Preparation method of 2,6-dibromo 17a-hydroxyprogesterone

A technology of hydroxyprogesterone and bromine, which is used in the preparation of 1,6-didehydro-17a-hydroxyprogesterone, and in the field of key intermediates in the synthesis of progestogen drug cyproterone acetate, can solve the problem of unsolved problems. DDQ dehydrogenation agent and other problems, to achieve the effect of high product yield, conducive to industrial production, and simple process operation

Inactive Publication Date: 2019-01-22
HUNAN KEREY BIOTECH
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AI Technical Summary

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 2,6-dibromo 17a-hydroxyprogesterone
  • Preparation method of 2,6-dibromo 17a-hydroxyprogesterone

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

[0029] The specific co...

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 2,6-dibromo 17a-hydroxyproxyprogesterone. The method includes the steps that 17a-hydroxyproxyprogesterone is reacted with bromine in a first organic solvent and an acid environment to obtain the dibromination product 2,6-dibromo 17a-hydroxyproxyprogesterone by making 2 and 6 sites of a 17a-hydroxyproxyprogesterone molecule subjected to dibromination,wherein a ratio of the 17a-hydroxyproxyprogesterone to the bromine to acid is 1g to (1.2 to 1.8 g) to (0.1 to 0.4 g), and a ratio of the 17a-hydroxyproxyprogesterone to the first organic solvent is 1g to (2 to 15 ml). The invention further provides a preparation method of 1,6-didehydro-17a-hydroxyproxyprogesterone correspondingly. The preparation methods of the 2,6-dibromo 17a-hydroxyproxyprogesterone and the 1,6-didehydro 17a-hydroxyproxyprogesterone have the advantages of simple and convenient process operation, safe and environment-friendly production, low production cost and the like. Compared with traditional production methods, the method has high product yield, good quality, and can reduce the product production cost by 30% to 35%; the solvent used in the process can be recovered and recycled, which is economical and environmentally friendly at the same time, and is very beneficial to industrial production.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and specifically relates to a progestin drug cyproterone acetate (abbreviated as CPA) synthesis key intermediate 2,6-dibromo17a-hydroxyprogesterone and The preparation method of 1,6-didehydro-17a-hydroxyprogesterone. 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 react...

Claims

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Application Information

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