JPH0579656B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing optically active cyclopentenolones, and more specifically, the present invention relates to a method for producing optically active cyclopentenolones, and more specifically, the present invention relates to a method for producing optically active cyclopentenolones.

embedded image In the formula, * represents an asymmetric carbon, R ₁ represents a lower alkyl group, and R ₂ represents a lower alkenyl group or a lower alkynyl group. The present invention relates to a method for producing optically active cyclopentenolones shown in the following. Cyclopentenolones represented by the above general formula () are known as important alcohol components of a group of carboxylic acid ester compounds called synthetic pyrethroids, which have excellent insecticidal activity. Since cyclopentenolone has an asymmetric carbon at the 4-position, two types of optical isomers exist, and the insecticidal activity as a carboxylic acid ester of these cyclopentenolone is usually determined by the racemic (S)-isomer. body or (R)-
It is also known that it is several times better than the body (for example, Matsuo et al., Pestic Sci., 11 , 202
(1980)). Therefore, it is desired to develop a method for producing the (S)-isomer cyclopentenolone represented by the above general formula (), and as such a method, the racemic form of the cyclopentenolone is mixed with phthalic acid. As a half ester, a method of resolution using an optically active amine (for example, JP-A-56-2929) or a racemic form of the cyclopentenolone as an organic carboxylic acid ester,
Biochemical optical resolution method using esterase (Japanese Unexamined Patent Publication Nos. 58-31994 and 58-47495)
etc. are known. However, in all of these methods, along with the target (S)-isomer cyclopentenolones, almost the same amount of the enantiomer, that is, the (R)-isomer or cyclopentenolones enriched therein, is produced. It turns out. As mentioned above, the (R)-isomer or cyclopentenolone enriched in it has inferior activity as an ester compared to the corresponding (S)-isomer or cyclopentenolone enriched in it, or the racemic compound, and is particularly difficult to use in industrial applications. In carrying out optical resolution on a large scale, the amount of optical resolution is extremely large, so in order to utilize the optical resolution technology as described above more effectively industrially, it is necessary to use these (R)-isomers or their There is a need for a technique to effectively utilize abundant cyclopentenolone in some way. Furthermore, in these methods, in order to obtain each optically active substance with high purity and good yield, efficient separation techniques are required, and such separation operations are particularly difficult when carried out on an industrial scale. is often an extremely important process, and is often subject to various restrictions from the economical and equipment standpoints. Among the optical separation methods described above, the optical resolution method using esterase separates optically active cyclopentenolones of high optical purity and the carboxone of optically active cyclopentenolone having the opposite absolute configuration to that of the cyclopentenolone. It is an extremely excellent optical resolution method for cyclopentenolones in terms of optical purity, but this method also separates the resulting optically active cyclopentenolones and the cyclopentenolones. A precise separation operation such as silica gel column chromatography is required for a mixture of optically active cyclopentenolone carboxylic acid esters having an absolute configuration opposite to that of pentenolone. Under these circumstances, the present inventors investigated various methods for producing optically active cyclopentenolones represented by the general formula (), and found that the sulfones of optically active cyclopentenolones were By hydrolyzing a mixture of an acid ester and a carboxylic ester of a cyclopentenolone having the opposite absolute configuration to that of the sulfonate ester under acidic conditions, the sulfonate ester can be obtained by inverting its asymmetric center. The carboxylic acid ester can be converted into an optically active cyclopentenolone while maintaining its asymmetric center, and thus the cyclopentenolone having one absolute configuration can be converted into an optically active cyclopentenolone. In addition, we have found that such a method, especially in combination with the above-mentioned optical resolution method using esterase, is an extremely advantageous method for producing optically active cyclopentenolones represented by the general formula (). The present inventors discovered that the present invention was completed. That is, the present invention is based on the general formula ()

embedded image In the formula, *, R ₁ and R ₂ have the same meanings as above, and X represents a lower alkyl group or a phenyl group which may have a methyl group at the para position. An optically active sulfonic acid ester represented by and a general formula () having an absolute configuration opposite to that of the sulfonic acid ester

[In the formula, *, R ₁ and R ₂ have the same meanings as above, and R ₃ represents a lower alkyl group. ] Optical activity represented by the general formula () having the opposite absolute configuration to that of the sulfonic acid ester represented by the above general formula () by hydrolyzing a mixture with a carboxylic acid ester represented by the above under acidic conditions. The present invention provides a method for producing cyclopentenolone. In the method of the present invention, an optically active sulfonic acid ester represented by the general formula () as a raw material, and an optically active carboxylic acid ester represented by the general formula () having an opposite absolute configuration to that of the sulfonic acid ester. The mixture has the general formula ()

[In the formula, R ₁ and R ₂ have the same meanings as above. ] General formula derived from cyclopentenolones ()

[In the formula, R ₁ , R ₂ and R ₃ have the same meanings as above. ] The general formula () obtained by asymmetric hydrolysis of the carboxylic acid ester shown by the action of an esterase produced by a microorganism or an animal pancreatic esterase.

