JPH0541998A - Production of optically active cyclopentenone derivative and optically active cyclopentenone esters - Google Patents

Abstract

(57) [Summary] [Object] To provide a method for producing a compound useful as an intermediate such as a prostaglandin. An optically active cyclopentenone derivative and an optically active cyclopentene characterized by reacting cyclopentenones with a carboxylic acid ester of an unsaturated alcohol in the presence of a lipase derived from Arthrobacter. Method for producing tenones.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active cyclopentenone derivative and an optically active cyclopentenone ester which are useful as intermediates for prostaglandins and the like.

[0002]

BACKGROUND OF THE INVENTION As a method for producing an optically active cyclopentenone derivative and optically active cyclopentenone esters, a cyclopentenone and an acylating agent are reacted in the presence of an enzyme such as porcine pancreatic lipase (PPL). There is known a method (Japanese Patent Laid-Open No. 167098/1990). However, this method uses a large amount of enzyme in an amount equal to or more than that of the racemic cyclopentenones used as raw materials, and
It had to react for a long time of up to 9 days, which was never satisfactory in industrial scale production.

[0003]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made earnest studies to find a more efficient production method of optically active cyclopentenone derivatives and optically active cyclopentenone esters, and as a result, cyclopentenones and acyl In the reaction with the agent, by using a specific enzyme called lipase derived from Arthrobacter, not only can the reaction be performed efficiently in a short time even with a small amount of enzyme,
The present invention was completed by finding out that a target product with high optical purity can be obtained, and further conducting various studies on it.

[0004]

That is, the present invention is based on the general formula [1] And a carboxylic acid ester of an unsaturated alcohol are reacted in the presence of a lipase derived from Arthrobacter genus [2]. And an optically active cyclopentenone derivative represented by the formula [3] The present invention relates to a method for producing an optically active cyclopentenone ester represented by

The present invention will be described in detail below. In the present invention, examples of the cyclopentenones represented by the general formula [1], which is a raw material, include 2-alkoxycarbonylalkyl-4-hydroxy-2-cyclopentenone and 2-
Alkoxycarbonylalkenyl-4-hydroxy-2
Examples thereof include cyclopentenone and 2-alkoxycarbonylalkynyl-4-hydroxy-2-cyclopentenone. These are, for example, Japanese Patent Application No. 3-1231.
It can be synthesized by the method shown in No. 0.

Examples of the carboxylic acid ester of unsaturated alcohol used include vinyl acetate, vinyl propionate, vinyl valerate, isopropenyl acetate, isopropenyl propionate and isopropenyl valerate. The amount used is usually 0.5 mol times or more, preferably 2 mol times or more with respect to the cyclopentenones [1]. Also, a carboxylic acid ester of unsaturated alcohol can be used as a solvent.

As the enzyme, lipase derived from Arthrobacter genus is used, and its form is purified enzyme,
Various materials such as those adsorbed on diatomaceous earth or the like or those immobilized on bead glass or the like can be used. The amount of the enzyme is usually 0.1 with respect to the cyclopentenones [1].
01 to 1 times by weight, preferably 0.03 to 0.5 times by weight,
More preferably, it is 0.05 to 0.2 times by weight.

In this reaction, a solvent may be used, and as the solvent, in addition to the above-mentioned carboxylic acid ester of unsaturated alcohol, aliphatic compounds such as hexane, heptane, benzene, toluene, dichloromethane, chloroform and dibutyl ether are used. Hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers and the like can be mentioned alone or in a mixture. The amount used is usually 0.5 to 10 times the weight of the cyclopentenones [1].

