the weight of the half ester mixture.

In addition, in this preferential crystallization treatment, ()−
() The optically active half ester is precipitated and separated at a yield higher than the optical excess of the optically active half ester represented by the general formula () contained in the solution after removing the diastereomeric salt.

The optically active half ester of the general formula () thus isolated is purified by recrystallization, etc., if necessary, and then subjected to the next reduction reaction.

Through such optical resolution treatment, the optically active half ester of the general formula () is separated from the half ester mixture, but the optically active amine of the general formula () used as the resolving agent here is separated by solvent extraction under basic conditions. It is recovered with a high recovery rate, which is a great advantage in industrial implementation.

The optically active half ester of the general formula () thus separated is selectively reduced to only the carboxylic acid of the half ester using a reducing agent capable of reducing ordinary carboxylic acids in the presence of a solvent inert to the reaction. By reducing to the desired general formula ()
can be an optically active lactone.

An example of a preferable reducing agent used in this reaction is diborane. This reduction method using diborane involves reducing the optically active half ester of the general formula () while successively generating diborane within the reaction system, or generating diborane outside the reaction system and introducing it in gaseous form into the reaction system. mosquito,
Alternatively, any method of reducing the optically active half ester of the general formula () by absorbing it in another inert solvent and then adding it to the reaction system can be used as necessary.

A preferred method of generating this diborane is to use a metal borohydride such as sodium borohydride, lithium borohydride, potassium borohydride, calcium borohydride, etc.
by acting with boron trifluoride or a boron trifluoride complex with a solvent such as ethyl ether, methanol, phenol, or
A method in which aluminum chloride is allowed to act on the metal boron hydride is mentioned.

In order to generate 1 mole of diborane, when a metal boron hydride is reacted with boron trifluoride or a boron trifluoride complex, at least 3/2 equivalent or more of the metal boron hydride is required,
At least 2 equivalents or more of boron trifluoride is required. Further, when a metal boron hydride and aluminum chloride are allowed to interact, at least 2 equivalents or more of the metal boron hydride are required, and at least 2/3 equivalents or more of aluminum chloride is required. Usually, 1.1 to 3.0 times these theoretical amounts are used.

These reactions can be carried out by adding boron trifluoride or boron trifluoride complex or aluminum chloride to a mixed solution of metal boron hydride and a solvent, or by adding boron trifluoride or boron trifluoride complex or aluminum chloride. This is done by adding a metal boron hydride to a mixed solution of solvents.

The diborane produced in this way is used in the reduction reaction by the method explained above, and the amount used is at least 1 mol per mol of the optically active half ester represented by the general formula (), which is the raw material. /
It is necessary to use 2 moles or more, but preferably 1/2 to 4 mole equivalents.

Examples of the solvent used in this reaction include ethylene glycol dimethyl ether, propylene glycol, tetrahydrofuran, benzene, toluene, and ethyl ether, which are inert to the reaction, alone or in a mixture thereof.

There are no particular restrictions on the amount used.

The reaction temperature is usually -70°C to 100°C, preferably -
The temperature is between 50° and 80°C.

There is no particular restriction on the reaction time.

After the reaction is complete, the unreacted reducing agent is treated with water or hydrochloric acid,
It is decomposed and removed using an aqueous acid solution such as sulfuric acid, phosphoric acid, or acetic acid, or an aqueous alkaline solution such as caustic soda or sodium carbonate.

Although the optically active lactone represented by the general formula () can be directly obtained from the optically active half ester of the general formula () by such a method, there is no method other than the method of directly reducing only the carboxylic acid of the optically active half ester. In addition, the half-ester carboxylic acid is converted into an active ester of N-hydroxysuccinimide or pentachlorophenol, or is reacted with ethyl chlorocarbonate to form a derivative such as an acid anhydride, and then selectively reduced. Even if I sway,
An optically active lactone represented by the general formula () can be obtained.

