JP2697096B2 - Separation method of optically active 4-hydroxy-2-cyclopentenones - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for separating optically active 4-hydroxy-2-cyclopentenones useful as pharmaceutical or agricultural chemical intermediates.

<Conventional technology> General formula (I) (In the formula, R ′ represents a hydrogen atom or a lower alkyl group, n represents an integer of 4 to 8, and * represents an asymmetric carbon atom.) An optically active 4-hydroxy-2-cyclopentene represented by the following formula: Tenones are represented by the general formula (III) (Wherein, R ″ represents a lower alkyl group, and R ′ and n have the same meanings as described above), using an esterase having an ability to hydrolyze the dl-cyclopentenone ester. The present inventors have found that the compound can be produced by asymmetric hydrolysis, but at this time, the compound of the general formula (II) (In the formula, R ″, R ′, n and * represent the same meanings as described above.) Optically active 2-cyclopentenone esters represented by Generally, column chromatography is used.

However, this method has a problem that it requires a large amount of solvent and silica gel, and cannot be separated and purified in large amounts at a time.

<Problem to be Solved by the Invention> The present invention overcomes the above-mentioned problems and solves the above general formula (I)
And an industrially advantageous method for separating optically active 4-hydroxy-2-cyclopentenone represented by the formula:

<Means for Solving the Problems> The present invention provides a compound represented by the general formula (I): (In the formula, R ′ represents a hydrogen atom or a lower alkyl group, n represents an integer of 4 to 8, and * represents an asymmetric carbon atom.) An optically active 4-hydroxy-2-cyclopentene represented by the following formula: Tenones and the following general formula (II) (Wherein R ″ represents a lower alkyl group, and R ′, n and * have the same meanings as above.) A mixture containing an optically active 2-cyclopentenone ester represented by the formula: Of 2-cyclopentenone ester (II) by crystallization from a mixed solvent of water and an organic solvent of
-A method for separating 4-hydroxy-2-cyclopentenone (I), which comprises recovering cyclopentenone (I).

As the water-soluble organic solvent used in the present invention,
Examples thereof include alcohols such as methanol, ethanol, n-propyl alcohol and isopropyl alcohol, ketones such as acetone and ethers such as tetrahydrofuran and dioxane, and preferably alcohols.

The ratio of these water-soluble organic solvents to water is
Crystallization temperature of 2-cyclopentenone esters (II), solubility of the esters (II) and 4-hydroxy-2-cyclopentenones (I) in water-soluble organic solvents or water, solubility in water It is appropriately determined depending on the total amount of the organic solvent and water, but is usually in the range of 0.25 to 10 by weight, preferably in the range of 0.5 to 2.

The total amount of the water-soluble organic solvent and water is determined by the ratio of the water-soluble organic solvent to water, the crystallization temperature of the 2-cyclopentenone ester (II), and the crystallization temperature of the ester (II). The hydroxy-cyclopentenone (I) is appropriately determined depending on the solubility in water or a water-soluble organic solvent, and is usually determined by the ester (II) and the 4-hydroxy-2-cyclopentenone ( It is 1 to 20 times by weight, preferably 1 to 10 times by weight, relative to the mixture of I).

As a method for crystallizing the ester (II), a mixture of the ester (II) and the 4-hydroxy-2-cyclopentenone (I) is mixed with a mixed solvent of an organic solvent soluble in water and water. If necessary, dissolve while heating, and then crystallize. The above mixture is dissolved in an organic solvent soluble in water, and the amount of water required for crystallization is added at the dissolution temperature to crystallize.

A method in which the above mixture is dissolved in an organic solvent soluble in water while heating, and water is added at the crystallization temperature of the ester (II) in the mixed solvent to crystallize the mixture is applied.

The crystallization temperature is not particularly limited,
Usually, the melting point of the ester (II) to be crystallized is 10
Temperatures lower than or equal to ° C are preferred.

At the time of crystallization, if necessary, a seed crystal of the ester (II) can be inoculated.

