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A New Method for Synthesizing 17α-Hydroxyprogesterone

A technology of hydroxyprogesterone and hydroxyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of low 3-position ketal protection yield, low overall yield, incomplete reaction, etc., and achieves easy industrial implementation and simple post-processing , the effect of less raw materials

Active Publication Date: 2016-06-08
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The 3-position ketal protection yield is not high, the content is not high, and there is an isomer with a 4-position double bond. This isomer cannot obtain the desired product during Grignard addition, so the final overall yield is low , the quality is difficult to meet the high standard requirements
[0012] The 3-position ether protection is reversible, the reaction is incomplete, the color is darker, the quality is poor, and the yield is not high, so the overall yield is low, and the quality is difficult to meet the high standard requirements

Method used

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  • A New Method for Synthesizing 17α-Hydroxyprogesterone

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Embodiment 117

[0038] Synthesis of embodiment 117α-hydroxyprogesterone (01)

[0039] At room temperature, in a 5000L enamel reaction kettle equipped with a thermometer and a stirrer, add 1000L of toluene, stir, add 200kg of 17β-cyano-17α-hydroxy-4-androsten-3-one (02) and 87kg of imidazole , lower the temperature to -5~0°C, add 153kg of trimethylchlorosilane, stir evenly, slowly add 2400kg of 2M methylmagnesium chloride solution dropwise, keep the temperature at -5~0°C for 2 hours, then slowly raise the temperature to 55°C~60 ℃, heat preservation reaction for 4 hours, after the plate reaction is complete, cool the ice brine to below 10 ℃, slowly transfer to the ammonium chloride aqueous solution cooled by circulating water, stir for 30 minutes, stand still for 30 minutes, separate the brine layer, and use 200kg Wash once with tap water, separate the tap water, add 6kg of activated carbon, decolorize at 55-60°C for 2 hours, heat-retain and filter, wash with an appropriate amount of toluene, t...

Embodiment 217

[0040] The synthesis of embodiment 217α-hydroxyprogesterone (01)

[0041] The synthesis method is the same as in Example 1, except that in this example, the 87kg of imidazole in Example 1 is replaced with 105kg of 2-methylimidazole. Finally, 195.92kg of 17α-hydroxyprogesterone (01) was obtained, with a weight yield of 97.96%, a molar yield of 92.91%, and a melting point of 216.0-220.0°C. The synthesis of embodiment 317α-hydroxyprogesterone

Embodiment 317

[0042] Synthetic method is the same as embodiment 1, and difference is only in the present embodiment, the methylmagnesium chloride solution 2400kg of 2M among the example 1 is reduced to 2000kg. Finally, 194.87kg of 17α-hydroxyprogesterone (01) was obtained, with a weight yield of 97.44%, a molar yield of 92.42%, and a melting point of 215.0-219.0°C. The synthesis of embodiment 417α-hydroxyprogesterone

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Abstract

The invention provides a novel method of synthesizing 17 alpha-hydroxyl progesterone (01). The novel method comprises the following steps: 1) in the presence of trimethylsilyl chloride and a methyl magnesium chloride solution, performing double-protection reaction on 17 bata-cyano-17 alpha-hydroxyl-4-androstene-3-one (02) to produce a compound (03); 2) heating up to perform grignard addition reaction, and transferring into an ammonium chloride aqueous solution to produce a compound (04); 3) preserving the heat and discoloring by active carbon, adding diluted acid water to reflux and perform hydrolysis reaction of double protection groups, and separating and purifying to obtain 17 alpha-hydroxyl progesterone (01). According to the novel method disclosed by the invention, the conventional 3-position ketal protection, 17 alpha-hydroxyl vinyl ether protection, grignard addition, re-hydration of protection groups on position 3 and position 17 and discoloring-refining are simplified into one-step operation.

Description

technical field [0001] The invention relates to the synthesis of pharmaceutical intermediates, in particular to a new method for synthesizing 17α-hydroxy progesterone. Background technique [0002] 17α-Hydroxyprogesterone is a common intermediate for the production of steroidal corticosteroids. Using it as a raw material, it can produce various common corticosteroids such as medroxyprogesterone, cyproterone megestrol, hydrocortisone, and prednisone. [0003] The most traditional production method: extract diosgenin from yam plants; saponin undergoes ring-opening, oxidation, and hydrolysis to obtain the key intermediate acetate dienolone (diene for short); 17α-Hydroxyprogesterone was obtained through four steps of oxidation, Ostrich oxidation, bromination, and debromination. Due to the gradual depletion of yam plant resources, the pollution during the extraction of saponin is large, so the price of saponin raw materials is high. In addition, the follow-up synthesis steps a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor 甘红星左前进谢来宾
Owner HUNAN KEREY BIOTECH
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