JPH0763391B2 - Process for producing optically active 4-hydroxycyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (In the formula, R is a linear alkyl group having 1 to 7 carbon atoms, an alkenyl group, an alkynyl group (however, excluding the propargyl group.)
Indicates. And a method for producing optically active 4-hydroxycyclopentenones.

The optically active 4-hydroxycyclopentenones represented by the above general formula (I) are useful as intermediates for agricultural chemicals, fragrances, pharmaceuticals, etc., but are extremely important as intermediates for prostaglandin derivatives, and particularly 4-hydroxy-2-allyl-2 wherein the substituent R is an allyl group
-Cyclopentenone is a very important compound as an intermediate to thiaprostaglandins having excellent pharmacological actions such as antiplatelet aggregation action, as described in JP-A-58-41836.

Furthermore, these optically active substances are converted into sulfonic acid esters with, for example, paratoluenesulfonic acid or methanesulfonic acid, and then reacted with a base or with sodium acetate, sodium dichloroacetate, etc. By hydrolyzing after converting to an ester,
It can be used by leading to 4-hydroxycyclopentenones having a configuration that is opposite to the original configuration.

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

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

(2) The method described in JP-A-58-47495.

However, any of the compounds obtained here are different from the target compound of the present invention, and therefore it is totally unpredictable whether such a method is applied to the method for obtaining the target compound of the present invention.

Moreover, all of these reference compounds are used only as pyrethroid insecticides which are pesticides, and are completely different in usage from the raw materials of prostaglandin such as the compound of the present invention.

Conventionally, 2-allyl-4-hydroxy-2-cyclopentenone in which R represents an allyl group among optically active 4-hydroxycyclopentenones represented by the general formula (I) is disclosed in JP-A-58-41836. Dl-2-allyl-4-hydroxy-2-cyclopentenone and an optically active formula Is dehydrated and condensed, and then separated and hydrolyzed to obtain optically active 2-allyl- of R (+) and S (-).
Methods for obtaining 4-hydroxy-2-cyclopentenone are known. However, this method has a drawback that 4-hydroxycyclopentenones are easily decomposed because the reaction with condensation and hydrolysis with lactone is performed at a high temperature. It is also a complicated method of separating and hydrolyzing diastereomers.

As described above, 4-hydroxycyclopentenones are extremely difficult to handle because they have the property of being easily decomposed not only at high temperatures but also under strongly acidic conditions.

Based on the above, the present inventors have completed the present invention as a result of investigations for easily producing the optically active 4-hydroxycyclopentenones represented by the general formula (I).

That is, the invention has the general formula (II) (In the formula, R'represents an alkyl group or an alkenyl group having 7 to 17 carbon atoms which may be substituted by halogen, and R has the same meaning as described above.) The cyclopentenone ester represented by And asymmetric hydrolysis using a microorganism belonging to the genus Pseudomonas or the genus Candida or an enzyme obtained therefrom, and a method for producing an optically active 4-hydroxycyclopentenone represented by the general formula (I). Is.

Hereinafter, the present invention will be described in detail.

The general formula (II) used as a raw material in the present invention
The dl-cyclopentenone ester represented by the general formula (III) (In the formula, R has the same meaning as described above.) By reacting the dl-4-hydroxycyclopentenone represented by the formula with an aliphatic carboxylic acid, the compound can be easily produced in a good yield.

Here, the following compounds are illustrated as dl-4-hydroxy cyclopentenones used as a raw material.

2-ethyl-4-hydroxy-2-cyclopentenone,
4-hydroxy-2-n-pentyl-2-cyclopentenone, 2-isopropyl-4-hydroxy-2-cyclopentenone, 4-hydroxy-2-n-butyl-2-cyclopentenone, 2-isobutyl- 4-hydroxy-2
-Cyclopentenone, 4-hydroxy-2-n-pentyl-2-cyclopentenone, 2-isopentyl-4-hydroxy-2-cyclopentenone, 4-hydroxy-2
-N-hexyl-4-cyclopentenone, 4-hydroxy-2-n-heptyl-2-cyclopentenone, 2-allyl-4-hydroxy-2-cyclopentenone, 2-
(2-cis-Butenyl) -4-hydroxy-2-cyclopentenone, 4-hydroxy-2- (w-butynyl)-
2-cyclopentenone, 2- (2-cis-pentenyl)
-4-hydroxy-2-cyclopentenone, 4-hydroxy- (2-trans-pentenyl) -2-cyclopentenone, 2- (3-cis-hexenyl) -4-hydroxy-2-cyclopentenone, 2 -(2-Pentynyl)-
4-hydroxy-2-cyclopentenone.

