JPH0717573B2 - Process for producing optically active esters of 2-cyclopenten-4-one-1-ol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention provides a compound of formula (I) (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.

<Prior Art> Optically Active 2-Cyclopentene-Indicated by the General Formula
Esters of 4-on-1-ol are important raw materials for producing pharmaceuticals, especially prostaglandins having various pharmacological actions such as antiulcer action, thrombolytic action and hypotensive action, but the production thereof is large. A method for producing an optically active ester of 2-cyclopenten-4-one-1-ol, which is difficult and industrially easy, has a high optical purity and a high yield, has been strongly desired.

From the above, the inventors of the present invention have earnestly studied a method for producing an optically active ester of 2-cyclopenten-4-one-1-ol industrially easily and with high optical purity in good yield. As a result, 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), which is brought into contact with an optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by the general formula (I) (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 formed by bonding with a diol derivative, and then decomposed and separated to obtain an optically active cyclopentenone ester complex represented by the general formula (I).
-A method for producing cyclopenten-4-one-1-ol esters was first developed, and a patent application (Japanese Patent Application No. 61-40641).
No.).

<Problems to be Solved by the Invention> The above-mentioned prior application method is an optically active compound represented by the general formula (I).
This is a very excellent method for producing cyclopenten-4-one-1-ol esters, but as a result of further investigations by the inventors to produce the esters more industrially, it was found that the A method called coordination exchange was found and the present invention was completed.

<Means for Solving Problems> The present invention is directed to an ester of 2-cyclopenten-4-one-1-ol represented by the general formula (III) and an optically active compound represented by the general formula (II). An optically active ester of 2-cyclopenten-4-one-1-ol represented by the general formula (I) obtained by contacting with a 6,6-diphenyl-2,4-hexadiyne-1,6-diol derivative; General formula (I
The guest molecule is allowed to act on the optically active cyclopentenone ester complex formed by binding to the optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by I). The molecule and the optically active ester of 2-cyclopenten-4-one-1-ol are coordinate-exchanged to form the guest molecule and the optically active 1,6-diphenyl-2, represented by the general formula (III). 4-hexadiyne-1,6
-Separating a complex consisting of a diol derivative as crystals,
A method for producing an optically active ester of 2-cyclopenten-4-one-1-ol represented by the general formula (I), characterized in that the above ester released by coordination exchange is recovered from the mother liquor. Is provided.

In the present invention, the ester of 2-cyclopenten-4-one-1-ol represented by the general formula (III) for forming an optically active cyclopentenone ester complex is, for example, 2-cyclopenten-4-one- Acid halides of saturated or unsaturated carboxylic acids which may be substituted with 1-ol and halogen (eg acid chlorides)
Can be easily produced by reacting in the presence of a base, and such 2-cyclopenten-4-one-
Examples of 1-ol esters include acetic acid ester, propionic acid ester, n-butyric acid ester, isobutyric acid ester, n-valeric acid ester, isovaleric acid ester, pivalic acid ester, methylethyl acetic acid ester, n-caproic acid ester. Ester, isocaproic acid ester, β-methylvaleric acid ester, t-butylacetic acid ester, diethylacetic acid ester, methyl-n-propylacetic acid ester, methylisopropylacetic acid ester, 2-
Methyl butane-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, trichloroacetic acid ester, crotonic acid ester, 4 -Pentenoic acid ester, 2-pentenoic acid ester, acrylic acid ester, 4-pentylic acid ester, methoxyacetic acid ester, ethoxyacetic acid ester, methoxypropionic acid ester, ethoxypropionic acid ester and the like are exemplified.

In the optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by the general formula (II), the substituent R ′ is specifically a chlorophenyl group, a bromophenyl group, Fluorophenyl group, naphthyl group, toluyl group, ethylphenyl group, t-butyl group, t
-Amyl group and the like are exemplified, and such a compound can be easily produced, for example, by the method described in JP-A-59-22469.

