Production method of methylprednisolone dehydrogenate

A technology of methylprednisolone and methylprednisolone, which is applied in the directions of microorganism-based methods, biochemical equipment and methods, microorganisms, etc., can solve the problems of easy crystallization, low solubility, low feeding concentration, etc. Feed concentration and conversion rate, improve dissolution and dispersion properties, and have significant economic benefits

Active Publication Date: 2021-04-06
HENAN LIHUA PHARMA
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that Methylprednisolone-Grignard can be biotransformed by Arthrobacter simplex to prepare methylprednisolone-Grignard; however, the solubility of Methylprednisolone-Grignard in water is very low. It is very difficult to form effective contact with microorganisms, which seriously affects the rate of conversion reaction and the yield of products, which has also become a difficult problem in the process of using Arthrobacter simplex to prepare methylprednisolone dehydrogenate
[0004] At present, the methods to solve the above problems mainly include crushing treatment and solvent treatment; wherein, the crushing treatment is to grind methylprednisolone Grignard into fine powder for micronization to Increase its solubility in the fermented liquid, although this way can improve the conversion rate of product to a certain extent, yet the range of improvement is limited, and the feeding concentration is low (below 4%), and it is easy to crystallize and separate out under high feeding concentration, which is not conducive to Actual production; solvent treatment is the use of solvents to dissolve methylprednisolone Grignard, although this method improves the solubility of methylprednisolone Grignard, but it will cause toxicity to microorganisms during biotransformation, thus to a large extent It restricts the dosage and conversion rate of the substrate, and the organic solvent may also adversely affect the quality of the product
[0005] For example, the Chinese patent whose publication number is CN101760495A discloses a kind of biological dehydrogenation preparation method of 6α-methylprednisolone intermediate, which is prepared by methylprednisolone After the nylon Grignard is crushed or dissolved in a solvent, Arthrobacter simplex AS1.754 and AS 1.94* are used to carry out 1 and 2 biological dehydrogenation. However, the feeding concentration of this method is below 4%, and the conversion rate of the substrate is only 70.1 -82.1%, its level of conversion of Arthrobacter simplex to methylprednisolone Grignard remains low

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 1. Pretreatment of methylprednisolone Grignard

[0050] The methylprednisolone Grignard substance used in this embodiment is specifically 11β, 17α-dihydroxy-pregn-4-ene-3,20-dione, and the dispersant is specifically ethanol.

[0051] Drinking water and the above-mentioned methylprednisolone Grignard substance were mixed at a mass ratio of 4:1, and then stirred and beaten at a stirring speed of 150 r / min for 20 minutes to obtain a slurry.

[0052] Add a dispersant to the above slurry, the mass ratio of the dispersant to the slurry is 0.03:1, stir and mix well, heat up to about 121°C for sterilization for 25 minutes, then cool down to room temperature to obtain methylprednisolone Grignard slurry.

[0053] 2. Bacteria culture

[0054] The fermentation medium used in this embodiment is: 2.5% glucose, 0.3% yeast extract, 0.4% potassium dihydrogen phosphate, and the pH value is 7.0-7.2.

[0055] Primary culture: activate Arthrobacter simplex, then put it into a 250mL Erlen...

Embodiment 2

[0065] 1. Pretreatment of methylprednisolone Grignard

[0066] The methylprednisolone Grignard substance used in this embodiment is specifically 11α, 17α, 21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate, and the dispersant is specifically methanol.

[0067] Drinking water and the above-mentioned methylprednisolone Grignard substance were mixed at a mass ratio of 3:1, and then stirred and beaten at a stirring speed of 200 r / min for 40 minutes to obtain a slurry.

[0068] Add a dispersant to the above slurry, the mass ratio of the dispersant to the slurry is 0.01:1, stir and mix well, heat up to about 121°C and sterilize for 35 minutes, then cool down to room temperature to obtain methylprednisolone Grignard slurry.

[0069] 2. Bacteria culture

[0070] The primary culture and secondary culture methods of the strains in this example are the same as in Example 1; the secondary culture medium is inserted into a 5L fermenter, and fermented and cultivated for about 15 hours at 30°...

Embodiment 3

[0076] 1. Pretreatment of methylprednisolone Grignard

[0077] The methylprednisolone Grignard substance used in this example is specifically 6α-methyl-11α-hydroxyl-16α, 17α-epoxy-pregn-4-ene-3,20-dione, and the dispersant is specifically dimethyl methyl formamide (DMF).

[0078] The drinking water and the above-mentioned methylprednisolone Grignard substance were mixed at a mass ratio of 4:1, and then stirred and beaten at a stirring speed of 130 r / min for 50 minutes to obtain a slurry.

[0079] Add a dispersant to the above slurry, the mass ratio of the dispersant to the slurry is 0.05:1, stir and mix well, heat up to about 125°C for sterilization for 20 minutes, then cool down to room temperature to obtain methylprednisolone Grignard slurry.

[0080] 2. Bacteria culture

[0081] The primary culture and secondary culture methods of the strains in this example are the same as in Example 1; the secondary culture solution is inserted into a 5L fermenter, and fermented and cu...

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Abstract

The invention provides a production method of a methylprednisolone dehydrogenate. The production method of the methylprednisolone dehydrogenate comprises the following steps: A) adding water into a methylprednisolone Grignard substance, and pulping to obtain slurry; and B) biologically converting the methylprednisolone Grignard substance in the slurry into a methylprednisolone dehydrogenized substance by using arthrobacter simplex. According to the production method, no organic solvent is used, and the toxic effect on microorganisms is small during biotransformation; according to the method, the methylprednisolone Grignard substance is added with water and pulped into slurry, so that the feeding concentration and the substrate conversion rate of the methylprednisolone Grignard substance are greatly improved, the yield of a methylprednisolone dehydrogenized substance product is high, and the method is particularly beneficial to industrial production of the methylprednisolone dehydrogenized substance.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a method for producing methylprednisolone dehydrogenate. Background technique [0002] Methylprednisolone (methylprednisolone for short) is an important glucocorticoid drug, which has pharmacological effects such as anti-inflammatory, anti-endotoxin, and immune suppression. First aid, can also be used for endocrine disorders, rheumatic diseases, collagen venereal diseases, skin diseases, allergic reactions, eye diseases, gastrointestinal diseases, blood diseases, leukemia, shock, cerebral edema, multiple neuritis, myelitis and prevent cancer chemotherapy causing vomiting etc. [0003] Methylprednisolone in C 1,2 The introduction of double bonds through positional dehydrogenation can significantly improve its anti-inflammatory and other activities; compared with chemical methods, microbial dehydrogenation has the advantages of mild reaction conditions, strong specificity, and h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/02C12P33/20C12R1/06
CPCC12P33/02C12P33/20
Inventor 张海涛牛志刚李合兴
Owner HENAN LIHUA PHARMA
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