In addition, in the above-mentioned optical resolution of a mixture of half esters, the optically active half ester represented by the general formula () can also be separated in the same manner as the optically active half ester of the general formula (), and this general formula () The optically active half ester of is reduced by another reduction method as described above, for example, using a reducing agent that is inert to carboxylic acids and capable of selectively reducing the ester, such as sodium borohydride.
The desired optically active lactone represented by the general formula () can be obtained.

Thus, according to the method of the invention, the general formula ()
The optically active lactones represented by are easily obtained in good yields and can be easily isolated from the reaction mixture by conventional separation means such as neutralization, extraction, concentration crystallization, etc. can do.

The present invention will be explained below with reference to Examples.

Example 1 17.7 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, 7 g of isopropyl alcohol, and 150 ml of toluene were charged into a four-necked flask equipped with a stirrer and a thermometer, and the mixture was heated for 7 hours. Heat to reflux. After the reaction is completed, the reaction solution is concentrated under reduced pressure to a volume of about 80 ml. Add 50 ml of hexane to this to crystallize, separate the crystals and (4S,5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one (-1) and (4S,5R). )−
19.2 g of a mixture of 1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidin-2-one (-1) (yield 97.1%, melting point 109
~111°C) was obtained. 80 ml of isopropyl alcohol and 80 ml of water are added to 13.2 g of this mixture and heated to 50°C.

To this, l-α-phenyl-β-(P-tolyl)
Add 7 g of ethylamine dropwise over an hour or so. Keep warm at the same temperature for 1 hour. After that, slowly cool it down to 31-32
Salt of (4S,5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one and d-α-phenyl-β-(P-tolyl)ethylamine prepared separately at °C Add a small amount of crystals as seed crystals, further slowly cool to 10°C, keep at 10°C for 2 hours, and collect the precipitated crystals. After drying the crystals, add 30 ml of water and 1.7 g of concentrated hydrochloric acid for acid decomposition, and then add 50 ml of ethyl acetate.
Add ml and process for extraction. After washing the extract twice with 20 ml of water, ethyl acetate was distilled off and (4S,5R)-
5.92 g (yield 44.8%) of 1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one (-1) was obtained.

α〕 ²⁰ ₃₆₅ +27.0゜(C=1, DMF) Melting point 140-142℃ Next, 3.96 g of (-1) obtained here was dissolved in 40 ml of tetrahydrofuran, and sodium borohydride was dissolved at −20℃. 0.5g was added little by little. Furthermore, 2.3 g of boron trifluoride-ether complex was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. After the reaction is complete, the reaction solution is poured into 50 ml of 2% hydrochloric acid and extracted twice with 50 ml of ethyl acetate. The organic layer was washed twice with 30 ml of water, and then ethyl acetate was distilled off. The concentrated residue was purified by column chromatography on silica gel,
(3S,4R)-(1,3-dibenzyl-2-keto-imidazolide)-2-keto-tetrahydrofuran
2.46g (yield 76.3%) was obtained.

Melting point 119-120℃ α〕 ²⁰ _D +62.9゜ (C=1, CHCl ₃ ) Example 2 In a flask similar to that used in Example 1, cis-
1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid 17.7g, methanol 10
g, toluene 180ml and acetic acid 0.2ml, 10
Heat to reflux for an hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain about 80 ml of concentrated solution.

Add 30 ml of hexane to this to crystallize, separate the crystals, and (4S, 5R)-1,3-dibenzyl-5
-Carboxy-4-methoxycarbonylimidazolidin-2-one (-2) and (4S,5R)-
1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one (-
2) mixture 17.9g (yield 97.5%, melting point 130-131
°C) was obtained. 50 ml of isopropanol and 50 ml of water are added to 12.3 g of this mixture and heated to 50°C. To this, 6.6 g of d-α-phenyl-β-phenylethylamine was added dropwise. Keep warm at the same temperature for 1 hour.
After that, it was slowly cooled and prepared separately at 30℃ (4S, 5R) −
1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one and d-
A small amount of a crystal of a salt of α-phenyl-β-phenylethylamine is added as a seed crystal, and the mixture is further slowly cooled to 20°C, kept at 20°C for 2 hours, and the precipitated crystals are separated. After acid decomposition by adding 30 ml of water and 16 g of concentrated hydrochloric acid to the separately dried crystals, 50 c.c. of methyl isobutyl ketone was added for extraction. Extract with water
After washing twice with 20 ml, methyl isobutyl ketone was distilled off and (4S,5R)-1,3-dibenzyl-
5-carboxy-4-methoxycarbonylimidazolidin-2-one (-2) 5.38 g (yield 43.5
%) was obtained.

