JPH05111393A - Production of optically active sulfur-containing compound - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the subject optically active compound useful as an intermediate for medicines, agricultural chemicals, etc., by bringing an enantiomeric mixture of specific aryl thioalcohol compounds into contact with esters in the presence of a hydrolase. CONSTITUTION:An enantiomeric mixture of compounds (e.g. 4-phenylthio-2- butanol) expressed by formula I [R1 is (substituted)aryl] is dissolved in n-hexane- benzene (1:1) and brought into contact with esters (e.g. isopropenyl acetate) expressed by formula II [R2 is H, (substituted)alkyl or (substituted)alkenyl] in the presence of a hydrolase (e.g. a lipase) and reacted while being stirred at ambient temperature for 3 days. The resultant reaction product is subsequently filtration through a glass filter and the organic solvent of the filtrate is distilled away. Reaction is then carried out at 37 deg.C for 28hr. The reaction solution is subsequently extracted with chloroform and the extract is then subjected to silica gel chromatography and purified to afford the objective optically active compound expressed by formula I.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active 4-position substitution-2-
The present invention relates to a method for producing butanol. Optically active
The 4-substituted-2-butanol is highly important as a synthetic intermediate for optically active physiologically active compounds used in medicine and agricultural chemicals.

[0002]

2. Description of the Related Art 4-substituted-2-butanol has one asymmetric carbon in the molecule. The synthesis of optically active 4-arylthio-2-butanol was recently reported (Chem. Lett., 2227.
P. (1987), and J. Chem. Soc. Chemm. Commun., P. 662.
(1991)). Utilization of this compound as an intermediate for the synthesis of an optically active drug such as a carbapenem antibiotic has been investigated (Japanese Patent Laid-Open No. 61-207373), and therefore a method for producing the compound and its derivative with high purity economically was established. Is desired. As a method for producing an optically active compound, a method for obtaining an optically active compound by asymmetric induction, a method for optically resolving a racemic mixture, a method for deriving from an optically active precursor, and the like can be considered. Each method has advantages and disadvantages,
For industrial use, there is a problem that has to be solved due to economical reasons. There is a method of utilizing an enzyme as one of the methods for producing an optically active compound by optically resolving a racemic mixture, and it is considered that if an appropriate enzyme is found, an effective method will be provided, and active use research is recently being conducted. Has become. Among the ester hydrolases, lipases are particularly readily available, so there are many studies (Angew. C
hem. Int. Ed., Vol. 28, p. 695 (1989), Journal of Synthetic Organic Chemistry, Vol. 49, p. 657 (1991), etc.). Although lipase was used for the synthesis of an optically active derivative of butanediol, which is considered to be an analog of glycerin, which is the alcohol component of lipase enzyme substrate, was recently reported (JP-A-2-39898, JP-A-2-39899). There are few examples applied to compounds containing a hetero atom such as sulfur.

[0003]

[Problems to be Solved by the Invention] Optically active 4-position substitution-2
-Evaluation of economical resolution of racemic raw material, which is cheap and easily available for synthesizing butanol, using an enzyme. We have found an enzyme that acts efficiently and stereospecifically on esters of 4-substituted-2-butanol, which has a structure different from that of fatty acid triglyceride, which is the original substrate for lipase enzymes. We decided to create a method to obtain the desired optically active substance with high purity and high yield.

[0004]

[Means for Solving the Problems] As a method for obtaining a 4-substituted-2-butanol having a high optical purity by a simple and economical method, the inventors have used an inexpensive racemic mixture as a raw material. As a result of diligent studies on various enzymes and their reaction conditions in order to devise a new method of reacting them with enzymes, several ester hydrolases showed extremely high asymmetry with respect to 4-substituted-2-butanol. They have a recognition ability and have found that they catalyze asymmetric hydrolysis and transesterification reactions in good yield, and completed the present invention. That is, the present invention is a method for producing an optically active 4-substituted-2-butanol using an enzyme.

