JPH0586002A - Optically active cyclopentene-alcohols, their production and utilization - Google Patents

Abstract

PURPOSE:To obtain new optically active cyclopentene-alcohols useful as a medicine and an agricultural chemical, especially an intermediate for prostaglanding and readily obtain an optically active lactone by carrying out cyclizing reaction using the new compounds. CONSTITUTION:Optically active cyclopentene-alcohols expressed by formula I (R1 is amino which may be substituted with alkyl; the mark * indicates asymmetric carbon atom), e.g. (+)-2-(N,N-dimethylcarbamoylmethyl)-3- cyclopenten-1-ol. The compound expressed by formula I is obtained by reacting cyclopentene esters expressed by formula II (R is alkyl) with an esterase having the ability to selectively hydrolyze only one of optical isomers of the compounds. The compounds expressed by formula II are obtained by reacting cyclopentene- alcohols expressed by formula III with a carboxylic acid expressed by the formula R2COOH or its derivative in the presence of a catalyst. The compounds expressed by formula I are subjected to cyclizing reaction in the presence of a catalyst to afford an optically active lactone expressed by formula IV.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active cyclopentene alcohol useful as a medicine, a pesticide, especially a prostaglandin intermediate, a method for producing the same, and use thereof.

[0002]

PRIOR ART [8] The optically active lactone represented by (in the formula, * represents an asymmetric carbon) is an important intermediate of prostaglandins. For the production method of this optically active lactone by a microorganism or enzyme, see J. Chem. Soc., Chem. Commun.,
1976, 189, J. Am. Chem. Soc., 99, 1625 (1977), J. Am.
Chem. Soc., Chem. Commun., 1979, 908 and the like are known, but none of them are satisfactory because the raw materials are difficult to synthesize and the manufacturing operation is complicated.

[0003]

DISCLOSURE OF THE INVENTION As a result of various studies on the production method of optically active lactones, the present inventors have found an optically active cyclopentene alcohol which is important as a key intermediate of the compound, and further By carrying out a ring closure reaction using an optically active cyclopentene alcohol, an optically active lactone can be easily obtained, and further, a method for industrially producing an optically active cyclopentene alcohol was found. The present invention has been reached.

[0004]

That is, the present invention is based on the general formula [1] (In the formula, R ₁ represents an amino group which may be substituted with an alkyl group, and * represents an asymmetric carbon atom.), An optically active cyclopentene alcohol, a method for producing the compound, and the compound. The present invention relates to a method for producing an optically active lactone represented by the formula [8], which is characterized by reacting the compound in the presence of a catalyst. Hereinafter, the present invention will be described in detail.

Optically active cyclopen which is the compound of the present invention
Substituent R of ten alcohols [1] ₁For example,
Amino group, methylamino group, ethylamino group, propyl
Amino group, dimethylamino group, diethylamino group, dip
Ropylamino group, methylethylamino group, methylpropy
Lumino group, ethylpropylamino group, etc.
it can.

The optically active cyclopentene alcohols [1] are represented by the general formula [2] (In the formula, R ₁ represents the same meaning as described above, and R ₂ represents an alkyl group.)
It can be produced by acting an esterase having the ability to selectively hydrolyze only one of the optical isomers of the compound.

The esterase having the ability to selectively hydrolyze only one of the optical isomers of cyclopentene esters in this reaction means a broadly defined esterase including lipase. Of these, lipase is preferred. In this reaction, as the esterase, an enzyme obtained from animals, plants, or microorganisms is used, and the usage forms thereof include purified enzyme, crude enzyme, enzyme-containing material, microorganism culture solution, culture, fungus body, and culture filtrate. , Or those obtained by treating them, if necessary, in various forms, 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 microorganisms that produce esterase include
There is no particular limitation as long as it is a microorganism that produces an esterase having the ability to selectively hydrolyze only one of the optical isomers of cyclontene esters. Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus,
Trichoderma, Candida, Saccharomyces,
Rhodotorula, Cryptococcus, Torulopsis,
Examples are microorganisms belonging to the genus Pichia, the genus Penicillium, the genus Aspergillus, the genus Rhizopus, the genus Mucor, the genus Aureopasidium, the genus Actinomucor, the genus Nocardia, the genus Streptomyces, the genus Hansenula, and the genus Achromobacter.

