JPH0710791B2 - Process for producing optically active 2-cyclopenten-4-one-1-ol esters - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (In the formula, R represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with halogen, and * represents an asymmetric carbon atom.) The optically active 2-cyclopenten-4-one-
The present invention relates to a method for producing 1-ol esters.

Esters of optically active 2-cyclopenten-4-one-1-ol are important raw materials for the production of prostaglandins, which are extremely valuable physiologically active substances, but their production is very difficult and Optically active 2-cyclopentene-4- with higher industrial purity and high optical purity
There has been a strong demand for a method for producing on-1-ol esters.

Therefore, the inventors of the present invention have earnestly conducted research on a method for industrially easily producing optically active 2-cyclopenten-4-one-1-ol esters with high optical purity and high yield. As a result, the present invention has been completed.

That is, the present invention has the general formula (III) (In the formula, R represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with halogen), and an ester of 2-cyclopenten-4-one-1-ol represented by the general formula (II) (In the formula, R'is a halogenated phenyl group, a lower alkylphenyl group, a naphthyl group or a tertiary lower alkyl group,
(* Indicates an asymmetric carbon atom) The optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by (In the formula, R represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with halogen, and * represents an asymmetric carbon atom.) The optically active 2-cyclopenten-4-one-
1-ol esters and optically active 1,6-diphenyl-2,4-hexadiyne-1,6 represented by the above general formula (II)
An optically active cyclopentenone ester complex obtained by bonding with a diol derivative, and then decomposing this complex, the optically active 2-cyclopenten-4-one-1- It provides a method for producing all-esters.

In the present invention, 2-cyclopentene-4- which is a raw material
The esters of on-1-ol include, for example, 2-cyclopenten-4-one-1-ol and an acid halide (eg, acid chloride) of a saturated or unsaturated carboxylic acid which may be substituted with halogen, in the presence of a base. It can be easily produced by reacting below.

Examples of the esters of 2-cyclopenten-4-one-1-ol include, for example, acetic acid ester, propionic acid ester, n-butyric acid ester, isobutyric acid ester, n
-Valeric acid ester, isovaleric acid ester, piparinic acid ester, methyl ethyl acetate ester, n-caproic acid ester, isocaproic acid ester, β-methyl valerian acid ester, t-butyl acetic acid ester, diethyl acetic acid ester, methyl-n- Propyl acetate,
Methyl isopropyl acetate, 2-methylbutane-
2-carboxylic acid ester, heptanoic acid ester, caprylic acid ester, chloroacetic acid ester, bromoacetic acid ester, dichloroacetic acid ester, β-chloropropionic acid ester, γ-chlorlacic acid ester, trichloric acid ester, crotonic acid ester, 4-pentene ester Acid ester,
2-Pentenoic acid ester, acrylic acid ester, 4-pentynoic acid ester, methoxyacetic acid ester, ethoxyacetic acid ester, methoxypropionic acid ester, ethoxypropionic acid ester, etc. are illustrated.

In addition, the other raw material which is the optically active 1,6-diphenyl-2,4-hexadiyne-1, represented by the general formula (II),
The 6-diol derivative can be easily synthesized, for example, by the method described in JP-A-59-22469.

In the general formula (II), the substitution device R ′ is specifically a chlorophenyl group, a promophenyl group, a fluorophenyl group, a naphthyl group, a toluyl group, an ethylphenyl group,
Examples thereof include t-butyl group and t-amyl group.

The production of an optically active cyclopentenone ester complex is
Cyclopenten-4-one-1-ol esters and optically active 1,6-diphenyl-2,4-hexadiyne-1,6-
A diol derivative (hereinafter referred to as an optically active diynediol) is brought into contact with an organic solvent to form 2-cyclopentene-
It is carried out by precipitating a complex formed by binding one of the optically active 4-on-1-ol and an optically active diynediol and separating the complex.

In this reaction, 2-cyclopenten-4-one-1
The -ol ester may be either a racemate or an optically active mixture having an excess of either one of the optically active substances, but the racemate is generally used.

