JPH0691838B2 - Process for producing optically active cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (In the formula, R ₁ is In a substituent represented, the X-Y is CH ₂ -CH ₂ or cis CH = CH, R is a lower alkyl group. R ₂ represents a hydrogen atom or R′CO—, and R ′ represents an alkyl group or an alkenyl group which may be substituted with a halogen atom. *
(Indicates an asymmetric carbon), and relates to a method for producing optically active cyclopentenones.

The optically active cyclopentenones represented by the above general formula (I) are useful compounds as intermediates for medicines or agricultural chemicals, and can be used as important intermediates of prostaglandin derivatives, for example.

Heretofore, as a method for producing the optically active cyclopentenones represented by the general formula (I), several methods as shown below are known.

1) Tetrahedron Letters., No.49,4959 (1973) 2) J. Am. Chem. Soc., 97 865 (1975) 3) Acta. Chimica. Academiae. Scientiarum. Hungari
ae., Tomus 102 (1), pp91 ~ 100 (1979) However, these methods are not always satisfactory in terms of yield, optical purity, etc. for the method of 1), and there is a problem that some by-products are produced, and the method of 2) is a raw material. There is a problem that the synthesis of triketone is not easy and the number of subsequent steps is large, and the method of 3) is a starting material (-)-
There are various problems that cis-2-oxobicyclo [3,3,0] -oct-6-en-3-ol must be an optically active substance and that the number of steps is large. It was not an advantageous manufacturing method.

From this, the present inventors have studied the method for industrially and easily producing an optically active cyclopentenone represented by the general formula (I) at high yield, high purity and low cost. The present invention has been reached.

That is, the present invention is represented by the general formula (II) (Wherein R ₁ has the same meaning as described above and R ′ represents an alkyl group or an alkenyl group which may be substituted with a halogen atom), and an esterase is allowed to act on the dl-cyclopentenone ester represented by By asymmetric hydrolysis,
In (I), the optically active 2-, wherein the substituent R is a hydrogen atom.
Substituted-4-hydroxy-2-cyclopentenone and general formula
In the method (I), the substituent R is R'CO-, and the hydroxyl compound is obtained as a mixture with an enantiomer of an optically active cyclopentenone ester.

Here, dl represented by the general formula (II) used as a raw material
-Cyclopentenone esters can be easily synthesized by, for example, rearranging a furancarbinol as shown by the following formula, isomerizing this, and further reacting it with an organic carboxylic acid.

Here, the organic carboxylic acids include saturated or unsaturated organic carboxylic acid anhydrides and organic carboxylic acid halides, for example, acetic anhydride, acetic acid chloride or bromide, propionic acid chloride or bromide, propionic anhydride, butyryl chloride or Bromide, caproyl chloride or bromide, caprylic chloride or bromide, stearin chloride or bromide caprinoyl chloride or bromide, dodecanoin chloride or bromide, palmitoyl chloride or bromide,
Examples include chloroacetyl chloride or bromide, dichloroacetyl chloride or bromide, and the like.

In the above reaction, dl-4-hydroxy-2-substituted-
The esterification reaction of 2-cyclopentenone with an organic carboxylic acid is carried out by applying a normal esterification condition and reacting with a base catalyst in the presence or absence of a solvent.

When a solvent is used in this reaction, examples of the solvent include an aliphatic or aromatic solvent such as tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, and hexane. Solvents such as group 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.

The organic carboxylic acids used in the reaction are dl-4-hydroxy-
It is necessary to be 1 equivalent or more with respect to 2-substituted-2-cyclopentenone, and the upper limit is not particularly limited, but it is preferably 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 dl-4-hydroxy-2-substituted-2-
It is 1 to 5 equivalents relative to cyclopentenone.

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, the general formula (II) which is the raw material of the present invention
The dl-cyclopentenone ester represented by
Obtained in good yield, these can be easily isolated from the reaction mixture by usual separation means such as extraction, liquid separation, concentration, distillation, etc., but when carrying out the method of the present invention, the reaction mixture is left as it is. Can be used.

Such asymmetric hydrolysis of dl-cyclopentenone esters is carried out by causing an esterase produced by a microorganism or an esterase derived from animals and plants to hydrolyze one of the optically active substances of the starting dl-cyclopentenone esters. Done.

The esterase-producing microorganism used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the dl-cyclopentenone esters represented by the general formula (1I), and is not particularly limited. It is not something that will be done.

