JP3024299B2 - Optically active cyclopentene alcohols, production method thereof and use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to optically active cyclopentene alcohols useful as pharmaceuticals and agricultural chemicals, particularly as prostaglandin intermediates, a process for producing the same, and uses thereof.

[0002]

[Prior Art] Equation [8] (In the formula, an asterisk represents an asymmetric carbon.) The optically active lactone represented by is an important intermediate of prostaglandins. A method for producing the optically active lactones using microorganisms or enzymes is described in J. Chem. Soc., Chem. Commun.,
1976, 189, J. Am. Chem. Soc., 99, 1625 (1977), J.
Chem. Soc., Chem. Commun., 1979, 908, etc. are known, but none of them are satisfactory because the synthesis of the raw material is difficult or the operation in production is complicated.

[0003]

The present inventors have conducted various studies on a process for producing an optically active lactone, and as a result, have found an optically active cyclopentene alcohol which is important as a key intermediate of the compound. By performing a ring closing reaction using optically active cyclopentene alcohols, an optically active lactone can be easily obtained, and further, a method for industrially and advantageously producing optically active cyclopentene alcohols has been found. The present invention has been reached.

[0004]

That is, the present invention provides a compound represented by the general formula [1]: (Wherein, 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 Is reacted in the presence of a catalyst to produce an optically active lactone represented by the formula [8]. Hereinafter, the present invention will be described in detail.

Optically active cyclopenes 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, methylpropyl
And amino group, ethylpropylamino group and the like.
it can.

The optically active cyclopentene alcohols [1] have the general formula [2] (Wherein, R ₁ represents the same meaning as described above, and R ₂ represents an alkyl group.)
The compound 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 the present reaction means esterase in a broad sense including lipase. Among them, lipase is preferred. In this reaction, enzymes obtained from animals, plants, and microorganisms are used as the esterase, and the forms of use include purified enzymes, crude enzymes, enzyme-containing substances, microbial cultures, cultures, cells, and culture broths. Alternatively, they can be used in various forms, such as those obtained by treating them, as required, and a combination of an enzyme and a microorganism can also be used. Alternatively, it can also be used as an immobilized enzyme immobilized on a resin or the like, or an immobilized cell.

[0008] Microorganisms producing esterase include:
The microorganism is not particularly limited as long as it is a microorganism that produces an esterase having the ability to selectively hydrolyze only one of the optical isomers of cyclonthene 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,
Microorganisms belonging to the genera Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureopacidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter are exemplified.

The cultivation of the above microorganisms is usually carried out according to a conventional method. For example, a culture solution can be obtained by liquid culture. For example, a sterilized liquid medium [malt extract / yeast extract medium (for 1 l of water) for molds and yeasts]
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). For bacteria, a sweetened broth medium (10 g of glucose, 5 g of peptone, 5 g of meat extract, 3 g of NaCl is dissolved in 1 liter of water, and p
H7.2)), and inoculate with microorganisms, usually 20 to 40
The culture is performed by reciprocating shaking culture at 1 ° C. for 1 to 3 days, and solid culture may be performed if necessary.

[0010] Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, lipases of the genus Pseudomonas (Lipase Amano P and Lipase Amano PS (both manufactured by Amano Pharmaceutical)), lipases of the genus Aspergillus (Lipase Amano AP and Lipase Amano A12 (both manufactured by Amano Pharmaceutical)), mucor Lipase [Lipase Amano M-AP (manufactured by Amano Pharmaceutical)],
Lipase of Candida Sylindrasse [Lipase M
Y (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (manufactured by Meito Sangyo)], lipase of the genus Arthrobacter [lipase joint BSL (Joint Sake Purification)], Lipase of the genus Chromobacterium (Toyo Brewery), Lipase of Rhizopus delemar (Talipase (manufactured by Tanabe Seiyaku)), Lipase of the genus Rhizopus [Lipase Saiken (Osaka Bacteria Research Institute)], etc. And animals,
Plant esterases can also be used, and specific examples of these esterases include stearpsin, pancreatin, pig liver esterase, and Wheat Germ esterase.

