JPH0685718B2 - Process for producing optically active cyclopentenol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides compounds of formula (II) (In the formula, R means an acyl group.) The present invention relates to a method for producing (+)-(1R, 4S) -4-hydroxy-2-cyclopentenyl esters (hereinafter referred to as compound (II)).

The compound (II) represented by the formula (II) is useful as an intermediate raw material for prostaglandins. Moreover, prostaglandins are useful as pharmaceuticals.

[Conventional technology]

The compound (II) is replaced by the compound represented by the general formula (I) (In the formula, R has the same meaning as described in the general formula (II).) (Hereinafter referred to as compound (I))
The following method is known as a method related to the method of obtaining the by the method of hydrolyzing in the presence of an enzyme.

(A) A method represented by a method of hydrolyzing 1,4-diacetyl-2-cyclopentenediol in the presence of a commercially available wheat germ lipase.

[See JP-A-51-76486 (hereinafter referred to as Document (a)). ] (B) cis-1,4-diacyl-2-cyclopentenediol can be added to CANDIDA CYLINDRC
EA) or a method of hydrolyzing with lipase obtained from cells of a bacterium of the genus RHIZOPUS SP.

[Tetrahedron Letters vo
L.25, No. 51, pp5875-5878, 1984 (hereinafter referred to as document (b).) [Problems to be solved by the invention] In the above document (a), the compound (I) and the compound (I
There is no description concerning the absolute structure of 1,4-diacyl-2-cyclopentenediol including I).

For example, in Example 1 described in Document (a), there is an example in which 1,4-diacetyl-2-cyclopentenediol is hydrolyzed by wheat germ lipase. However, there is no mention of the absolute structures of 1,4-diacetyl-2-cyclopentenediol and 4-hydroxy-2-cyclopentenyl acetate described in this example. The yield is also low at 30%.

In other words, it is not clear whether the compound (II) having high optical activity can be obtained, since the related art (a) which is a related art does not describe the absolute structures of the raw material and the product. Also, the yield is as low as 30%, which is not industrially satisfactory.

Even in the method described in the above-mentioned document (b), the yield of cis-4-hydroxy-2-cyclopentenylacetate is 86% even in the case of pig liver esrase, which gives the best results. The purity is as low as 70% ee,
Industrially, it is never satisfactory.

As described above, depending on the methods described in these documents (a) and (b), there is a problem that compound (II) cannot be synthesized from compound (I) in high yield and with high stereoselectivity.

[Means for Solving Problems] and [Action] The present inventors stereoselectively hydrolyze cis-1,4-diacyl-2-cyclopentenediols represented by the above general formula (I). We searched for possible enzymes. As a result, the hydrolysis by the enzyme derived from the pancreas of the animal was extremely efficient, and (+)-(1R, 4S)-represented by the general formula (II).
It has been found to give 4-hydroxy-2-cyclopentenyl esters. The configuration of the present invention will be specifically described below.

The starting compound (I) and the target compound (II)
R in R means an ordinary acyl group as RC (O).

R is a hydrogen atom, a lower alkoxy group, a hydrogen group, a saturated or unsaturated hydrocarbon group having 1 to 30 carbon atoms which may be substituted with a lower alkoxycarbonyl group, a lower alkoxy group, a halogen atom, a hydroxyl group or a carboxy group. It means a phenyl group, a furyl group or a thienyl group which may be substituted by a group.

More specifically, R is a hydrogen atom, a methyl group, an ethyl group,
It means a propyl group, a butyl group, a chloromethyl group or a 1-hydroxyethyl group.

The enzyme derived from the pancreas of an animal used as a hydrolase does not necessarily have to be a purified product. For example, commercially available steapsin or pancreatin can also achieve the object of the present invention.

Examples of the animal from which the enzyme is derived include mammals, particularly common livestock such as cattle, horses, pigs, sheep, and rabbits.