The optically active cyclopentenone ester complex includes esters of 2-cyclopenten-4-one-1-ol and an optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative (hereinafter referred to as an optically active diynediol). Is contacted with an organic solvent inert to the reaction to precipitate a complex formed by bonding one of the optically active 2-cyclopenten-4-one-1-ol and the optically active diynediol. , Can be easily obtained by separating this.

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 starting ester used in this reaction is the amount of the optically active 2-cyclopentene-4 which is to form a complex.
It is appropriately selected depending on the content in the starting ester of the ester of -one-1-ol, but is usually an optically active 2-cyclopenten-4-one-which is intended to form a complex with an optically active diynediol. The amount of ester of 1-ol 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 relative to the optically active diyne diol.
It is a double equivalent, preferably 2 to 4 equivalents.

As the optically active diynediol used in this complex formation reaction, a compound having the substituent R ′ as described above is used. The optically active 2-cyclopentene obtained by complex formation ability, yield and decomposition of the formed complex is used. -4-on-1
Considering the optical purity of the -ol ester and the like, an optically active diynediol having a bromophenyl group, a chlorophenyl group or a fluorophenyl group as the substituent R'is preferably used.

As the organic solvent used in this complex formation reaction, ethyl ether, benzene, toluene, acetonitrile, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane,
Examples include dichloroethane, hexane, petroleum ether, ligroin, and other solvents inert to the reaction, or a mixed solvent thereof.

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 the 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 a crystal, and by separating this, the optically active cyclopentenone ester complex can be obtained with high optical purity. , And can be obtained in good yield, and if necessary, can be further purified by recrystallization or the like by the method described above.

By allowing a guest molecule to act on the optically active cyclopentenone ester complex thus obtained, the optically active 2-cyclopenten-4-one-1 forming the complex is formed.
The -ol ester is coordinate-exchanged with the guest molecule to newly form a complex of the optically active diyneol and the guest molecule, and the optically active ester of 2-cyclopenten-4-one-1-ol is released.

There is no particular limitation on the method of performing the above-mentioned coordination exchange for such a complex, and any method is adopted, but typically, the following method is used.

(1) An optically active cyclopentenone ester complex is mixed with a guest molecule to form a uniform solution, and an insoluble or sparingly soluble organic solvent is added to the coordination-exchanged product complex.
A method in which the formed complex is precipitated as crystals and then separated.

(2) An optically insoluble or sparingly soluble organic solvent is mixed with the optically active cyclopentenone ester complex, the guest molecule, and the coordination-exchanged product complex, heated to form a uniform solution, which is then cooled and deposited. A method for separating the formed complex.

(3) The method of the above (2), wherein the crystals are separated by stirring and holding in a slurry state without heating to form a uniform solution.

(4) A method in which an optically active cyclopentenone ester complex and an excess amount of guest molecules are mixed and heated to form a uniform solution, which is then cooled to separate the formed complex to be precipitated.

Of course, the present invention is not limited to these methods, and a complex of an optically active diynediol and a guest molecule that is coordinate-exchanged by bringing the guest molecule into contact with an optically active cyclopentenone ester complex by appropriately combining these methods. Any method may be used as long as it can be separated and separated as crystals.

Here, as the guest molecule, ketones (eg, acetone, methyl ethyl ketone, diethyl ketone, cyclopentanone, cyclohexanone), cyclic ethers (eg, tetrahydrofuran, dioxane, tetrahydropyran), aliphatic amines (eg, dimethylamine, diethylamine, triethylamine) ), Cyclic amines (eg pyridine, quinoline), aromatic amines (eg aniline), aromatic aldehydes (eg benzaldehyde, salicylaldehyde), aliphatic sulfoxides (eg dimethylsulfoxide, diethylsulfoxide), aliphatic amides (For example, N, N-dimethylformamide) is used, and the amount thereof is not less than the amount necessary to form a complex with the optically active diindole, and is usually the optically active diindole. 1 equivalent or more relative to the Le, preferably 2 to 10 equivalents.