The esterase in the present invention means an esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Cydudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Examples include microorganisms belonging to Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a standard method.

For example, a 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, 3 g of yeast extract dissolved in 1 water, pH
6.5), and for bacteria, a broth containing sugar (10 g of glucose, 5 g of peptone, 5 g of meat extract, and 3 g of Nacl are dissolved in 1 of water to have a pH of 7.2)] and inoculated with a microorganism, and usually 20 to 40
The culture may be performed by reciprocal shaking culture at ℃ for 1 to 3 days, and if necessary, solid culture may be performed.

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 [lipase P (manufactured by Amano Pharmaceuticals)], Aspergillus lipase [lipase AP (amano pharmaceuticals)], Mucor lipase [lipase MAP (manufactured by Amano Pharmaceuticals), Candida cylindrasse lipase [lipase MY ( [Meito Sangyo]], Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter lipase (Nippon Kagaku) ), Chromobacterium lipase (Toyo Brewing Co.), Rhizopus derema lipase [Talipase (Tanabe Seiyaku)], Rhizopus lipase [Lipase Saiken (Osaka Bacterial Research Institute)].

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

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

As the esterase used in this reaction, an enzyme obtained from an animal, a plant or a microorganism is used, and its usage forms include a purified enzyme, a crude enzyme, an enzyme-containing material, a microorganism culture solution, a culture, a bacterium, a culture medium It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also 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 asymmetric hydrolysis reaction of the present invention is usually carried out by vigorously stirring a mixture of the starting dl-cyclopentenone esters and the above-mentioned enzyme or microorganism 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
It is in the range of 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.

By such a reaction, an optically active substance of either one of the starting dl-cyclopentenone esters is hydrolyzed to produce optically active cyclopentenones in which the substituent R ₂ in the general formula (I) is hydrogen. On the other hand, the cyclopentenone ester which is the other optically active substance of the raw material compounds remains as a hydrolysis residue as it is, and as a result, in the method of the present invention, the above-mentioned two products are obtained as a hydrolysis product and a hydrolysis residue. The optically active compounds of the species will be obtained simultaneously.

After the completion of such a hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether, the solvent is distilled off from the organic layer and then the concentrated residue is further distilled, or it is carried out by a method such as treatment by column chromatography or recrystallization, whereby the general formula (I) In which the substituent R ₂ is a hydrogen atom, is an optically active 2-substituted-4-hydroxy-
2-Cyclopentenone and the substituent R _{2 in the} general formula (I) are R′CO—, and the above hydroxyl compound can separate enantiomers of optically active cyclopentenone esters. .

The optically active cyclopentenone esters obtained here may be further hydrolyzed, if necessary, to obtain an antipodal 2-substituted-4-hydroxy-2-cyclopentenone from the one obtained previously. .

When a lipase belonging to the genus Pseudomonas or the genus Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, optically active cyclopentenones can be obtained in a high yield with a relatively high optical purity.

In addition, in the case of this hydrolysis, in addition to the buffer solution, it is also possible to use an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane, and by using these, asymmetric hydrolysis is advantageously performed. It can be carried out.

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

Raw Material Production Example 1 A flask was charged with 1,000 ml of water and 0.5 g of 2 potassium hydrogen phosphate, and the pH was adjusted to 4.5 with 5% phosphoric acid.

To this, 20 g of 2- (ω-methoxycarbonylhexyl) -furfuryl alcohol is added, and the mixture is heated and stirred for 14 hours. After that, the pH of the reaction solution is adjusted to 7.0 and the reaction is continued for 6 hours.

After completion of the reaction, extraction is performed twice with 200 ml of toluene. The organic layer is concentrated under reduced pressure to obtain a concentrated residue (18.6 g).

18.6 g of this concentrated residue are dissolved in 100 ml of dichloromethane and 30 ml of pyridine are added. 12.7 g of acetyl chloride is added over 2 hours while keeping the internal temperature at 0 to 10 ° C. After incubating at the same temperature for 1 hour, react at 25-30 ° C for 3 hours.

After completion of the reaction, the organic layer was washed successively with water, 1% dilute hydrochloric acid, 1% aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated under reduced pressure to give 20.6 g of a concentrated residue.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 2), and 4-acetoxy-2- (ω-methoxycarbonylhexyl)-
18.2 g of 2-cyclopentenone are obtained.

mp 53 ° C. Example 1 100 ml of 0.3M phosphate buffer (pH 7.5), 4-acetoxy-2- (ω-methoxycarbonylhexyl) -2-cyclopentenone 4 in a flask equipped with a stirrer and a thermometer.
g, 2 ml of dichloromethane, and 400 mg of Pseudomonas lipase (amanolipase “P”) are charged, and the mixture is vigorously stirred at 25 to 30 ° C. for 18 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene.
The organic layers were combined and concentrated under reduced pressure to obtain 3.98 g of a concentrated residue.

