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Method for preparing 16,17α-epoxy progesterone by biological method

An epoxy progesterone, biological method technology, applied in the direction of microorganism-based methods, biochemical equipment and methods, microorganisms, etc., can solve the problems of severe reaction conditions, low effective reaction, large energy consumption, etc., and achieve mild reaction conditions. Effect

Active Publication Date: 2021-01-05
山东宝利甾体生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The limiting factor of this process level is that the effective reaction of Oppenauer oxidation is relatively low, which causes many by-products in the reaction process, which affects the conversion rate and yield. 17α-epoxy progesterone, in addition, the traditional chemical process uses a large amount of organic solvents, severe reaction conditions, and has to use a steam distillation device, resulting in high energy consumption and high emissions, resulting in 16,17α-epoxy progesterone The Oppenauer oxidation reaction has become the bottleneck of the development of the entire steroid drug industry, so providing a method that can improve the yield of 16,17α-epoxy progesterone, has a mild reaction, and can realize green manufacturing has become an urgent problem to be solved

Method used

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  • Method for preparing 16,17α-epoxy progesterone by biological method
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  • Method for preparing 16,17α-epoxy progesterone by biological method

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Experimental program
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Effect test

Embodiment 1

[0035] The Arthrobacter simplex AS1.94 of the present invention comes from the Institute of Microbiology, Chinese Academy of Sciences, and the bacteria used for transformation or fermentation are obtained through slant culture and seed culture.

[0036] Incline culture

[0037] Incline medium: glucose 10g / L, yeast extract 10g / L, agar powder 20g / L.

[0038] Culture condition: 33±1℃

[0039] Culture time: 48h

[0040] seed culture

[0041] Seed medium: glucose 10g / L, yeast extract 5g / L, corn steep liquor 12g / L, potassium dihydrogen phosphate 2.5g / L.

[0042] Wash the slant culture with sterile normal saline to make a bacterial suspension, the bacterial concentration is greater than 1.0×108CFU / ml, 2.5m 3 For seed tanks, the inoculation amount is 1%, the rotation speed is 120r / min, and the ventilation is 1:0.5. The pressure of the seed tank is 0.05MPa, and the cultivation time is 22h. According to 1L of water, the fermentation substrate 3-hydroxy-5-ene-16,17α-epoxy is 2.5g, ...

Embodiment 2

[0046] Incline, seed culture method as described in Example 1.

[0047]According to 1L of water, the fermentation substrate 3-hydroxy-5-ene-16,17α-epoxy is 2.5g, the components and weight of the fermentation medium are glucose 12g, yeast extract 4g, corn steep liquor 35g, potassium dihydrogen phosphate 1.0g , foam enemy (defoamer GPE, Jiangsu Sterick Chemical Co., Ltd.) 0.2g ratio in 25m 3 The ventilated mechanical stirring fermenter is equipped with 18m 3 Fermentation liquid, adjust the initial pH to 6.7, sterilize with conventional hot and humid steam, cool to 33±1°C, inoculate the seed culture liquid at 25m under conventional aseptic conditions according to 12% inoculation amount 3 in the fermentation broth of the fermenter. The speed of the fermenter is 80r / min, the ventilation rate is 1:0.5, the pressure is 0.05MPa, the incubation time is 72h, sampling, TLC analysis, the conversion of the substrate is complete, the sample is extracted with ethyl acetate, and the upper l...

Embodiment 3

[0051] Incline, seed culture method as described in Example 1.

[0052] According to 1L of water, the fermentation substrate 3-hydroxy-5-ene-16,17α-epoxy is 2.5g, the components and weight of the fermentation medium are glucose 15g, yeast extract 5g, corn steep liquor 40g, potassium dihydrogen phosphate 1.2g , foam enemy (defoamer GPE, Jiangsu Sterick Chemical Co., Ltd.) 0.3g ratio in 25m 3 The ventilated mechanical stirring fermenter is equipped with 18m 3 For the fermentation broth, adjust the initial pH to 8.0, sterilize with conventional steam, cool to 33±1°C, and inoculate the seed culture solution at 25m under conventional aseptic conditions according to the inoculum size of 15%. 3 in the fermentation broth of the fermenter. The rotation speed of the fermenter is 80r / min, the ventilation rate is 1:0.5, the pressure of the seed tank is 0.05MPa, the incubation time is 72h, sampling, TLC analysis, the conversion of the substrate is complete, the sample is extracted with e...

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Abstract

The invention discloses a method for preparing 16,17[alpha]-epoxyprogesterone by virtue of a biological process. By conducting biological fermentation on a 3-hydro-5-ene-16,17[alpha]-epoxy substance by virtue of autologous cholesterol oxidase of Arthrobacter simplex AS1.94, so that biological manufacturing of the 16,17[alpha]-epoxyprogesterone is achieved; therefore, a conventional chemical process is replaced and the conversion rate and yield of the 16,17[alpha]-epoxyprogesterone are improved, wherein the 3-hydro-5-ene-16,17[alpha]-epoxy substance serves as a substrate and the Arthrobacter simplex AS1.94 is a catalysis strain; and by conducting the fermentation, the yield of the 16,17[alpha]-epoxyprogesterone is greater than 90%, and the purity of the 16,17[alpha]-epoxyprogesterone is greater than 98.5%.

Description

technical field [0001] The invention relates to a production method of a steroid drug intermediate, in particular to a method for preparing 16,17α-epoxy progesterone by using microorganisms to ferment 3-hydroxy-5-ene-16,17α-epoxide. Background technique [0002] 16,17α-Epoxyprogesterone is used as an intermediate in the manufacture of almost all steroid hormones including dexamethasone, betamethasone, 6α-methylprednisone, prednisone, and prednisone. Steroid hormone drugs are an important class of drugs second only to antibiotics. They have various functions such as anti-inflammatory, anti-immune, contraceptive, anti-cancer, and endocrine regulation. They are widely used in rheumatism, cardiovascular diseases, collagen diseases, and lymphatic leukemia. , human organ transplantation, bacterial encephalitis, skin diseases, endocrine disorders, senile diseases, hormone-dependent tumors and other diseases. [0003] At present, the preparation methods of 16,17α-epoxy progesterone...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P33/20C12P33/02C12R1/06
CPCC12P33/02C12P33/20
Inventor 张安全李九州别松涛
Owner 山东宝利甾体生物科技有限公司
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