Further, as the organic solvent, ethyl ether, benzene, toluene, acetonitrile, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, dichloroethane, hexane, petroleum ether, a solvent inert to the reaction such as ligroin and the like as described above are used. Examples thereof include mixed solvents thereof, and the amount to be used is appropriately determined according to each processing condition.

The treatment temperature is arbitrary from −20 ° C. to the boiling point of the solvent or guest molecule used, but is usually in the range of −10 ° C. to 100 ° C.

By carrying out such a treatment, a complex consisting of an optically active diynediol coordinated with an optically active ester of 2-cyclopenten-4-one-1-ol and a guest molecule is separated as a crystal, and the produced complex is The guest molecule can be separated from the complex by decomposing it by distillation or drying to recover the optically active diynediol, which can be reused as a raw material of the optically active cyclopentenone ester complex.

On the other hand, the mother liquor after separation of the product complex contains the optically active ester of 2-cyclopenten-4-one-1-ol which has undergone coordination exchange. By carrying out distillation or the like, the objective optically active ester of 2-cyclopenten-4-one-1-ol can be recovered with high optical purity and in good yield.

<Effects of the Invention> Thus, according to the method of the present invention, optically active 2-cyclopenten-4-one-, which is extremely efficient and industrially advantageous, is used.
The 1-ol esters can be recovered in high yield with high optical purity.

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

Example 1 (+)-in a 4-necked flask equipped with a stirrer and a thermometer.
1,6-diphenyl-1,6-di (o-chlorophenyl) -2,
4-hexadiyne-1,6-diol 75.6 g, (+)-2-
62.7 g of n-butyric acid ester of cyclopenten-4-one-1-ol and 90 ml of dichloromethane are charged and dissolved at 40 ° C. Next, add 210 ml of hexane at the same temperature, and add 30
After keeping warm for 2 minutes, cool to 20 ℃ and keep warm for 2 hours. The precipitated white crystals were separated, and (+)-1,6-diphenyl-1,6-di (o-chlorophenyl) 2,4-hexadiyne-1,6-diol and (+)-2-cyclopentene-4- 82.5 g of a 1: 1 complex of on-1-ol with n-butyric acid ester was obtained.

m.p 110-112 ° C. [α] ²⁰ _D ▼ + 121.5 ° (c = 1, methanol) 10 g of this complex and 8 g of acetone are mixed and kept under reflux for 3 hours. After that, 50 ml of n-hexane is added, and the mixture is cooled to 0 to 5 ° C and then kept at the same temperature for 1 hour.

Separate the precipitated white crystals and use (+)-1,6-
Diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol 1: 2 complex with acetone 9.2 g
Got

m.p100.4 ℃ This crystal was treated under reduced pressure at 20mm Hg, 60 ℃ (+)-
1,6-diphenyl-1,6-di (o-chlorophenyl) -2,
7.4 g of 4-hexadiyne-1,6-diol (recovery rate 99.7%)
Recovered.

m.p 131.8 ° C ▲ [α] ²⁰ _D ▼ + 124.6 ° (c = 1, methanol) On the other hand, the mother liquor when the above crystals were separated was concentrated, and the concentrated residue was further distilled under reduced pressure (+ ) -2-Cyclopentene-
2.5 g of 4-but-1-ol n-butyrate (recovery rate
96.9%).

[Α] ²⁰ _D ▼ + 107.2 ° (c = 1, methanol) Examples 2 to 7 The same procedure as in Example 1 was carried out except that the guest compound for exchange shown in Table 1 was used in place of acetone. The results shown in Table-1 were obtained.

In Example 7, the guest compound for exchange was the same as in Example 1, but the amount used was changed.

