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Method for preparing betamethasone intermediate

A technology of betamethasone and bacteria strains, applied in the field of steroid biopharmaceuticals, can solve the problems of low dosage of recombinant strains, chemical synthesis pollution, and many by-products, and achieve the risk of increasing impurities, abundant sources, and cheap prices Effect

Active Publication Date: 2019-07-30
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Aiming at the defects of synthesizing DB11 in the prior art, the present invention aims to provide a new method for synthesizing DB11 by microbial fermentation, aiming at solving the pollution problem existing in the chemical synthesis process and the low feeding amount of recombinant strains, low conversion rate, side effects too many products

Method used

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  • Method for preparing betamethasone intermediate
  • Method for preparing betamethasone intermediate
  • Method for preparing betamethasone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Arthrobacter simplex CPCC 140451 was used as the transformed strain.

[0065] (1) Strain slant culture process: use a 500mL eggplant-shaped bottle, according to the following ratio: glucose 13g / L, yeast extract 16g / L, agar 18g / L, pH7.0-8.0 to prepare slant medium, each eggplant-shaped After sterilizing 100mL of bottled liquid at 121°C for 30 minutes, set up the slope, and place it in a 32°C incubator for 2 days after the slope solidified and formed. After culturing at 32°C for 2 days, the eggplant-shaped bottles were collected and placed in a refrigerator at 4°C until use.

[0066] (2) Strain shake flask culture process: use 500mL shake flask, according to the following ratio: glucose 11.8g / L, corn steep liquor 6g / L, peptone 8g / L, KH 2 PO 4 4g / L, pH7.0-8.0 to prepare shake flask seed medium and fermentation transformation medium, each shake flask liquid 100mL, in which 1.0g / L compound I was added as induction before the fermentation transformation medium was sterilize...

Embodiment 2

[0068] Embodiment 2: Take Arthrobacter simplex CPCC 140451 as the transformation strain

[0069] (1) Strain slant culture and shake flask culture process: same as Example 1, the difference is that 1.5 g / L compound I was added as induction before the fermentation transformation medium was sterilized.

[0070] (2) Feed conversion process: add 10% ammonia water to the cultured 100mL fermentation broth, adjust the pH value to 9.5, weigh 6g of compound I, put it into a shaker flask, add 0.1% DMF (V / V), shake well Afterwards, the transformation was carried out at 34°C and 220rpm for 70 hours. After the transformation was completed, the temperature was raised to 70°C to terminate the reaction. Take 1mL of the transformation solution, add 20mL of acetone and sonicate it for 30min, and perform HPLC analysis after centrifugation. The conversion rate was 93.136%.

Embodiment 3

[0071] Embodiment 3: Take Arthrobacter simplex CPCC 140451 as the transformation strain

[0072] (1) Strain slant culture and shake flask culture process: same as Example 1, the difference is that 2.0 g / L compound I was added as induction before the fermentation transformation medium was sterilized.

[0073] (2) Feed conversion process: add 15% aqueous sodium hydroxide solution to the cultured 100mL fermentation broth, adjust the pH value to 10.0, weigh 5g of compound I, put it into a shaker flask, add 0.1% DMSO (V / V) After shaking well, transform at 32°C transformation temperature and 220rpm rotation speed for 65 hours. After the transformation is completed, raise the temperature to 80°C to terminate the reaction. Take 1mL transformation solution, add 20mL acetone and sonicate for 30min, and perform HPLC analysis after centrifugation. The transformation rate is 94.632%. .

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Abstract

The invention provides a method for preparing a betamethasone intermediate. By using one of a single strain Arthrobacter simplex CPCC 140451 or a single strain Nocardioide simplex ACCC 10205, the hydrolysis and dehydrogenation processes of the compound I are conducted in a same system, and it is achieved that beta methyl epoxide is obtained through one-step fermentable conversion. The technology is simple, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of steroid biopharmaceuticals, and in particular relates to a method for synthesizing betamethasone epoxy hydrolyzate, namely DB11, by fermentation with a single microorganism. Background technique [0002] Betamethasone is a glucocorticoid widely used in clinical practice. It has various pharmacological effects such as anti-inflammation, anti-allergy and immunity, and can be used to treat rheumatoid arthritis and lupus erythematosus. Betamethasone epoxy hydrolyzate is an important intermediate in the synthesis of betamethasone, the trade name is DB11, CAS: 981-34-0, the chemical name is: 9β, 11β-epoxy-16β-methylpregna-1,4 -diene-17α, 21-diol-3,20-dione, white or almost white crystalline powder, odorless, bitter taste. Almost insoluble in water, slightly soluble in methanol or acetone, its structural formula is as follows: [0003] [0004] Currently, the technological process routes for synthesizing DB11 are mai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/02C12P33/20C12P33/06C12R1/06C12R1/365
CPCC12P33/02C12P33/06C12P33/20
Inventor 曹桂阳钱先来陈肖鹏陈茂林
Owner ZHEJIANG XIANJU PHARMA
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