α] ²⁰ ₃₆₅ +27.9° (C=1, DMF) Melting point 149-150°C Next, 3.68 g of (-2) obtained here was dissolved in 50 ml of ethylene glycol dimethyl ether and cooled to 10°C.

Separately, add boron triboride, 3.0 g of ether complex, and 30 ml of ethylene glycol dimethyl ether to a 4-necked flask. While passing _N2 gas,
Sodium borohydride 0.9g in small doses 10-20
Add over 1 hour at °C. The generated diborane is blown into the ethylene glycol dimethyl ether solution of (-2) together with _N2 gas. After adding sodium borohydride, gradually raise the internal temperature to 60°C for 2 hours or more. Meanwhile, the ethylene glycol dimethyl ether solution (-2) is kept at 10°C. Further at room temperature 2
Keep warm for hours. After completion of the reaction, post-treatment and purification were carried out according to Example 1 to obtain 2.91 g (yield 90.3%) of (3S,4R)-(1,3-dibenzyl-2-keto-imidazolide)-2-keto-tetrahydrofuran. Obtained.

Melting point 117-119℃ α〕 ²⁰ _D +62.4゜ (C=1, CHCl ₃ ) Example 3 Into the same flask as used in Example 1, cis-
1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid 17.7g, ethanol 9g
Add 180 ml of toluene and heat under reflux for 10 hours. After the reaction is complete, concentrate the reaction solution until the volume is about 80 ml. 40 ml of hexane was added to this to crystallize, and the crystals were separated to form (4S, 5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one (-1) and (4S, 5R). -1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidine-2
-one (-3) mixture 18.5g (yield 96.8%,
(melting point 94-95°C).

12.7g of this mixture, 50ml of ethanol and 50ml of water
ml and heat to 50°C. 7.0 g of l-α-phenyl-β-(P-tolyl)ethylamine is added dropwise to this. (4S, 5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidine-2 was then slowly cooled and separately prepared at 30-31°C
-on and d-α-phenyl-β-(P-tolyl)
Add a small amount of crystals of salt with ethylamine as seed crystals, further slowly cool to 10°C, keep at 10°C for 2 hours, and collect the precipitated crystals. 30 ml of water and 1.6 g of concentrated hydrochloric acid are added to the separately dried crystals for acid decomposition, and then 50 ml of ethyl acetate is added for extraction and separation. After washing the extract twice with 20 ml of water, ethyl acetate was distilled off to give (4S, 5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one 5.4 g (yield 42.5 %) was obtained.

α] ²⁰ ₃₆₅ +19.1° (C=1, DMF) Melting point 114-115°C Next, 3.82 g of (-3) obtained here was dissolved in 40 ml of tetrahydrofuran, and 0.3 g of lithium borohydride was added at -20°C. was added little by little.

Furthermore, 2.3 g of boron trifluoride-ether complex was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. After the reaction is complete, add 30 ml of 4% hydrochloric acid and extract twice with 50 ml of ethyl acetate. The organic layer is diluted with 20 ml of water.
After washing twice, ethyl acetate is distilled off. The concentrated residue is purified by column chromatography using a mixture of toluene and ethyl acetate (mixing ratio 5:2). (3S, 4R) − (1,
3-dibenzyl-2-keto-imidazolide)-2
-keto-tetrahydrofuran 2.60 g (yield 80.6
%) was obtained.