The reaction temperature is usually 10 to 50 ° C., and the reaction time is usually 0.5 to 50 hours. The progress of the reaction can be traced by measuring the optical purity of the cyclopentenone derivative [2] by using, for example, liquid chromatography equipped with a filler for an optically active compound, and by this, the reaction end point can be determined. You can also decide.
Ordinary (not necessarily for optically active compounds)
The ratio of alcohols (cyclopentenones [1] and / or optically active cyclopentenone derivatives [2]) and esters (optically active cyclopentenone esters [3]) was measured by liquid chromatography or the like. The reaction end point can also be when the ratio becomes approximately 1: 1. After the reaction is complete, if necessary, the reaction mass may contain hexane, heptane, benzene, toluene, dichloromethane, chloroform, chlorobenzene, dichloroethane, ethyl acetate, ethyl ether, or other aliphatic or aromatic hydrocarbons, ethers, ketones, esters, halogenated carbons. A solvent such as hydrogen is added, for example, the enzyme is filtered off, and the filtrate is concentrated to give an optically active cyclopentenone derivative represented by the general formula [2] and an optically active cyclopentenone represented by the general formula [3]. Esters can be obtained.
In addition, for example, by subjecting it to an ordinary chromatographic treatment, the optically active cyclopentenone represented by the general formula [2] and the optically active cyclopentenone ester represented by the general formula [3] are separated. You can also

The optically active cyclopentenone ester [3] thus obtained is reacted with a lower alcohol such as methanol, ethanol or propanol in the presence of an acid catalyst to give an optically active cyclopentenone. The derivative [2] may be an antipodal optically active cyclopentenones. Further, the optically active cyclopentenone derivative [2] is selectively inverted and then reacted with the lower alcohols described above in the presence of an acid catalyst to give an optically active enantiomer. It can also lead to active cyclopentenones.

[0011]

Industrial Applicability According to the method of the present invention, an optically active cyclopentenone derivative [2] and an optically active cyclopentenone ester [3] can be obtained in a short time with a high optical yield, which is industrially advantageous. is there.

[0012]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the examples. Example 1 Structural formula 2 g of 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone [1-1], 0.25 g of Arthrobacter lipase (manufactured by Shin Nihon Kagaku) and 25 ml of vinyl acetate Keep at ℃,
It was stirred. On the way, the reaction solution was checked by liquid chromatography. Fourteen hours after the start of stirring, 4 (S) -hydroxy-2- (6-methoxycarbonylhexyl) -2-
The optical purity of cyclopentenone [2-1] is 98.5% e.
Since e was exceeded, the reaction was stopped, the Arthrobacter lipase was removed by filtration, the filtration residue was washed with ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrate was separated and purified by column chromatography to obtain [2-1] 0.94 g (optical purity 98.8% ee) and 4 (R) -acetoxy-2.
1.24 g (90% ee) of-(6-methoxycarbonylhexyl) -2-cyclopentenone [3-1] was obtained. The compounds [2-1], [2-2], [2-
3], [2-4], [2-5], 4 (R) -hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone, 4 (R) -hydroxy-2- (6- Methoxycarbonyl-3-cishexenyl) -2-cyclopentenone, 4 (R) -hydroxy- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone, 4
(R) -Hydroxy-2- (6-methoxycarbonyl-
2-hexynyl) -2-cyclopentenone and 4
(R) -Hydroxy-2- (6-methoxycarbonyl-
The optical purity of 2-cishexenyl) -2-cyclopentenone was measured by using an optically active column (Sumipax OA-450).
0: manufactured by Sumitomo Chemical Co., Ltd. is used as compounds [3-1], [3-2],
The optical purities of [3-3], [3-4] and [3-5] were measured by liquid chromatography using an optically active column (Chiralcel OD: manufactured by Daicel).

Comparative Example 1 Pseudomonas lipase (Amano P: manufactured by Shin Nihon Kagaku Co., Ltd.) was used in place of 0.25 g of Arthrobacter lipase.
The reaction was performed in the same manner as in Example 1 except that 25 g was used. It was 17 hours after the initiation of the reaction that the optical purity of the compound [2-1] exceeded 98.5% ee. Thereafter, the same post-treatment and purification procedure as in Example 1 were carried out to give compound [2-1] 0.6.
0 g (optical purity 98.7% ee) and compound [3-1]
1.63 g (42.2% ee) respectively was obtained.

Comparative Example 2 Porcine pancreatic lipase (Sigma: No. L-3126) was replaced with 2 instead of 0.25 g of Arthrobacter lipase.
The reaction was performed in the same manner as in Example 1 except that g was used. Alcohol / ester = 63/3 at 24 hours after the start of the reaction
7, and the optical purity of the compound [2-1] was 70% ee. Furthermore, 0.6 g of porcine pancreatic lipase was added, and the reaction was continued until 72 hours after the start of the reaction.
The optical purity of was only increased to 77% ee.