This reaction is carried out using cyclopentene esters [2]
The mixture is usually stirred vigorously in a buffer solution. Examples of the buffer include a commonly used buffer of an inorganic acid salt such as sodium phosphate and potassium phosphate, and a buffer of an organic acid salt such as sodium acetate and sodium citrate. PH 8 to 11 for a culture solution or an alkaline esterase, and pH for a culture solution of a non-alkaliphilic microorganism or an esterase having no alkali resistance.
5 to 8 are preferred. The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 0.5 to 70 hours, but is not limited thereto. In addition, at the time of asymmetric hydrolysis, an organic solvent inert to the reaction, such as toluene, chloroform, methyl isobutyl ketone, or dichloromethane, can be used in addition to the buffer solution.

According to 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]. General formula [3] which is the other optically active substance of cyclopentene esters [2] (In the formula, R ₁ and R ₂ have the same meanings as described above, and the symbol # represents an asymmetric carbon having a configuration opposite to that of the symbol *.) Optically active cyclopentene esters represented by It will remain as it is. After completion of the reaction, the reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether or the like, and the solvent is distilled off from the organic layer. Active cyclopentene alcohols [1] and optically active cyclopentene esters [3] can be separated and purified.

The optically active cyclopentene ester [3] obtained here is further hydrolyzed if necessary, and the optically active cyclopentene alcohol [1] obtained above is different from the enantiomerically active optically active cyclopentene ester [3]. It can be alcohols.

The above-mentioned cyclopentene esters [2]
Is represented by the general formula [4] (Wherein, R ₁ has the same meaning as described above), and a cyclopentene alcohol represented by the general formula [5] R ₂ COOH [5] (wherein, R ₂ has the same meaning as described above) in the presence of a catalyst. ) Or a derivative thereof.

In this reaction, examples of the carboxylic acid or a derivative thereof include acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, acid anhydrides thereof, and acid halides such as acid chloride and acid bromide. Can be.

This reaction is carried out in the presence or absence of a solvent. When a solvent is used, the solvent may be, 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, solvents that are inert to the reaction such as an aprotic polar solvent can be mentioned, these alone or Used mixed. The amount used is not particularly limited.

The carboxylic acid or its derivative used in this reaction is required to be at least 1 equivalent to the cyclopentene alcohol [4], and the upper limit is not particularly limited, but is preferably 1 to 6 equivalents, more preferably 4 equivalents.
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 hydrogen carbonate. Further, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can be used as the catalyst. In using such a catalyst, for example, when an acid halide is used as the carboxylic acid or a derivative thereof, pyridine and triethylamine are particularly preferably used as the catalyst. The amount of the catalyst used varies depending on the type of the carboxylic acid or its derivative, the combination of the catalyst, and the like, and is not necessarily specified. For example, when an acid halide is used, one equivalent or more of the acid halide is used.

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 ordinary separation means, for example, operations such as extraction, liquid separation, and concentration, and can be purified by column chromatography or the like, if necessary.

The above-mentioned cyclopentene alcohols [4] are represented by the formula [6] Can be produced by reacting a lactone 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]
Is usually 1 equivalent or more, preferably 1.1 to 50 equivalents, to lactone [6].

In this reaction, a solvent can be used. Such solvents include, for example, 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 as a mixture.

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] are obtained by usual separation means, for example, pH adjustment, extraction, liquid separation, concentration and the like, and can be purified by column chromatography or the like, if necessary.

The lactone [6] is commercially available cis-
It can be produced by a so-called ordinary Bayer-Villiger reaction in which a peracid such as peracetic acid acts on bicyclo [3.2.0] hept-2-en-6-one.

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

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

In this reaction, a solvent is usually used,
Examples of the solvent include water and solvents inert to the reaction of ketones such as acetone, tetrahydrofuran, benzene, toluene, dichloromethane, hexane, heptane, ethers, and hydrocarbons. Used. The amount used is not particularly limited. The reaction temperature is usually from −70 to 150 ° C., but is preferably from −20 to 100 ° C. The reaction time is not particularly limited.

After completion of the reaction, an optically active lactone [8] is obtained in a high yield by ordinary separation means such as extraction, liquid separation, concentration, and distillation. Can 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, and especially prostaglandin intermediates. Yes, the optically active lactone [8] can be produced efficiently and industrially advantageously by the method of the present invention using the optically active cyclopentene alcohol [1].

