JPS6192578A - Production of optically active 4-hydroxycyclopentenones - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for agricultural chemicals, perfume, and drugs such as prostaglandin derivatives, etc., by hydrolyzing asymmetrically a specific cyclopentenone ester by the use of an enzyme or a microorganism. CONSTITUTION:1 equivalent dl-4-hydroxycyclopentenone shown by the formula I (R is 1-7C straight-chain alkyl, alkenyl, or alkynyl) is reacted with 1-4 equivalents aliphatic carboxylic acid in the presence(absence) of a solvent by the use of a catalyst at -20-150 deg.C, to give (A) a dl-cyclopentenone ester shown by the formula III (R' is alkyl or alkenyl which may be replaced with halogen). The component A is hydrolyzed with (B) an enzyme such as esterase produced from a microorganism belonging to the genus Pseudomonas, Aspergillus, etc. or a microorganism (e.g., lipase of Aspergillus) in a buffer solution such as 0.05-2M buffer aqueous solution of phosphate, etc., at 10-60 deg.C for 10-70hr with vigorous stirring, to give the titled compound shown by the formula III ( is asymmetric carbon).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (I) (where k is a straight-chain alkyl group, alkenyl group, or alkynyl group having 1 to 7 carbon atoms (excluding propargyl group).
shows. ) The present invention relates to a method for producing optically active 4-hydroxycyclobentenones shown in the following.

Optically active 4-hydroxycyclobentenones represented by the above general formula (I) are useful as intermediates for GL drugs, aroma II alcohols, and pharmaceuticals, but are particularly important as intermediates for prostaglandin derivatives. In particular, 4-hydroxy-2-allyl-2-cyclobentenone in which substituent k is an allyl group is disclosed in JP-A-58-41336.
As described in the publication, it is an extremely important compound as an intermediate to thiaprostaglandins, which have excellent pharmacological effects such as antiplatelet aggregation effects.

Furthermore, these optically active substances can be converted into sulfonic acid esters using, for example, para-toluenesulfonic acid or methanesulfonic acid, and then reacted with a base, or by reacting with sodium acetate, sodium dichloroacetate, etc. By converting it into an ester and then hydrolyzing it, 4- and droxycyclobentenones having a configuration opposite to the original configuration can be obtained and used.

Conventionally, the following method has been known as an asymmetric hydrolysis method for obtaining compounds similar to the 4-hydroxycyclobentenones specified in the present invention.

(1) The method described in JP-A-59-140888.

R'C00R'C00 (2) The method described in JP-A-58-47495.

However, all of the compounds obtained here are different from the target compound of the present invention, and therefore it cannot be predicted at all whether such a method will be applied to the method for obtaining the target compound of the present invention.

Moreover, all of these cited compounds are used only as pyrethroid insecticides, which are agricultural chemicals, and their uses are completely different from those used as raw materials for prostaglandins like the compounds of the present invention. .

Conventionally, among the optically active 4-hydroxycyclobentenones represented by the general formula (I), 2-allyl-4-hydroxy-2-cyclobentenone in which K represents an allyl group has been disclosed in JP-A-58-41836. There is a description in the official gazette, dl-
2-allyl-4-hydroxy-2-cyclopentenont The optically active lactone represented by the formula is dehydrated and condensed, separated and hydrolyzed to form optically active 2-allyl-4- of R(+) and SH.
Methods for obtaining hydroxy-2-cyclobentenone are known. However, this method has the disadvantage that 4-hydroxycyclobentenones are easily decomposed because the reactions are carried out at high temperatures during condensation with lactone and hydrolysis. Furthermore, it is a complicated method of separating and hydrolyzing diastereomers.

As described above, 4-hydroxycyclobentenones are very difficult to handle because they have the property of being easily decomposed not only at high temperatures but also under strong acid pouring conditions.

Under these circumstances, the present inventors conducted studies to produce optically active 4-hydroxycyclobentenones represented by the general formula (Il) in a container, and as a result, they arrived at the present invention.

That is, the present invention provides de-cyclobentenone represented by the general formula (nl (wherein R/ represents an alkyl group or alkenyl group which may be substituted with halogen, and K has the same meaning as above). This is a method for producing optically active 4-hydroxycyclobentenones represented by the general formula (Il), which is characterized in that esters are asymmetrically hydrolyzed using enzymes or microorganisms.

The present invention will be explained in detail below.

The above-mentioned -a formula (I
The d/-cyclobentenone esters represented by rl are d represented by the general formula @) (wherein R has the same meaning as above).
By reacting /-4-hydroxycyclobentenones with aliphatic carboxylic acids, they can be easily produced with good yield.

Here, the following compounds are exemplified as dl-4-hydroxycyclobentenones used as raw materials.

