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Novel preparation method of 6-methyl-17alpha-hydroxyprogesterone and precursor thereof

A technology of hydroxyprogesterone and a new method, applied in the direction of steroids, chemical recovery, organic chemistry, etc., can solve problems such as difficulties, serious pollution treatment, high production costs, etc., achieve yield and quality improvement, reduce production costs, and react mild effect

Pending Publication Date: 2021-11-02
佳尔科生物科技南通有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The object of the present invention is to provide a kind of preparation method of 6-methyl-17α-hydroxyprogesterone and its precursor, to solve the existing 6-methyl-17α-hydroxyprogesterone and The preparation method of its precursor 6-methylene-17-alpha hydroxyprogesterone, the process of introducing the 6-position methylene is seriously polluted and difficult to handle, while the overall process is complicated, the reaction time is long, the production cost is high, and the yield is low technical issues

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 33g17-alpha hydroxyprogesterone, 330g solvent ethyl acetate to the autoclave, then add 0.03g molecular sieve catalyst containing 0.1% rhodium, 0.03g triphenylphosphine; Air more than 3 times to ensure that there is no oxygen in the reactor; after the nitrogen replacement is completed, slowly introduce CO / H2 (V:V=1:1) into the autoclave, and react at 80°C and 3.3Mpa for 6 hours, HPLC After the tracking reaction is complete, cool and release the pressure, filter out the rhodium catalyst supported on molecular sieve; add 4g of potassium borohydride, carry out the reduction reaction at 50°C, and after the HPLC tracking reaction is complete, add dropwise glacial acetic acid to consume excess potassium borohydride; evaporate under reduced pressure Solvent, crystallized by cooling, filtered, washed with 10 g of ethyl acetate, and the obtained solid was vacuum-dried at 50 ° C to obtain 31 g of 6-methylene-17-α-hydroxyprogesterone with a content of 98.8% (HPLC, normalization ...

Embodiment 2

[0032] Add 33g17-alpha hydroxyprogesterone, 250g solvent ethyl acetate to the autoclave, then add 0.16g molecular sieve catalyst containing 0.1% rhodium, 0.03g triphenylphosphine; Air more than 3 times to ensure that there is no oxygen in the reactor; after the nitrogen replacement is completed, slowly introduce CO / H2 (V:V=1:1) into the autoclave, and react at 120°C and 5Mpa for 10 hours, followed by HPLC After the reaction is complete, cool and release the pressure, filter out the molecular sieve loaded rhodium catalyst; add 5.4g potassium borohydride, carry out the reduction reaction at 50 ° C, after the HPLC tracking reaction is complete, add dropwise glacial acetic acid to consume excess potassium borohydride; evaporate under reduced pressure The solvent was removed, cooled and crystallized, filtered, washed with 10 g of ethyl acetate, and the obtained solid was vacuum-dried at 50° C. to obtain 32 g of 6-methylene-17-α-hydroxyprogesterone with a content of 99.2% (HPLC, norm...

Embodiment 3

[0034] Add 33g17-alpha hydroxyprogesterone, 165g solvent ethyl acetate to the autoclave, then add 0.33g molecular sieve catalyst containing 0.1% rhodium, 0.03g triphenylphosphine; Air more than 3 times to ensure that there is no oxygen in the reactor; after the nitrogen replacement is completed, slowly introduce CO / H2 (V:V=1:1) into the autoclave, and react at 40°C and 1.5Mpa for 2 hours, HPLC After the tracking reaction is complete, cool and release the pressure, filter out the rhodium catalyst supported on molecular sieve; add 2.7g potassium borohydride, carry out the reduction reaction at 50 ° C, after the HPLC tracking reaction is complete, add dropwise glacial acetic acid to consume excess potassium borohydride; reduce pressure Evaporate the solvent, cool and crystallize, filter, wash with 10g ethyl acetate, and dry the obtained solid in vacuum at 50°C to obtain 31.5g of 6-methylene-17-αhydroxyprogesterone with a content of 99.1% (HPLC, normalization method) , yield 92%. ...

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PUM

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Abstract

The invention discloses a novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and a precursor 6-methylene-17-alpha-hydroxyprogesterone thereof. The 6-methylene-17-alpha-hydroxyprogesterone is prepared through a hydroformylation reaction via CO / H2 under the conditions that 17-alpha-hydroxyprogesterone is used as a raw material and a rhodium-loaded molecular sieve is used as a catalyst, and conducting reducing by using potassium borohydride. The 6-methyl-17alpha-hydroxyprogesterone is prepared through hydrogenation via a cheap catalyst, namely raney nickel by taking the 6-methylene-17-alpha-hydroxyprogesterone as a raw material. According to the invention, a 6-position methyl group is obtained by introducing a formyl group and then conducting reducing and hydrogenating, the catalyst can be recycled and reused, and the method is friendly to environment, simple in process, high in yield and low in cost.

Description

technical field [0001] The invention belongs to the technical field of steroid drugs and chemical industry, and in particular relates to a new preparation method of 6-methyl-17α-hydroxy progesterone and its precursor. Background technique [0002] Megestrol acetate (Megestrol) belongs to 17α-hydroxyprogesterone derivatives, is a highly efficient synthetic progesterone, its progesterone effect is about 75 times that of progesterone when taken orally, and about 50 times that of progesterone when injected . This product has obvious anti-estrogenic effect, no estrogenic or androgenic activity, no protein assimilation. It can inhibit the release of hypothalamic gonadotropin-releasing hormone (GnRH), and act on the pituitary gland to reduce its sensitivity to GnRH, thereby blocking the release of pituitary gonadotropin and producing a significant ovulation inhibitory effect. Used together as a short-acting contraceptive. When this product is used alone in larger doses, it can a...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/0045Y02P20/584
Inventor 王彩霞周革
Owner 佳尔科生物科技南通有限公司
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