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Method for reducing impurities in ethyl diketone 11a hydroxylation process by using mixed solvent

A mixed solvent and ethyl diketone technology is applied in the field of using mixed solvents to reduce impurities in the hydroxylation process of ethyl diketone 11a. It can solve the problems of many impurity points and cumbersome and difficult treatment processes, and achieve high conversion rate of substrates. The effect of increasing the average yield and improving the conversion rate

Active Publication Date: 2020-08-28
HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the 11a-hydroxylation of ethyl diketone mainly adopts the method of microbial cell transformation, and the literature "11a-hydroxylation of L-ethyl stetenedione biocatalysis" and "Metarhizium anisopliae to steroid C11-a hydroxylation reaction "Technology Research" has been reported, the strains used are Ochrax Aspergillus and Metarhizium anisopliae, the conversion rate is 30-60%, and the yield is about 30%. There are many impurities in the conversion process. The crystallization method needs to be repeated 4 to 5 times to remove impurities, and the processing process is very cumbersome and difficult

Method used

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  • Method for reducing impurities in ethyl diketone 11a hydroxylation process by using mixed solvent
  • Method for reducing impurities in ethyl diketone 11a hydroxylation process by using mixed solvent
  • Method for reducing impurities in ethyl diketone 11a hydroxylation process by using mixed solvent

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Experimental program
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Effect test

Embodiment 1

[0042] Such as figure 1 As shown, Metarhizium anisopliae was inoculated on a potato dextrose agar (PDA) medium for culture, and cultured at 28° C. for 3-10 days.

[0043] Take one ring and transfer it to the culture medium of the shaker flask, the rotation speed of the shaker culture is 150rpm, the culture temperature is 27°C, the liquid medium is 8.5g / L glucose, 8.5g / L soybean powder, 4g / L silkworm chrysalis powder, and cultivate for 14h .

[0044] The cultivation time of the small tank was 16 hours, the cultivation temperature was 27°C, and the ventilation volume was 0.5vvm.

[0045] Feed transformation after collecting the bacteria, the mass ratio of the substrate to the bacteria is 1:7, the substrate DL-18-methyl-40estrenene-3,17-dione is dissolved in 500mL of a mixed solvent of DMF and DMSO, and the temperature is 55 °C, volume ratio DMF:DMSO=5:1, feed concentration 4g / L, feed amount 56g, conversion at 24°C for 24h, temperature raised to 70°C for 5min, and reaction term...

Embodiment 2

[0047] Such as figure 1 As shown, Metarhizium anisopliae was inoculated on a potato dextrose agar (PDA) medium for culture, and cultured at 28° C. for 3-10 days.

[0048] Take one ring and transfer it to the shake flask culture medium, the shaker culture speed is 160rpm, the culture temperature is 29°C, the liquid medium is 8.5g / L glucose, 8.5g / L soybean powder, 8.5g / L silkworm chrysalis powder, and culture 15h.

[0049] The cultivation time of the small tank was 30 hours, the cultivation temperature was 32°C, and the ventilation volume was 0.8vvm.

[0050] Feed transformation after collecting the bacteria, the mass ratio of the substrate to the bacteria is 1:1, the substrate is dissolved in DMF and DMSO, the temperature of the melting material is 60°C, the transformation is 24h, DMF:DMSO=8:1, the feeding concentration is 4g / L, Feed amount 50g, use solvent 500ml, transform at 32°C for 40h, raise the temperature to 70°C for 5min, stop the reaction, extract the bacteria with 500...

Embodiment 3

[0052] Such as figure 1 As shown, Metarhizium anisopliae was inoculated on a potato dextrose agar (PDA) medium for culture, and cultured at 28° C. for 3-10 days.

[0053] Take one ring and transfer it to the culture medium of the shaker flask, the rotation speed of the shaker culture is 180rpm, the culture temperature is 30°C, the liquid medium is 8.5g / L glucose, 8.5g / L soybean powder, 4g / L silkworm chrysalis powder, and cultivate for 16h .

[0054] The cultivation time of the small tank was 24 hours, the cultivation temperature was 27°C, and the ventilation volume was 1.2vvm.

[0055] After collecting the bacteria, the mass ratio of the substrate to the bacteria is 1:10, the substrate is dissolved in DMF and DMSO, and the transformation takes 24 hours. DMF:DMSO=10:1, the feeding concentration is 4g / L, the feeding amount is 60g, and the solvent is used 500ml, melt temperature 70°C, transform at 40°C for 24h, raise the temperature to 70°C for 5min, terminate the reaction, ext...

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Abstract

The invention relates to a method for reducing impurities in an ethyldiketone 11a hydroxylation process by using a mixed solvent. The method comprises the following steps: a Metarhizium anisopliae strain is cultured to obtain Metarhizium anisopliae thalli, and the thalli are collected; after the thalli are collected, feeding and conversion are conducted, specifically, a substrate DL-18-methyl-gon-40-en-3,17-dione is dissolved with the mixed solvent prepared from DMF and DMSO, the collected thalli are fed into the substrate, and the substrate is converted into 11a-hydroxy-18-methyl-estr-4-ene-3,17-dione. The method provided by the invention can obviously reduce the generation of impurities in the ethyl diketone biological hydroxylation product, especially the generation of 10a-OH ethyl diketone and 6 beta-ethyl diketone, increases the conversion rate, simplifies the after-treatment process and increases the average yield.

Description

technical field [0001] The invention relates to a method for reducing impurities in the hydroxylation process of ethyl diketone 11a by using a mixed solvent. Background technique [0002] The prior art discloses the application of biotransformation in steroid synthesis, mainly including hydroxylation, side chain degradation, double bond reduction and the like. Compared with chemical methods, biotransformation has the characteristics of mild reaction, less pollution and high yield. Therefore, in the synthesis of steroids, the advantages of the two are usually used together. Although microbial transformation has unique advantages, industrial applications are often restricted by practical difficulties. Among them, the 11a hydroxylation of ethyl diketone is a key step in the entire synthesis process during the synthesis of desogestrel. The case of low yield and many impurities. Therefore, reducing the content of impurities and improving the conversion rate are the main proble...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/10C12N1/14C12R1/645
CPCC12P33/10C12N1/14
Inventor 陈海林蔡啸宋盟军应娟狄飞飞汪洋胡甜
Owner HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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