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of 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 a 90% aqueous acetic acid solution and stirred in an ice bath. 35% while
Hydrogen peroxide solution (60.6 ml) -90% acetic acid aqueous solution (1
(70 ml) was dropped slowly and left in the refrigerator overnight. 600 ml of water and sodium bicarbonate 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 further added to separate an aqueous layer and an organic layer. The aqueous layer was washed with ethyl acetate-hexane (4: 1) 100
The mixture was extracted three times with water, all the 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).
C.), 19.75 g of lactone [6] (yield: 63.
7%). Spectral data IR (neat, cm ^-1 ): 1770 (C = O) ¹ H NMR (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 was placed in a reactor.
(8.516 mmol) and 10 ml of THF were charged, and 20 ml of a 40% aqueous dimethylamine solution (15 ml) was stirred.
9.6 mmol) and then stirred at room temperature for 4 hours. 10% hydrochloric acid was added to the reaction mixture to adjust the pH to about 2, and the mixture was extracted eight times with 30 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, evaporated, and further subjected to column chromatography (Merck silica gel). 40 g, developing solvent: ethyl acetate) to give 2- (N, N-dimethylcarbamoylmethyl) -3-cyclopentene-1
791 mg (yield 55%) of -ol [4-1] 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 was placed in a reactor.
(4.14 mmol) and 15 ml of methylene chloride
Was added and dissolved, and 1517 mg of dimethylaminopyridine was added.
After adding (12.44 mmol), 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 five times with 3 ml of methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and after the solvent was distilled off, column chromatography (Merck silica gel 30).
g, developing solvent: ethyl acetate).
706 mg of (N, N-dimethylcarbamoylmethyl) -3-cyclopenten-1-ol acetate [2-1]
(80.7% yield). 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 was placed 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 stirred for 7 hours in a thermostat at 35 ° C. The reaction solution was extracted 10 times with 10 ml of ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. After distilling off the solvent, column chromatography (Merck silica gel 30) was performed.
g, developing solvent: n-hexane: ethyl acetate = 2: 1)
253 mg of (+)-2- (N, N-dimethylcarbamoylmethyl) -3-cyclopenten-1-ol [1-1] (yield 45.2%, optical rotation [α] _D = + 5). 70 ° (c = 2.41, CHCl ₃ ), optical yield 26% ee and 176 mg of (−)-2- (N, N-dimethylcarbamoylmethyl) -3-cyclopenten-1-ol acetate [3-1] {Yield 25.1%, optical rotation [α] _D = -44.2 ° (c = 2.26, CHCl ₃ ), optical yield 77% ee ”were obtained.

Example 4 A reactor was charged with 50 mg of the compound [1-1] obtained above, 1 ml of water and 3 ml of dichloromethane, and 0.1 ml of 60% perchloric acid was added with vigorous stirring, followed by stirring for 2 hours. . After neutralizing the reaction solution with aqueous sodium bicarbonate, the mixture was extracted three times with 3 ml of dichloromethane, and the combined organic layers were washed with water.
Concentrated to give 20 mg of optically active lactone [8] (yield 68)
%, Optical rotation [α] _D = + 21 ° (CHCl ₃ )}.

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

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

────────────────────────────────────────────────── ─── Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 235/30 C12P 41/00 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. The general formula [1] (Wherein, R ₁ represents an amino group which may be substituted with an alkyl group, and * represents an asymmetric carbon atom). 2. The general formula [2] (Wherein, 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], wherein an esterase having an ability to selectively hydrolyze only one of the optical isomers of the compound is acted on. 3. The cyclopentene ester represented by the general formula [2] is converted to a compound represented by the general formula [4]: (Wherein, R ₁ has the same meaning as described above), and a cyclopentene alcohol represented by the general formula [5] R ₂ COOH [5] (wherein, R ₂ has the same meaning as described above) in the presence of a catalyst. The method according to claim 2, which is obtained by reacting with a carboxylic acid represented by the formula (1) or a derivative thereof. 4. The cyclopentene alcohol represented by the general formula [4] is a compound represented by the formula [6] Is obtained by reacting a lactone represented by the formula with an amine represented by the general formula [7] HR ₁ [7] (wherein R ₁ has the same meaning as described above). The method according to claim 3, wherein 5. A compound of the formula [8] characterized by reacting an optically active cyclopentene alcohol of the formula [1] in the presence of a catalyst. (Wherein, * represents the same meaning as described above). 6. The general formula [2] (Wherein, R ₁ and R ₂ have the same meanings as described above). 7. The general formula [9] (Wherein, R ₁ , R ₂ and * mark have the same meanings as described above).