The present invention will be described in more detail below. The present invention provides a compound of the general formula [I] CH ₃ CH (OH) CH ₂ CH ₂ SR ₁ [I] (wherein R ₁ represents an optionally substituted aryl group).
In the presence of a hydrolase, a mixture of enantiomers of 4-substituted-2-butanol represented by the formula [II] R ₂ COOR ₃ [II] (wherein R ₂ may be hydrogen or may be substituted) R ₃ represents an alkyl group or an optionally substituted alkenyl group,
Is an optionally substituted alkyl group or an optionally substituted alkenyl group), and is brought into contact with an ester represented by
(Wherein R ₁ has the same meaning as described above) and is a method for producing 4-substituted-2-butanol. In this reaction, S-
4-substituted-2-butanol remains in the reaction system as it is.
A fatty acid ester of 4-substituted-2-butanol in the R-form is produced. In the general formula [I], the optionally substituted aryl group for R ₁ is a phenyl group, an alkylphenyl group,
An aryl group such as an alkoxyphenyl group or a halophenyl group. In the general formula [II], the alkyl group which may be substituted or the alkenyl group which may be substituted, for R ₂ is, for example, a straight chain or branched chain group such as a methyl group, an ethyl group, an isopropyl group and an undecyl group. And an ethenyl group, an isopropenyl group, an undecenyl group, or a linear or branched alkenyl group, wherein R ₃ may be an optionally substituted alkyl group or an optionally substituted alkenyl group. A linear or branched alkyl group such as a methyl group, an ethyl group, an isopropyl group or a hexyl group, and a linear or branched alkenyl group such as an ethenyl group, an isopropenyl group or a hexenyl group. is there. In addition, the hydrolase used is characterized in that it specifically acts on the compound having the (R) -configuration in the 4-substituted-2-butanol derivative.

The 4-position substituted-2-butanol as a raw material is prepared by the method described in the literature (Bull. Chem. Soc. Jpn., Vol. 53, page 3615 (19).
80)) makes it easy to synthesize. The fatty acid esters can be synthesized by reacting 4-substituted-2-butanol with carboxylic acid anhydride or carboxylic acid chloride by a conventional method. From the viewpoint of easy availability, these raw material compounds are preferably a racemate (equal mixture of enantiomers), but the enantiomeric mixture ratio is not particularly limited, and any mixing ratio may be used. The hydrolase used in the present invention is classified into ester hydrolase, and examples thereof include lipase produced by microorganisms, lipoprotein lipase produced by microorganisms, esterase derived from animal tissues and the like. Commercially available enzymes, such as Pseudomonas-derived lipase B (manufactured by Wako Pure Chemical Industries), lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.), lipoprotein lipase (manufactured by Wako Pure Chemical Industries), heat-resistant lipase (manufactured by Kurita Kogyo Co., Ltd.), derived from Candida bacteria Use lipase AY (manufactured by Amano Pharmaceuticals), lipoprotein lipase derived from Alcaligenes bacteria (manufactured by Seikagaku Corporation), lipase LP derived from chromobacteria (manufactured by Toyo Brewing Co.), esterase derived from pig liver (manufactured by Sigma), etc. You can The enzymes used are characterized by high stereospecificity, and all of the exemplified enzymes act specifically on the R-form. As the usage form of the enzyme,
It may be a purified enzyme, a crude enzyme, or a state of being contained in cells or tissues, and any form may be used. It is also possible to fix it to a solid phase carrier before use.

When carrying out the enzymatic reaction of the present invention, the reaction is usually carried out in an organic solvent. In this case, the organic solvent is not particularly limited as long as it does not deactivate the enzyme. The concentration of 4-substituted-2-butanol is usually 0.1-50%
And preferably 1 to 20%. When carrying out this type of reaction, the compound of the general formula [II] acts as an acylating agent by transesterification. At that time, the alcohol component is released, but when an unsaturated enol ester is used, the alcohol component becomes a ketone or aldehyde due to tautomerism, and the reaction proceeds to the end without the reverse reaction. Advantageous and convenient. General formula [II]
The amount of the compound used is 1 with respect to 4-substituted-2-butanol.
It may be a molar equivalent or more. The reaction temperature depends on the enzyme used, but is usually 0 to 60 ° C, preferably 5 to 55 ° C.
℃. The enzyme is usually used in a non-uniformly dispersed state without being dissolved, but the reaction proceeds sufficiently even in this state. The amount of enzyme used is usually 4 -substituted-2-butanol, which is the substrate.
0.1 to 50% is sufficient. In this reaction, the enzyme generally proceeds in a dispersed state and progresses in a heterogeneous system. Therefore, it is preferable to carry out the reaction with stirring or shaking, but it may be carried out in a stationary state.

