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Method for preparing compound 6beta, 19beta-epoxy-4-androstene-3, 17-diketone

A compound and androstene technology, which is applied in the field of preparation of compound 6β,19β-epoxy-4-androstene-3,17-dione, can solve the problems of high cost and large usage amount, and achieve cost saving , the effect of improving the reaction speed, improving product quality and yield

Inactive Publication Date: 2012-05-09
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, this cyclization condition also has certain disadvantages: 1. still need to use the first class solvent-benzene (carcinogen) or carbon tetrachloride (toxicity and environmental pollution) etc. that are restricted in the drug production in the reaction; 2. iodine diacetate Benzene PhI(OAc) 2 The usage is large, and the cost is high when applied to industrial production

Method used

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  • Method for preparing compound 6beta, 19beta-epoxy-4-androstene-3, 17-diketone
  • Method for preparing compound 6beta, 19beta-epoxy-4-androstene-3, 17-diketone
  • Method for preparing compound 6beta, 19beta-epoxy-4-androstene-3, 17-diketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of the compound shown in formula 3a

[0031]

[0032] Add 16.5g compound 3β-acetoxy-androst-5-en-17-one (formula 2) (purchased from Zhejiang Shenzhou Pharmaceutical Co., Ltd.) into the reaction kettle, stir with 125mL dioxane and 25mL water Dissolve and cool down to 0°C. Slowly add 2.5mL of 1N perchloric acid and control the temperature at 0°C. Add 7.59g of N-bromoacetamide (NBA) in batches, react at 0°C, and follow the complete reaction by TLC. Pour into ice water, extract with chloroform, wash twice with 10% sodium sulfite 100mL, wash with water, concentrate under reduced pressure, centrifuge, add 500mL ethyl acetate to the wet product, reflux with 0.8g activated carbon, filter, concentrate under reduced pressure, centrifuge, and dry About 12.7 g of bromoalcoholate 3a was obtained, and the yield was about 60%.

[0033] mp: 174-176°C; EI MS (70eV, m / z): 428 (M + , 10%); 1 H NMR (300MHz, CDCl 3)δ5.44-5.48(m, 1H, 3-H), 4.23-4.33(m, ...

Embodiment 2

[0034] Embodiment 2: the preparation of the compound shown in formula 3b

[0035]

[0036] Add 30 g of compound 3β-acetoxy-androst-5-en-17-one (Formula 2) into the reaction kettle, stir and heat the solution with 600 mL of acetone, and cool down to -30°C. Slowly add 50% acetic acid (82.5 mL) and control the temperature at -30°C. Calcium hypochlorite (41 g in total) was added in batches, and after the addition was completed and the insulation reaction was completed, the reaction was followed by TLC. About 150 mL of 10% sodium sulfite was added dropwise to stop the reaction. Concentrate the acetone under reduced pressure, add 900mL ice water, stir for half an hour, centrifuge, rinse with water until neutral, and shake dry. Add 900 mL of ethyl acetate to the wet product, reflux 1.5 g of activated carbon, filter, concentrate under reduced pressure, centrifuge, and dry to obtain about 24 g of chloroalcohol compound 3b, with a yield of about 70%.

[0037] mp: 224-226°C; EI MS ...

Embodiment 3

[0038] Embodiment 3: the preparation of the compound shown in formula 4a

[0039]

[0040] Add 20 g of bromoalcoholate 3a, 400 mL of cyclohexane, 12 g of anhydrous sodium carbonate, 5 g of iodine, 11 g of N-chlorosuccinimide (NCS), and 1.6 g of benzoyl peroxide. Illumination, heating and reflux. TLC followed the reaction. After the reaction was complete, the temperature was lowered, and 100 mL of 5% sodium thiosulfate was added to wash, washed with water, and concentrated. Subsequently, 100 mL of methanol and 15 mL of aqueous solution of 4 g of potassium carbonate were added, and the temperature was raised to reflux until the reaction was complete. Concentrate under reduced pressure, add water and concentrate until thick, cool down, stir, centrifuge, and dry to obtain 14.3 g of cyclized product, with a yield of about 80%.

[0041] mp: 170-172°C; EI MS (70eV, m / z): 383 (M + , 50%); 1 H NMR (300MHz, CDCl 3 )δ4.01(d, 1H, 6-H), 3.98(m, 1H, 3-H), 3.88(d, 1H, 19-H a ), 3.86...

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Abstract

The invention relates to a method for preparing a major midbody of a 19-bit dishorn methyl steroid compound, in particular to a method for preparing a compound 6beta, 19beta-epoxy-4-androstene-3, 17-diketone, which comprises the following steps of: 1, halogen alcoholization reaction: 3beta-acetoxyl-androstane-5-alkene-17-ketone takes halogen alcoholization reaction or chlorine alcoholization reaction to generate 3beta-acetoxyl-5alpha-bromo / chloro-6beta-hydroxyl-17-ketone; 2, illumination cyclization reaction: compounds obtained in the first step take cyclization reaction under the illumination condition in the existence of iodine, halide and catalysis quantity of radical initiators to obtain 3beta-hydroxyl-5alpha-halogenate-6beta, 19beta-epoxy-17-ketone; and 3, oxidation elimination reaction: (1) the compounds obtained in the second step take oxidation reaction under the effect of oxidizing agents to generate corresponding oxides; and (2) the obtained oxides take elimination reaction through being heated under the alkaline condition to generate 6beta, 19beta-epoxy-4-androstene-3, 17-diketone.

Description

technical field [0001] The invention relates to a preparation method of a main intermediate of a 19-position deangling methyl steroid compound, in particular to a preparation method of a compound 6β, 19β-epoxy-4-androstene-3,17-dione. Background technique [0002] Compound 6β, 19β-epoxy-4-androstene-3,17-dione (Formula 1) is the main intermediate for preparing the 19-position deangular methyl steroid compound. Studies have shown that the 19-position deangling methyl steroid compound has stronger biological activity than the corresponding steroid compound. Many steroidal contraceptives, such as norethindrone series, and anti-early pregnancy drugs mifepristone (RU-486), cemipristone, nandrolone series and other products are steroids with a 19-position deangling methyl structure compound. [0003] At present, for 6β, the preparation of 19β-epoxy-4-androstene-3,17-dione mainly obtains 5α-chloro-6β-hydroxyl intermediate (formula 3b) through chlorohydrinization addition reaction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00
Inventor 王友富杨亚玺王荣王均良
Owner ZHEJIANG SHENZHOU PHARMA
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