Example 2 Structural formula 4-hydroxy-2- (6-methoxycarbonyl-3)
-Cishexenyl) -2-cyclopentenone [1-2]
A mixed liquid of 1.19 g, Arthrobacter lipase (manufactured by Shin Nippon Chemical Co., Ltd.) and 12 ml of vinyl acetate was kept at 25 ° C. and stirred. On the way, the reaction solution was checked by liquid chromatography. The reaction was stopped 13 hours after the start of the reaction. Thereafter, the same post-treatments and purification operations as in Example 1 were carried out, and 4 (S) -hydroxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone [2-2] 0.54 g ( Optical purity 99.8% ee)
And 4 (R) -acetoxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone [3-2] 0.77 g (88% ee) were obtained.

Comparative Example 3 Pseudomonas lipase (Amano P: manufactured by Shin Nihon Kagaku Co., Ltd.) was used in place of 0.14 g of Arthrobacter lipase.
The reaction was performed in the same manner as in Example 2 except that 14 g was used. It was 16 hours after the initiation of the reaction that the optical purity of the compound [2-2] exceeded 98.5% ee. Thereafter, the same post-treatment and purification procedure as in Example 2 were carried out to give compound [2-2] 0.4
0 g (optical purity 98.6% ee) and compound [3-2]
0.75 g (50.5% ee) respectively was obtained.

Comparative Example 4 The reaction was carried out in the same manner as in Example 2 except that 1.19 g of porcine pancreatic lipase (Sigma: No. L-3126) was used instead of 0.14 g of Arthrobacter lipase. 75 hours after the start of the reaction, alcohol / ester = 63/37, and the optical purity of the compound [2-2] was 4
It was 0% ee. Furthermore, 0.3 g of porcine pancreatic lipase was added, and the reaction was continued for 130 hours after the reaction started. At this time, alcohol / ester was 50/50. Thereafter, the same post-treatment and purification operation as in Example 2 were carried out to give the compound [2-
2] 0.58 g (optical purity 50% ee) and compound [3
-2] 0.70 g was obtained.

Example 3 Structural formula 4-hydroxy-2- (6-methoxycarbonyl-3)
-Hexynyl) -2-cyclopentenone [1-3] 1.
18 g, Arthrobacter lipase (Nippon Chemical)
A mixed solution of 0.12 g, 12 ml of vinyl acetate and 3 ml of hexane was kept at 20 ° C. and stirred. On the way, the reaction solution was checked by liquid chromatography, and 4 (R)
Stirring was continued until the -hydroxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone disappeared. The reaction was completed in 20 hours. Thereafter, post-treatment and purification were carried out according to Example 1 to give 4 (S) -hydroxy-2- (6-methoxycarbonyl-3-hexynyl)-.
0.51 g (optical purity 100% ee) of 2-cyclopentenone [2-3] and 4 (R) -acetoxy-2- (6-
0.78 g (75% ee) of methoxycarbonyl-3-hexynyl) -2-cyclopentenone [3-3] was obtained.

Example 4 (1) Structural formula 4-hydroxy-2- (6-methoxycarbonyl-2)
-Hexynyl) -2-cyclopentenone [1-4] 2.
36 g, Arthrobacter lipase (Nippon Kagaku)
3 g of a mixture of 0.4 g and 23 ml of vinyl acetate
It was kept at 0 ° C. and stirred. On the way, check the reaction solution, 4
(S) -Hydroxy-2- (6-methoxycarbonyl-
The reaction was stopped when the optical purity of 2-hexynyl) -2-cyclopentenone [2-4] exceeded 98% ee, and the lipase was removed by filtration. Then, post-treatment was carried out according to Example 1 to give [2-4] (optical purity 98% ee) and 4
(R) -acetoxy-2- (6-methoxycarbonyl-
2-hexynyl) -2-cyclopentenone [3-4]
2.66 g of a mixture having an optical purity of 92% ee was obtained.

