Method for preparing drospiroenonand intermediate

A drospirenone and compound technology, applied in the direction of steroids, organic chemistry, etc., can solve the problem of high toxicity of chromium oxidant, and achieve the effect of reducing toxicity and short steps

Inactive Publication Date: 2009-08-12
2Y CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The present invention aims to solve the above problems, overcome the problems of long reaction process and high toxicity of oxidants containing heavy metal chromium, and provide a new method for preparing drospirenone

Method used

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  • Method for preparing drospiroenonand intermediate
  • Method for preparing drospiroenonand intermediate
  • Method for preparing drospiroenonand intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of 3-trimethylsilyloxyandrost-5-ene-15β,16β-methylene-17-one-step i

[0050]5 g of triethylamine was added to a solution of 10 g of 3-hydroxyandrost-5-ene-15β,16β-methylene-17-one and 200 mL of dichloromethane. At 0°C, 5.5 g of trimethylchlorosilane was added dropwise into the reaction solution. Stir at room temperature for 3 hours. Then pour the reaction solution into 100mL water, let it stand still, and separate the water layer. The organic layer was washed with 100 mL of water and 100 mL of saturated brine, and dried over anhydrous magnesium sulfate. After spin-drying, 12 g of a light yellow solid was obtained with a yield of 97.7%. The plies showed essentially no impurities. TLC: ethyl acetate: petroleum ether = 1:1

[0051] 1 H-NMR (400MHz, CDCl 3 )δ: 0.11(s, 6H), 0.97(s, 3H), 1.06(s, 3H), 2.23-1.05(m, 19H), 3.43(m, 1H), 5.40(d, 1H)

Embodiment 2

[0053] Preparation of 15β,16β-methylene-3β-hydroxy-17α-pregna-17β-hydroxy-21-hydroxymethyl-5-ene-step ii

[0054] Under the protection of nitrogen, 1.5 g of metallic lithium was added into 100 mL of tetrahydrofuran. At 0°C, a solution of 9 g of 3-trimethylsiloxyandrost-5-ene-15β,16β-methylene-17-one and 100 mL of tetrahydrofuran was added to the above solution. After 30 minutes, 16 g of chloropropyl trimethylsilyl ether was added dropwise to the reaction solution, keeping the temperature at 0°C. The reaction solution was stirred overnight at room temperature.

[0055] At 0°C, 8 mL of methanol was added to the reaction solution and stirred overnight. The reaction solution was poured into 300 mL of water, stirred for 1 hour and then filtered. The filter cake was washed with water until neutral and dried to obtain 7.08 g of off-white solid, with a yield of 81.3%. The plies showed essentially no impurities. TLC: dichloromethane: methanol = 4:1

Embodiment 3

[0057] Preparation of 15β,16β-methylene-3β-hydroxy-17α-pregna-17β-hydroxy-21-hydroxymethyl-5-ene-step ii

[0058] Under nitrogen protection, at 0°C, add 0.02 g of lithium metal to a solution of 0.124 g of 3-trimethylsilyloxyandrost-5-ene-15β, 16β-methylene-17-one and 5 mL of tetrahydrofuran , and then added 0.222 g of chloropropyltrimethylsilyl ether. The reaction solution was stirred overnight at room temperature.

[0059] Add 5 mL of methanol and stir overnight. Add 10 mL of water, stir for 1 hour and then filter. The filter cake is washed with water until neutral, and dried to obtain 0.1 g of off-white solid with a yield of 83.4%. The plies showed essentially no impurities. TLC: dichloromethane: methanol = 4:1

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Abstract

The invention relates to a new method for preparing drospirenone (6 beta, 7 beta; 15 beta, 16 beta- dimethylene-3-oxo-17 alpha- pregna-4-alkene-21, 17- carboxyl lactone) and an intermediate product obtained by the method, that is, 3- androstane protected by hydroxy group-5- alkene-15 beta, 16 beta- methylene-17-ketone. The invention uses the 3- androstane protected by hydroxy group-5- alkene-15 beta, 16 beta-methylene-17-ketone being available in the market as the starting material, which forms loop coils by the steps such as the hydroxy group protection, addition, hydrolysis, oxidation, and finally forms triatomic ring to prepare the drospirenone.

Description

technical field [0001] The invention relates to a new method for preparing drospirenone and the intermediate product 3-hydroxyl-protected androst-5-ene-15β, 16β-methylene-17-one of the method, belonging to the technical field of synthetic steroid methods. Background technique [0002] Drospirenone (Drospi renone, 6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregna-4-ene-21, 17-carboxylide), is a highly effective, low toxicity , a new generation of steroidal contraceptives without side effects. Compared with other progestogens also obtained by synthetic means, the pharmacological activity of drospirenone is more similar to that of natural progesterone in the human body. Drospirenone has anti-mineralocorticoid and anti-androgen effects, but It has no pharmacological activity on adrenocortical hormone and estrogen receptors. Oral contraceptives containing the progestin drospirenone have favorable effects on bone metabolism and are therefore particularly indicated for women at risk ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J53/00
Inventor 刘星吕小银何训贵王元
Owner 2Y CHEM
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