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3), and 4R (+)-hydroxy-2- (ω-methoxycarbonylhexyl) -2-cyclopentenone 1.01 g [▲ [α] ²⁰ _D
▼ + 15.1 ° (C = 1, methanol) (88% ee), m.p58
C] and 4S (−)-acetoxy-2- (ω-methoxycarbonylhexyl) -2-cyclopentenone 2.60 g
[▲ [α] ²⁰ _D ▼ -43.1 ° C (C = 1, methanol), m.p41
C.] was obtained.

Example 2 4 g of 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone and 400 mg of Pseudomonas lipase (amanolipase “P”) are charged into a flask and vigorously stirred at 40 ° C. for 5 hours.

After completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to give 4R (+)-hydroxy-2- (6-methoxycarbonylhexyl)-.
2-cyclopentenone 0.98g [▲ [α] ²⁰ _D ▼ + 14.9 °
(C = 1, methanol) (86.7% ee)] and 4S (-)
-Acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone 2.66 g [▲ [α] ²⁰ _D ▼ -4
3.5 (C = 1, methanol)] was obtained.

Example 3 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 800 mg of Arthrobacter lipase (manufactured by Shin Nippon Kagaku Co., Ltd.) was used as the lipase in Example 1, and 4R (+)-hydroxy-2- was used.
(Ω-methoxycarbonylhexyl) -2-cyclopenteno 1.21 g [▲ [α] ²⁰ _D ▼ + 16.1 ° (C = 1, methanol) and 4S (−)-acetoxy-2- (ω-methoxycarbonylhexyl)- 2-cyclopentenone 2.54 g
[[[Α] ²⁰ _D -40.4 ° (C = 1, methanol)] was obtained.

Example 4 4.0 g of 4-acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone and 300 mg of Arthrobacter lipase (manufactured by Shin Nihon Kagaku Co., Ltd.) were charged in a flask, and charged in the same manner as in Example 2. Simultaneous hydrolytic reaction, post-treatment 4R
(+)-Hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone [▲ [α] ²⁰ _D ▼ + 15.
8 ° (C = 1, methanol) (92.3% ee)] and 4S
(-)-Acetoxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone [▲ [α] ²⁰ _D ▼ -42
(C = 1, methanol)] was obtained.

Example 4 The reaction and post-treatment were carried out in the same manner as in Example 2 except that the lipase in Example 2 was replaced with Chromobacterium lipase (manufactured by Toyo Shuzo, Lipase LP), and 4R (+)-hydroxy- was used.
2- (ω-methoxycarbonylhexyl) -2-cyclopentenone 0.99 g [▲ [α] ²⁰ _D ▼ 13.9 ° (C = 1, methanol) (81.2% ee)] and 4S (−)-acetoxy-
There were obtained 1.4 g of 2- (ω-methoxycarbonylhexyl) -2-cyclopentenone [▲ [α] ²⁰ _D -69.0 ° (C = 1, methanol)].

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location (C12P 41/00 C12R 1:01) (72) Inventor Yasumitsu Ando 4-chome Takashi, Takarazuka-shi, Hyogo 2-1 Sumitomo Chemical Co., Ltd. (72) Inventor Ken Mitsuda 4-2-1 Takashi Takarazuka-shi, Hyogo Sumitomo Chemical Co., Ltd.

Claims (1)

[Claims] 1. A general formula (In the formula, R ₁ is In a substituent represented, the X-Y is CH ₂ -CH ₂ or cis CH = CH, R is a lower alkyl group. R'represents an alkyl group or an alkenyl group which may be substituted with a halogen atom), and a lipase derived from a microorganism belonging to the genus Pseudomonas, Arthrobacter or Chromobacter. A general formula characterized by the action of asymmetric hydrolysis (In the formula, R ₁ has the same meaning as described above, R ₂ represents a hydrogen atom or R′CO—, wherein R ′ represents an alkyl group or an alkenyl group which may be substituted with a halogen atom.
(* Indicates an asymmetric carbon) A process for producing optically active cyclopentenones.