[In the formula, *, R ₁ and R ₂ have the same meanings as above. ] An optically active cyclopentenolone represented by
A mixture with a carboxylic acid ester represented by the general formula () having the opposite absolute configuration to the cyclopentenolone is added with the general formula () X-SO ₂ -Y () [wherein, X is the same as above] Y represents a halogen atom. ] It can be easily obtained by reacting with the sulfonic acid halide shown below. Therefore, according to the method of the present invention, optically active cyclopentenolones obtained by an optical resolution method using esterase and carboxylic acid esters having an absolute configuration opposite to that of the cyclopentenolones can be separated without separating them. , all of which can be led to cyclopentenolones with one absolute configuration,
As a result, all of the cyclopentenolones represented by the general formula () can be converted into one optically active form without requiring any separation operation. An example of the above process is schematically shown as follows.

[ka]

[In the formula, *, R ₁ , R ₂ , R ₃ , X and Y have the same meanings as above. ] As described above, according to the method of the present invention, for example, the (R)-isomer or the general formula (
The cyclopentenolone represented by is not only converted into a racemate without separation, but also
It is extremely efficient because it is directly converted to the more useful (S)-isomer or cyclopentenolones enriched in it, represented by the general formula ( Together with this, the (S)-isomer cyclopentenolone represented by the general formula () can be produced extremely advantageously on an industrial scale. The present invention will be explained in detail below. In the method of the present invention, a mixture of an optically active sulfonic acid ester represented by the general formula () and an optically active carboxylic acid ester represented by the general formula () having an opposite absolute configuration to that of the sulfonic acid ester is hydrated. When decomposing, the reaction is usually carried out at a temperature in the range of 20 to 100°C, but in view of the time required for the reaction, a range of 70 to 100°C is more preferable. Furthermore, although the hydrolysis reaction is carried out under acidic conditions, the use of acid is not essential, and the sulfonic acid by-produced by the hydrolysis of the sulfonic acid ester in the mixture causes the hydrolysis reaction to take place under acidic conditions. Since the liquid condition is acidic, the hydrolysis reaction of the carboxylic acid ester in the mixture can proceed efficiently without using a new acid. However, in order to capture a part of the sulfonic acid by-produced during the hydrolysis reaction, the reaction can also be carried out in the presence of an alkaline earth metal carbonate in an amount of 1 equivalent or less relative to the sulfonic acid ester contained. Examples of carbonates include calcium carbonate and barium carbonate. In the hydrolysis reaction, it is not essential to use an organic solvent other than water, but if necessary, for example, alicyclic ethers such as tetrahydrofuran and dioxane, lower aliphatic ketones such as acetone and methyl ethyl ketone, dimethyl formamide,
Organic solvents that are mutually soluble in water, such as aprotic polar solvents such as dimethyl sulfoxide, can also be used in combination. In addition, an appropriate buffer can be used to keep the hydrolysis conditions acidic and stable. After hydrolyzing the reaction solution as described above,
After concentration if necessary, the desired optically active cyclopentenolone can be easily obtained by conventional means such as extraction with an organic solvent. Further, a mixture of an optically active cyclopentenolone represented by the general formula () and an optically active carboxylic acid ester represented by the general formula () having the opposite absolute configuration to that of the cyclopentenolone can be prepared by the general formula Typical examples of the sulfonic acid halide represented by the general formula () used to produce a mixture of the optically active sulfonic acid ester represented by () and the optically active carboxylic acid ester represented by the above general formula () include Examples include methanesulfonic acid halide and p-toluenesulfonic acid halide, and methanesulfonic acid chloride and p-toluenesulfonic acid chloride are usually used from the viewpoint of easy availability. The amount of these sulfonic acid halides to be used is not particularly limited and may be 1 mol or more per 1 mol of optically active cyclopentenolone as a raw material, but usually 1 to 1.2 mol is sufficient to achieve the purpose. Ru. In addition, it is preferable that the reaction is carried out in the presence of a trialkylamine as a dehydrohalogenating agent. Such a trialkylamine includes triethylamine, and the amount used is 1 mole of the commonly used sulfonic acid halide. The amount is 1 to 1.5 mol. The above reaction is usually carried out in an inert organic solvent, and examples of such solvents include lower aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethyl Ethers such as ether, isopropyl ether, and tetrahydrofuran, dichloromethane, dichloroethane,
Examples include halogenated hydrocarbons such as carbon tetrachloride, and mixed solvents thereof. Moreover, the reaction temperature is usually carried out in the range of -40°C to 30°C. Furthermore, an esterase is applied to the carboxylic acid ester represented by the general formula (), and the esterase is combined with an optically active cyclopentenolone represented by the general formula () and the cyclopentenolone having the opposite absolute configuration to that of the cyclopentenolone. When asymmetrically hydrolyzing the carboxylic acid ester represented by the general formula (), the microorganism that produces the esterase used during the hydrolysis asymmetrically hydrolyzes the carboxylic acid ester represented by the general formula (). Any microorganism may be used as long as it can produce an esterase having the ability, and is not particularly limited (here, esterase means esterase in a broad sense including lipase).
Specific examples of such microorganisms include Enterobacter, Arthrobacter, Previbacterium, Pseudomonas, Alcaligenes,
Flavobacterium, Micrococcus, Chromobacterium, Mycobacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candeida, Satucharomyces, Rhodotorula, Cryptococcus,
Examples include microorganisms belonging to the genus Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, and Streptomyces. Representative strain names belonging to each of these genera are illustrated below.

