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Preparation process of betamethasone intermediate

A technology of preparation process and volume of fermentation liquid, applied in the field of preparation technology of betamethasone intermediates, can solve the problems of low feeding concentration, ineffectiveness, limited conversion effect, etc., and achieves the improvement of fermentation mode, reduction of production cost, and cost saving of auxiliary materials. Effect

Inactive Publication Date: 2011-05-25
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Chinese patent 00136645.9 is a way to improve the yield by using batch feeding, but the conversion effect of dehydrogenating the compound shown in formula I to the compound shown in formula II is limited or even invalid
In US4839282, the method of adding divalent cobalt ions to increase the yield during fermentation is only suitable for very low feed concentration below 0.1%

Method used

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  • Preparation process of betamethasone intermediate
  • Preparation process of betamethasone intermediate
  • Preparation process of betamethasone intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] a. Fermentation broth culture medium (mass percentage): glucose 0.4%, corn steep liquor 0.1%, peptone 0.1%, KH 2 PO 4 0.20%, the rest is water; pH 7.0, filter to remove the sediment, each 500ml shake flask is filled with 200ml fermentation medium, the bottom of the shake flask is covered with 50ml thick ceramic beads with a diameter of 4mm, and sterilized at 121°C for 30 minutes.

[0032] b. 16β-Methyl-17α,21-dihydroxy-pregna-4-ene-3,20-dione, through ordinary mechanical crushing or grinding, the particle size reaches about 100 mesh.

[0033] Operation process: Inoculate the simple Arthrobacter bacteria that has grown on the slope into a sterilized fresh fermentation medium, the rotation speed of the shaker is 200r / min, and the culture temperature is 30°C. After culturing for 22 hours, 1.0 g (feeding concentration of 0.5%) mechanically crushed 16β-methyl-17α,21-dihydroxy-pregn-4-ene-3,20-dione was introduced. The rotating speed of the shaker is 200r / min, and the culture temp...

Embodiment 2

[0036] a. Fermentation broth medium (mass percentage): glucose 0.8%, corn steep liquor 0.6%, peptone 0.5%, KH 2 PO 4 0.10%, the rest is water; pH 7.2, filter to remove the sediment, each 500ml shake bottle with a volume of 200ml, cover the bottom with 40mm thick glass beads with a diameter of 6mm, and sterilize at 121°C for 30 minutes.

[0037] b. 16β-Methyl-17α,21-dihydroxy-pregna-4,9(11)-diene-3,20-dione, through ordinary mechanical crushing or grinding, the particle size reaches about 120 mesh.

[0038] Operation process: Scrape three full loops of simple Arthrobacter cells that have grown on the inclined surface, and inoculate them into sterilized fresh fermentation medium. The rotation speed of the shaker is 200r / min, and the culture temperature is 30℃. After culturing for 20 hours, 1 g (feeding concentration of 0.5%) mechanically crushed 16β-methyl-17α,21-dihydroxy-pregna-4,9(11)-diene-3,20-dione was added. After casting, the shaker rotates at 200r / min and the culture tempera...

Embodiment 3

[0041] a. Fermentation broth medium (mass percentage): glucose 0.6%, corn steep liquor 0.8%, peptone 0.3%, KH 2 PO 4 0.15%, the rest is water; pH 7.1, filter to remove the sediment, each 500ml shake bottle with 200ml, 25ml thick ceramic beads with a diameter of 2mm on the bottom, and sterilize at 121°C for 30min.

[0042] b. 16β-Methyl-17α,21-dihydroxy-pregn-4-ene-3,11,20-trione, through ordinary mechanical crushing or grinding, the particle size reaches about 140 mesh.

[0043] Operation process: Scrape three full loops of simple Arthrobacter cells that have grown on the inclined surface, and inoculate them into sterilized fresh fermentation medium. The rotation speed of the shaker is 200r / min, and the culture temperature is 30℃. After culturing for 22 hours, 1 g (feeding concentration of 0.5%) mechanically crushed 16β-methyl-17α,21-dihydroxy-pregna-4-ene-3,11,20-trione was added. After casting, the shaker rotates at 200r / min and the culture temperature is 33°C. After 65 hours of...

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Abstract

The invention discloses a preparation process of a compound shown in a formula II. The compound is prepared from a compound shown in a formula I by biological fermentation and dehydrogenation, and in the processes of biological fermentation and dehydrogenation, an inert grinding material is added in fermentation liquid. In the invention, the fermentation manner is improved under a condition of using a common arthrobacter simplex strain; and a proper amount of inert grinding material is added in the fermentation liquid so that the yield and the quality of a compound product (namely a betamethasone intermediate) in the formula II are improved under the condition that the feeding concentration is maintained to be over 0.5%, and the production cost of betamethasone is reduced. In addition, no chemical solvent is used in the preparation process, and thus the cost for auxiliary materials is saved.

Description

Technical field [0001] The invention relates to a preparation process of a biological drug intermediate, in particular to a preparation process of a betamethasone intermediate. Background technique [0002] Betamethasone (Betamethasone), the chemical name is: 16β-methyl-11β, 17α, 21-trihydroxy-9α-pregnant-1,4-diene-3,20-dione. The molecular formula is: C 22 H 29 FO 5 ; Molecular weight: 392.47. Now it is mostly used to treat active rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, severe dermatitis, acute leukemia, etc. Its structural formula is as follows: [0003] [0004] The conventional method for preparing betamethasone is generally obtained by a series of chemical reactions of the compound of formula I, wherein the compound of formula II (ie: betamethasone intermediate) is obtained by dehydrogenating the compound of formula I A critical step. The dehydrogenation methods used in industrial production, in the past, commonly used chemical metho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/02C12R1/06
Inventor 林伟应明华张直庆
Owner ZHEJIANG XIANJU PHARMA
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