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Method for preparing (S)-[3, 5-di (trifluoromethyl) phenyl] ethanol by using Cyberlindnera saturnus

A technology of trifluoromethyl and wheel head, which is applied in the field of preparation of -[3,5-diphenyl]ethanol, can solve the problems of low substrate concentration and low product yield, and achieve high optical purity

Active Publication Date: 2020-12-08
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The reported whole-cell catalyzed asymmetric reduction of 3,5-bistrifluoromethylacetophenone to (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol mainly has catalytic substrates. The concentration of the substance is low, the yield of the product is not high, etc.

Method used

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  • Method for preparing (S)-[3, 5-di (trifluoromethyl) phenyl] ethanol by using Cyberlindnera saturnus
  • Method for preparing (S)-[3, 5-di (trifluoromethyl) phenyl] ethanol by using Cyberlindnera saturnus
  • Method for preparing (S)-[3, 5-di (trifluoromethyl) phenyl] ethanol by using Cyberlindnera saturnus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: the acquisition of wet thalline

[0030] Slant medium composition: glucose 15g / L, peptone 20g / L, yeast extract 10g / L, (NH 4 ) 2 SO 4 2g / L, KH 2 PO 4 2g / L, NaCl 1g / L, MgSO 4 ·7H 2 O 0.5g / L, agar 20g / L, solvent is water, pH value 6.5.

[0031] Seed medium composition: glucose 15g / L, peptone 20g / L, yeast extract 10g / L, (NH 4 ) 2 SO 4 2g / L, KH 2 PO 4 2g / L, NaCl 1g / L, MgSO 4 ·7H 2 O 0.5g / L, the solvent is water, and the pH value is 6.5.

[0032] Composition of fermentation medium: glucose 34.36g / L, yeast extract 14.89g / L, NH 4 Cl 30.34g / L, CaCl 2 0.11g / L, KH 2 PO 4 1.01g / L, the solvent is water, and the pH value is 7.5.

[0033] Inoculate the slant medium with Cyberlindnera saturnus ZJPH1807 and culture at 30°C for 24 hours to obtain slant cells.

[0034] Pick a ring of bacteria from the mature slant and insert it into a 250mL shake flask with 100mL seed medium, cultivate at 30°C and 200rpm for 12h to obtain a seed liquid, and then trans...

Embodiment 2

[0035] Embodiment 2: the gas phase detection method of product

[0036] After the reaction, an equal volume of ethyl acetate was added to the conversion solution for extraction, and the concentration of the product and unreacted substrate in the extract was analyzed by gas chromatography and quantified by an internal standard method. The detection method of gas chromatography is as follows: the gas chromatograph is Agilent7820A, and the chromatographic column is Varian CP-Chirasil-Dex chiral capillary gas chromatographic column (25m×0.25mm×0.25μm, df=0.25). Quantitative analysis of substrates and products was carried out with dodecane (4.4 mM) as the internal standard, the carrier gas was nitrogen, and a hydrogen flame ionization detector (FID) was used.

[0037] Gas phase (GC) detection conditions: carrier gas flow rate 2ml / min, sample volume 1μL, split ratio 15:1, inlet temperature 250°C, detector temperature 250°C, column temperature 80°C for 2min, then 5°C / min to 180°C. ...

Embodiment 3

[0043] Embodiment 3: the influence of auxiliary substrate kind on catalytic result

[0044] The wet thalline 1g that embodiment 1 method gained is resuspended in 10mL Na 2 HPO 4 -NaH 2 PO 4 Buffer (0.1M, pH7.0), add substrate 3,5-bistrifluoromethylacetophenone and auxiliary substrate, transform at 30°C, 200rpm for 24h, after the reaction, add an equal volume of Extracted with ethyl acetate, the product in the reaction extract and the unreacted substrate concentration adopt the gas chromatography of embodiment 2 to analyze and detect, and the gas phase detection chromatogram sees figure 2 , the yield of the target product (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol and the corresponding excess value (e.e. value) were obtained by calculation. The results are shown in Table 1. The mass addition of wet bacteria is 100g / L in terms of buffer volume, the added amount of substrate is 51.23g / L in terms of buffer volume, and the auxiliary substrates (glucose, maltose, lactose, sucr...

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Abstract

The invention discloses a method for preparing (S)-[3, 5- di (trifluoromethyl) phenyl] ethanol by using Cyberlindnera saturnus, which comprises the following steps: forming a conversion system in a buffer solution with the pH value of 6.0-8.0 by using wet microbe body obtained by fermentation culture of Cyberlindnera saturnus ZJPH1807 as an enzyme source and 3, 5 bis (trifluoromethyl) acetophenoneas a substrate, and carrying out conversion reaction at 25-45 DEG C at 100-200rpm; after the reaction is finished, separating and purifying a conversion reaction solution to obtain (S)-[3, 5-bis (trifluoromethyl) phenyl] ethanol; in a phosphate buffer solution system with the pH value of 7.5, the addition amount of microbe body is 150 g / L, 128.07 g / L (500 mM) of a substrate is added, conversion is performed for 24 h, and the yield of the product is 80.97%.

Description

[0001] (1) Technical field [0002] The invention relates to a preparation method of (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol, in particular to the asymmetric reduction of 3,5-bistrifluoromethylphenylethyl alcohol by Saccharomyces saturnii The ketone is (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol. [0003] (2) Background technology [0004] (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol, molecular formula C 10 h 8 f 6 O, is a key chiral intermediate for the preparation of NK-1 receptor antagonist-aprepitant. Aprepitant is the first neurokinin-1 (NK-1) receptor blocker approved by the U.S. FDA in 2003, and it is also a widely used NK-1 receptor antagonist. NK-1 receptors (mainly present in the central nervous system and its periphery) bind to block the effect of substance P and inhibit nausea and vomiting. It has the advantages of high selectivity, strong affinity and long half-life. Its new antiemetic target provides a new option for preventing postoperative nausea and vom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P7/22C12N1/16C12R1/645
CPCC12P41/002C12P7/22C12N1/16
Inventor 王普毕顺德
Owner ZHEJIANG UNIV OF TECH
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