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Preparation method of drospirenone

A drospirenone and dihydroxy technology, applied in the field of preparation of drospirenone, can solve the problems of low product yield, high production cost, poor product quality and the like, and achieve high yield and purity, low cost and short preparation steps Effect

Active Publication Date: 2013-01-23
HANGZHOU FST PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to solve the problems of high production cost, low product yield and poor product quality in the existing drospirenone preparation method, and provide a preparation method of drospirenone, which has high efficiency and low production cost , less by-products, no special requirements for production equipment, mild reaction conditions, stable process, easy operation and no damage to the environment, suitable for large-scale industrial production, and the product obtained by this method is of stable quality, high yield and purity, without purification

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0034] (1) Preparation of 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androst-17-one

[0035]Add 220ml of THF, 13g of cuprous chloride and 58g of zinc powder into the reaction flask, heat to 65°C and keep reflux reaction for 4h, then add 14.5g of 3β, 5-dihydroxy-15β, 16β after cooling to room temperature -methylene-5β-androst-6-en-17-one, then dropwise add 63g diiodomethane to the reactor, control the rate of addition to keep the reaction temperature at room temperature, and keep the temperature until TLC after the addition of diiodomethane The test showed that the substrate point completely disappeared, and 60g of acetic acid solution with a mass concentration of 36% was added dropwise, and the precipitated solid was collected and dried to obtain 13.1g of 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene Base-5β-androst-17-one. TLC: petroleum ether: ethyl acetate = 1:2.

[0036] (2) Preparation of 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androst-17β-hydroxy-21-carboxylic acid met...

Embodiment 2

[0043] The other steps of this example are the same as in Example 1, except that the 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androst-17-one in step (1) preparation:

[0044] Add 225ml of THF, 15g of cuprous chloride and 60g of zinc powder into the reaction flask, heat to 70°C and keep reflux reaction for 3h, then add 15g of 3β,5-dihydroxy-15β,16β- Methylene-5β-androst-6-en-17-one, then dropwise add 64g of diiodomethane to the reactor, control the rate of addition to keep the reaction temperature at room temperature, keep the reaction until TLC detection after the addition of diiodomethane is completed It shows that the substrate point has completely disappeared, and 64g of acetic acid solution with a mass concentration of 34% is added dropwise, and the precipitated solid is collected and dried to obtain 13.3g of 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene -5β-androst-17-one. TLC: petroleum ether: ethyl acetate = 1:2.

Embodiment 3

[0046] The other steps of this example are the same as in Example 1, except that the 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androst-17-one in step (1) preparation:

[0047] Add 230ml of THF, 17g of cuprous chloride and 62g of zinc powder into the reaction flask, heat to 75°C and keep reflux reaction for 3.5h, then add 15.5g of 3β, 5-dihydroxy-15β after cooling to room temperature, 16β-methylene-5β-androst-6-en-17-one, then dropwise add 65g diiodomethane to the reactor, control the rate of addition so that the reaction temperature is maintained at room temperature, and keep the insulation reaction until the diiodomethane is added dropwise. TLC detection showed that the substrate point completely disappeared, and 65g of acetic acid solution with a mass concentration of 33% was added dropwise, and the precipitated solid was collected and dried to obtain 13.4g of 3β,5-dihydroxy-6β,7β,15β,16β-diethylene Methyl-5β-androst-17-one. TLC: petroleum ether: ethyl acetate = 1:2.

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Abstract

The invention discloses a preparation method of drospirenone, which aims at solving the problems of high production cost, low yield, and poor product quality in the existing preparation method of the drospirenone. The preparation method comprises the steps of: taking 3beta, 5-dyhydroxy-15beta, 16beta-methylene-5beta-androstane-6 alkene-17-ketone as materials, firstly, reacting with diiodomethane and zinc-copper couple, introducing 6beta and 7beta cyclopropane structures, then orderly carrying out condensation reaction and esterification reaction in THF (tetrahydrofuran) solution of lithium metal and 3-methyl bromopropionate and DMF (dimethyl formamide) solution of sodium ethoxide, finally oxidizing by sodium hypochlorite, and dewatering the toluenesulfonic acid to obtain the drospirenone. According to the preparation method, the efficiency is high, the production cost is low, by-products are few, special demands on production equipment do not exist, the reaction condition is mild, the process is stable, the operation is convenient, the environment is prevented from being damaged, and the large-scale industrial production is facilitated. The product obtained by the method is stable in quality, high in yield and purity and free of purification.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing drospirenone using 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6en-17-one as a raw material . Background technique [0002] Drospirenone (Drospirenone, 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 methods, drospirenone has anti-mineralocorticoid and anti-androgen effects, but has no pharmacological activity on adrenocortical hormone and estrogen receptors. Drospirenone has been used for a long time The pharmaceutical composition for oral administration with contraceptive effect is prepared, and the market prospect is broad. [0003] European patent EP0076189 discloses a method for synthesizing drospirenone, which requires propynyl alcohol to introduce side c...

Claims

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Application Information

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IPC IPC(8): C07J53/00
Inventor 徐伟沈学全包戚明郑列为
Owner HANGZHOU FST PHARMA
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