Cultivation of the above-mentioned microorganisms is usually carried out according to a conventional method, and for example, liquid culture can be carried out to obtain a culture solution. For example, a sterilized liquid medium (malt extract / yeast extract medium for molds and yeasts (water 1 liter)
5 g of peptone, 10 g of glucose, 3 g of malt extract,
3 g of yeast extract is dissolved to adjust the pH to 6.5, and for bacteria, a sweetened broth medium (glucose 10 g, peptone 5 g, meat extract 5 g, NaCl 3 g is dissolved in 1 liter of water, p
H7.2)]] is inoculated with a microorganism and usually 20-40
The culture may be performed by reciprocal shaking culture at 1 ° C 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, for example, Pseudomonas lipase [Lipase Amano P, Lipase Amano PS (both manufactured by Amano Pharmaceuticals]], Aspergillus lipase [Lipase Amano AP, Lipase Amano A12 (both manufactured by Amano Pharmaceuticals)], Mucor. Genus lipase [Lipase Amano M-AP (manufactured by Amano Pharmaceuticals)],
Candida Cyrindrasse Lipase [Lipase M
Y (manufactured by Meito Sangyo)], lipase of Alcaligenes genus [lipase PL (manufactured by Meito Sangyo)], lipase of Achromobacter genus [lipase AL (manufactured by Meito Sangyo)], lipase of genus Arthrobacter [lipase combination] BSL (purified joint liquor)], chromobacterium genus lipase (manufactured by Toyo Brewing Co.), Rhizopus derema lipase (talipase (manufactured by Tanabe Seiyaku)), Rhizopus genus lipase [Lipase Saiken (Osaka Bacterial Research Institute)], etc. In addition, animals and
A plant esterase can also be used, and specific esterases thereof include steapsin, pancreatin, pig liver esterase, Wheat Germ esterase and the like.

This reaction is carried out by cyclopentene esters [2]
And a mixture of the above-mentioned enzyme or microorganism with a vigorous stirring in a buffer solution. As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate and potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate and sodium citrate, etc. is used, and the pH thereof is an alkaliphilic bacterium. PH of 8 to 11 for the culture broth and alkaline esterase, and pH for the culture broth of microorganisms that are not alkalophilic and esterases that do not have alkali tolerance
5-8 are preferable. 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 0.5 to 70 hours, but it is not limited thereto. In addition, in the case of asymmetric hydrolysis, an organic solvent inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, etc. can be used in addition to the buffer solution.

By this reaction, only one of the optical isomers of the cyclopentene ester [2] is hydrolyzed to produce the desired optically active cyclopentene alcohol represented by the general formula [1]. Of the cyclopentene esters [2], the other optically active compound represented by the general formula [3] (In the formula, R ₁ and R ₂ have the same meanings as described above, and the # mark represents an asymmetric carbon having a configuration opposite to that of the * mark.) The optically active cyclopentene esters represented by It will remain as it is. After completion of this reaction, the reaction solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography to obtain an optical compound. Active cyclopentene alcohols [1] and optically active cyclopentene esters [3] can be separated and purified.

The optically active cyclopentene ester [3] thus obtained is further hydrolyzed, if necessary, and the optically active cyclopentene alcohol [1] obtained previously is an antipodal optically active cyclopentene ester. It can be alcohols.

Cyclopentene esters mentioned above [2]
Is a general formula [4] (In the formula, R ₁ has the same meaning as described above.) The cyclopentene alcohol represented by the general formula [5] R ₂ COOH [5] (in the formula, R ₂ has the same meaning as described above). ) And a carboxylic acid or a derivative thereof.