After the crystallization of the ester (II), the ester (II) can be separated as a crystal by, for example, an operation such as excess, and 4-hydroxy-2-
The cyclopentenones (I) can be recovered, for example, by adding a large amount of water to the mixed solvent or distilling off the water-soluble organic solvent to the residue after addition of methyl isobutyl ketone, toluene, ethyl acetate or ethyl acetate. Extraction is performed by adding a solvent such as ether, and the solvent is distilled off from the organic layer.

Recrystallization of the recovered 4-hydroxy-2-cyclopentenones (I) is carried out using an organic solvent such as an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene, an ester such as methyl acetate or ethyl acetate,
Ethers such as isopropyl ether or butyl ether, halogenated hydrocarbons such as dichloromethane, dichloroethane or chloroform, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, alcohols such as isopropyl alcohol or hexane, heptane, petroleum ether or ligroin The reaction is performed in an aliphatic hydrocarbon solvent alone or in a mixed solvent thereof.

The use amount of these organic solvents is not particularly limited,
Usually, 4-hydroxy-2-cyclopentenones (I)
Range from 1 to 20 times by weight.

The temperature at the time of recrystallization is not particularly limited, and is appropriately set depending on the type and amount of the solvent to be used.
The temperature is about 10 ° C. lower than the melting point of hydroxy-2-cyclopentenone (I).

Examples of the method of recrystallization include the same method as the method of crystallizing the esters (II).

Upon recrystallization, the 4-hydroxy-2-cyclopentenones (I) are recrystallized similarly to the crystallization of the esters (II).
Seed crystals can also be inoculated.

Further, the recrystallization operation can be repeated as necessary.

From the mixture after performing the recrystallization operation, 4-hydroxy-
The removal of the 2-cyclopentenones (I) is performed, for example, by excess.

A mixture of 4-hydroxy-2-cyclopentenones (I) and esters (II) has the general formula (III) (Wherein R ′ represents a hydrogen atom or a lower alkyl group;
Represents a lower alkyl group, and n represents an integer of 4 to 8, respectively. The dl-cyclopentenone ester represented by the formula (1) can be produced by asymmetric hydrolysis of one of the optically active forms of the ester using an esterase having the ability to hydrolyze the ester.

The above esterase may be produced by a microorganism or may be derived from animals and plants.

In addition, esterase means esterase in a broad sense including lipase.

Specific examples of esterase-producing microorganisms include, for example, Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium , Bacillus,
Lactobacillus, Trichoderma, Candida,
Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Achromo Microorganisms belonging to the genus Bacter are exemplified.

The cultivation of the microorganism is usually performed according to a conventional method. For example, a culture solution can be obtained by performing liquid culture.

For example, a sterilized liquid medium [for colds and yeasts, malt extract / yeast extract medium (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in water 1;
6.5), for bacteria, a sweetened broth medium (10 g of glucose, 5 g of peptone, 5 g of meat extract and 3 g of NaCl in water 1)
Is dissolved and adjusted to pH 7.2)].
The culture is carried out by reciprocating shaking culture at 4040 ° C. for 1 day to 3 days, and solid culture may be performed if necessary.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following.

Pseudomonas lipase [lipase P (manufactured by Amano Pharmaceutical)], Aspergillus lipase [lipase AP (manufactured by Amano Pharmaceutical)], Mucor lipase [lipase M-AP]
(Manufactured by Amano Pharmaceutical Co., Ltd.)), lipase of Candida syrindrasse [lipase MY (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (name Sugar industry)),
Lipase of the genus Arthrobacter (Shin Nippon Chemical), lipase of the genus Chromobacterium (manufactured by Toyo Brewery), lipase of Rhizopus delemar [Talipase (manufactured by Tanabe Seiyaku)]
A lipase belonging to the genus Rhizobus [Lipase Saiken (Osaka Bacteria Research Institute)].

In addition, examples of animal and plant-derived esterases include the following.

Stearpsin, pancreatin, pig liver esterase, Wheat Germ esterase.

As the esterase used in this asymmetric hydrolysis reaction, an enzyme obtained from an animal, a plant, or a microorganism is used. As the use form, a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, The cells can be used in various forms, such as cells, culture broths and processed products thereof, if necessary, and enzymes and microorganisms can be used in combination. Alternatively, it can be used as an immobilized enzyme immobilized on a resin or the like, or an immobilized cell.

