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Bio-preparation method for (R)-3,5-bis(trifluoromethyl) phenyl ethanol

A technology of trifluoromethyl and phenethyl alcohol, applied in the field of medicine, can solve the problems of unsuitability for industrial production, low catalytic activity, stimulation of antibiotic resistance and the like

Pending Publication Date: 2017-02-15
SHANGHAI INST OF PHARMA IND +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

However, the carbonyl reductase mentioned in the current patents CN102382780 A and CN 104212841 A has a higher conversion rate only at a lower substrate concentration
And in CN 104212841 A, the price of the ionic liquid used in order to increase the substrate concentration is relatively expensive, and there are some potential hazards such as stimulating antibiotic resistance, so it is not suitable for industrial production
Applied and Environmental Microbiology 2013, 79(4), p1378-1384 reported that the carbonyl reductase QNR derived from Microbacteriumluteolum JCM 9174 showed good activity for quinuclidone, but showed low catalytic activity for similar substrate alicyclic ketones, Therefore there is still no relevant literature report to use it for the reduction of aromatic ketone substrates, including for the substrate 3,5-bis(trifluoromethyl)acetophenone involved in the present invention

Method used

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  • Bio-preparation method for (R)-3,5-bis(trifluoromethyl) phenyl ethanol
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  • Bio-preparation method for (R)-3,5-bis(trifluoromethyl) phenyl ethanol

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preparation example Construction

[0091] The invention provides a method for preparing (R)-3,5-bis(trifluoromethyl)phenethyl alcohol, comprising the steps of:

[0092] (a) In a liquid reaction system, the compound of formula II is used as a substrate, and in the presence of a coenzyme, under the catalysis of carbonyl reductase, an asymmetric reduction reaction is carried out to form a compound of formula I, namely (R)-3,5- Bis(trifluoromethyl)phenethyl alcohol;

[0093]

[0094] Wherein, in the reaction system, the concentration of the compound of formula II is 50-1000 g / L; and

[0095] (b) optionally isolating the compound of formula I from the reaction system after the reaction in the previous step.

[0096] In the present invention, the above reaction can be coupled or not coupled with the coenzyme regeneration system.

[0097] Preferably, the above reactions are coupled with a coenzyme regeneration system in the same system, thereby further improving production efficiency, reducing production costs an...

Embodiment 1

[0139] Embodiment 1: Construction of carbonyl reductase engineering bacteria

[0140] The QNR target gene and alcohol dehydrogenase gene were entrusted to a commercial company to carry out the whole gene synthesis, cloned into the pET28a(+) vector, transformed into Escherichia coli DH5α competent cells, cultured on the plate, picked a single positive transformant colony and extracted the plasmid for sequencing After confirmation, the recombinant plasmid is extracted, introduced into BL21 (DE3) strain, cultured in LB, and genetically engineered bacteria capable of inducing the expression of recombinant carbonyl reductase and alcohol dehydrogenase are obtained.

Embodiment 2

[0141] Embodiment 2: the preparation of recombinant carbonyl reductase, alcohol dehydrogenase

[0142] Inoculate the genetically engineered bacterium stored in glycerol in the previous step into the LB liquid medium containing kanamycin, cultivate for 13 hours at 37°C and 220rpm to obtain the seed medium, and inoculate the seed culture medium in a proportion of 1.5%. On the liquid medium containing 50ug / ml kanamycin resistance, then cultivate to OD at 37℃, 220rmp 600 If the value is >2.0, add lactose with a final concentration of 1.0%, cool down to 25°C, continue to cultivate for 3 hours, add lactose with a final concentration of 0.5%, and cultivate for 20 hours, put it in a tank, and centrifuge to obtain bacteria, which is ready for biotransformation.

[0143] The medium formula is:

[0144] raw material Mass content (%) Yeast extract 2.4 soy peptone 1.2 Sodium chloride 0.3 glycerin 0.5 Dipotassium phosphate 0.2 Magnesium Sulfat...

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Abstract

The invention provides a bio-preparation method for (R)-3,5-bis(trifluoromethyl) phenyl ethanol (I). The method specifically comprises the following steps: (a) an asymmetric reduction reaction is performed in a liquid reaction system with a compound shown in the formula II as a substrate in presence of a coenzyme under catalysis of carbonyl reductase, and a compound shown in the formula I is prepared, wherein in the reaction system, the concentration of the compound shown in the formula II is 50-1,000 g / L; (b) the compound shown in the formula I is optionally separated from the reaction system subjected to the reaction in the step (a). The invention further provides the reaction system. The reaction system comprises (i) a waterborne solution, (ii) the substrate which is the compound shown in the formula II, (iii) the coenzyme, (iv) carbonyl reductase, (v) a co-substrate and (vi) an enzyme for regenerating the coenzyme.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of (R)-3,5-bis(trifluoromethyl)phenethyl alcohol. Background technique [0002] Aprepitant (Aprepitant, trade name Emend), chemical name 5-[2(R)-[1(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4 -fluor ophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one, a neurokinin-1 (NK-1 ) receptor inhibitor, as an auxiliary drug for the treatment of cancer. The drug was approved for marketing in the United States by the FDA in 2003 and in China in 2014. It is mainly used for the prevention and treatment of acute and delayed nausea and vomiting symptoms caused by chemotherapy. [0003] The structural formula of aprepitant is as follows: [0004] [0005] (R)-3,5-bis(trifluoromethyl)phenethyl alcohol is a key intermediate in the synthesis of aprepitant, which can be prepared by biocatalysis and chemical synthesis. Chemical synthesis oft...

Claims

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Application Information

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IPC IPC(8): C12P7/22
CPCC12P7/22
Inventor 张福利陈少欣汤佳伟倪国伟谭支敏郭翔聂鑫孙文霞
Owner SHANGHAI INST OF PHARMA IND
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