In this reaction, examples of the carboxylic acid or its derivative include acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, acid anhydrides thereof or acid halides such as acid chlorides or acid bromides. You can

This reaction is carried out in the presence or absence of a solvent. When a solvent is used, the solvent is, for example,
Tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform,
Carbon tetrachloride, dimethylformamide, aliphatic or aromatic hydrocarbons such as hexane, ethers, ketones, halogenated hydrocarbons, aprotic polar solvents and the like inert solvents to the reaction can be mentioned, and these can be used alone or Used as a mixture. The amount used is not particularly limited.

The carboxylic acid or its derivative used in this reaction is required to be 1 equivalent or more with respect to the cyclopentene alcohol [4], and the upper limit is not particularly limited, but it is preferably 1 to 6 equivalents, more preferably 4
It is about equivalent.

Examples of the catalyst include organic or inorganic basic substances such as dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine, picoline, imidazole, sodium carbonate, sodium methylate and potassium hydrogencarbonate. Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst. When using such a catalyst, for example, when an acid halide is used as the carboxylic acid or its derivative, pyridine and triethylamine are particularly preferably used as the catalyst. The amount of the catalyst used varies depending on the kind of the carboxylic acid or its derivative and the combination of the catalyst and cannot be specified. However, when an acid halide is used, it is used in an amount of 1 equivalent or more based on the acid halide.

The reaction temperature is usually -30 ° C to 100 ° C, preferably -20 ° C to 80 ° C. After the reaction,
Cyclopentene esters [2] can be obtained in good yield by a conventional separation means such as extraction, separation, concentration and the like, and can be purified by column chromatography or the like, if necessary.

The cyclopentene alcohols [4] are represented by the formula [6] It can be produced by reacting the lactone represented by the following with an amine represented by the general formula [7] HR ₁ [7] (wherein R ₁ has the same meaning as described above).

The amines [7] used in this reaction include, for example, ammonia, monomethylamine, dimethylamine, monoethylamine, diethylamine, dipropylamine, and the like. It can also be used. Amines [7]
The amount used is usually 1 equivalent or more, preferably 1.1 to 50 equivalents, relative to the lactone [6].

A solvent may be used in this reaction. Examples of such a solvent include water, acetone,
Tetrahydrofuran, benzene, toluene, hexane,
Examples thereof include ketones such as acetonitrile and dimethylformamide, ethers, hydrocarbons, aprotic polar solvents and the like, and these can be used alone or in combination.

The reaction temperature is usually from -70 to 150 ° C, but is preferably from 0 to 150 ° C. The reaction time is not particularly limited. After completion of the reaction, cyclopentene alcohols [4] can be obtained by a usual separation means such as pH adjustment, extraction, liquid separation, concentration, etc., and can be purified by column chromatography or the like, if necessary.

The above-mentioned lactone [6] is commercially available cis-
It can be produced by a so-called usual Bayer-Villiger reaction in which a peroxyacid such as peracetic acid is allowed to act on bicyclo [3.2.0] hept-2-en-6-one.

An optically active lactone represented by the formula [8] can be produced by reacting an optically active cyclopentene alcohol [1] which is a compound of the present invention in the presence of a catalyst.

In this reaction, an acid or basic catalyst is usually used as the catalyst, preferably an acid catalyst. Examples of acid catalysts include protic acids such as sulfuric acid and perchloric acid. The amount of the catalyst used is usually 0.1 equivalents or more, preferably 1 to 10 equivalents, relative to the optically active cyclopentene alcohol [1].