【table】

[Table] All of these strains are American Type.
It is preserved at the Culture Collection (ATCC), the Department of Fermentation Engineering, Faculty of Engineering, Osaka University (OUT), or the Institute for Fermentation (IFO) in Osaka City, and can be obtained from these institutions. For culturing the above-mentioned microorganisms, a culture solution is usually obtained by performing liquid culture according to a conventional method. For example, a sterilized liquid medium [malt extract/yeast extract medium for molds and yeasts (5.0 g of peptone in 1 part water,
Dissolve 10.0g of glucose, 3.0g of malt extract, and 3.0g of yeast extract to adjust pH to 6.5). For bacteria, use sweetened bouillon medium (10.0g of glucose in 1 part of water,
Dissolve 5.0 g of peptone, 5.0 g of meat extract, and 3.0 g of NaC to give a pH of 7.2)] and inoculate it with microorganisms.
Carry out reciprocal shaking culture at 40°C for 1 to 3 days. Further, solid culture may be performed as necessary. In the present invention, among the above microorganisms, Enterobacter, Arthrobacter, Plevibacterium, Pseudomonas, Alkalinecenes, Chromobacterium, Mycobacterium, Bacillus, Trichoderma, Candeida, Rhodotorula Microorganisms belonging to the genera Torulopsis, Aspergillus, Rhizopus, Mucor, Nocardia, and Streptomyces are particularly preferred in terms of esterase activity and asymmetric yield. Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include Pseudomonas lipase (manufactured by Amano Pharmaceutical);
Aspergillus lipase (Lipase AP (Amano Pharmaceutical)), Mucor lipase M-AP (Amano Pharmaceutical)), Candida cylindrace lipase (Lipase MY (Meito Sangyo)), Alcaligenes lipase (Lipase PL (Meito Sangyo Co., Ltd.)), Achromobacter lipase (Lopase AL (Meito Sangyo Co., Ltd.)), Arthrobacter lipase (Lipase Joint BSL (Joint Sake Refining)), Chromobacterium lipase ( Examples include lipase of Rhizopus deremer (Talipase (manufactured by Tanabe Seiyaku)), and lipase of Rhizopus (Lipase Saiken (Osaka Bacteria Research Institute)). Furthermore, stearpsin and pancreatin can be used as animal pancreatic esterase. The asymmetric hydrolysis of this step is carried out using a culture solution in which the above-mentioned microorganisms are cultured, bacterial cells isolated from the culture solution, a culture solution containing esterase, or crude esterase isolated from the bacterial cells or culture solution by various enzyme separation methods. This is carried out by mixing a purified esterase and an esterase-containing extract or concentrate, or an aqueous solution containing animal pancreatic esterase with a carboxylic acid ester represented by the general formula (), and stirring or shaking the mixture. Furthermore, immobilized bacterial cells or immobilized esterase can also be used. At this time, the appropriate reaction temperature for asymmetric hydrolysis is 10 to 70°C, and in the case of a thermophilic bacteria culture solution or a thermostable esterase obtained by culturing thermophilic bacteria, the temperature is 50 to 65°C. culture solution or 20 to 50℃ for esterases that are not particularly thermostable.
is preferred. The reaction time is usually 3 to 48 hours, but the reaction time can be shortened by raising the reaction temperature or increasing the amount of enzyme. The pH during the reaction is preferably 8 to 11 for a culture solution of an alkalophilic microorganism or an alkaline esterase, and 5 to 8 for a culture solution of a microorganism that is not an alkaliphile or an esterase that does not have alkali resistance. It also neutralizes organic carboxylic acids produced by hydrolysis,
In order to keep the pH constant during the reaction, it is preferable to use a buffer; use an inorganic acid salt buffer such as sodium phosphate or potassium phosphate, or an organic acid salt buffer such as sodium acetate or sodium citrate. be able to. The concentration of the carboxylic acid ester represented by the general formula (), which is the substrate, is 1 to 50 wt% based on the reaction solution.
and preferably 5 to 25 wt%. The carboxylic acid ester represented by the general formula () used here can be produced by a conventional method for ester production, for example, a method in which a cyclopentenolone represented by the general formula () is reacted with an anhydride of an organic carboxylic acid. Alternatively, it can be easily produced by reacting an organic carboxylic acid chloride in the presence of an organic base. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. In the following examples, chemical purity was determined by gas chromatography and (R)- and (S)-