After completion of the reaction, the insoluble matter is removed by an operation such as centrifugation or filtration, and then the ordinary purification method such as distillation or column chromatography is applied to separate and purify the residue and the product to obtain an optical activity. You can get a body. The optically active substance once obtained can be converted into the ester and the hydroxyl group while maintaining the configuration by acylation or deacylation. Most of what was removed as insoluble matter in the second type of reaction was an enzyme, and this was reusable.

[0009]

EXAMPLES The present invention will be described in more detail below with reference to examples.

Example 1 Racemic 4-phenylthio-2-butanol (455 mg) and isopropenyl acetate (500 mg) were dissolved in n-hexane-benzene (1: 1) (12.5 ml), and lipase PS (manufactured by Amano Pharmaceutical Co., Inc., Pseudomonas bacterium) was dissolved. 125 mg was added, and the mixture was reacted at room temperature for 3 days with occasional stirring. The insoluble matter was filtered off with a glass filter, the organic solvent in the filtrate was distilled off, and the mixture was reacted in a shaking incubator at 37 ° C for 28 hours. After 2.5 ml of acetone was added to the reaction solution to homogenize it, the mixture was filtered through Celite, most of the organic solvent was distilled off under reduced pressure, and then extracted with chloroform. The extract was subjected to silica gel column chromatography under the same conditions as in Example 1 to give 4-phenylthio-2-butyl acetate fraction 278 mg (yield 49%) and 4-phenylthio-2-butanol fraction 201 mg (recovery 44%). The former had a specific rotation of [α] _D = -6.8 ° (C = 1.00, EtOH), and had an optical purity of 88.7% ee (R-form) by HPLC analysis. In addition, the specific rotation of the latter is [α] _D = 32.6 ° (C = 1.05, EtOH), which was analyzed by HPLC after acetylation and had an optical purity of 93.
It was 4% ee (S-body). (S) -4-phenylthio-2-butanol: NMR spectrum; 7.25 (m, 5H), 3.90 (m, H), 3.01 (t, 2
H), 2.27 (S, H), 1.75 (m, 2H), 1.18 (d, 3H) (CDCl ₃ ) optical rotation; [α] _D = 33.6 ° (C = 1.1, EtOH) (R) -acetic acid 4 -Phenylthio-2-butyl: NMR spectrum; 7.20 (m, 5H), 4.95 (m, H), 2.93 (t, 2
H), 2.00 (S, 3H), 1.85 (m, 2H), 1.20 (d, 3H) (CDCl ₃ ) optical rotation; [α] _D = -7.7 ° (C = 1.0, EtOH)

INDUSTRIAL APPLICABILITY The present invention can provide an industrially excellent production method for producing an optically active 4-substituted-2-butanol useful as an intermediate raw material for agricultural medicine in high purity and in a high yield in a simple manner. ..

Claims (1)

[Claims] 1. A general formula [I] CH ₃ CH (OH) CH ₂ CH ₂ SR ₁ [I] (wherein R ₁ represents an optionally substituted aryl group).
The enantiomer mixture of the compound represented by the formula [II] R ₂ COOR ₃ [II] (wherein R ₂ is hydrogen, an optionally substituted alkyl group or a substituted group) in the presence of a hydrolase. An alkenyl group which may be represented by R ₃
Is an optionally substituted alkyl group or an optionally substituted alkenyl group), and is brought into contact with an ester represented by
(Wherein R ₁ has the same meaning as described above).