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Biological dehydrogenation preparation method of 6 alpha-methylprednisolone intermediate

An intermediate and dehydrogenation technology, which is applied in the field of preparation of steroidal drug intermediates, can solve problems such as differences in the production of dehydrogenation products, no disclosure of strain preservation information, technical solutions that cannot be implemented, etc., to achieve the effect of avoiding residues and flexible selection

Active Publication Date: 2013-02-13
TIANJIN JINYAO GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the technical solution disclosed in this application neither discloses any preservation information of the strains used for biological dehydrogenation, nor discloses the formula of the medium used for biological dehydrogenation. Because in the prior art, different bacterial strains and different mediums There is a big difference in the yield of producing dehydrogenate during production, which causes the technical scheme disclosed in this patent application to be unable to be implemented.

Method used

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  • Biological dehydrogenation preparation method of 6 alpha-methylprednisolone intermediate
  • Biological dehydrogenation preparation method of 6 alpha-methylprednisolone intermediate
  • Biological dehydrogenation preparation method of 6 alpha-methylprednisolone intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Using 11β, 17α-dihydroxy-pregna-4-ene-3,20-dione as a substrate;

[0049] Arthrobacter simplex (AS1.94 *) to carry out slant cultivation, primary cultivation and secondary cultivation in sequence, the cultivation temperature is 31°C, the substrate dissolved in DMF is dropped into a 5L fermenter, the feeding concentration is 1%, and the reaction temperature is 31°C. The reaction time was 60 hours. After the reaction was completed, the temperature was raised to 70° C. to terminate the reaction. The fermentation broth was extracted with ethyl acetate, and the organic phase was concentrated. The conversion rate of the substrate was measured to be 73.5%.

Embodiment 2

[0050] Example 2: Using 17α, 21-dihydroxy-pregn-4-ene 3,11,20-triketone-21-acetate as the substrate;

[0051] Arthrobacter simplex (AS1.94 * ) to carry out slant cultivation, primary cultivation and secondary cultivation in sequence, the cultivation temperature is 32°C, the substrate dissolved in tetrahydrofuran is put into a 5L fermenter, the feeding concentration is 2%, and the reaction temperature is 32°C. The reaction time was 48 hours. After the reaction was completed, the temperature was raised to 70° C. to terminate the reaction. The fermentation broth was extracted with ethyl acetate, and the organic phase was concentrated. The conversion rate of the substrate was measured to be 77.3%.

Embodiment 3

[0052] Example 3: Using 11β, 17α, 21-trihydroxy-pregna-4-ene-3,20-dione-21-acetate as the substrate;

[0053] Arthrobacter simplex (AS1.754) is carried out slant culture, primary culture and secondary culture successively, and culture temperature is 33 ℃, and the substrate that dissolves in dioxane is put into 5L fermentation tank, and feeding concentration is 1%, The reaction temperature was 33°C. The reaction time was 36 hours. After the reaction was completed, the temperature was raised to 70° C. to terminate the reaction. The fermentation broth was extracted with ethyl acetate, and the organic phase was concentrated. The conversion rate of the substrate was measured to be 81.6%.

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Abstract

The invention relates to a biological dehydrogenation preparation method of a 6 alpha-methylprednisolone intermediate, which uses a compound of formula (1) as a substrate and obtains a compound of formula (2) by adopting a simple arthrobacterium biological dehydrogenation method. The process comprises the following steps of: crushing the formula (1) compound or dissolving the formula (1) compound by using a solvent; adding to a fermentation tank with cultivated arthrobacterium to perform biotransformation; extracting, separating, and refining; drying, and then obtaining a dehydrogenation matter, i.e. the formula (2) compound. The invention can achieve the biotransformation rate of 70-90 percent.

Description

Technical field: [0001] The invention relates to a preparation method of a steroid drug intermediate, in particular to a method for preparing a pregnant drug intermediate through biological dehydrogenation. Background technique: [0002] 6α-methylprednisolone (methylprednisolone, CAS: 83-43-2; referred to as methylprednisolone) is a corticosteroid drug, it has anti-inflammatory, anti-endotoxin, immune suppression, anti-shock and other pharmacological effects, can Made into clinical injections, it has a very important role in clinical practice. The molecular formula is as follows: [0003] [0004] The 1,2-position dehydrogenation process is a key step in the production process of methylprednisolone, which directly affects the quality and yield of methylprednisolone. The dehydrogenation process in the prior art generally uses SeO 2 Dehydrogenation, SeO 2 It is a highly toxic substance, with large pollution, and the reaction yield is low, generally only 55%, the product...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P33/02C12R1/06
Inventor 陈立营陈松赵琳
Owner TIANJIN JINYAO GRP
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