The optical isomer ratio of the compound is a value determined by high performance liquid chromatography using an optically active stationary phase after derivatization with N-3,5-dinitrophenyl carbamate. Example 1 () Asymmetric hydrolysis step 3N sodium hydroxide aqueous solution is added to 250 g of 0.2M monopotassium phosphate aqueous solution to prepare a pH6.5 buffer solution. To this buffer, 3.0 g of Arthrobacter esterase (lipase combination BSL) was added, followed by 98.6 g of racemic 2-methyl-3-(2-propynyl)-4-oxo-2-cyclopenten-1-yl acetate. and stir vigorously at 40°C for 17 hours while controlling the pH to 6.5±0.2 with a 3N aqueous sodium hydroxide solution. The reaction solution was then extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give (R)-
4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one and (S)-
A mixture of 2-methyl-3-(2-propynyl)-4-oxo-2-cyclopenten-1-yl acetate, each containing 46.4% and 51.1%.
It is. ) 79.37g was obtained. In addition, by separating a part of the above mixture by silica gel column chromatography,
(R)-4-hydroxy-3-methyl-2-(2-
propynyl)-2-cyclopenten-1-one ([α] ²³ _D ; -19.5° (c = 1.42, chloroform),
(R)-body/(S)-body=94.8/5.2) and (S)-2
-Methyl-3-(2-propynyl)-4-oxo-
2-cyclopenten-1-yl acetate ([α] ²³ _D ; +39.4° (c = 1.25, chloroform),
(R)-isomer/(S)-isomer = 1.0/99.0) was obtained. () Sulfonic acid esterification step Add 1.5 g of the mixture obtained in () to 3 g of acetone.
Add 0.65 g of triethylamine to the solution dissolved in -
A solution of 0.62 g of methanesulfonic acid chloride dissolved in 2 g of acetone was added at -15 to 0°C.
Add dropwise over 10 minutes at 0°C. After stirring at the same temperature for 1 hour and 30 minutes, the reaction solution was poured into 30 ml of 1% hydrochloric acid solution and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated.
(R)-2-methyl-3-(2-propynyl)-4-
Oxo-2-cyclopenten-1-yl methanesulfonate and (S)-2-methyl-3-(2-propynyl)-4-oxo-2-cyclopentene-1
1.80 g of a mixture of -yl acetate was obtained. () Hydrolysis Step Add 0.09 g of calcium carbonate and 10 ml of water to 1.80 g of the mixture obtained in () and heat under reflux for 1 hour and 30 minutes. The reaction mixture was cooled, poured into 5% aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated.
(S)-4-hydroxy-3-methyl-2-(2-
propynyl)-2-cyclopenten-1-one
1.20g (chemical purity; 96.4%, [α] ^23D ; +19.2° ₍ c
=
1.14, chloroform), (R)-form/(S)-form =
5.6/94.4). The product is characterized by racemic 4-hydroxy-3 in R, NMR spectra and retention time properties by gas chromatography, with the exception of photochromatability.
-Methyl-2-(2-propynyl)-2-cyclopenten-1-one. Example 2 () Asymmetric hydrolysis step A 3N aqueous sodium hydroxide solution is added to 125 g of a 0.2M aqueous potassium phosphate solution to prepare a buffer solution with a pH of 6.5. Add 1.5 g of Arthrobacter esterase (lipase joint BSL) to this buffer,
Then racemic 2-methyl-3-(2-propenyl)-4-oxo-2-cyclopentene-1-
Add 49.8 g of yl acetate, and stir vigorously at 40°C for 17 hours while controlling the pH to 6.5±0.2 with a 3N aqueous sodium hydroxide solution. The reaction solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give (R)-4-hydroxy-3-methyl-2-(2-propenyl)-
2-Cyclopenten-1-one and (S)-2-methyl-3-(2-propenyl)-4-oxo-2-
A mixture of cyclopenten-1-yl acetates (each as determined by gas chromatography analysis)
Contains 44.7% and 55.0%. ) 43.14g was obtained. In addition, when a part of the above mixture is separated by silica gel column chromatography, (R)-4-
Hydroxy-3-methyl-2-(2-propenyl)
-2-cyclopenten-1-one ([α] ²⁵ _D ;-
14.9° (c=1.19, chloroform), (R)-isomer/
(S)-isomer=99.2/0.8) and (S)-2-methyl-3
-(2-propenyl)-4-oxo-2-cyclopenten-1-yl acetate ([α] ²⁵ _D ; +29.8°
(c=1.22, chloroform), (R)-form/(S)-
body = 0/100) was obtained. () Sulfonic acid esterification step Add 1.5 g of the mixture obtained in () to 3 g of acetone.
Add 0.60 g of triethylamine to the solution dissolved in -
A solution of 0.58 g of methanesulfonic acid chloride dissolved in 2 g of acetone was added at -15 to 0°C.
Add dropwise over 15 minutes at 0°C. After stirring at the same temperature for 3 hours, the reaction mixture was poured into 30 ml of 1% hydrochloric acid and extracted with methylene chloride. Wash the methylene chloride layer with water,
After drying with anhydrous magnesium sulfate and concentrating, (R)
-2-Methyl-3-(2-propenyl)-4-oxo-2-cyclopenten-1-yl methanesulfonate and (S)-2-methyl-3-(2-propenyl)-4-oxo-2-cyclopentene 1.92 g of a mixture of -1-yl acetate was obtained. () Hydrolysis Step Add 0.09 g of calcium carbonate and 10 ml of water to 1.92 g of the mixture obtained in () and heat under reflux for 2 hours. The reaction solution was cooled and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give (S)-4-hydroxy-3-methyl-2-
(2-propenyl)-2-cyclopenten-1-one 1.27 g (chemical purity; 85.0%, [α] ²³ _D ; +5.66° (
c.
= 0.92 g, chloroform), (R)-isomer/(S)-isomer = 10.1/89.9) were obtained. The product has . The R, NMR spectrum and retention time characteristics determined by gas chromatography were consistent with racemic 4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one.