The amount of the raw material ester used in this reaction is such that optically active 2-cyclopentene-4-
It may be appropriately selected depending on the content of the ester of on-1-ol in the raw material ester, but is usually an optically active compound which is intended to form a complex with an optically active diynediol.
The esters of cyclopenten-4-one-1-ol are
The amount is 0.75 to 2 times equivalent, preferably 1 to 2 times equivalent. Therefore, when a racemate is used as the raw material ester, it is 1.5 to 4 times equivalent, preferably 2 to 4 times equivalent to the optically active diynediol.

As the optically active diynediol used in this complex formation reaction, a compound having the substituent R ′ as described above is used, and the optically active 2-cyclopentene-containing complex formation ability, yield, and decomposition of the formed complex are used. 4-on-1-
Considering the optical purity of the all-esters and the like, an optically active diyne diol in which the substituent R ′ has a promophenyl group, a chlorophenyl group or a fluorophenyl group is preferably used.

As 2-cyclopenten-4-one-1-ol esters, 2-cyclopentene-esters as described above are used because they efficiently form a complex and have a good yield.
Among the 4-on-1-ol esters, in particular, propionic acid ester, lactic acid ester, isolactic acid ester, valeric acid ester, isovalerianic acid ester, pivalic acid ester, caproic acid ester, isocaproic acid ester, chloroacetic acid. Ester, bromoacetate, dichloroacetate, β-chloropropionate, γ-chlorolactate, methoxyacetate are preferably used.

As the organic solvent used in this complex formation reaction, ethyl ether, benzene, toluene, acetonitrile, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, dichloroethane, hexane, petroleum ether, ligroin, etc. Alternatively, a mixed solvent thereof and the like are exemplified.

The reaction temperature is arbitrary in the range of -20 ° C to the boiling point of the solvent used, but is usually in the range of 0 to 80 ° C. When the ester of 2-cyclopenten-4-one-1-ol and the optically active diyne diol are brought into contact with each other in the organic solvent by such a method, any one of the optically active substance and optically active diyne diol in the raw material ester is contacted. Easily combine with to form predominantly 1: 1 complexes.

When this reaction solution is cooled or a complex-insoluble solvent such as hexane or petroleum ether is added to the reaction solution, the complex precipitates as crystals, which are separated to give the desired optically active 2-cyclopentene-4- A complex in which an on-1-ol ester and an optically active diynediol are bonded can be obtained in good optical purity and in good yield, and if necessary, further purified by recrystallization or the like as described above. can do.

By decomposing the optically active cyclopentenone ester complex thus obtained, optically active esters of 2-cyclopenten-4-one-1-ol can be obtained.

As the decomposition method at this time, for example, the complex is heated under reduced pressure or treated by column chromatography.

In the method of heating under reduced pressure, the degree of reduced pressure and the temperature are appropriately selected depending on the respective conditions, but generally 1 to
It is the temperature at which the optically active esters of 2-cyclopenten-4-one-1-ol are distilled out under a pressure of about 100 mmHg.

In addition, the developing solvent in column chromatography includes the reaction solvent exemplified above, and may be 1 type or 2 types depending on the ester.
It is possible to appropriately select one or more species.

By this decomposition treatment, the desired optically active ester of 2-cyclopenten-4-one-1-ol represented by the general formula (I) can be obtained in good yield with good optical purity.

If necessary, the optically active diynediol recovered by the decomposition treatment can be purified by recrystallization or the like and reused.

In the method of the present invention, the optically active substance of the ester of 2-cyclopenten-4-one-1-ol forming a complex is determined according to the optical coordination of the optically active diindiol raw material. By selectively using the above optical coordination, any of S-coordinate and R-coordinate can be obtained as an optically active ester of 2-cyclopenten-4-one-1-ol after complex decomposition.

Therefore, by utilizing this reaction, when a racemic substance or an optically active mixture in which an optically active substance of either one is optically excessive is used as a raw material ester, the complex after the complex formation reaction is separated. 2-Cyclopenten-4-one-1- having an optical configuration opposite to that used for complex formation in a reaction liquid (for example, liquid after complex separation)
Since all the esters are present in an optically excessive amount as a reaction residue, for example, the liquid is concentrated, and the residue is heated and distilled under reduced pressure to recover the esters, which are used before. Has a reverse optical coordination to that obtained previously by contacting with an optically active diynediol having a reverse optical coordination under the same conditions as described above to form a complex, which is decomposed to obtain a complex. Esters of 2-cyclopenten-4-one-1-ol can be obtained.

Thus, according to the method of the present invention, the optically active ester of 2-cyclopenten-4-one-1-ol represented by the general formula (I) is industrially easily produced with high optical purity and high yield. be able to.

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

Reference Example 1 Racemic 2-cyclopenten-4-one-1-ol
To a solution of 9.8 g dissolved in 50 ml of benzene, 10.7 g of n-butyryl chloride and 7.9 g of pyridine are added, and the mixture is allowed to stand at room temperature for 12 hours and then 50 ml of water is added to separate the separated benzene layer.
The benzene layer was washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give racemic 2-cyclopenten-4-one-1-ol n- having a boiling point of 134 ° C (23 / mmHg).
16.0 g of butyric acid ester was obtained.

Example 1 (−)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol ([α ▲] ²⁰
_D ▼ -122 ° (methanol c = 1.0)) 4.83g ether 5m
3.36 g of racemic 2-cyclopenten-4-one-1-ol n-butyric acid ester was added to a solution dissolved in a mixed solvent of 1 and petroleum ether 10 ml, and the mixture was allowed to stand at room temperature for 12 hours.

Then, crystallized colorless prism-like (-)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol and (-)-2-cyclopentene- 4.69 g of 1: 1 crude complex of 4-on-1-ol with n-butyric acid ester was collected by filtration. The filtered material was recrystallized once from a mixed solvent of 5 ml of ether and 10 ml of petroleum ether to give the complex 3.84.
got g. This complex is heated under reduced pressure to a boiling point of 134C / 23mm.
0.94 g of n-butyric acid ester of (−)-2-cyclopenten-4-one-1-ol having Hg [α ▲] ²⁰ _D ▼ -134 ° (methanol c = 1.0) was obtained.

The filtrate collected when the above 1: 1 crude complex was collected by filtration was distilled under reduced pressure to obtain n-butyric acid ester 2.05 of crude (+)-2-cyclopenten-4-one-1-ol. 2.05 g of this crude ester and (+)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol ([α ▲] ²⁰ _D ▼ + 122 ° (methanol c = 1.
0)) 5.89 g was dissolved in a mixed solvent of 5 ml of ether and 10 ml of petroleum ether and left at room temperature for 12 hours.

Then, crystallized colorless prism-like (+)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol and (+)-2-cyclopentene- 4.95 g of a 1: 1 crude complex of 4-on-1-ol with n-butyric acid ester was collected by filtration. The filtered material was recrystallized once from a mixed solvent of 5 ml of ether and 10 ml of petroleum ether to give a complex of 4.10.
got g. When this complex is heated under reduced pressure, the boiling point is 134 ° C / 2.
0.94 g of butyric acid ester of (+)-2-cyclopenten-4-one-1-ol having a 3 mmHg [α ▲] ²⁰ _D ▼ + 107 ° (methanol c = 1.0) was obtained.

Examples 2 to 6 2-Cyclopenten-4-one-1-used in Example 1
Example 1 except that, instead of the all n-butyric acid ester, the raw material esters shown in Table 1 were used in equimolar amounts thereof.
The reaction and post-treatment were carried out in the same manner as in 1. to obtain optically active esters shown in Table 1.

Example 7 (+)-in a four-necked flask equipped with a stirrer and a thermometer.
1,6-diphenyl-1,6-di (o-chlorophenyl) -2,
4-hexadiyne-1,6-diol 12.6 g, (±) -2-
Cyclopenten-4-one-1-ol n-butyric acid ester (10.45 g) and dichloromethane (15 ml) were charged, and the mixture was heated at 40 ° C. and dissolved.

Next, 35 ml of hexane is added at the same temperature, the mixture is kept warm for 30 minutes, cooled to 20 ° C., and kept at the same temperature for 2 hours.

