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Method for preparing 1,6-didehydro-17 alpha-hydroxyprogesterone

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: 2019-01-18
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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  • Method for preparing 1,6-didehydro-17 alpha-hydroxyprogesterone

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preparation example Construction

[0023] B. Preparation of debrominated compounds

[0024] 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%.

[0025] C. Crude refined

[0026] 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%.

[0027...

Embodiment 1

[0035] The preparation of step A, two bromines

[0036] 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%;

[0037] Step B, synt...

Embodiment 2

[0042] The preparation of step A, two bromines

[0043] 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 method for preparing 1,6-didehydro-17 alpha-hydroxyprogesterone. The method comprises the step that a dibromine material of 2,6-dibromine 17alpha-hydroxyprogesterone reacts with a debromination reagent in a second organic solvent for debromination, and thus 1,6-didehydro-17alpha-hydroxyprogesterone is obtained, wherein the debromination reagent is one or more of lithium bromide, lithium chloride, lithium carbonate and sodium carbonate, the ratio of the dibromine material to the debromination reagent is 1g to (1.7-2.5 g), and the ratio of the dibromine material to the second organic solvent is 1g to (13-24 ml). Compared with a traditional production method of 1,6-didehydro-17alpha-hydroxyprogesterone, the preparation method provided by the invention has many advantages of easy process operation, safe and environment-friendly production, low production cost, and the like; the product yield is high, the quality is good, and the production cost of the product can be reduced by 30-35%; and the solvents used in the process can be recycled, thus, economy and environmental protection are achieved, and industrial production is facilitated.

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 The keto approach. 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 protection, oxidation, cracking...

Claims

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Application Information

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IPC IPC(8): C07J7/00
Inventor 甘红星吴来喜胡爱国
Owner HUNAN KEREY BIOTECH
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