Claims (1)

[Claims] 1 General formula (V) [Formula] [In the formula, R ₁ represents a lower alkyl group, R ₂ represents a lower alkenyl group or a lower alkynyl group, and R ₃ represents a lower alkyl group. ] The carboxylic acid ester represented by the formula is reacted with esterase produced by microorganisms or animal pancreatic esterase to asymmetrically hydrolyze it, resulting in the general formula () [Formula] [In the formula, * represents an asymmetric carbon. , R ₁ and R ₂
has the same meaning as above. ] An optically active cyclopentenolone represented by
General formula () having the opposite absolute configuration to that of the cyclopentenolones [Formula] [wherein *, R ₁ , R ₂ and R ₃ have the same meanings as above. [In the formula, X represents a lower _alkyl group or methyl is added to the para position. Represents a phenyl group which may have a group. ] [Formula] [In the formula, *, R ₁ , R ₂ and X are Same meaning as above. ] A mixture of an optically active sulfonic acid ester represented by the formula () and an optically active carboxylic acid ester represented by the general formula () is obtained, and then the mixture is hydrolyzed under acidic conditions. A general formula () having an absolute orientation opposite to that of the cyclopentenolones represented by the above general formula () [Formula] [In the formula, *, R ₁ and R ₂ represent the same meanings as above. ] A method for producing an optically active cyclopentenolone.