Example 5 (1) Structural formula 4-hydroxy-2- (6-methoxycarbonyl-2)
-Cishexenyl) -2-cyclopentenone [1-5]
A mixed solution of 2.38 g, Arthrobacter lipase (manufactured by Shin Nippon Kagaku Co., Ltd.) 0.4 g and vinyl acetate 23 ml was kept at 30 ° C. and stirred. On the way, the reaction solution was checked, and when the optical purity of 4 (S) -hydroxy-2- (6-methoxycarbonyl-2-cishexenyl) -2-cyclopentenone [2-5] exceeded 98% ee. The reaction was stopped. Thereafter, post-treatment was carried out according to Example 1, and [2-
5] (optical purity 98.2% ee) and 4 (R) -acetoxy-2- (6-methoxycarbonyl-2-cishexenyl) -2-cyclopentenone [3-5] (optical purity 91.2% 2.60 g of a mixture of ee) was obtained.

Reference Example 1 Reaction was carried out in the same manner as in Example 1 to carry out [2-1] and [3-
2.24 g of the concentrate of 1] was obtained. This concentrate 2.2
Dissolve 4 g in anhydrous THF (15 ml), and add triphenylphosphine (2.05 g) and formic acid (0.45) at 10 ° C or lower.
g was added. Then, 1.36 g of azodicarboxylic acid diethyl ester was added at 10 ° C or lower, and the mixture was reacted at 10 ° C for 2 hours and further at room temperature for 15 hours. After checking the reaction liquid by liquid chromatography and confirming the disappearance of [2-1], the reaction liquid was concentrated under reduced pressure, 30 ml of t-butyl methyl ether was added to the residue, and 50 ml of hexane was further added to remove insoluble matter. It was removed by filtration. The filtrate is concentrated and 4 as a residue
(R) -formyloxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone and [3-1]
A mixture of 4 (R) -formyloxy-2- (6-methoxycarbonylhexyl) -2-obtained here
To a mixture of cyclopentenone and [3-1], 9 g of methanol and 3 g of 30% sulfuric acid were added and reacted at 40 ° C for 5 hours. After the reaction was completed, the reaction solution was cooled to 10 ° C. or lower, adjusted to pH 4.0 with 10% caustic soda water, and then methanol was distilled off under reduced pressure. 30m ethyl acetate in the residue
l was added for extraction, and the organic layer was washed with water. The obtained organic layer is concentrated under reduced pressure, the residue is purified by column chromatography,
1.92 g of 4 (R) -hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone (optical purity 94.0% ee) was obtained.

Reference Example 2 1 g of the compound [3-1] obtained in Example 1 and 1 g of 30% sulfuric acid
And 3 g of methanol were reacted at 40 ° C. for 5 hours.
After completion of the reaction, the reaction solution was cooled to 10 ° C. or lower, adjusted to pH 4.0 with 10% caustic soda water, and then methanol was distilled off. The concentrate was extracted with 10 ml of ethyl acetate, the obtained organic layer was washed with water, and concentrated under reduced pressure to give 2- (6-
Methoxycarbonylhexyl) -4 (R) -hydroxy-2-cyclopentenone 0.83 g (optical purity 90%)
Got

Reference Example 3 0.5 g of the compound [3-2] obtained in Example 2, 0.15 g of 35% hydrochloric acid and 2 ml of methanol were reacted at 40 to 45 ° C. for 4 hours. Then, post-treatment and purification were carried out in the same manner as in Reference Example 1 to obtain 0.41 g of 2- (6-methoxycarbonyl-3-cishexenyl) -4 (R) -hydroxy-2-cyclopentenone (optical purity of 88.2%). ) Got.

Reference Example 4 0.5 g of [2-1] obtained in Example 1, 1.1 g of triphenylphosphine, 0.2 g of formic acid, and 10 ml of THF were added, and after cooling to 10 ° C. or lower, diethyl azodicarboxylic acid ester was added. 0.73 g was added, and the mixture was reacted at 10 ° C. for 2 hours and further at room temperature for 15 hours. After checking the reaction liquid by liquid chromatography and confirming the disappearance of [2-1], the reaction liquid was concentrated under reduced pressure, and t-butyl methyl ether 1 was added to the residue.
5 ml and 25 ml of hexane were added, and the precipitated crystals were removed by filtration. The filtrate was concentrated to obtain 4 (R) -formyloxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone as a residue. To the residue obtained above, 5 g of methanol and 1 g of 50% sulfuric acid were added,
The reaction was carried out at 6 ° C for 6 hours. After completion of the reaction, post-treatment and purification were carried out according to Reference Example 1, and 4 (R) -hydroxy-2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone (0.48 g, optical purity 98.5% ee) was obtained.