These compounds can be easily obtained by the following methods.

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

Acetic acid, acetic acid chloride, acetic acid bromide, acetic anhydride, propionic acid, propionic acid chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic chloride or bromide, caprinoyl chloride or bromide, dodecanoin Chloride or bromide, palmitoyl chloride or bromide, chloroacetyl chloride or bromide, dichloroacetyl chloride or bromide.

The reaction of such dl-4-hydroxycyclopentenones with an aliphatic carboxylic acid is carried out by applying a usual esterification condition and reacting with a catalyst in the presence or absence of a solvent.

When a solvent is used in this reaction, the solvent may be, for example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane or the like. Solvents such as aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like which are inert to the reaction may be used alone or as a mixture. The amount used can be used without particular limitation.

Aliphatic carboxylic acids used in the reaction are raw materials dl-4-
It is required to be 1 equivalent or more with respect to the hydroxycyclopentenones, and the upper limit is not particularly limited, but it 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 hydrogencarbonate. The amount used is not particularly limited, but is usually 1 to 5 equivalents relative to dl-4-cyclopentenone alcohol.

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

Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst.

The reaction temperature is usually -20 ° C to 150 ° C, preferably -1
It is in the range of 0 ° C to 120 ° C.

The reaction time is not particularly limited.

By such a reaction, dl-represented by the general formula (II)
Cyclopentenone esters can be obtained easily and in good yield, and these can be separated by usual separation means such as extraction, separation,
Although it can be easily isolated from the reaction mixture by concentration, distillation, etc., the reaction mixture can be directly used in the next step.

The optically active 4-hydroxycyclopentenones represented by the general formula (I) have the ability to hydrolyze either one of the dl-cyclopentenone esters represented by the general formula (II). It is carried out by hydrolyzing one of the optically active substances of the esters using a microbial esterase or animal and plant esterase.

The esterase-producing microorganism used in this reaction is not particularly limited as long as it is an esterase-producing microorganism that has the ability to asymmetrically hydrolyze dl-cyclopentenone esters. Esterase means a broad sense of esterase including lipase.)

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

Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida Genus, Saccharomyces, Rhodotorula, Cryptococcus, Torrlopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Microorganisms belonging to the genus Achromobacter can be mentioned.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a conventional method. For example, sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (5 g of peptone, 10 g of glucose, 3 g of malt extract in 1 water)
g, yeast extract 3g to pH 6.5), and for bacteria use sweetened broth medium (water 1g glucose 10g, peptone 5)
g, meat extract 5 g, and Nacl 3 g are dissolved to adjust the pH to 7.2)], and the microorganism is inoculated, and the reciprocal shaking culture is usually performed at 20 to 40 ° C. for 1 to 3 days. Moreover, you may perform solid culture as needed.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings.

Pseudomonas lipase (manufactured by Amano Pharmaceuticals) Lipase of genus Aspergillus (lipase AP (manufactured by Amano Pharmaceuticals)), Lipase M-Ap of genus Mucor (manufactured by Amano Pharmaceuticals), lipase of Candida syrindasse (lipase MY (manufactured by Meito Sangyo) )) Alcaligenes lipase (Lipase PL (manufactured by Meito Sangyo)), Achromopactor lipase (lipase)
AL (manufactured by Meito Sangyo), lipase of genus Arthrobacter (combined lipase BSL (manufactured by joint liquor)), lipase of genus Chromobacterium (manufactured by Toyo Brewing Co., Ltd.), lipase of Rhizopus delemar (talipase manufactured by Tanabe Seiyaku) ), Lipase of the genus Rhizopus (Lipase Saiken (Osaka Bacteria Research Institute)).

Animal / plant esterases can also be used, and specific esterases thereof include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Germ esterase.

Esterase (hydrolase) used in this reaction,
As the use form of the enzyme obtained from animals, plants and microorganisms, there are various forms such as purified enzyme, crude enzyme, enzyme-containing product, microbial culture solution, culture product, fungus body, culture solution and processed product thereof. It can be used as necessary, and the enzyme and the microorganism can be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

The hydrolysis method in the method of the present invention is carried out by vigorously stirring dl-cyclopentenone esters and an enzyme or a microorganism obtained from a microorganism belonging to the genera Alcaligenes, Pseudomonas or Candida in a buffer solution.

As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate or potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, etc. is used, and its pH is an alkalophilic bacterium. PH of 8 to 11 for the culture solution and alkaline esterase, and for the culture solution of microorganisms that are not alkalophilic and esterase that does not have alkali tolerance
A pH of 5-8 is preferred.

The concentration is usually 0.05 to 2M, preferably 0.05 to 0.5M.