In this reaction, a solvent is usually used,
Examples of the solvent include water, solvents such as acetone, tetrahydrofuran, benzene, toluene, dichloromethane, hexane, heptane, and other ketones, ethers, hydrocarbons, and other inert solvents, which may be used alone or in combination. Used. The amount used is not particularly limited. The reaction temperature is usually -70 to 150 ° C, but it is preferably -20 to 100 ° C. The reaction time is not particularly limited.

After the completion of the reaction, the optically active lactone [8] can be obtained in good yield by an ordinary separation means such as extraction, liquid separation, concentration, distillation and the like. It can also be used for purification.

[0030]

The optically active cyclopentene alcohols [1], which are the compounds of the present invention, are important intermediates for the production of optically active lactones [8] useful as pharmaceuticals, agricultural chemicals, especially prostaglandin intermediates. Thus, the optically active lactone [8] can be efficiently and industrially advantageously produced by the method of the present invention using the optically active cyclopentene alcohol [1].

[0031]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the examples.

Production Example 1 27.0 g (0.22 mol) of commercially available cis-bicyclo [3.2.0] hept-2-en-6-one was dissolved in 160 ml of 90% acetic acid aqueous solution and stirred in an ice bath. While 35%
Hydrogen peroxide water (60.6 ml) -90% acetic acid aqueous solution (1
70 ml) of the mixed solution was slowly added dropwise and left in the refrigerator overnight. Water (600 ml) and baking soda powder were added to the reaction solution to adjust the pH to about 7, and 200 ml of a mixed solution of ethyl acetate-hexane (4: 1) was added to separate the water layer and the organic layer. The aqueous layer was mixed with ethyl acetate-hexane (4: 1) 100
The mixture was extracted 3 times with ml, all organic layers were mixed, washed with 50 ml of saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate.
After distilling off the solvent, distillation under reduced pressure (0.35 torr, 65-70
19.75 g of lactone [6] (yield 63.
7%). Spectral data IR (neat, cm ^-1 ): 1770 (C = O) ¹ HNMR (60 MHz, δ, CCl ₄ ): 2.31-2.96
(4H, m), 3.26-3.70 (1H, m), 4.90-5.23 (1H, m), 5.42-
5.88 (2H, m)

Example 1 1.056 g of the lactone [6] obtained above in a reactor
(8.516 mmol) and 10 ml of THF were charged, and while stirring, 20 ml of 40% dimethylamine aqueous solution (15
9.6 mmol) was added, and then the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 2 with 10% hydrochloric acid, extracted 8 times with 30 ml of ethyl acetate, the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off, followed by column chromatography (Merck silica gel). 40 g, developing solvent: ethyl acetate) and purified, 2- (N, N-dimethylcarbamoylmethyl) -3-cyclopentene-1
791 mg of all- [4-1] (55% yield) was obtained. Spectral data IR (cm ^-1 , neat): 3530 (OH), 16
60 (C = O) ¹ H NMR (60 MHz, δ, CCl ₄ ): 2.20-2.63
(5H, m), 2.89 (3H, s) 3.01 (3H, s), 3.33-3.65 (1H, m),
4.23-4.66 (1H, m), 5.26-5.80 (2H, m)

Example 2 700 mg of the compound [4-1] obtained above in a reactor
Charge (4.14 mmol) and methylene chloride 15 ml
And dissolved to give 1517 mg of dimethylaminopyridine.
(12.44 mmol) was added, and then 0.58 ml (8.28 mmol) of acetyl chloride purified by distillation was slowly added dropwise, followed by stirring at room temperature for 4 hours. 3 ml of water was added to the reaction solution, and the mixture was extracted 5 times with 3 ml of methylene chloride. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off, followed by column chromatography (Merck silica gel 30
g, developing solvent: ethyl acetate),
(N, N-Dimethylcarbamoylmethyl) -3-cyclopenten-1-ol acetate [2-1] 706 mg
(Yield 80.7%) was obtained. Spectral data IR (cm ^-1 , neat): 1740 (-CO-N), 1650
(CH ₃ -CO-) ¹ H NMR (60 MHz, δ, CCl ₄ ): 1.96 (3H,
s), 2.10-2.57 (2H, m), 2.58-2.86 (3H, m), 5.27-5.56 (1
H, m), 5.59-5.83 (2H, m),