The asymmetric hydrolysis reaction is generally carried out by vigorously stirring a mixture of the starting ester (III) and the above enzyme or microorganism in a buffer solution.

As the buffer, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, or the like is used, and its pH is 8 to 11 in a culture solution of an alkaliphilic bacterium or an alkaline esterase. PH 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

The reaction temperature is usually from 10 to 60 ° C, and the reaction time is generally from 10 to 70 hours, but is not limited thereto.

After the completion of the asymmetric hydrolysis reaction, the 4-hydroxy-2-cyclopentenone (I) and the 2-cyclopentenone ester (II) are removed by, for example, removing the hydrolysis reaction solution with methyl isobutyl ketone, acetic acid, or the like. The extraction is performed with a solvent such as ethyl or ethyl ether, and the solvent is distilled off from the organic layer.

The raw material esters (III) are represented by the general formula (IV) (Wherein, R ′ and n represent the same meaning as described above). A 3-hydroxy-4-cyclopentenone represented by the following formula is reacted with a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof, It can be produced by simultaneously performing the acylation and the rearrangement reaction.

As lower aliphatic carboxylic acids, acetic acid, propionic acid, butyric acid, valeric acid, chloroacetic acid, dichloroacetic acid, bromoacetic acid and the like, and as metal salts thereof, lithium salts, sodium salts, potassium salts of these lower aliphatic carboxylic acids, Calcium salt, copper salt, zinc salt, palladium salt, lead salt, tin salt,
Manganese salts and cobalt salts are respectively exemplified. In this reaction, the amount of the lower aliphatic carboxylic acid used for the 3-hydroxy-4-cyclopentenone (IV) is usually 1
The use amount of the metal salt is usually 0.01 to 5 equivalent times or more, preferably 0.01 to 0.5 equivalent times. The amount of the acid anhydride of the aliphatic carboxylic acid used is at least one equivalent of the raw material cyclopentenone (IV).

In this reaction, it is very important to use the above-described three components of the lower aliphatic carboxylic acid, its metal salt and its acid anhydride. And both the rearrangement reaction and the acylation do not proceed sufficiently simultaneously.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene,
Solvents which are inert to the reaction, such as chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, hexane, etc., alone or in a mixture, are not particularly limited. Further, a lower aliphatic carboxylic acid can be used as a solvent.

The reaction temperature is usually from 0 to 150 ° C., preferably from 3 to
It is in the range of 0 to 140 ° C.

The reaction time is not particularly limited, but is usually 0.5 to 10 hours. When the reaction time becomes longer, the formed general formula (III)
Since the dl-cyclopentenone esters represented by the formula (1) are partially decomposed, unnecessary extension of time is not preferred.

As a reaction method, for example, a 3-hydroxy-4-cyclopentenone represented by the general formula (IV), a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof are simultaneously charged into a reaction vessel and reacted. A 3-hydroxy-4-cyclopentenone represented by the formula (IV) is reacted with a lower aliphatic carboxylic acid and an acid anhydride thereof for a certain period of time (usually 0.1 to 5 hours, but is particularly limited. After that, a method such as a method of adding a metal salt of a lower aliphatic carboxylic acid to further react is exemplified.

Thus, the dl-cyclopentenone ester represented by the general formula (III) can be obtained from the 3-hydroxy-4-cyclopentenone represented by the general formula (IV).

The raw material cyclopentenone (IV) has the general formula (V) (Wherein, R ′ and n have the same meanings as described above.).

<Effect of the Invention> According to the present invention, the optically active 4-hydroxy-2-cyclopentenone represented by the general formula (I) can be efficiently and industrially separated.

<Example> Hereinafter, the present invention will be described with reference to examples.

Reference Example 1 5 g of sodium acetate was dissolved in 4560 g of water, and adjusted to pH 4.2 by adding acetic acid. 2- (1-
(Hydroxy-7-methoxycarbonylheptyl) -furan (114 g) was charged, and stirring was continued under a nitrogen stream at 100 ° C. until the raw material disappeared.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 500 ml of methyl isobutyl ketone and separated, and methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2- (6-methoxycarbonyl). Hexyl) -4-cyclopentenone and 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone were obtained as a mixture (92 g, yield 80.7%).