Reference Example 5 [2-2] obtained in Example 2 0.48 g, triphenylphosphine 1.05 g, formic acid 0.22 g and THF 8
After charging ml, the mixture was cooled to 5 ° C, 0.7 g of azodicarboxylic acid diethyl ester was added at 10 ° C or lower, and 10 to 15 ° C was added.
At room temperature for 4 hours, and at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated. Then, post-treatment was carried out according to Reference Example 4 to obtain 0.55 g of 4 (R) -formyloxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone. 5.0 g and 3 of 4 (R) -formyloxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone obtained here
0.15 g of 0% hydrochloric acid water was reacted at 40 to 45 ° C for 5 hours. Thereafter, post-treatment and purification were carried out according to Reference Example 4 and 4
(R) -Hydroxy-2- (6-methoxycarbonyl-
3-cishexenyl) -2-cyclopentenone 0.45
g (optical purity 98.9%) was obtained.

Reference Example 6 [1-3] 2.36 g, Arthrobacter lipase (manufactured by Shin Nippon Chemical Co., Ltd.) 0.24 g, vinyl acetate 20 m
A mixture of 1 and 3 ml of hexane was kept at 20 ° C. and stirred. On the way, the reaction solution was checked by liquid chromatography to check that 4 (R) -acetoxy-2- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone [3-3] and 4 (S) -hydroxy. The reaction was terminated when the production ratio with-(6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone [2-3] was approximately 1: 1 and post-treatment was carried out according to Example 1. [3-3] and [2
2.62 g of a mixture of -3] was obtained. Obtained here [3
-3] and [2-3] were added with 15 ml of THF, 2.62 g of triphenylphosphine and 0.46 g of formic acid,
The reaction solution was cooled to 5 ° C., 1.4 g of azodicarboxylic acid diethyl ester was added at the same temperature, and the mixture was stirred at 5 to 10 ° C. for 4 hours and further at room temperature for 20 hours. After completion of the reaction, Reference Example 1
The post-treatment is carried out in accordance with the procedure of 4 (R) -formyloxy-2
-(6-Methoxycarbonyl-3-hexynyl) -2-
2.70 g of a mixture of cyclopentenone and [3-3]
Got (3) 4 (R) -formyloxy-2- (6-methoxycarbonyl-3-hexynyl) -obtained in (2)
13 ml of methanol and 3 g of 30% sulfuric acid were added to a mixture of 2-cyclopentenone and [3-3], and the mixture was reacted at 40 ° C. for 5 hours. After the reaction is complete, pour with caustic soda
The mixture was adjusted to H4.5, and then post-treated and purified according to Reference Example 1 to give 4 (R) -hydroxy- (6-methoxycarbonyl-3-hexynyl) -2-cyclopentenone 2.26.
g (optical purity 91% ee) was obtained.

Reference Example 7 [2-4] obtained in Example 4 (optical purity 98% ee)
And a mixture of [3-4] (optical purity 92% ee) 1.
To 33 g, 1.31 g of triphenylphosphine, 0.39 g of formic acid and 10 ml of THF were added, and at 5 ° C. or lower, 0.87 g of diethyl azodicarboxylic acid was added, and 1
The reaction was carried out at 0 ° C. for 5 hours and further at room temperature for 18 hours.
After completion of the reaction, the reaction solution was concentrated, triphenylphosphine oxide was removed by filtration with t-butyl methyl ether and hexane, and post-treatment and purification were carried out in the same manner as in Reference Example 1 to give 4 (R) -formyloxy. 1.48 g of a mixture of 2- (6-methoxycarbonyl-2-hexynyl) -2-cyclopentenone and [3-4] was obtained. Methanol 6 was added to 1.48 g of the mixture of 4 (R) -formyloxy-2- (6-methoxycarbonyl-2-hexynyl) -2-cyclopentenone and [3-4] obtained here.
g and 1.48 g of 30% sulfuric acid were added, and the mixture was reacted at 40 ° C. for 5 hours. After completion of the reaction, pH of the reaction solution with caustic soda water
It was adjusted to 4.5, and methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with water, the organic layer was concentrated, and further purified by column chromatography to obtain 4 (R) -hydroxy-
2- (6-methoxycarbonyl-2-hexynyl) -2
-Cyclopentenone 1.12 g (optical purity 94.8% e
e) was obtained.