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

After the reaction is completed, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., and the solvent is distilled off from the organic layer. After the removal, the concentrated residue is further distilled or treated by column chromatography or the like to obtain an optically active 4-hydroxycyclopentenone as a hydrolysis product and an optically active cyclopentenone ester as a hydrolysis residue. Each class can be separated.

The optically active cyclopentenone esters recovered here can be further hydrolyzed and used as a raw material for the production of a symmetrical body.

In addition, the optically active 4-
Among the hydroxycyclopentenones, R (+)-2-allyl-4-hydroxy-2-cyclopentenone, in which R is an allyl group, is extremely useful as a prostaglandin intermediate and, for that reason, high optical purity. It is more preferable to obtain the compound by the method described above, but in the asymmetric hydrolysis reaction of the present invention, the substituent R ′ of the cyclopentenone ester represented by the general formula (II) is a long-chain compound having a carbon number of 7 to 17 as the starting compound. When the chain aliphatic carboxylic acid ester is used, it is more efficient and the target R (+)-2- with high optical purity is obtained.
Allyl-4-hydroxy-2-cyclopentenone can be obtained.

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

Reference Example 1 3 g of dl-4-acetoxy-2-allyl-2-cyclopentenone, 400 mg of lipase PL (manufactured by Meito Co., Ltd.) and 150 mg of 0.1M phosphate buffer aqueous solution (pH 7) were mixed, and the mixture was mixed at 20 to 25 ° C. for 20 minutes.
Stir vigorously for hours. After completion of the reaction, Glauber's salt is added to the reaction solution, and the mixture is extracted with methyl isobutyl ketone. The extract was concentrated, and the concentrated residue was purified by column chromatography with a mixed solvent of ethyl acetate: toluene = 3: 5 (weight ratio), and R (+)-
2 allyl-4-hydroxy-2-cyclopentenone 0.8g
(Yield 34.6%) {▲ α] ²⁰ _D ▼ + 17.1 ° (C = 1, chloroform)} and l-4-acetoxy-2-allyl-2-
Cyclopentenone 2.0 g {▲ α] ²⁰ _D ▼ -55 ° (C = 1,
Chloroform)} was obtained.

R (+)-2-allyl-4-hydroxy-2 obtained here
After using cyclopentenone as an ester of (+)-α-methoxy-α- (trifluoromethyl) -phenylacetic acid, diastereomers were separated by high performance liquid chromatography and the optical purity was measured. The purity was 85%.

Reference Example 2 3 g of dl-4-acetoxy-2-n-pentyl-2-cyclopentenone and 400 mg of lipase PL (manufactured by Meito Co.) were added to 0.1M.
20-25 at 30 ℃ in 150 ml of phosphate buffer solution (pH7)
Stir vigorously for hours. After completion of the reaction, post-treatment and chromatographic purification were carried out according to Example 1 to obtain R (+)-4-hydroxy-2.
-N-pentyl-2-cyclopentenone 1.0 g (yield 41.6
%) {▲ α] ²⁰ _D ▼ + 12.0 °} and l-4-acetoxy-
2-n-pentyl-2-cyclopentenone 2.5 g {▲ α]
²⁰ _D ▼ -50.5 °} was obtained.

Reference Examples 3 and 4 1 g of dl-4-acetoxy-2-allyl-2-cyclopentenone and 100 ml of 0.1 M phosphate buffer aqueous solution (pP7) were used, and the type and amount of lipase are as shown in Table 1. The reaction and post-treatment were carried out according to Example 1 except for the above. The results are shown in Table-1.

Examples 1 to 5 Using the starting material cyclopentenoester shown in Table 2 (1 g), a 0.1 M phosphate buffer aqueous solution (pH 7) (100 ml) and the lipase shown in Table 2, the reaction and post-treatment were carried out according to Example 1. .

The results are shown in Table-2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:72) (56) References JP-A-59-88443 (JP, A) ) JP-A-58-47495 (JP, A) JP-A-59-140888 (JP, A)

Claims (1)

[Claims] 1. A general formula (In the formula, R ′ represents an alkyl group or an alkenyl group having 7 to 17 carbon atoms which may be substituted with halogen, and R represents a linear alkyl group, an alkenyl group or an alkynyl group having 1 to 7 carbon atoms (provided that A general formula characterized by asymmetric hydrolysis of cyclopentenoesters represented by the formula (1) using a microorganism belonging to the genera Alcaligenes, Pseudomonas or Candida or an enzyme obtained from these (In the formula, R has the same meaning as described above, and * indicates an asymmetric carbon.) A method for producing an optically active 4-hydroxycyclopentenone.