68.0 g of acetic acid, 20.4 g of acetic anhydride and 1.2 g of anhydrous sodium acetate are added to 48.0 g of the above mixture, and the mixture is heated at 120 ° C. for 4 hours. The reaction solution was checked by gas chromatography, and after confirming that no reaction raw material was detected in the reaction solution, the reaction was terminated. The reaction solution is concentrated under reduced pressure, 800 ml of toluene and 400 ml of water are added to the concentrated residue, and the mixture is extracted and separated to obtain an organic layer. The organic layer is washed with 8% aqueous sodium bicarbonate and then further washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated, and concentrated to give 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone (55.2 g).
(98% yield).

bp. 180-185 ° C / 0.6 mmHg Reference Example 2 3-Hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone obtained in Reference Example 1 and 4
A mixture of 24 g of a mixture of -hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone, 36 g of propionic acid, 31 g of propionic anhydride and 1.6 g of sodium propion was reacted at 120 to 125 ° C for 5 hours.

The reaction mixture was concentrated under reduced pressure.
After adding l, the mixture was extracted with 400 ml of toluene. 3% of organic layer
Washed with aqueous sodium bicarbonate and water.

Thereafter, the same treatment as in Reference Example 1 was carried out to give 4-propionyloxy-2- (6-methoxycarbonylhexyl) -2-.
28.1 g (95% yield) of cyclopentenone was obtained.

Example 1 dl-4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 40 obtained in Reference Example 1
g, 0.3 molar phosphate buffer (pH 7.5) 1 and 4 g of Pseudomonas lipase (Amanolivase "P")
Was vigorously stirred at 40 ° C. for 7 hours. The organic layer obtained by extracting the reaction mixture with toluene was concentrated under reduced pressure.
39.8 g of residue was obtained. A mixture of 10 g of this residue, 30 g of methanol and 40 g of water was stirred at 40 ° C. for about 30 minutes, and then cooled,
It was kept at 5 ° C. for 2 hours. After separating the precipitated crystals, the liquid was concentrated under reduced pressure to distill off methanol. The organic layer obtained by extracting the residue with 30 ml of methyl isobutyl ketone was concentrated under reduced pressure to obtain 2.64 g of a concentrated residue.

To the concentrated residue was added 15 g of toluene and 9 g of heptane, and the mixture was stirred at 40 ° C for about 30 minutes, cooled, and cooled at 20 ° C to 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl)-.
About 100 ml of crystals of 2-cyclopentenone were inoculated and cooled to 5 ° C. It was kept at 0-5 ° C for 2 hours. The precipitated crystals were filtered and dried to obtain 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl) -2-clopentenone 1.91.
g was obtained. ▲ [α] ²⁰ _D ▼ + 16.6 ゜ (c = 1, methanol), mp. 61.0-61.5 ° C. Example 2 Residue 8 obtained after completion of the asymmetric hydrolysis reaction of Example 1
10 g of 9.8 g, 25 g of isopropyl alcohol and water
After stirring 35 g of the mixture at 40 ° C. for about 30 minutes,
For 2 hours. After separating the precipitated crystals, the liquid was concentrated under reduced pressure to distill off isopropyl alcohol, and the obtained residue was extracted with 30 g of ethyl acetate. The organic layer was concentrated under reduced pressure, and about 24 g of ethyl acetate was distilled off. To about 8.5 g of the obtained ethyl acetate solution, 6 g of n-hexane was added, and the mixture was stirred at 35 ° C for 1 hour and then cooled. 4R (+)-hydroxy-2-at 25 ° C
Approximately 100 mg of (6-methoxycarbonylhexyl) -2-cyclopentenone crystals were inoculated and cooled to 5 ° C. 3
Maintained at ６6 ° C. for 2 hours. The precipitated crystals were filtered and dried to obtain 1.87 g of 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone. ▲
[Α] ²⁰ _D ▼ + 16.3 ゜ (c = 1, methanol), mp.60.0
660.5 ° C. Reference Example 3 2 g of sodium acetate was dissolved in 1500 g of water, and acetic acid was added to adjust the pH to 4.5. 2- (1-
30 g of (hydroxy-7-ethoxycarbonylheptyl) -furan is charged, and stirring is continued under a nitrogen stream at 100 ° C. until there is no more raw material.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 100 ml of methyl isobutyl ketone and separated, and methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2- (6-ethoxycarbonyl). 24.6 g of hexyl) -4-cyclopentenone and 4-hydroxy-2- (6-ethoxycarbonylhexyl) -2-cyclopentenone were obtained as a mixture (82% yield).