Reference Example 8 [2-5] obtained in Example 5 (optical purity 98.2% e)
e) and [3-5] (optical purity 91.2% ee) in a mixture of 2.60 g, triphenylphosphine 3.04
g, 0.46 g of formic acid and 10.4 ml of THF and 0.1 g of triethylamine are added, and then 1.74 g of azodicarboxylic acid diethyl ester is added at 5 ° C. or lower to give 5-1.
The reaction was carried out at 0 ° C. for 5 hours and further at room temperature for 10 hours.
T-butyl methyl ether and hexane were added to the reaction solution,
Thereafter, post-treatment was carried out according to Reference Example 1, and 4 (R) -formyloxy-2- (6-methoxycarbonyl-2-cishexenyl) -2-cyclopentenone and [3-
2.82 g of a mixture of 5] was obtained. 4 obtained here
2.82 g of a mixture of (R) -formyloxy-2- (6-methoxycarbonyl-2-cishexenyl) -2-cyclopentenone and [3-5], 9 g of methanol,
2.1 g of 40% sulfuric acid was added and reacted at 40 ° C. for 4 hours. Thereafter, post-treatment was carried out according to Reference Example 1, and 2.26 g of 4 (R) -hydroxy-2- (6-methoxycarbonyl-2-cishexenyl) -2-cyclopentenone (optical purity 94.3% ee). Got

Production Example 1 6-methoxycarbonyl-1-carboxy-cis-3-
To a mixed solution of 25.1 g of hexene, 13.8 g of furan (0.20 mol) and 100 ml of chloroform was added 15.5 g (0.074 mol) of trifluoroacetic anhydride at room temperature, and the mixture was reacted at 20 to 25 ° C for 24 hours. After completion of the reaction, the reaction solution was poured into 200 ml of 5% sodium carbonate water, the organic layer was separated, and then washed with water. By concentrating the organic layer, 1-oxo-
14.5 g (yield 91%) of 1-furyl-7-methoxycarbonyl-cis-4-heptene was obtained.

Production Example 2 Next, 12.8 g (0.054 mol) of 1-oxo-1-furyl-7-methoxycarbonyl-cis-4-heptene obtained in Production Example 1 was dissolved in 100 ml of methanol and 50 ml of chloroform and hydrogenated. 20.4 g (0.054 mol) of sodium borohydride
Added at -20 ° C. After keeping the temperature at the same temperature for 2 hours, the reaction solution was poured into ice and extracted with toluene. After separating the organic layer,
Further washing with water and concentrating the organic layer results in 1-hydroxy-1-furyl-7-methoxycarbonyl-cis-4-.
12.3 g (yield 96%) of heptene was obtained.

Production Example 3 Next, 1-hydroxy-1-furyl-7-obtained in Production Example 2
Methoxycarbonyl-cis-4-heptene 11.3 g (0.047
(Mol) 473 g of water and 0.34 g of acetic acid were added, the pH was adjusted to 4.3 with 5% KOH water, and the mixture was heated with stirring at 100 ° C. until the raw material was consumed. 4-hydroxy-2- in the reaction system
(6-methoxycarbonyl-3-cishexenyl) -2
-Cyclopentenone [1-2] and 3-hydroxy-
2- (6-methoxycarbonyl-3-cishexenyl)
2-cyclopentenone (production ratio 65:35) was present. Next, raise the pH of the reaction solution to 7.0 and
The reaction was continued for another 10 hours until the hydroxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone disappeared. After completion of the reaction, the reaction solution was extracted twice with 300 ml of ethyl acetate. The organic layer was concentrated, and the obtained residue was purified by chromatography with toluene: ethyl acetate = 5: 3. 4-Hydroxy-2- (6-methoxycarbonyl-3-cishexenyl) -2-cyclopentenone [1-2] (7.97 g, yield 71%) was obtained. n _D ²⁰ 1.
5023

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[Procedure amendment]

[Submission date] April 28, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 1

[Correction method] Change

[Correction content]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

[0004]

