JPH0575395B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to a method for producing optically active propargyl alcohol derivatives. Prior Art For the resolution of racemates, a diastereomer method using an optically active resolving reagent is generally used industrially. However, depending on the type of resolving reagent, the number of racemates that form diastereomers is limited.
The development of resolution reagents with various optical activities is desired. A part of the present inventors conducted research with the aim of discovering new optically active compounds, and as a result, a new optically active propargyl alcohol represented by the following general formula () was discovered in its racemic form. l
- It was discovered that it could be optically resolved and produced by contacting it with brucine, and a patent application was filed earlier as Japanese Patent Application No. 57-33011. He discovered that it could also be produced by bringing it into contact with l-sparteine in a solvent, separating the diastereomers obtained by utilizing the difference in solubility, and then decomposing the diastereomers. -A patent application was filed as No. 164969.

[Chemical formula] (In the formula, R represents an alkyl group, a phenyl group, a phenyl group substituted with a halogen atom or an alkyl group, or a naphthyl group.) Object and structure of the invention The present inventors further conducted research and found that the formula To achieve the objective by esterifying the racemic form of the phenylpropargyl alcohol derivative () and asymmetrically hydrolyzing this in the presence of a microorganism belonging to the genus Rhodotorula that has the ability to asymmetrically hydrolyze the racemic form. The inventors have discovered that optically active phenylpropargyl alcohol derivatives can be obtained, leading to the present invention. That is, according to the present invention, the general formula ()

[Formula, R is an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a halogen atom, or
a phenyl group substituted with an alkyl group of 3 or a naphthyl group, and R' represents an alkyl group having 1 to 4 carbon atoms. General formula () characterized by asymmetric hydrolysis in the presence of microbial cells belonging to the genus Rhodotorula that have decomposition ability