40 g of acetic acid, 5.1 g of acetic anhydride and 2.1 g of sodium acetate are added to 12.7 g of the above mixture, and heated at 110 ° C. for 4 hours.

After completion of the reaction, post-treatment was carried out according to Reference Example 1 to give 4-acetoxy-2- (6-ethoxycarbonylhexyl) -2.
-14.9 g of cyclopentenone (95.1% yield) were obtained.

bp. 189 to 198 ° C./0.5 mmHg Example 3 4 g of 4-acetoxy-2- (6-ethoxycarbonylhexyl) -2-cyclopentenone obtained in Reference Example 3, 4 g
A mixture of 100 ml of a molar phosphate buffer (pH 7.5) and 0.4 g of Pseudomonas lipase (Amano lipase “P”) was vigorously stirred at 25 to 30 ° C. for 10 hours. The organic layer obtained by extracting the reaction mixture with toluene was concentrated under reduced pressure.
3.88 g of residue were obtained. This residue was dissolved in 19.5 g of acetone, and 19.5 g of water was added at 35 ° C. Then, cool it down to 0-5
C. for 2 hours. After separating the precipitated crystals, the liquid was concentrated under reduced pressure to distill off acetone. Residue 40ml
, And the obtained organic layer was concentrated under reduced pressure to obtain 1.2 g of a concentrated residue.

6 g of isopropyl ether and 2.4 g of petroleum ether were added to the concentrated residue, and the mixture was stirred at 40 ° C. for about 30 minutes, cooled, and cooled.
Approximately 10 mg of 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone crystals were inoculated at 0 ° C, cooled to 5 ° C, and then kept at 5 ° C for 2 hours.
The precipitated crystals were filtered and dried to obtain 0.8 g of 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone. ▲ [α] ²⁰ _D ▼ + 14.1 ゜ (c
= 1, methanol), mp. 49.0-49.5 ° C Example 4 4-propionyloxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
A mixture of 5 g, 100 ml of 0.3 molar phosphate buffer (pH 6.0) and 0.3 g of Arthrobacter lipase (manufactured by Shin Nippon Chemical) was vigorously stirred at 30 to 35 ° C. for 10 hours. The organic layer obtained by extracting the reaction mixture with methyl isobutyl ketone was concentrated under reduced pressure to obtain 4.92 g of a residue. This residue was dissolved in 20 g of dioxane, and 30 g of water was added at 35 ° C. Thereafter, it was cooled and kept at 0-5 ° C for 2 hours. After separating the precipitated crystals, the liquid was concentrated under reduced pressure. Water and methyl isobutyl ketone were added to the residue for extraction, and the obtained organic layer was concentrated under reduced pressure.

10 g of xylene and 7 g of heptane were added to the obtained concentrated residue, and the mixture was stirred at 40 ° C. for about 30 minutes, then cooled, and 4R (+) at 20 ° C.
About 10 mg of crystals of -hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone were inoculated and
C. and then kept at 0-5.degree. C. for 2 hours. The precipitated crystals are filtered and dried to give 4R (+)-hydroxy-2-
0.84 g of (6-methoxycarbonylhexyl) -2-cyclopentenone was obtained. ▲ [α] ²⁰ _D ▼ + 16.2 ゜ (c = 1,
Methanol), mp. 60.0-60.5 ° C Reference Example 4 Dissolve 3.1 g of potassium monohydrogen phosphate in 4160 g of water,
The pH was adjusted to 4.2 by adding phosphoric acid. 106 g of 2- (1-hydroxy-7-methoxycarbonylpentyl) -furan is charged into this buffer aqueous solution, and stirring is continued under a nitrogen stream at 100 ° C. until there is no more raw material.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 600 ml of methyl isobutyl ketone and separated, and methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2--6 (-methoxycarbonyl). 84.3 g of a mixture of (butyl) -4-cyclopentenone and 4-hydroxy-2- (6-methoxycarbonylbutyl) -2-cyclopentenone was obtained (yield: 79.5%).