That is, the present invention is based on the general formula [1] Of cyclopentenones and unsaturated alcohols
A general formula [2] characterized by reacting a carboxylic acid ester having 2 to 4 carbon atoms in the presence of a lipase derived from Arthrobacter. And an optically active cyclopentenone derivative represented by the formula [3] The present invention relates to a method for producing an optically active cyclopentenone ester represented by

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0005

[Correction method] Change

[Correction content]

The present invention will be described in detail below. In the present invention, examples of the cyclopentenones represented by the general formula [1], which is a raw material, include 2-alkoxycarbonylalkyl-4-hydroxy-2-cyclopentenone and 2-
Alkoxycarbonylalkenyl-4-hydroxy-2
Examples thereof include cyclopentenone and 2-alkoxycarbonylalkynyl-4-hydroxy-2-cyclopentenone. These are, for example , francs and alkokis.
Sicarbonyl alkynes (or alkoxycarbonyl
Alkanes, alkoxycarbonyl alkenes)
Reaction in the presence of trifluoroacetic anhydride (alkoxy
Carbonyl) -1-oxo-1-furyl alkynes (or
Or corresponding alkanes, alkenes)
To reduce (alkoxycarbonyl) -1-hydroxy
-1-furyl alkynes (or corresponding alkanes,
Alkenes), and control the pH with an aqueous solvent system.
Can be synthesized by isomerization
It Also, 2-alkoxycarbonylalkynyl-4-
Partially hydrogenated hydroxy-2-cyclopentenone
2-alkoxycarbonylalkenyl-4-hydroxy
-2-cyclopentenone, and in the same way
2-alkoxycarbonylalkenyl-4-hydroxy
2-Cyclopentenone to 2-alkoxycarbonyl
Alkyl-4-hydroxy-2-cyclopentenone, 2
-Alkoxycarbonylalkynyl-4-hydroxy-
2-Cyclopentenone to 2-alkoxycarbonyl
Ruquil-4-hydroxy-2-cyclopentenone can also be synthesized (Japanese Patent Application No. 3-12310) .

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction content]

The unsaturated alcohol used has 2 to 4 carbon atoms
As the carboxylic acid ester of, for example, vinyl acetate, vinyl propionate, vinyl valerate, isopropenyl acetate, isopropenyl propionate,
Isopropenyl valerate and the like can be mentioned, and the amount used is usually 0.5 with respect to the cyclopentenones [1].
It is a molar ratio or more, preferably 2 molar times or more. Further, a carboxylic acid ester of unsaturated alcohol having 2 to 4 carbon atoms can be used as a solvent.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction content]

A solvent may be used in this reaction, and the solvent is the carbon of the above-mentioned unsaturated alcohol.
In addition to carboxylic acid esters of the number 2 to 4 , for example, hexane,
Examples thereof include aliphatic hydrocarbons such as heptane, benzene, toluene, dichloromethane, chloroform and dibutyl ether, aromatic hydrocarbons, halogenated hydrocarbons, ethers and the like, singly or in a mixture. The amount used is usually 0.5 to 10 times the weight of the cyclopentenones [1]. ─────────────────────────────────────────────────── ───

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[Submission date] June 10, 1992

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[0001]

TECHNICAL FIELD The present invention relates to an optically active cyclopentenone derivative [2] and an optically active cyclopentenone ester which are useful as intermediates for prostaglandins and the like.
[3] A manufacturing method.

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[0002]

2. Description of the Related Art As a method for producing an optically active cyclopentenone derivative [2] having an ester group at a side chain terminal and an optically active cyclopentenone ester [3] , cyclopentenones [1] and an acylating agent are used. There is known a method of reacting lactic acid with the presence of an enzyme such as porcine pancreatic lipase (PPL) (JP-A-2-167098). However, this method uses the racemic cyclopentenones that are the raw materials.
In addition to using a large amount of enzyme equal to or more than the weight of [1] ,
The reaction had to be carried out for a long time of 5 to 9 days, which was never satisfactory in industrial scale production.

Claims (1)

[Claims] 1. A general formula [1] Represented by the general formula [2], characterized by reacting a cyclopentenone with a carboxylic acid ester of an unsaturated alcohol in the presence of a lipase derived from Arthrobacter. And an optically active cyclopentenone derivative represented by the formula [3] A method for producing an optically active cyclopentenone ester represented by: