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Method for preparing steroidal drug intermediate

A technology of steroidal drugs and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of many by-products and low yield of target products, and achieve the effects of improving production efficiency and reducing production costs

Active Publication Date: 2018-09-21
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the synthetic route of steroidal drug intermediates, the appropriate upstream intermediates are usually selected and carried out by biotransformation methods, but the general biotransformation method converts the target product with low yield and many by-products

Method used

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  • Method for preparing steroidal drug intermediate
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  • Method for preparing steroidal drug intermediate

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preparation example Construction

[0023] The preparation method of a steroid drug intermediate according to one embodiment of the present invention comprises the following steps: using Nocardia simplex to carry out microbial transformation of the first compound to obtain a steroid drug intermediate, the first compound is shown in general formula I, steroid The body drug intermediate is shown in general formula II,

[0024]

[0025] In the general formula I and the general formula II, R is H, a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group or a phenyl group.

[0026] In this embodiment, the first compound represented by the above general formula I is selected as the substrate, and only Nocardioides simplex is used for biotransformation, and the substrate is simultaneously dehydrogenated at positions 1 and 2 and acetate at position 21 Hydrolysis to obtain steroid drug intermediates, hydrolysis of 21-position acetate can effectively promote the dehydrogenation of 1 and 2 positions, so that mo...

Embodiment 1

[0048] Pack 12 liters of fermentation medium in a 20 liter fermenter, and inoculate 600 mL of Nocardia simplex seed liquid (thalline concentration: 2.4×10 9 cells / ml), culture was started, and the culture conditions were temperature of 31° C., rotation speed of 160 rpm, and culture time of 24 hours.

[0049] The sample was diluted 30 times, and detected with a spectrophotometer at 580 nm, and the OD value was 0.62. 240 g of 4,9(11)-pregna-17-hydroxy-3,20-dione-21-acetate and 9.6 g of PPE were added to the fermenter to start the fermentative transformation. The culture conditions during fermentation transformation were temperature 31±1°C, rotation speed 180rpm, air flow 0.2-0.3vvm, and samples were taken after 72 hours of transformation for HPLC analysis. The results are shown in Table 1:

[0050] Table 1

[0051]

[0052] After the conversion is completed, the fermented liquid is extinguished and filtered to obtain a filter cake with a wet weight of 390g, which is dried t...

Embodiment 2

[0066] Pack 12 liters of fermentation medium in a 20 liter fermenter, and inoculate 600 mL of Nocardia simplex seed liquid (thalline concentration: 3.2×10 9 cells / ml), culture was started, and the culture conditions were temperature of 31° C., rotation speed of 160 rpm, and culture time of 24 hours.

[0067] The sample was diluted 30 times, and detected with a spectrophotometer at 580 nm, and the OD value was 0.56. 240 g of 4,9(11)-pregna-17-hydroxy-3,20-dione-21-acetate and 9.6 g of PPE were added to the fermenter to start the fermentative transformation. The culture conditions during fermentation transformation were temperature 31±1°C, rotation speed 180rpm, air flow rate 0.2~0.3vvm, after 72 hours of transformation, samples were taken and sent to HPLC analysis, the results are shown in Table 5:

[0068] table 5

[0069]

[0070] After the conversion is completed, the fermentation broth is extinguished and filtered to obtain a filter cake with a wet weight of 373g, whic...

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Abstract

The invention relates to a method for preparing a steroidal drug intermediate. The method comprises the steps that microbial conversion is conducted on a first compound with Nocardioides simplex to obtain the steroid drug intermediate, the first compound is shown as a formula I, the steroidal drug intermediate is as shown in a formula II, and in the formula I and the formula II, R is H, a halogenatom, an alkyl group, an alkoxy group, a hydroxyl group or a phenyl group. The method selects 4, 9 (11)-pregnant-17-hydroxy group-3,20 dioxin-21-acetate as a substrate, uses only the Nocardioides simplex for biotransformation, dehydrogenation at position 1,2 and hydrolysis of acetate at position 21 are simultaneously conducted on the substrate, 1,4,9 (11)-pregnene-17,21-diol-3,20-dione is obtained, products formed through transformation are mainly the 1,4,9(11)-pregnene-17,21-diol-3,20-dione, the proportion of by-products is low, the purified products are white or off-white crystals, relativesubstrate weight yield is 75%-85%, a target product yield is high, after a HPLC analysis, the purity is >=99%, and external standard content is 98%.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of steroidal pharmaceutical intermediates. Background technique [0002] Steroids have a variety of biological activities, and their applications are very extensive, some of which are used to treat diseases or develop production, such as hydrocortisone for the treatment of allergic diseases, progesterone for contraceptives, spironolactone for diuretics, synthetic steroids Hormone diosgenin, cardiotonic Digoxin, bufotoxin, etc. are all steroidal compounds. Steroid drug intermediates can be further synthesized to obtain 3TR, fluocinolone, triamcinolone acetonide and other series of drugs that are widely used in clinical practice. [0003] In the synthetic route of steroidal drug intermediates, the appropriate upstream intermediates are usually selected and carried out by biotransformation methods, but the general biotransformation met...

Claims

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Application Information

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IPC IPC(8): C12P33/02C12P33/00C07J7/00C12R1/365
CPCC07J7/008C12P33/005C12P33/02
Inventor 王敬华刘喜荣孟浩陈宏
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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