85.5 g of acetic acid, 25.5 g of acetic anhydride and 1.7 g of potassium acetate are added to 53.0 g of the above mixture, and heated at 120 ° C. for 4 hours.

Thereafter, post-treatment was carried out according to Reference Example 1 to give 4-acetoxy-2.
59.7 g (yield 94%) of-(4-methoxycarbonylbutyl) -2-cyclopentynone was obtained.

Example 5 8 g of 4-acetoxy-2- (4-methoxycarbonylbutyl) -2-cyclopentenone obtained in Reference Example 4, 100 ml of 0.3 molar phosphate buffer (pH 7.5) and Pseudomonas lipase (Amano lipase " P ") 0.8 g of the mixture is stirred vigorously at 25-30 ° C for 10 hours. The reaction mixture was extracted with toluene, and the resulting organic layer was concentrated under reduced pressure.
6 g of residue were obtained. 20 g of methanol and 25 g of water are added to this residue.
And stirred at 35 ° C. for about 30 minutes.

Thereafter, it is cooled and kept at 5 ° C. for 3 hours. After separating the precipitated crystals, the liquid is concentrated under reduced pressure to distill off methanol. The residue is extracted with ethyl acetate, and the obtained organic layer is concentrated under reduced pressure.

15 g of acetone and 12 g of hexane are added to the resulting concentrated residue, and the mixture is stirred at 35 ° C for 1 hour, cooled, and kept at 3 to 5 ° C for 2 hours. 4R (+)-
Hydroxy-2- (4-methoxycarbonylbutyl)-
2-cyclopentenone is obtained.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication // C07B 57/00 340 7419-4H C07B 57/00 340 346 7419-4H 346 (C12P 41/00 C12R 1:38) (C12P 41/00 C12R 1:06)

Claims (4)

(57) [Claims] 1. The compound of the general formula (I) (Wherein R ′ represents a hydrogen atom or a lower alkyl group;
n represents an integer of 4 to 8, and * represents an asymmetric carbon atom. ) An optically active 4-hydroxy-2-cyclopentenone represented by the following general formula (II): (Wherein R ″ represents a lower alkyl group, and R ′, n and * have the same meanings as described above.) A mixture containing optically active 2-cyclopentenone esters represented by Using a mixed solvent of water and an organic solvent under the following conditions, an optically active 2-cyclopentenone ester (II) is crystallized and separated from the mixed solvent by crystallization treatment, and the optically active 4-hydroxy-2
-A method for separating optically active 4-hydroxy-2-cyclopentenone (I), comprising recovering cyclopentenone (I). Condition: "Weight ratio of organic solvent soluble in water / water is 0.25 to 10
A mixed solvent having a range of optically active 4-hydroxy-
1 to 20 times by weight of the total amount of 2-cyclopentenone (I) and optically active 2-cyclopentenone ester (II). " 2. The separation method according to claim 1, wherein the recovery of the optically active 4-hydroxy-2-cyclopentenone (I) is carried out by recrystallization from an organic solvent. 3. An optically active 4-hydroxy-2-cyclopentenone represented by the formula (I) and a compound represented by the formula (II):
A mixture containing an optically active 2-cyclopentenone ester represented by the general formula (III) (Wherein, R ′, n and R ″ have the same meanings as described above.) The optical activity of the dl-cyclopentenone ester represented by the following formula is determined using Pseudomonas lipase or Arthrobacter lipase. The separation method according to claim 1 or 2, which is obtained by asymmetric hydrolysis of any one of the isomers. 4. The separation method according to claim 1, wherein the organic solvent soluble in water is an alcohol.