2-ethyl-4-hydroxy-2-cyclobentenone,
4-Hydroxy-2-n-pentyl-2-cyclobentenone, 2-isopropyl-4-hydroxy-2-cyclobentenone, 4-hydroxy-”l-n-butyl-2
-Cyclobentenone, 2-isobutyl-4-hydroxy-2-cyclobentenone, 4-hydroxy-2-n-pentyl-2-cyclobentenone, 2-isopentyl-4
-Hydroxy-2-cyclobenzonone, 4-hydroxy-2n-hexyl-4-cyclobentenone, 4-hydroxy-2-n-hebutyl-2-cyclobentenone, 2-
Allyl-4-hydroxy-2-cyclobentenone, 2-
(2-cis-butenyl)-4-hydroxy-2-cyclobentenone, 4-hydroxy-2-(W-butynyl)-
2-cyclobentenone, 2-(2-cis-pentenyl)
-4-hydroxy-2-cyclobentenone, 4-hydroxy-(2-1-lance-pentenyl)-2-cyclobentenone, 2-(3-cis-hexenyl)-4-hydroxy-2-cyclobentenone , 2-(2-pentynyl)
-4-Hydroxy-2-cyclobentenone.

These compounds can be easily obtained by the methods shown below.

(R has the same meaning as above, and X represents a halogen atom.) Examples of the aliphatic carboxylic acids that are the other raw material include the following compounds.

Acetic acid, acetic acid chloride, acetate bromide, acetic anhydride, propionic acid, propionic acid chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic acid chloride or bromide, cabrinoyl chloride or bromide, dodecatuin Chloride or bromide, valmitoyl chloride or bromide, chloracetyl chloride or bromide, dichloroacetyl chloride or bromide.

It takes dI! The reaction between -4-hydroxycyclobentenones and aliphatic carboxylates is carried out under normal esterification conditions using a catalyst in the presence or absence of a solvent.

In this reaction, when a solvent is used, examples of the solvent include aliphatic or Examples include solvents that are inert to the reaction, such as aromatic hydrocarbons, ethers, and halogenated hydrocarbons, either alone or as a mixture. As for its usage, it can be used without any particular restrictions.

Aliphatic carboxylic acids used in the reaction are raw materials dl!
1 equivalent or more is required relative to 4-hydroxycyclobentenones, and the upper limit is not particularly limited, but is preferably 1 to 4 equivalents.

Examples of the catalyst include organic or inorganic basic substances such as triethylamine, tri-n-butylamine, pyridine, picoline, sodium carbonate, sodium methylate, and potassium hydrogen carbonate. The amount used is not particularly limited, but is usually 1 to 5 moles per dl-4-cyclobentenone alcohol.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Furthermore, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as catalysts.

The reaction temperature is usually between -20°C and 150°C, preferably between -10°C and 120°C.

There is no particular restriction on the reaction time.

Through such a reaction, the general formula (dJ represented by [1
- Cyclobenzonone esters are easily obtained in good yields and can be easily isolated from the reaction mixture by conventional separation means such as extraction, separation, concentration, distillation, etc. The reaction mixture can proceed to the next step.

Optically active 4-hydroxycyclobentenones represented by general formula (I) are dI! represented by general formula 4! - It is carried out by hydrolyzing one of the optically active forms of the cyclobentenone esters using a microbial esterase or an animal or plant esterase that has the ability to hydrolyze the optically active form of either one of the cyclobentenone esters.

The microorganism that produces the esterase used in this reaction is dI! - Any microorganism that produces an esterase capable of asymmetrically hydrolyzing cyclobentenone esters may be used, and is not particularly limited. (Esterase in the present invention means esterase in a broad sense including lipase.) .

Specific examples of such microorganisms include microorganisms belonging to the following genera.

Enzolobacter genus, Arthrobacterium + - Genus, Candida, Satucharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptococcus Examples include microorganisms belonging to the genus Myces, Hansenula, and Achromobacter.

For culturing the above-mentioned microorganisms, a culture solution is usually obtained by carrying out liquid culture according to a conventional method. For example, a sterilized liquid medium [for mold and yeast, malt extract/yeast extract medium (11! of water, 5 g of peptone, 10 f of glucose, 3! L of malt extract).

Dissolve 3f of yeast extract and adjust the pH to 6.5), and for bacteria, sweetened bouillon medium (1/1 water, 10f glucose, 5g peptone, meat extract sy).

Dissolve Nacl 3 f/ and adjust the pH to 7.2)]
Microculture may also be performed.

Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Pseudomonas lipase (Ohno Pharmaceutical), Aspergillus lipase (Lipase AP (Ohno Pharmaceutical)), Mucor lipase M-Ap (Ohno Pharmaceutical), Candida cylindrasse lipase (Lipase MY (Polysaccharide Sangyo)) ) Alkaline earth metal lipase (Lipase PL
(manufactured by Polysaccharide Sangyo)), lipase of the genus Achromobacter (Lipase AL (manufactured by Polysaccharide Sangyo)), lipase of the genus Arthrobacter (Lipase Joint BSL (manufactured by Joint Sake Refining)), lipase of the genus Chromobacterium (Toyo Jozoya), Rhizopus
Delemer lipase (Talipase (Tanabe Seiyaku)), Rhizopus lipase (Lipase Saiken (Osaka Bacteria Research Institute)).

