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Preparation method of chlormadinone acetate

A technology of chlormadinone acetate and chlormadinone, which is applied in the direction of steroids and organic chemistry, can solve the problems of low synthesis yield, difficult environmental protection treatment, low product purity, etc., and achieve high synthesis yield , good product quality, and easy process operation

Inactive Publication Date: 2018-02-16
HUNAN KEREY BIOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The purpose of the present invention is to solve many side reactions existing in the production of chlormadinone acetate, many impurities, low product purity, low synthetic total yield, difficult environmental protection treatment, high production cost and many other defects, to provide a new acetic acid The preparation method of chlormadinone

Method used

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  • Preparation method of chlormadinone acetate

Examples

Experimental program
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Embodiment 1

[0035] A. Preparation of 6 dehydrogenates

[0036] In a 2000ml three-necked bottle, add 100g of 17a hydroxyprogesterone, 200ml of dioxane, and 80g of acetic acid solution of 25% hydrobromic acid, stir to make the system strongly acidic, control the temperature at 25-30°C, and slowly add 80g dropwise The solution made of bromine and 600ml dioxane should be dripped in 1.0-1.5 hours. After the dripping, keep warm at 25-30°C for 4-6 hours. TLC confirms the reaction end point. After the reaction, 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 for 3-4 hours, centrifuge, wash with water until neutral, and dry under vacuum below 40°C to obtain bromine: 6-bromo-17a hydroxyprogesterone 126.8g, HLPC content 98.5%, moisture content 4.2%; In the three-necked flask, add 1000ml DMF, heat to 50-55°C...

Embodiment 2

[0044] A. Preparation of 6 dehydrogenates

[0045] In a 2000ml three-neck flask, add 100g 17a hydroxyprogesterone, 200ml toluene, 80g 25% hydrobromic acid aqueous solution, stir to make the system strongly acidic, control the temperature at 25-30°C, slowly add 80g bromine and 600ml The solution made of DMF should 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 confirms the reaction end point. After the reaction, slowly add 200ml of 30% Sodium hydrosulfite aqueous solution to completely destroy bromine, and then 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 under vacuum below 40°C to obtain bromide: 123.8g of 6-bromo-17a hydroxyprogesterone, HLPC content 98.8%, moisture content 4.0%; then add the above dibromide to a 2000...

Embodiment 3

[0053] A. Preparation of 6 dehydrogenates

[0054] In a 2000ml three-necked bottle, add 100g 17a hydroxyprogesterone, 200ml chloroform, 80g 25% hydrobromic acid acetic acid solution, stir to make the system strong acidic, control the temperature at 25-30°C, slowly add 80g bromine and The solution made of 600ml chloroform should 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 confirms the reaction end point. After the reaction, slowly add 200ml 30% Sodium hydrosulfite aqueous solution to completely destroy bromine, then concentrate under reduced pressure to recover 90-95% chloroform, after concentration, cool down to 10-15°C, add 600ml tap water, stir and crystallize for 3-4 hours, centrifuge, and wash with water until Neutral, vacuum-dried below 40°C to obtain bromine: 122.8g of 6-bromo-17a hydroxyprogesterone, HLPC content 98.7%, moisture content 4.5%; then add the above-mentioned dibromine to a 2000ml three-necked bo...

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Abstract

A preparation method of chlormadinone acetate includes: using 17a hydroxyl progestin as a raw material, dissolving the same in an organic solvent, reacting with bromine under acid catalysis to obtaina bromination product, and enabling the bromination product to react with lithium bromide and lithium carbonate in the organic solvent for debromination to obtain 6 dehydrogenation product in the organic solvent; dissolving the 6 dehydrogenation product in the organic solvent to react with organic peroxy acid to obtain epoxide; dissolving the epoxide in the organic solvent to be in additive reaction with hydrogen chloride gas, and dehydrating in a strong acid solution to obtain chlormadinone; dissolving chlormadinone in the organic solvent to react with acetic anhydride under acid catalysis toobtain chlormadinone acetate. HPLC content is 99.0-99.5%, and total yield of four-step synthetic reaction is 80-82%. Compared with conventional synthetic methods, the preparation method is simple andconvenient to operate, economical, environment-friendly and high in synthetic total yield and in product quality, and cost is lowered by 40-45%; the solvent used in the method can be recycled, so that industrial production is facilitated greatly.

Description

technical field [0001] The invention belongs to the preparation process of steroid hormone drugs, and in particular relates to a preparation method of the progestin drug chlormadinone acetate. Background technique [0002] Chlormadinone acetate, chemical name: 6-chloro-17a-acetoxy-pregna-4,6-diene-3,20-dione, is a high-efficiency progestogen drug that can inhibit ovulation. It is combined with long-acting estrogen to make long-acting oral contraceptives, which are mainly used for female contraception clinically. Due to good curative effect and low side effects, the market application prospect is broad. The traditional production method of chlormadinone acetate is to use 17a hydroxyprogesterone as raw material, diacetylate with acetic anhydride, chlorinate bleaching powder, etherify with triethyl orthoformate, and dehydrogenate with DDQ (or tetrachlorobenzoquinone) and other four-step reactions, and its synthetic route is shown in the attached figure 1 . The diacetylation ...

Claims

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Application Information

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IPC IPC(8): C07J7/00
Inventor 甘红星左前进胡爱国谢来宾
Owner HUNAN KEREY BIOTECH
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