Biological preparation method of (S)-1-(2-iodine-5-fluorophenyl) ethanol

Abstract

The invention discloses a biological preparation method of (S)-1-(2-iodine-5-fluorophenyl) ethanol. The biological preparation method comprises the following steps: taking a certain concentration of prochiral ketone 2'-iodine-5'-fluoroacetophenone as a substrate, adding a certain amount of genetically engineered bacteria, at the temperature of 20 to 50 DEG C, reacting in a reaction system converted by a buffer solution with the pH of 5.5 to 10.5, and after the reaction is completed, separating and purifying a reaction solution to obtain a corresponding product, wherein the genetically engineered bacteria are genetically engineered bacteria containing a carbonyl reductase EbSDR8 mutant encoding gene; and the nucleotide sequence of the carbonyl reductase EbSDR8 mutant encoding gene is SEQ IDNO.3. The method is mild in reaction condition, high in substrate adaptation and environmentally-friendly, and reconstitution cells of the enzyme can be used for efficiently catalyzing asymmetric reduction of high-concentration prochiral ketone in an isopropanol-containing reaction system without adding any coenzyme, so that generated chiral alcohol (ee being greater than or equal to 99%) with high optical purity has an excellent industrialized application prospect.

Description

Technical field [0001] The present invention relates to the technical field of biochemical industry, in particular to a biological preparation method of (S)-1-(2-iodo-5-fluorophenyl)ethanol. Background technique [0002] Lung cancer is the leading cause of death from cancer worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer patients. Among NSCLC patients, the proportion of ALK-positive is about 3% to 5%, about 4.1% in Eastern population, about 2.5% in European and American population, and as high as 5.3% in China. Compared with the existing ALK inhibitors, the potential advantage of loratinib is that the blood-brain barrier is more permeable and the treatment effect of ALK mutations resistant to TKI is better, including crizotinib and alectinib EML4-ALK mutation type that is resistant to Ceritinib (typically such as G1202R mutation). [0003] S-1-(2-iodo-5-fluorophenyl)ethanol is a chiral intermediate for lung cancer drug loratinib. The general ...

AI Technical Summary

Problems solved by technology

The Chinese invention patent with the publication number CN106399398A discloses a biological preparation method of (R)-3,5-bis(trifluoromethyl)phenethyl alcohol (I), which comprises the following steps: (a) reacting in the liquid state In the system, the compound of formula II is used as a substrate in the presence of a coenzyme, and under the catalysis of carbonyl reductase, an asymmetric reduction reaction is carried out to form the compound of formula I; wherein, in the reaction system, the concentration of the compound of formula II is 50~ 1000g / L; and (b) optionally isolate the compound of formula I from the reaction system after the step (a) reaction, this method is troublesome, and coenzymes also exist, the reaction system is more complicated, and the cost is higher

[0004] Moreover, the existing biocatalysis is far from meeting the requirements of industrial production. How to prepare S-1-(2-iodo-5-fluorophenyl)ethanol with high yield and high efficiency is a crucial issue in this field

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