The solvent or dispersant used for hydrolysis is preferably a buffer solution, and examples thereof include buffer solutions of inorganic acid salts such as sodium phosphate and potassium phosphate, and buffer solutions of organic acid salts such as sodium acetate and citric acid. It The concentration of these salts used for buffering varies depending on the type of buffer solution, but is 0.02
~ 2M is preferred.

A two-layer system reaction using an organic solvent such as heptane is also possible, but it is not particularly required.

The pH value of the reaction solution at the start of the reaction is preferably in the range of 7 to 10,
During the reaction, it is preferably maintained at 5 to 10.

The reaction temperature is preferably 10 to 50 ° C, and the reaction is slow in the low temperature region of this range, and the enzyme partially loses its activity in the high temperature region, so 20 to 40 ° C is most preferable.

The reaction time varies depending on the reaction temperature, the type and amount of the enzyme used, etc., and varies from one in which the reaction is completed in 1 to 2 hours to one in which several days are required until the reaction is completed.

After completion of the reaction, extract with an organic solvent such as ethyl acetate, and extract (+)-(1R, 4S) -4-hydroxy-2-cyclopentenyl esters from the organic solvent layer by column chromatography, distillation, recrystallization, etc. Can be isolated.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to examples.
The present invention is not limited to these examples.

Example 1. Cis-1,4-diacetyl-2-cyclopentenediol
2.03 g (11.0 mmol) of 0.5 M sodium phosphate buffer (pH
7.0) Suspended in 44 ml and steapsin (Tokyo Kasei) 0.2
After adding 03 g, the mixture was stirred at 30 ° C for 25 hr (hydrolysis rate 94%, during which the reaction time was 14 hours, sodium carbonate 0.46 g
Was added to adjust the pH. ).

90 ml of ethyl acetate was added to the reaction mixture, and the mixture was shaken, filtered through Celite and then separated, and the aqueous layer was further extracted with 40 ml of ethyl acetate × 3 times. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.59 g of a colorless oily substance. This oily substance (which crystallizes if left to stand) was subjected to column chromatography on silica gel [silica gel, hexane / ethyl acetate = 2/1 (v / v) to recover raw materials,
It was switched to hexane / ethyl acetate = 1/1 (v / v). ] (1), (1R, 4S) -4-hydroxy-2-cyclopentenyl acetate 1.41 g (yield 90
%) Was obtained. The optical rotation of this product is [α ▲] ²⁵ _D ▼ + 67.4
The optical purity at 96 (c = 0.52, chloroform) was 96% ee.

Example 2 The enzyme was changed to pancreatin (Tokyo Kasei) and almost the same as in Example 1 (reaction time 24 hr, hydrolysis rate 95%).
When (1) was performed, 1.37 g (yield 87%) of (+)-(1R, 4S) -4-hydroxy-2-cyclopentenyl acetate was obtained. The optical rotation of this product is [α ▲] ²⁵ _D
It was 97% ee at ▼ + 68.7 ° (c = 0.58, chloroform).

〔The invention's effect〕

As illustrated in Examples 1 and 2, by using an enzyme derived from animal pancreas as a hydrolase, the compound of the general formula (I)
Cis-1,4-diacyl-2-cyclopentene represented by the formula (II) is represented by (+)-(1
R, 4S) -4-Hydroxy-2-cyclopentenyl esters can be hydrolyzed in high yield and stereoselectively.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuaki Miyaji 1 722, Tsuboi-cho, Funabashi, Chiba Prefecture NISSAN CHEMICAL INDUSTRIES CO., LTD. ) P. 5875-5878

Claims (3)

[Claims] 1. A general formula (I) (In the formula, R means an acyl group as RC (O).) An enzyme derived from the pancreas of an animal selected from pancreatin and steapsin is used as a cis-1,4-diacyl-2-cyclopentenediol. The general formula (II) is characterized by being hydrolyzed using (In the formula, R has the same meaning as described in the general formula (I).) (+)-(1R, 4S) -4-hydroxy-2
-Method for producing cyclopentenyl esters. 2. The method according to claim 1, wherein R is a methyl group. 3. The method according to claim 1, wherein R is a hydrogen atom.