The white crystals that separate out are separated, and (+)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol and (+)-2-cyclopentene-4 are prepared. −
13.7 g of 1: 1 complex of on-1-ol with n-butyric acid ester
Got

mp 110-112 ° C. [α ▲] ²⁰ _D ▼ + 121.5 ° (c = 1, methanol) Next, 13.5 g of the complex obtained here was heated and distilled under reduced pressure,
3.31 g of n-butyric acid ester of (+)-2-cyclopenten-4-one-1-ol was obtained.

bp 134 ° C./23 mmHg [α ▲] ²⁰ _D ▼ + 107.2 ° (c = 1, methanol) Example 8 In a flask similar to that used in Example 7, (+)-1,6-diphenyl-1,6- 4.83 g di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol, chloroacetic acid ester of (±) -2-cyclopenten-4-one-1-ol 3.
72 g and 12 ml of dichloromethane are added and dissolved by heating at 40 ° C. Next, add 15 ml of petroleum ether at 35-40 ° C, and add 20 ° C.
After cooling to, the temperature is kept at the same temperature for 2 hours.

Separate the precipitated white crystals, and add (+)-1,6-diphenyl
1,6-di (o-chlorophenyl) -2,4-hexadiyne-
4.61 g of a complex of 1,6-diol and (+)-2-cyclopenten-4-one-1-ol chloroacetic acid ester was obtained.

mp 108 to 110 ° C. [α ▲] ²⁰ _D ▼ + 110.8 ° (c = 1, methanol) Next, 4.3 g of the complex obtained here was mixed with toluene: ethyl acetate = 1.
Column chromatography was performed using a mixed solution of 0: 2 as a developing solvent to obtain (+)-2-cyclopentene-4.
1.1 g of chloroacetic acid ester of 1-on-1-ol was obtained.

mp 74 to 75 ° C. [α ▲] ²⁰ _D ▼ + 103 ° (c = 1, methanol) Examples 9 to 11 2-Cyclopenten-4-one-1-used in Example 8
The optically active esters shown in Table 2 were obtained by reacting and post-treating in the same manner as in Example 8 except that the raw material esters shown in Table 2 were used instead of the all chloroacetic acid ester.

Example 12 In a flask similar to that used in Example 8, (+)-1,6-
4.83 g of diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol, 3.40 g of methoxyacetic acid ester of (±) -2-cyclopenten-4-one-1-ol and dichloromethane Add 12 ml and dissolve by heating at 40 ° C. Next, 10 ml of petroleum ether is added at 35 ° C to 40 ° C, cooled to 20 ° C and kept at the same temperature for 2 hours.

The white crystals that separate out are separated, and (+)-1,6-diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol and (+)-2-cyclopentene-4 are prepared. −
On-1-ol complex with methoxyacetic acid ester, 5.
Obtained 55 g.

mp 120 to 121 ° C. [α ▲] ²⁰ _D ▼ + 117.1 ° (c = 1, methanol) Next, 5 g of the complex obtained here was heated and distilled under reduced pressure (+)-
1.4 g of methoxyacetic acid ester of 2-cyclopenten-4-one-1-ol was obtained.

[Α ▲] ²⁰ _D ▼ + 97.4 ° (c = 1, methanol) ▲ η ²⁰ _D ▼ 1.4811

Claims (1)

[Claims] 1. A general formula (III) (In the formula, R represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with halogen), and an ester of 2-cyclopenten-4-one-1-ol represented by the general formula (II) (In the formula, R'is a halogenated phenyl group, a lower alkylphenyl group, a naphthyl group or a tertiary lower alkyl group,
(* Indicates an asymmetric carbon atom) The optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by (In the formula, R represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted with halogen, and * represents an asymmetric carbon atom.) The optically active 2-cyclopenten-4-one-
1-ol esters and optically active 1,6-diphenyl-2,4-hexadiyne-1,6 represented by the above general formula (II)
An optically active cyclopentenone ester complex obtained by bonding with a diol derivative, and then decomposing this complex, the optically active 2-cyclopenten-4-one-1- A method for producing all-esters.