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A kind of method for producing prednisolone by microbial one-step fermentation

A technology of prednisolone and fermentation method is applied in the field of producing prednisolone by one-step fermentation of microorganisms, which can solve the problems of low conversion rate, large fluctuation, long process route and the like, and achieve the effect of simple and easy process.

Active Publication Date: 2022-07-26
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the process route is long, there are many by-products, and the environment is not friendly
[0003] In recent years, the high-efficiency production of prednisolone by biological fermentation has become a hot spot. The substrate used in this process is crude hydrocortisone acetate, which uses phytosterol 9-hydroxyesterification as the starting material, and is oxidized, removed, and produced. The crude product of hydrocortisone acetate is then fermented and refined to produce prednisolone, which creates a new hormone process line, greatly shortens the process cycle, and realizes environmentally friendly development, especially one-step fermentation. Hydrocortisone acetate 1,2-position dehydrogenation and C21-position hydrolysis two-step transformation, the efficiency is greatly improved, and the use of biological fermentation, no pollution, in line with the concept of sustainable development, but the conversion rate is generally not high in China (10 %-70%), with large fluctuations; the feed concentration is low, only 3%-4%, which greatly limits the industrial production of this process

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The invention provides the following technical solutions: a method for producing prednisolone by one-step fermentation of microorganisms, comprising the following steps:

[0019] 1) Microcrystal: DMF: material = 2.5:1, after heating and dissolving, slowly and uniformly adding the dissolving solution into the water separation tank, and adding the temperature to 20-25°C in 60-120 minutes into 2.5 times the water, stirring for 0.5- 1h, discharging and drying to obtain crude hydrocortisone acetate microcrystals. The particle size of the material can be controlled at D98≤30um, D90≤20um.

[0020] 2) Sterilization of microcrystals: drinking water:material=2:1, stir evenly, heat up to 121-125°C for sterilization for 35 minutes, cool down to 30-35°C, put into a fermenter for culturing bacteria, and carry out biological fermentation .

[0021] 3) Fermentation: glucose 1.5%, potassium dihydrogen phosphate 0.5%, yeast extract 1.0%, corn steep liquor 1.0%, pH 8.0-8.2, after steril...

Embodiment 2

[0024] The invention provides the following technical solutions: a method for producing prednisolone by one-step fermentation of microorganisms, comprising the following steps:

[0025] 1) Microcrystal: DMF: material = 2.5:1, after heating and dissolving, slowly and uniformly adding the dissolving solution into the water separation tank, and adding the temperature to 20-25°C in 60-120 minutes into 2.5 times the water, stirring for 0.5- 1h, discharging and drying to obtain crude hydrocortisone acetate microcrystals. The particle size of the material can be controlled at D98≤30um, D90≤20um.

[0026] 2) Sterilization of microcrystals: drinking water:material=2:1, stir evenly, heat up to 121-125°C for sterilization for 35 minutes, cool down to 30-35°C, put into a fermenter for culturing bacteria, and carry out biological fermentation .

[0027] 3) Fermentation: glucose 1.5%, potassium dihydrogen phosphate 0.5%, yeast extract 1.0%, corn steep liquor 1.0%, pH 8.0-8.2, after steril...

Embodiment 3

[0030] The invention provides the following technical solutions: a method for producing prednisolone by one-step fermentation of microorganisms, comprising the following steps:

[0031] 1) Microcrystal: DMF: material = 2.5:1, after heating and dissolving, slowly and uniformly adding the dissolving solution into the water separation tank, and adding the temperature to 20-25°C in 60-120 minutes into 2.5 times the water, stirring for 0.5- 1h, discharging and drying to obtain crude hydrocortisone acetate microcrystals. The particle size of the material can be controlled at D98≤30um, D90≤20um.

[0032] 2) Sterilization of microcrystals: drinking water:material=2:1, stir evenly, heat up to 121-125°C for sterilization for 35 minutes, cool down to 30-35°C, put into a fermenter for culturing bacteria, and carry out biological fermentation .

[0033] 3) Fermentation: glucose 1.5%, potassium dihydrogen phosphate 0.5%, yeast extract 1.0%, corn steep liquor 1.0%, pH 8.0-8.2, after steril...

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PUM

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Abstract

The invention discloses a method for producing prednisolone by one-step microbial fermentation, which belongs to the field of microbial fermentation, adopts specific strains, uses cheap fermentation medium, and through fermentation, realizes hydrocortisone acetate C1, 2 dehydrogenation and C21 In situ hydrolysis, through the microcrystal treatment of the fermentation substrate, the use of special strains preserved by the company, through primary, secondary and tertiary fermentation, to produce prednisolone, and the crude hydrocortisone acetate is fermented before feeding. Process treatment, material particle size and crystal form are more conducive to fermentation transformation, the microcrystal condition of fermentation substrate used in the present invention is: DMF:material=2.5:1. The method can significantly improve the level of the hydrocortisone acetate crude product transformed by Arthrobacter uricide, the process is simple and easy, and the industrialized production has been realized. In addition, the method provided by the present invention has certain reference significance for the fermentation transformation of other strains.

Description

technical field [0001] The present invention relates to the field of microbial fermentation, more particularly, to a method for producing prednisolone by one-step microbial fermentation. Background technique [0002] The traditional synthetic production of prednisolone is based on prednisone acetate as raw material, and the carbonyl protecting agent (mainly urea) is used to protect the ketone carbonyl at C3 and C20 positions, and the ketone carbonyl at C11 position is reduced by borohydride, Then the protecting groups at C3 and C20 positions are deprotected and acid hydrolyzed to obtain prednisolone. The disadvantage of this method is that the process route is long, the by-products are many, and the environment is not friendly. [0003] In recent years, the high-efficiency production of prednisolone by biological fermentation has become a hot spot. The substrate used in this process is hydrocortisone acetate crude product, and phytosterol 9-hydroxyester is used as the start...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P33/02C12P33/00C12R1/06
CPCC12P33/02C12P33/005
Inventor 张海涛李合兴孟栋梁王国永
Owner HENAN LIHUA PHARMA