A method for making an optically active phenylpropargyl alcohol derivative is provided, where R is as defined above. DETAILED DESCRIPTION OF THE INVENTION The racemic form of the phenylpropargyl alcohol derivative of the general formula () used as a starting material in the present invention is obtained when R in the formula () is an o-chlorophenyl group and R' is a methyl group (O-acetyl −
Taking o-chlorophenylpropargyl alcohol as an example, it can be synthesized from the corresponding ketone as follows. i.e. 1500 ml of liquid ammonia held at approximately -35°C.
After adding 80 g of sodium metal to the solution, acetylene gas was blown in at a rate of 1000 ml/min for 120 minutes.
Add 500 g of o-chlorobenzophenone to the obtained liquid ammonia solution containing sodium acetylide,
After carrying out the reaction at about -35°C for 120 minutes, the reaction solution is brought to room temperature and the ammonia gas is evaporated. Next, hydrolysis treatment is performed and distillation is performed to reduce the boiling point to 154 ~
1-o-chlorophenyl- with 7℃/1mHg
Racemic form of 1-phenylpropargyl alcohol
Obtain 495g. Take 20g of this and dissolve it in 200ml of benzene.
3.6 g of sodium hydride is added to this solution, and after the evolution of hydrogen has stopped, 7 g of acetic acid chloride dissolved in 100 ml of anhydrous benzene is added dropwise with stirring. After completing the dropwise addition, react with benzene at reflux temperature for 24 hours.
After treatment with acid, the benzene layer is dried, the solvent is removed and the residue is washed with petroleum ether. 15 g of white crystals are thus obtained. When this is recrystallized from ethyl alcohol, O with a melting point of 114-115℃ is
A racemic form of -acetyl-o-chlorophenylpropargyl alcohol is obtained. O-acetyl-o synthesized according to the above synthesis example
- A racemic form of a chlorophenylpropargyl alcohol derivative (hereinafter referred to as an O-acetyl monoacetylene alcohol derivative) is then prepared by using a microorganism belonging to the genus Rhodotorula that has the ability to asymmetrically hydrolyze the racemic form. A l-monoacetylene alcohol derivative can be obtained in high yield and with high optical purity by asymmetric hydrolysis of only the handed body. The microorganism used in this case has esterase activity that asymmetrically hydrolyzes O-acetylmonoacetylene alcohol derivatives, has strong resistance to the organic solvents shown below, and has a high asymmetric hydrolysis yield. The above-mentioned strain belonging to the genus Rhodotorula is used in consideration of the optical purity of the optically active monoacetylene alcohol derivative obtained. Specific examples of such strains are as follows. (1) Bacillus genus Bacillus sphaericus (IFO3528) Bacillus coagulans (IFO3886) (2) Rhodotorula genus Rhodotorula minuta (IFO0387) Rhodotorula lactosa (IFO1058) Rhodotorula pallida (IFO0715) All of the above strains are known. It is readily available through preservation institutions such as the Fermentation Research Institute. In the present invention, these microbial cells are d1-
As a method for acting on a monoacetylene alcohol derivative, a culture cultured in a liquid medium as shown in Example 1, or bacterial cells isolated from a culture solution, or a processed product thereof, such as a crude enzyme, a purified enzyme, or an enzyme-containing extract solution, can be used. It can also be used in the form of immobilized bacteria, bacteria, or enzymes on a carrier. Useful carriers include natural products such as alginic acid, carrageenan, collagen, cellulose, acetylcellulose, agar, cellophane, and collodion, or polymeric substances such as polyacrylamide, polystyrene, polyethylene glycol, polypropylene glycol, polyurethane, and polybutadiene. can be mentioned. Immobilization can be carried out according to conventional methods under mild conditions that do not impair esterase activity. Next, the asymmetric hydrolysis reaction conditions will be explained in detail using the d1-O-acetylmonoacetylene monoalcohol derivative as an example. d1-O-acetylmonoacetylene alcohol is dissolved in an organic solvent at a concentration of 0.1-10% by weight.
As an organic solvent, it does not impair esterase activity.
There is no particular limitation as long as the solvent dissolves d1-O-acetylmonoacetylene alcohol, but preferably pentane, hexane, heptane, octane,
Nonpolar solvents such as benzene, toluene, and carbon tetrachloride are preferred, and among these, pentane, hexane, heptane, and octane are particularly preferred. These organic solvents may be used alone or in a water-organic solvent two-layer suspension system, but when used alone, it is preferable to use one saturated with water. Further, when using a water-organic solvent two-layer system, it is preferable to use the water and organic solvent at a volume ratio of 1:1 to 1:5. The appropriate amount of bacterial cells to be used is a weight ratio of 0.1 to 10, calculated from the dry bacterial weight to d1-O-acetylmonoacetylene monoalcohol, and preferably
It is best to use a weight ratio of 0.1 to 2. reaction is 30
The reaction time is 10 to 50 hours. The reaction is carried out under stirring or shaking, and is carried out in a closed container to prevent the solvent from evaporating during the reaction. After the reaction, the microbial cells are centrifuged, and in the case of an organic solvent only system, the solvent is dried using Glauber's salt, or in the case of an organic solvent-water two-layer suspension system, the water and organic layers are separated and the organic After drying the layer with Glauber's salt, the solvent is removed. Dissolve the remaining liquid substance in chloroform and use a column chromatograph to remove l
- Separate into monoacetylene alcohol derivative and d-O-acetyl monoacetylene alcohol derivative. The developing solvent at that time may be arbitrarily selected depending on the substituent of R shown in the general formula (). The optically active monoacetylene alcohol thus obtained has an optical purity of 100% regardless of the substituent group of R. The optically active propargyl alcohol derivative obtained by the present invention can be used as a resolution reagent for various racemates,
Or starting raw materials for pharmaceuticals, pesticides, fragrances, etc.
It has many uses. Examples Examples of the present invention will be described below, but it goes without saying that the present invention is not limited to these examples. Example 1 In a flask with a shoulder, 1% by weight of molasses, 2.5% by weight of corn steep liquor, 0.5% by weight of ammonium sulfate, and a mixed solution of inorganic salts (20g of MgSO ₄ 7H ₂ O,
FeSO ₄・7H ₂ O5g, CaCl ₂ 2g, MnCl ₂・4H ₂ O0.2
After sterilizing 100 ml of medium (PH7.0) containing 1) 1 ml of distilled water containing 0.1 g of NaMoO ₄ 2H ₂ O and 0.1 g of NaCl, Rhodotorula minuta (IFO-
0378) was inoculated from a slant medium with two platinum loops and incubated at 30℃ for 94 hours.
Culture was performed with back and forth shaking for hours. The bacterial cells collected from this culture solution by centrifugation were washed twice with distilled water to obtain washed bacterial cells. This was further freeze-dried to obtain freeze-dried bacterial cells. 50 mg of this freeze-dried bacterial cell was suspended in 20 ml of water (PH7.0) and 0.5% by weight of O-acetyl-1-o-chlorophenyl-1-phenylpropargyl alcohol (synthesized according to the above method) was added to the n- The mixture was mixed and suspended with 100 ml of heptane solution, and reacted at 30° C. with stirring for 48 hours. The bacterial cells were separated from the reaction solution, the aqueous layer and the n-heptane layer were separated, and the n-heptane layer was dried with Glauber's salt, and then the n-heptane was removed. The remaining crystals were subjected to column chromatography using Wakogel C-300 and developed with chloroform to separate the hydrolysis product 1-o-chlorophenyl-1-phenylpropargyl alcohol and the unreacted O-acetyl derivative. . The former [α] ²⁵ _D (CH ₃ OH1%)
The temperature was −129°, and the yield was 68%. Examples 2 to 6 Various optically active phenylpropargyl alcohols having different R in the general formula () were synthesized by asymmetric hydrolysis in the same manner as in Example 1. The results obtained are shown in the table below.

【table】

【table】

Claims (1)

[Claims] 1 General formula () [Chemical formula] (wherein, R is an alkyl group having 1 to 5 carbon atoms, a phenyl group, or a halogen atom, or a halogen atom having 1 to 5 carbon atoms)
a phenyl group substituted with an alkyl group of 3 or a naphthyl group, and R' represents an alkyl group having 1 to 4 carbon atoms. An optically active phenyl of the general formula () [Chemical formula] (wherein R is as defined above), which is characterized by being asymmetrically hydrolyzed in the presence of a microbial cell belonging to the genus Rhodotorula having a chiral hydrolyzing ability. Method for producing propargyl alcohol derivatives.