Method for preparing (S)-1-(3,5-bis(trifluoromethyl)) phenylethanol by microbial transformation

A microbial transformation, trifluoromethyl technology, applied in the direction of microorganism-based methods, biochemical equipment and methods, microorganisms, etc., to achieve good application prospects, mild reaction conditions, and low cost effects

Inactive Publication Date: 2011-11-23
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently known strains (such as Rhodotorula, etc.) that can be used for the preparation of (S)-1-(3,5-bistrifluoromethyl)phenylethanol through biological asymmetric reduction, and the enantiomeric excess value does not exceed 88.5 %

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The strains preserved in the laboratory were screened. The conversion conditions are: in 20mL 0.1M sodium phosphate buffer, pH 8.0, add the substrate 1-(3,5-ditrifluoromethyl) phenyl ethyl ketone at a concentration of 50 mmol / L, and the auxiliary substrate maltose concentration is 50g / L, wet cell concentration 300g / L, 30°C, and shaker rotation speed of 200r / min for 30h. The results are shown in Table 1.

[0038] Table 1: The results of asymmetric reduction of 1-(3,5-ditrifluoromethyl)phenyl ethyl ketone catalyzed by different strains

[0039] Strain Substrate concentration / (mmol / L) Maltose concentration / (g / L) Time / h Yield / % e.e. value / % Pichia membranaefaciens Hansen 50 50 30 46.8 98.2(S) Red yeast (Rhodotorula qlutis) 2.102 50 50 30 31.7 80.3(S) Saccharomyces cerevisiae B5 50 50 30 35.3 91.4(S) Candida mogii (Candida mogii) IFFI 01257 50 50 30 39.5 97.5(S) Aureobasidium pullulans ACCC 30142 50 50 30 44.5 51.6(S) Aureobasidium pullulans ...

Embodiment 2

[0041] Example 2: Preparation of (S)-1-(3,5-ditrifluoromethyl)phenylethanol

[0042] Slant culture: The final concentration of each component of the medium is: glucose 10g / L, yeast powder 3g / L, peptone 5g / L, agar 20g / L, solvent is water, pH 6.5, sterilize at 121℃ for 20 minutes, after sterilization Cool, prepare slant, inoculate Candida tropicalis 104 strain (CCTCC No: M 209034), cultivate at 30°C for 3 to 5 days as slant seeds.

[0043] Seed culture: The final concentration of each component of the medium is: glucose 50g / L, yeast powder 13g / L, NH 4 Cl 3g / L, KH 2 PO 4 1g / L, K 2 HPO 4 1g / L, MgSO 4 ·7H 2 O 0.4g / L, solvent is water, pH 6.5, sterilize at 121°C for 20 minutes, cool after sterilization, insert the inclined plane seed, 30°C, shaker speed 200r / min, culture for 20 hours, as seed liquid;

[0044] Fermentation culture: The final concentration of each component of the medium is: glucose 50g / L, yeast powder 13g / L, NH 4 Cl 3g / L, KH 2 PO 4 1g / L, K 2 HPO 4 1g / L, MgSO 4 ·7H 2 O 0...

Embodiment 3～7

[0047] Using Candida tropicalis 104 (CCTCC No: M 209034), fermented and cultured according to the method in Example 2, the wet bacteria were added to a 250 mL Erlenmeyer flask containing 20 mL of 0.1 M, pH 8.0 phosphate buffer (wet bacteria The final concentration of the body is 300g / L), and maltose with a final concentration of 50g / L is added as an auxiliary substrate, and the concentration of the substrate 1-(3,5-ditrifluoromethyl)phenyl ethyl ketone is 10~90mmol / L , At 30 ℃, 200r / min conversion 30h. After the reaction, the cells were removed by centrifugation to obtain the supernatant. The supernatant was extracted with ethyl acetate, an appropriate amount of anhydrous MgSO 4 After drying and filtering, the content and enantiomeric excess of (S)-1-(3,5-ditrifluoromethyl)phenylethanol were analyzed by gas chromatography. The results are shown in Table 2.

[0048] Table 2: The influence of different substrate concentrations on yield and enantiomeric excess

[0049] Example ...

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Abstract

The invention provides a method for preparing (S)-1-(3,5-bis (trifluoromethyl)) phenylethanol by microbial transformation. The (S)-1-(3,5-bis (trifluoromethyl)) phenylethanol is prepared according to The invention provides a method for preparing (S)-1-(3,5-bis (trifluoromethyl)) phenylethanol by microbial transformation. The (S)-1-(3,5-bis (trifluoromethyl)) phenylethanol is prepared according tothe following steps: 1-(3,5-bis (trifluoromethyl)) phenylethanol functioning as substrate is catalyzed by fermentation products of Candida tropicalis 104 functioning as enzyme source so as to be reducthe following steps: 1-(3,5-bis (trifluoromethyl)) phenylethanol functioning as substrate is catalyzed by fermentation products of Candida tropicalis 104 functioning as enzyme source so as to be reduced asymmetrically at 28-34 DEG C, and transformation solution is separated and purified after the asymmetric reduction reaction. The Candida tropicalis 104 is chosen to be used as enzyme-producing stred asymmetrically at 28-34 DEG C, and transformation solution is separated and purified after the asymmetric reduction reaction. The Candida tropicalis 104 is chosen to be used as enzyme-producing strain after optimum strain seeking, and 1-(3,5-bis (trifluoromethyl)) phenylethanol is catalyzed to be reduced asymmetrically in a single-phase aqueous system so as to generate (S)-1-(3,5-bis (trifluoroain after optimum strain seeking, and 1-(3,5-bis (trifluoromethyl)) phenylethanol is catalyzed to be reduced asymmetrically in a single-phase aqueous system so as to generate (S)-1-(3,5-bis (trifluoromethyl)) phenylethanol which has an enantiomeric excess value of over 99 percent and can be well applied.methyl)) phenylethanol which has an enantiomeric excess value of over 99 percent and can be well applied.

Description

(1) Technical field [0001] The invention relates to a biotransformation preparation method of an important chiral drug intermediate (S)-1-(3,5-bistrifluoromethyl)phenylethanol, belonging to the technical field of biocatalysis. (2) Background technology [0002] (S)-1-(3,5-ditrifluoromethyl)phenylethanol is an important chiral drug intermediate, which can be used to synthesize NK-1 receptor antagonists, which can effectively treat depression and Other psychiatric disorders, with good potential efficacy in the treatment of a range of central and peripheral nervous system depression. [0003] Currently known preparation methods mainly have three paths: [0004] (1) Chemical method. Mainly take rare metals (rhodium, ruthenium, etc.) Expensive, not suitable for industrialized production. [0005] (2) Enzyme conversion method. The asymmetric reduction of 1-(3,5-bistrifluoromethyl)phenylethanone by using the extracted and purified enzyme (such as carbonyl reductase) has the ad...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P7/22C12R1/74
Inventor 王普何军邀孙立明唐俊
Owner ZHEJIANG UNIV OF TECH
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