Method for producing androstane dienedione through fermentation of arthrobacter simplex

A technology of androstadiene dione and Arthrobacter simplex is applied in the optimization field of substrate pretreatment, which can solve the problems of low transformation efficiency, high cost, low recovery rate and the like

Pending Publication Date: 2022-04-08
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the raw materials for the early synthesis of steroidal drugs are directly extracted from animal tissue fluid, the recovery rate is low, the cost is high, and it cannot meet the production needs; the later synthesis method uses dioscin as the starting material and undergoes chemical synthesis methods, which is the industrialization of steroidal drugs Production provides abundant raw materials, but with the increasing depletion of dioscin, more abundant resources and methods are urgently needed to replace them; and the emergence of phytosterols has brought new changes to the field of steroids. It is obtained from various crops, and the important steroid drug intermediates androstenedione (AD) and androstenedione (ADD) are obtained by using biological selective side chain degradation technology, and then androstenedione and androstenedione Steadienedione is used as the starting material for further preparation to obtain steroid drugs, wherein ADD is an important starting material for the synthesis of estrogens
[0003] The main method of preparing ADD at present is: one, adopt mycobacteria to degrade phytosterols to obtai

Method used

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  • Method for producing androstane dienedione through fermentation of arthrobacter simplex
  • Method for producing androstane dienedione through fermentation of arthrobacter simplex
  • Method for producing androstane dienedione through fermentation of arthrobacter simplex

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Fermentation medium components: glucose: 10g / L, peptone: 3g / L, corn steep liquor: 10g / L, potassium dihydrogen phosphate: 1g / L, yeast extract: 1g / L, manganese chloride: 0.003g / L, sulfuric acid Ferrous iron 0.03g / L, Tween 0.04g / L, foam enemy 0.04g / L, initial pH of fermentation = 7.0, substrate is water analysis pretreatment AD substrate.

[0035] The fermentation process is as follows: first-level seed cultivation, adding culture medium in a jacketed 50L fermenter with a filling coefficient of 0.6, sterilizing, cooling to 33°C, inserting Arthrobacter simplex, inoculum size 10%, fermentation in two Stage: ① Cell growth stage: after inoculation, adjust the air flow to 3.0m 3 / h, the stirring rate is 200r / min, the temperature is controlled at 33°C, cultured for 9h, the bacterial concentration is monitored at 20%, and feeding is carried out. ② Microbial transformation stage: feed concentration 10g / L, adjust air flow rate 1.0m 3 / h, the stirring rate is 300r / min, the tempera...

Embodiment 2

[0038] Fermentation medium components: glucose: 10g / L, peptone: 3g / L, corn steep liquor: 10g / L, potassium dihydrogen phosphate: 1g / L, yeast extract: 1g / L, manganese chloride: 0.003g / L, sulfuric acid Ferrous iron 0.03g / L, Tween 0.04g / L, foam enemy 0.04g / L, initial pH of fermentation = 7.0, substrate is water analysis pretreatment AD substrate.

[0039] The fermentation process is as follows: first-level seed cultivation, adding culture medium in a jacketed 50L fermenter with a filling coefficient of 0.6, sterilizing, cooling to 33°C, inserting Arthrobacter simplex, inoculum size 10%, fermentation in two Stage: ① Cell growth stage: after inoculation, adjust the air flow to 3.0m 3 / h, the stirring rate is 200r / min, the temperature is controlled at 33°C, cultivated for 8h, and the bacterial concentration is monitored at 30%, before feeding. ② Microbial transformation stage: feed concentration 10g / L, adjust air flow rate 1.0m 3 / h, the stirring rate is 300r / min, the temperature i...

Embodiment 3

[0042] Fermentation medium components: glucose: 30g / L, soybean peptone: 5g / L, corn steep liquor: 30g / L, potassium dihydrogen phosphate: 5g / L, yeast extract: 4g / L, manganese chloride: 0.003g / L, Ferrous sulfate 0.03g / L, Tween 0.12g / L, foam enemy 0.2g / L, initial pH of fermentation = 7.0, substrate is water analysis pretreatment AD substrate.

[0043] The fermentation process is as follows: first-level seed cultivation, adding culture medium in a jacketed 50L fermenter with a filling coefficient of 0.6, sterilizing, cooling to 33°C, inserting Arthrobacter simplex, inoculum size 10%, fermentation in two Stage: ① Cell growth stage: after inoculation, adjust the air flow rate to 4.0m 3 / h, the stirring rate is 300r / min, the temperature is controlled at 33°C, cultivated for 7h, and the bacterial concentration is monitored at 40%, before feeding. ② Microbial transformation stage: feed concentration 10g / L, adjust air flow rate 2.0m 3 / h, the stirring rate is 400r / min, the temperature ...

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Abstract

The invention belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a method for producing androstane dienedione by fermentation of arthrobacter simplex, which mainly comprises the following steps: optimizing fermentation culture medium components, feeding points and substrates for whole-cell transformation of arthrobacter simplex to obtain an ADD crude product with high conversion rate, and extracting and refining by mixing acetone and water to obtain the androstane dienedione. And an ADD fine product is obtained. The method effectively solves the problems that in the prior art, the conversion efficiency is not high, byproducts are difficult to separate, the process is tedious and not suitable for industrial mass production, and the like, the fermentation feeding concentration is increased to 30-60 g/L, and the conversion rate is increased to 97% or above.

Description

technical field [0001] The invention belongs to the technical field of preparation of steroid hormone drugs, in particular to a high-efficiency method for Arthrobacter simplex CPCC 140451 to ferment and produce androstadienedione (ADD), especially the medium components used, the optimization of feeding points and Optimization of substrate pretreatment. Background technique [0002] Steroidal drugs have strong anti-infection, anti-allergic, anti-viral and anti-shock pharmacological effects, and are an important class of drugs in clinical practice. Most of the raw materials for the early synthesis of steroidal drugs are directly extracted from animal tissue fluid, the recovery rate is low, the cost is high, and it cannot meet the production needs; the later synthesis method uses dioscin as the starting material and undergoes chemical synthesis methods, which is the industrialization of steroidal drugs Production provides abundant raw materials, but with the increasing depleti...

Claims

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Application Information

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IPC IPC(8): C12P33/02C12N1/20C07J1/00C12R1/06
Inventor 刘建蒋随新谢长庚王小飞张小强曹桂阳余启银
Owner ZHEJIANG XIANJU PHARMA
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