Example 3 700 mg of the compound [2-1] obtained above in a reactor
(3.32 mmol), lipase (lipase Amano A1
2) 700 mg and 0.1 M phosphate buffer (pH 7.
2) 20 ml was charged, and the mixture was stirred in a constant temperature bath at 35 ° C. for 7 hours. The reaction solution was extracted 10 times with 10 ml of ethyl acetate, the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off, followed by column chromatography (Merck silica gel 30).
g, developing solvent; n-hexane: ethyl acetate = 2: 1 to)
And purified by (+)-2- (N, N-dimethylcarbamoylmethyl) -3-cyclopenten-1-ol [1-1] 253 mg (yield 45.2%, optical rotation [α] _D = + 5). .70 ° (c = 2.41, CHCl ₃ ), optical yield 26% ee} and (−)-2- (N, N-dimethylcarbamoylmethyl) -3-cyclopenten-1-ol acetate [3-1] 176 mg {Yield 25.1%, optical rotation [α] _D = −44.2 ° (c = 2.26, CHCl ₃ ), optical yield 77% ee} were obtained.

Example 4 To a reactor was charged 50 mg of the compound [1-1] obtained above, 1 ml of water and 3 ml of dichloromethane, 0.1 ml of 60% perchloric acid was added with vigorous stirring, and then the mixture was stirred for 2 hours. .. The reaction solution was neutralized with aqueous sodium hydrogen carbonate, extracted 3 times with 3 ml of dichloromethane, and the organic layers were combined and washed with water.
Concentrated and optically active lactone [8] 20 mg {yield 68
%, Optical rotation [α] _D = + 21 ° (CHCl ₃ )} was obtained.

Examples 5 to 6 Example 3 except for the type and amount of lipase and the reaction time.
The same experiment was performed and the results shown in Table 1 were obtained. Table 1

Example 7 An optically active lactone [8] was prepared in the same manner as in Example 4 except that the compound [1-1] obtained in Example 6 was used.
{Yield 78%, optical rotation [α] = + 94 ° (c = 1.4, methanol)} was obtained.

Claims (7)

[Claims] 1. A general formula [1] (In the formula, R ₁ represents an amino group which may be substituted with an alkyl group, and * represents an asymmetric carbon atom.) An optically active cyclopentene alcohol. 2. A general formula [2] (In the formula, R ₁ represents the same meaning as described above, and R ₂ represents an alkyl group.)
A process for producing an optically active cyclopentene alcohol represented by the general formula [1], which comprises allowing an esterase having the ability to selectively hydrolyze only one of the optical isomers of the compound to act. 3. A cyclopentene ester represented by the general formula [2] has the general formula [4] (In the formula, R ₁ has the same meaning as described above.) The cyclopentene alcohol represented by the general formula [5] R ₂ COOH [5] (in the formula, R ₂ has the same meaning as described above). 3.) The method according to claim 2, which is obtained by reacting with a carboxylic acid or a derivative thereof. 4. A cyclopentene alcohol represented by the general formula [4] has the formula [6] A lactone represented by the formula [7] HR ₁ [7] (in the formula, R ₁ has the same meaning as described above), and is obtained by reacting the lactone. The method according to claim 3, wherein 5. An optically active cyclopentene alcohol represented by the general formula [1] is reacted in the presence of a catalyst. (In the formula, * indicates the same meaning as described above.) A process for producing an optically active lactone. 6. A general formula [2] (In the formula, R ₁ and R ₂ have the same meanings as described above.) A cyclopentene ester. 7. A general formula [9] (In the formula, R ₁ , R ₂ and * have the same meanings as described above.) An optically active cyclopentene ester.