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Preparation method of 1,6-didehydro-17a-hydroxyprogesterone product

A technology of hydroxyprogesterone and double dehydrogenation, applied in the direction of steroids, organic chemistry, etc., can solve the problems of DDQ dehydrogenation agent, etc., and achieve the effect of high product yield, low production cost and good quality

Inactive Publication Date: 2019-03-12
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it is still necessary to use figure 1 DDQ shown in , dehydrogenates the 1-position of 6-dehydro-17a-hydroxyprogesterone, so this still does not solve the problem of needing to use the relatively expensive and toxic DDQ dehydrogenating agent

Method used

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  • Preparation method of 1,6-didehydro-17a-hydroxyprogesterone product

Examples

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preparation example Construction

[0025] B. Preparation of debrominated compounds

[0026] Dissolve the above bis-bromide in an organic solvent, add lithium chloride and lithium carbonate, heat up to 40-80°C and stir to dissolve, then keep warm at 40-120°C for 2-6 hours, TLC confirms the reaction end point, after the reaction, Adjust the pH to neutral, concentrate under reduced pressure to recover the organic solvent, then cool; add tap water, stir and crystallize at 5-25°C for 3-6 hours, centrifuge, wash, and dry to obtain the debrominated product: 1,6-didehydro- 17a-hydroxyprogesterone crude product, HLPC content 97.0-98.5%, weight yield 62.5.-65.0%.

[0027] C. Crude refined

[0028] Decolorize and recrystallize the above-mentioned crude debrominated product with activated carbon in low-carbon alcohols below C4 to obtain 1,6-didehydro-17a-hydroxyprogesterone product, the HPLC content is 99.0-99.5%, and the melting point is 228-232°C. This step The weight yield of the synthesis reaction is 50-55%.

[0029...

Embodiment 1

[0037] The preparation of step A, two bromines

[0038] In a 2000ml three-necked flask, add 100g 17a hydroxyprogesterone, 200ml dioxane, 80g 25% hydrobromic acid acetic acid solution, stir to make the system strongly acidic, control the temperature at 25-30°C, and slowly add 140g The solution made of bromine and 600ml dioxane should be dripped within about 1.0-1.5 hours. After the dripping, continue to keep warm at 25-30°C for 4-6 hours. TLC confirms the reaction end point. After the reaction, slowly Slowly add 200ml of 30% hydrosulfite aqueous solution to completely destroy bromine, then concentrate under reduced pressure to recover 90-95% of dioxane, after concentration, cool down to 10-15°C, add 600ml of tap water, stir and crystallize Centrifuge for 3-4 hours, wash with water until neutral, and dry under vacuum below 40°C to obtain 144.8g of bisbromide 2,6-dibromo-17a-hydroxyprogesterone, HLPC content 98.2%, moisture content 3.5%, weight yield 144.8%;

[0039] Step B, sy...

Embodiment 2

[0044] The preparation of step A, two bromines

[0045] In a 2000ml three-necked flask, add 100g 17a hydroxyprogesterone, 500ml toluene, 80g 25% hydrobromic acid aqueous solution, stir to make the system strongly acidic, control the temperature at 25-30°C, slowly add 140g bromine and 300ml The solution made of DMF will be dropped within about 1.0-1.5 hours. After the drop, continue to keep warm at 25-30°C for 4-6 hours. TLC will confirm the reaction end point. After the reaction, slowly add 200ml of 30% Sodium hydrosulfite aqueous solution to completely destroy bromine, then wash twice with 600ml tap water, separate the water, dry with 50g anhydrous magnesium sulfate, and concentrate under reduced pressure to recover 90-95% of the mixed solvent of toluene and DMF. After concentration, Cool down to 10-15°C, add 600ml of tap water, stir and crystallize for 3-4 hours, centrifuge, wash with water until neutral, and dry in vacuum below 40°C to obtain the dibromo 2,6-dibromo-17a-hyd...

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Abstract

The invention provides a preparation method of a 1,6-didehydro-17a-hydroxyprogesterone product. The preparation method comprises the following steps: firstly, enabling 17a-hydroxyprogesterone to reactwith bromine in a first organic solvent and an acidic environment to obtain a dibromide 2,6-dibromo 17a-hydroxyprogesterone; enabling the above dibromide to react with a debromination reagent in a second organic solvent for double debromination to obtain 1,6-didehydro-17a-hydroxyprogesterone; and finally, performing heating refluxing on the 1,6-didehydro-17a-hydroxyprogesterone crude product in lower alcohol under C4, and performing discoloring and recrystalization to obtain the 1,6-didehydro-17a-hydroxyprogesterone product. Compared with a traditional production method, the preparation method of the 1,6-didehydro-17a-hydroxyprogesterone product, disclosed by the invention, has the advantages of simple process operation, safe and environmentally friendly production, low production cost and the like. Compared with the traditional production method, the method is high in product yield and high in quality, and the production cost of the product can be reduced by 30 to 35 percent; the solvent used in the process can be recycled and reused, so that the method is economical, environmentally friendly and very advantageous for industrial production.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically relates to a key intermediate in the synthesis of progesterone drug cyproterone acetate (CPA for short) 1,6-didehydro-17a-hydroxy luteum Process for the preparation of ketone products. Background technique [0002] Cyproterone acetate, referred to as CPA, commonly known as cyproterone, the chemical name is 6-chloro-1.2a-methine-17a-hydroxy-pregna-1,4-diene-3,20-di Ketone-17-acetate is a kind of progestin drug, which is mainly used clinically for female contraception, female acne, and the treatment of hirsutism and alopecia caused by excessive male androgen secretion, and is also used for male benign The treatment of diseases such as prostatic hypertrophy and early prostate cancer has a huge market. The production method of CPA is to extract diosgenin from the yam plant, and obtain the key intermediate 17a-hydroxyl by 8-step reactions such as pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor 胡爱国谢来宾甘红星
Owner HUNAN KEREY BIOTECH
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