Melting point 119-120℃ α〕 ²⁰ _D +62.9゜ (C=1, CHCl ₃ ) Example 4 13.2 g of mixture of (-1) and (-1) obtained according to the method of Example 1, 70 ml of methanol Fill a flask with 60 ml of water and warm to 55°C.
7 g of d-α-phenyl-β-(P-tolyl)ethylamine is added dropwise to this. After that, slowly cool it to 35~
A mixture of separately prepared (4S,5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidin-2-one and d-α-phenyl-β-(P-tolyl)ethylamine at 36°C. Add a small amount of salt crystals as seed crystals, further slowly cool to 15°C, keep warm at 15°C for 2 hours, and separate the precipitated crystals to obtain a liquid. The liquid was concentrated, and 30 ml of water and 2.2 g of hydrochloric acid were added to the resulting concentrated residue for acid decomposition, and then 50 ml of ethyl acetate was added to give (4S, 5R)-
(4S,5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidine- containing an excess of 1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one 2-one and (4S, 5R)
The mixture of -1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-ones is extracted and separated. Dilute the extract with 20ml of water.
After washing twice, ethyl acetate is distilled off. The obtained solid is heated and dissolved in 70 ml of toluene and 20 ml of hexane. Thereafter, the mixture is slowly cooled, seeded with crystals of (4S, 5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one, and then slowly cooled to 15°C. After incubating at 15°C for 2 hours, separate the precipitated crystals. Dry the separate crystals to obtain 6.2 g of (4S,5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidin-2-one (-1).
(47.0%).

α〕 ²⁰ ₃₆₅ +26.6゜(C=1, DMF) Melting point 139-140℃ Note that (4S, 5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidine- There were 8.3 g of crystalline salts of 2-one and d-α-phenyl-β-(P-tolyl)ethylamine, yield 41.5%.

Next, 3.96 g of (-1) obtained here was dissolved in 50 ml of ethylene glycol dimethyl ether, and the mixture was heated at -10°C.
Cool to

Separately, add 3.0 g of boron triboride-ether complex and 30 ml of ethylene glycol dimethyl ether to a four-necked flask. Next, while cooling the internal temperature to -10°C, 0.9 g of sodium borohydride is added little by little over 1 hour. The mixture is further kept warm at the same temperature for 2 hours. Decant out the insoluble solids and wash with 10 ml of cold ethylene glycol dimethyl ether. First, a solution of diborane obtained by tecanting in ethylene glycol dimethyl ether (
-1) Add to the solution for 2 hours or more. After keeping warm for another 2 hours, return to room temperature and keep warm for 2 hours. After the reaction is complete, add 30 ml of 4% hydrochloric acid and extract with 50 ml of ethyl acetate. After washing the organic layer twice with 40 ml of water,
The solvent was distilled off, and the residue was purified by column chromatography to obtain 2.58 g (yield: 80%) of (3S, 4R)-(1,3-dibenzyl-2-keto-imidazolide)-2-keto-tetrahydrofuran. Ta.

α〕 ²⁰ _D +62.8゜ (C=1, CHCl ₃ ) Melting point 120-121℃

Claims (1)

[Claims] 1 General formulas () and () (In the formula, R represents a benzyl group and R' represents a lower alkyl group.) To a mixture of half esters represented by the general formula () (In the formula, R ₁ and R ₂ each represent a hydrogen atom, a halogen atom, or a lower alkyl group.) The optically active half ester represented by the above general formula () is separated by the action of an optically active amine represented by General formula () characterized in that only the carboxylic acid of the half ester is reduced with diborane (In the formula, R has the same meaning as above.) A method for producing an optically active lactone. 2 General formula () (In the formula, R represents a benzyl group.) A dicarboxylic acid represented by the general formula () R′OH () (In the formula, R′ represents a lower alkyl group) is reacted with an alcohol represented by the general formula () R′OH () (wherein, R′ represents a lower alkyl group). General formulas () and () (In the formula, R and R' have the same meanings as above.) A mixture of half esters represented by (In the formula, R ₁ and R ₂ each represent a hydrogen atom, a halogen atom, or a lower alkyl group.) The optically active half ester represented by the above general formula () is separated by the action of an optically active amine represented by General formula () characterized in that only the carboxylic acid of the half ester is reduced with diborane (In the formula, R has the same meaning as above.) A method for producing an optically active lactone.