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Method of producing methylprednisolone dehydrogenation article

A methylprednisolone, dehydrogenation technology, applied in microorganism-based methods, biochemical equipment and methods, microorganisms, etc., can solve the problems of high cost, poor product quality, low reaction yield, etc., and avoid residues. , lower cost, and the effect of environmental protection

Inactive Publication Date: 2008-04-02
ZHEJIANG XIANJU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The original dehydrogenation process 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 quality is poor, and traces of SeO remain in the product 2 hard to remove
[0003] After searching, there are currently more than 10 synthetic methods of methylprednisolone, all of which were developed in the 1950s and 1960s. The common disadvantages are low yield and high cost.
The synthetic method published in American Chemical Abstracts (see CA59P14074) in 1959 has a total of 10 steps of chemical reactions, but the dehydrogenation and replacement two-step reactions are all very poor, and the dehydrogenation reaction yield is only 55%, resulting in too high a cost , unable to achieve industrial production

Method used

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Effect test

Embodiment 1

[0014] Embodiment 1 of the present invention: Arthrobacter was subjected to slant culture, primary seed cultivation, secondary seed cultivation and tertiary seed cultivation in sequence; 6a-methyl-11β, 17a-dihydroxy-pregna-4-ene-3 20-diketones are pulverized by airflow to a fineness of less than 10um, accounting for more than 90%, and they are put into the fermenter that has cultivated Arthrobacter, the feeding concentration is 1.5%, the oxidation temperature is 30°C, the oxidation time is 47 hours, and it is heated above 70°C. tank, then centrifuged and dried to obtain the crude product, the conversion rate was 88.66%, the substrate was 7.23%, and the main impurity was 2.79%; then it was extracted and refined with methanol, glacial acetic acid, T reagent and active carbon, and after drying, methylprednisolone was obtained. Hydrogen, content 96.29%, maximum impurity content 1.10%, yield 71.18%.

Embodiment 2

[0015] Example 2 of the present invention: Arthrobacter was sequentially cultured on slant, first-level seed culture, second-level seed culture and third-level seed culture; 20-triketone-21-acetate is pulverized by air flow to a fineness of less than 10um, accounting for more than 90%, and put it into the fermenter that has cultivated Arthrobacter, the feeding concentration is 0.5%, the oxidation temperature is 31 ° C, the oxidation time is 42 hours, and heated Put it in a tank above 70°C, then centrifuge and dry to get the crude product, the conversion rate is 92.16%, the substrate is 1.56%, and the main impurity is 4.54%. Nisolone dehydrogenate, the content is 96.30%, the maximum impurity content is 1.23%, and the yield is 78.75%.

Embodiment 3

[0016] Example 3 of the present invention: Arthrobacter was placed in a fermenter for cultivation; 6a-methyl-11β, 17a-dihydroxy-pregna-4-ene-3,20-diketone-21-acetate was treated with 15 Dissolve twice the weight of dioxane, put it into the fermenter that has cultivated Arthrobacter, the feeding concentration is 1.0%, the oxidation temperature is 30°C, the oxidation time is 55 hours, and the tank is heated above 70°C, then centrifuged, dried to obtain the crude product, and transformed The yield is 89.17%, the substrate is 6.46%, and the main impurity is 2.67%. Then, it is extracted and refined with methanol, glacial acetic acid, T reagent and activated carbon. After drying, methylprednisolone dehydrogenate is obtained, with a content of 96.99%, and the maximum impurity content 0.85%, yield 82.36%.

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Abstract

The invention discloses a method for preparing dehydrogenated methyl-prednisone which adopts the medium product of the methyl-prednisone as the fermentation substrate and carries out biological dehydrogenation with the arthrobacter. Compared with the prior art, the invention adopts the medium product of the methyl-prednisone as the fermentation substrate, and substitutes the biological dehydrogenation with arthrobacter for the chemical dehydrogenation technique in the prior art, thereby increasing the harvest rate from 55 to 70-85 percent, decreasing greatly the cost, and improving the purity of the product to more than 97 percent, accomplishing the industrialized production of methyl-prednisone, and completely avoiding the residue of the deadly poison of SeO2 through the green technique.

Description

Technical field: [0001] The invention relates to a method for preparing methylprednisolone dehydrogenate, belonging to the technical fields of medicinal chemistry and biopharmaceuticals. Background technique: [0002] Methylprednisolone is a corticosteroid drug, it has anti-inflammatory, anti-endotoxin, immune suppression, anti-shock and other pharmacological effects, can be made into clinical injections, and has very important clinical effects. Because the production technology of methylprednisolone drug is very complex and the production cycle is long, it is a technology-intensive product. Wherein, the 1-position dehydrogenation process of methylprednisolone is a key step in the production process of methylprednisolone, which directly affects the quality and yield of methylprednisolone. The original dehydrogenation process 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%, ...

Claims

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Application Information

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IPC IPC(8): C12P33/02C12R1/06
Inventor 林伟应明华张直庆
Owner ZHEJIANG XIANJU PHARMA
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