Further, animal/plant esterases can also be used, and specific examples of these esterases include the following.

, Steapsin, Pancreatin, Pig Liver Esterase, Wh@t Germ Esterase.

Esterase (hydrolase) used in this reaction,
Enzymes obtained from animals, plants, and microorganisms can be used in various forms such as purified enzymes, crude enzymes, enzyme-containing products, microbial culture fluids, cultures, bacterial cells, culture oral products, and processed products. Enzymes and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or the like.

This hydrolysis reaction is usually carried out by vigorously stirring the dJ-cyclobentenone ester and the above-mentioned enzyme or microorganism in a buffer solution.

As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. The pH is preferably 8 to 11 for culture solutions of microorganisms and alkaline esterases, and the pH is preferably 5 to 8 for culture solutions of microorganisms that are not alkalophilic and esterases that do not have alkali resistance.

The concentration is usually 0.05-2M, preferably 0.05-0
．． It is in the range of 5M.

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

After the reaction is complete, in order to separate the hydrolysis product and hydrolysis residue from the reaction solution, the hydrolysis solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, or ethyl ether, and the solvent is distilled from the organic layer. After removal, the concentrated residue is further distilled or treated with column chromatography to obtain optically active 4-hydroxycyclobentenones, which are hydrolysis products, and optically active cyclobentenone esters, which are hydrolysis residues. Each class can be separated.

The optically active cyclobentenone esters recovered here can be further hydrolyzed and used as a raw material for producing a symmetry body.

Note that the optically active 4-
R (+) -2-allyl-4-hydroxy-2- in which the inside and outside of hydroxycyclobentenones are allyl groups
Cyclobentenone is extremely useful as a prostaglandin intermediate, and for this reason, it is more preferable to obtain the compound with high optical purity. When using a long-chain aliphatic carboxylic acid ester in which the substituent R1 of the cyclobentenone ester shown is a C7-17 long-chain aliphatic carboxylic acid ester, the desired R1-) can be obtained more efficiently and with high optical purity.
-1-2-allyl-4-hydroxy-2-cyclobenzonone can be obtained.

The present invention will be explained below with reference to Examples.

Example 1 dl! -4-acetoxy-2-allyl-2-cyclobentenone 3F, Lipase PL (manufactured by Nagoya Co., Ltd.) 400η and 0.1M phosphate buffer aqueous solution (pII 7) 1
50 μm and stir vigorously for 20 hours at 20-25°C. After the reaction is completed, Glauber's salt is added to the reaction solution, and extracted with methyl isobutyl ketone. The extract was concentrated, and the concentrated residue was purified by column chromatography using a mixed solvent of ethyl acetate:toluene = 3:5 (weight ratio), and purified with R (publication-2-allyl-4-hydroxy-2-cyclobenzonone). 89 (yield 34
．． 6%) (α]o+17.1° (c=1, chloroform)) and E-4-acetoxy-2-allyl-2-cyclobentenone 2°oy (α]D-55° (C=1, chloroform) )) was obtained.

Here, one core R (+) -2-allyl-4-hydroxy-2-cyclobentenone (+1-α-methoxy-α
-(TriIlolomethyl)-phenylacetic acid was converted into an ester, the diastereomers were separated using high performance liquid chromatography, and the optical purity was measured. As a result, the optical purity was 8.
It was 5chi.

Example 2 d/-4-acetoxy-2-n-pentyl-2-cyclobenzonone 3f and Lipase PL (manufactured by Octosuga Co., Ltd.) 40
0 to 0.1 M phosphate buffer aqueous solution (PH7)
Stir vigorously for 20-25 hours at 150-30°C.

After completion of the reaction, post-treatment and chromatographic purification were performed according to Example 1 to obtain R(+)-4-hydroxy-2-n-pentyl-2.
-Cyclopenguone 1.0'l (yield 41.6%
) (α), +12.0°) and 1-4-acetoxy-2-n-pentyl-2-cyclobentenone 2.59
(α)o-50,5°) was obtained.

Example 3.4 (1/-4-acetoxy-2-allyl-2-cyclobenzonone]f, 0.1 M')/e Using Huffer aqueous solution (pH 7) 100-, type and amount of lipase The reaction and post-treatment were carried out in accordance with Example 1 except that the conditions were as shown in Table 1.The results are shown in Table 1.

Examples 5 to 9 As shown in Table 2, 1 g of raw material cyclopentenone ester, 0°IMIJ acid buffer water III [(PH7)10
The reaction and post-treatment were carried out according to Example 1 using the lipases shown in Table 2.

The results are shown in Table-2.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. General formula ▲ Mathematical formula characterized by asymmetric hydrolysis of cyclopentenone esters represented by an alkyl group, an alkenyl group, or an alkynyl group (excluding a propargyl group) using an enzyme or a microorganism, There are chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above, and the * mark indicates an asymmetric carbon.) Method for producing optically active 4-hydroxycyclopentenones shown by