Example 8 (+)-in a 4-necked flask equipped with a stirrer and a thermometer.
1,6-diphenyl-1,6-di (o-chlorophenyl) -2,
4-hexadiyne-1,6-diol 14.49 g, (+)-2-
Charge 11.16 g of chloroacetic acid ester of cyclopenten-4-one-1-ol and 36 ml of dichloromethane at 40 ° C.
Dissolves in. Then add 45 ml petroleum ether at 35-40 ° C. Then, it is cooled to 20 ° C. and kept warm for 2 hours. Separate the precipitated white crystals from (+)-1,6-diphenyl-1,6-
Di (o-chlorophenyl) -2,4-hexadiyne-1,6-
Diol and (+)-2-cyclopenten-4-one-1
13.85 g of a complex of ol with chloroacetic acid ester was obtained.

m.p 108-110 ° C. ▲ [α] ²⁰ _D ▼ 110.8 ° (c = 1, methanol) Using 10 g of this complex, the same treatment as in Example 1 was performed to obtain white crystals (+)-1,6. -Diphenyl-1,6-di (o
-Chlorophenyl) -2,4-hexadiyne-1,6-diol and acetone in a 1: 2 complex of 9.1 g (m.p 100.5 ° C) was obtained, and this crystal was treated in the same manner as in Example 1 (+ ) -1,6-Diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol (7.32 g, recovery rate 100%) was recovered.

On the other hand, the solvent was distilled off from the mother liquor when the crystals were filtered off,
The concentrated residue was purified by column chromatography with a mixed solvent of ethyl acetate: toluene = 2: 10 to give (+)-2-cyclopenten-4-one-1-ol chloroacetic acid ester (2.63 g).
(Recovery rate 99.8%) was obtained.

m.p73 to 74.5 ° C ▲ [α] ²⁰ _D ▼ + 103 ° (c = 1, methanol) Example 9 (+)-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 14.49 g, (+)-2-
Charge 10.2 g of methoxyacetic acid ester of cyclopenten-4-one-1-ol and 12 ml of dichloromethane, 40
Dissolve at ℃. Then 30 ml of petroleum ether are added at 36-40 ° C.

Then, it is cooled to 20 ° C. and kept warm 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-
16.7 g of all complex with methoxyacetic acid ester was obtained.

m.p 120-121 ° C. [α] ²⁰ _D ▼ + 117.1 ° (c = 1, methanol) Using 10 g of this complex, the same treatment as in Example 1 was carried out to give white crystals (+) −1. , 6-Diphenyl-1,6-di (o
-Chlorophenyl) -2,4-hexadiyne-1,6-diol and acetone in a 1: 2 complex of 9.15 g (m.p100.3 ° C) was obtained, and this crystal was treated in the same manner as in Example 1 (+ ) -1,6-Diphenyl-1,6-di (o-chlorophenyl) -2,4-hexadiyne-1,6-diol 7.35 g (recovery rate 99.4%) was recovered.

On the other hand, the mother liquor obtained by separating the crystals by filtration was subjected to the same treatment as in Example 1 (+)-2-cyclopentene-4-.
2.59 g (collection rate 99.4%) of methoxy-acetic acid ester of on-1-ol was obtained.

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

Claims (2)

[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) General formula (I) obtained by contacting with an 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)
-A guest molecule is allowed to act on an optically active cyclopentenone ester complex formed by bonding with a diol derivative, and the guest molecule and optically active 2-cyclopenten-4-one-1
-A complex consisting of a guest molecule formed by a coordinate exchange with an ester and an optically active 1,6-diphenyl-2,4-hexadiyne-1,6-diol derivative represented by the general formula (II). Is isolated as crystals and the above-mentioned esters are recovered from the mother liquor, which is an optically active 2-cyclopenten-4-one-1 represented by the general formula (I).
-Method for producing ol esters. 2. Guest molecules are ketones, cyclic ethers,
The production method according to claim 1, which is an aliphatic amine, a cyclic amine, an aromatic amine, an aromatic aldehyde, an aliphatic sulfoxide, or an aliphatic amide.