JPH0722512B2 - Process for producing optically active α-perfluoroalkylpropionic acid derivative - Google Patents

Description

Detailed Description of the Invention [Industrial applications]

The present invention has the general formula (In the formula, Rf is a perfluoroalkyl group, and R is
It is a hydroxyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted thiol group. And a method for producing an optically active α-perfluoroalkylpropionic acid derivative represented by Among the optically active α-perfluoroalkylacrylic acid derivatives represented by the general formula (I) obtained by the present invention, 2-trifluoromethyl-3 having a hydroxyl group at the β-position.
-Hydroxypropionic acid is a compound that can lead to 5-trifluoromethyluracil useful as an intermediate for medical products.

[Prior art]

Heretofore, a method for producing an optically active α-perfluoroalkylpropionic acid derivative has not been known.

[Problems solved by the invention]

The present inventor has found that an optically active α useful as an intermediate for medical products.
As a result of extensive studies on a method for producing a perfluoropropionic acid derivative, the present invention has been completed and found.

[Constitution of the invention]

The present invention has the general formula in the presence of esterase or cellulase. (In the formula, Rf is a perfluoroalkyl group.) And α-perfluoroalkylacrylic acid represented by the general formula RH- (III) (wherein, R is a hydroxyl group, a substituted or unsubstituted amino group or a substituted amino group). Alternatively, it is an unsubstituted thiol group. (In the formula, R and Rf are the same as above.) An optically active α-perfluoropropionic acid derivative represented by the formula is produced. The α-perfluoroalkylacrylic acid represented by the general formula (II) of the present invention is a compound that is industrially easily available. Examples of the Rf group of this compound include a trifluoromethyl group and a pentafluoroethyl group. The compounds represented by the general formula (III) are also industrially easily available compounds, and examples include water, ammonia, alkylamines such as diethylamine and dipropylamine, and arylthiols such as thiophenol. can do. The present invention needs to be carried out in the presence of esterase or cellulase. As an esterase, pig liver
Examples include esterase, α-chymotrypsin, lipase-MY (manufactured by Meito Sangyo Co., Ltd., Candida cylindracea) and the like, and examples of cellulase include Trichoderma viride and the like. The reaction is preferably carried out in a buffer solution, and a KH ₂ PO ₄ —Na ₂ HPO ₄ buffer solution can be preferably used. The reaction temperature is preferably in the range of 30 to 45 ° C. in order to efficiently obtain the desired product. Hereinafter, the present invention will be described in more detail with reference to Examples. Example 1 KH ₂ PO ₄ (0.45 g) and Na ₂ HPO ₄ (7.57 g) were dissolved in distilled water to give a solution of 1.7. L In this buffer solution (pH 8.0, 50 ml)
ipase-MY (Candida cylindracea, 5 g manufactured by Meito Sangyo Co., Ltd.) was suspended and stirred in a constant temperature bath at 40 to 41 ° C. for 15 minutes. Α-Trifluoromethylacrylic acid (1.5g, 10mmol) in the solution
Was added, and the mixture was reacted at 40 to 41 ° C for 3 days. The reaction mixture was acidified with 1N hydrochloric acid (10 ml), and the product was extracted 3 times with ethyl acetate (50 ml). The extract was dried over magnesium sulfate, ethyl acetate was distilled off, and the residue was distilled under reduced pressure to obtain (+)-2-trifluoromethyl-3-hydroxypropionic acid. bp.91 ° C / 0.6mmHg Yield 48% The optical purity was determined by synthesizing a hydroxy ester compound by a conventional method, and obtaining the ester compound from this compound and (+)-α-methoxy-α-trifluoromethylphenylacetic acid chloride. Obtained and integrated by ¹⁹ F-NMR. Examples 2-3 pig liver esterase (manufactured by 90μ Sigma) and α-chym
Using otrypsin (manufactured by 1 g Sigma), the reaction was carried out under the above conditions, and the post-treatment was carried out in exactly the same manner. The results are shown in Example 1.
The results are shown in Table 1. The optical purity was determined in the same manner as in Example 1. Example 4 Pig liver was added to the buffer solution (pH 8.0, 50 ml) used in Example 1.
Add esterase (90μ Sigma) and add 40-41 in a constant temperature bath.
Stirred at 15 ° C for 15 minutes. 2-trifluoromethylpropenoic acid (1.5 g, 10 mmol) and diethylamine (8.8 g,
(12 mmol) was added and the mixture was reacted at 40 to 41 ° C. for 92 hours. The reaction mixture was acidified with 1N hydrochloric acid (10 ml), and the product was extracted 3 times with ethyl acetate (50 ml). After the extract was dried over magnesium sulfate, ethyl acetate was distilled off, and the residue was subjected to silica gel chromatogram using hexane-diethyl ether (5: 1) as a solvent for distilling 2-trifluoromethyl-3-. N, N-diethylaminopropionic acid was obtained. Yield 39% ¹ H NMR (DMSO-d ₆ ): δ1.17 (CH ₃ ), (3.16 to 3.83)
(6H), 4.00 (m, CH), 8.30 (br.1H) ¹⁹ F NMR (DMSO-d ₆ ; external standard CF ₃ CO ₂ H): δ-10.8 ppm
(D, J _CF3-CH = 8.5Hz) The optical purity is "New NMR shift reagent (+) that can measure optical purity" commercially available from Daiichi Pure Chemicals Co., Ltd.
Alternatively, it was determined using a lanthanide complex of (-) di (perfluoro-2-propoxypropionyl) methane. Example 5 Pig liver was added to the buffer solution (pH 8.0, 50 ml) used in Example 1.
Add esterase (manufactured by 90μ Siguma) 40-41 in a constant temperature bath
Stirred at 15 ° C for 15 minutes. Add thiophenol (1.3
g, 12 mmol) and α-trifluoromethylacrylic acid (1.5
g, 10 mmol) was added and reacted at 40 to 41 ° C. for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid (10 ml), and the product was extracted 3 times with ethyl acetate (50 ml). After the extract was dried over magnesium sulfate, ethyl acetate was distilled off, and the residue was purified by silica gel chromatogram using hexane-diethyl ether (5: 1) as a distilling solvent to obtain the target compound.
-Trifluoromethyl-3-phenylthiopropionic acid was obtained. Yield 64% ¹ H NMR (DMSO-d ₆ ): δ 3.20 to 3.30 (3H), 7.4 (Ar-
H), 11.7 (Co ₂ H) ¹⁹ F NMR (DMSO-d ₆ ; external standard CF ₃ CO ₂ H): δ-10.3 (d,
J _CF3-CH = 8.0 Hz) The optical purity was measured in the same manner as in Example 4.
The results are summarized in Table 2 together with the results of Example 4.

Claims (1)

[Claims] 1. The general formula in the presence of esterase or cellulase The general formula consisting of reacting α-perfluoroacrylic acid represented by and a compound represented by the general formula RH A method for producing an optically active α-perfluoroalkylpropionic acid derivative represented by: (wherein, Rf is a perfluoroalkyl group, R is a hydroxyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted thiol group. is there.).