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Drospirenone intermediate, and preparation method thereof, application thereof in preparation of drospirenone

An intermediate, drospirenone technology, applied in the field of medicinal chemistry, can solve the problems of unsuitability for industrial production and high toxicity, and achieve the effects of simple preparation, stable quality, and reduced pollution

Active Publication Date: 2013-10-23
SHANGHAI ACEBRIGHT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the oxidant used in this route is still a chromium reagent, which is highly toxic and not suitable for industrial production.

Method used

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  • Drospirenone intermediate, and preparation method thereof, application thereof in preparation of drospirenone
  • Drospirenone intermediate, and preparation method thereof, application thereof in preparation of drospirenone
  • Drospirenone intermediate, and preparation method thereof, application thereof in preparation of drospirenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] One, preparation formula II compound

[0034] Heat 60mL dimethyl sulfoxide (DMSO), 40mL tetrahydrofuran (THF), and 10g potassium tert-butoxide to 60°C for 30 minutes, then cool to 0~-10°C, add 16g trimethyl bromide sulfide, and Stir at 0°C for 30 minutes, then add 10 g of compound of formula I, react at 0°C for 1 hour, monitor the completion of the reaction by TLC, crystallize in ice water, filter, and dry to obtain 10.3 g of compound of formula II.

[0035] TLC monitoring conditions are: cyclohexane: ethyl acetate = 1:2.

[0036] 2. Compound of formula III: 3β, 5β-dihydroxy-6β, 7β, 15β, 16β-dimethylene-5β-androsta-21, 17-carboxylate-21-ethyl formate

[0037] Dissolve 12g of sodium ethoxide in 100mL of absolute ethanol, heat to 30-35°C, add 30mL of condensing agent diethyl malonate, raise the temperature to an internal temperature of 35-40°C, stir for 10 minutes, then add 10g of the compound of formula II , heated to reflux, reflux reaction for 3 hours, TLC monitored ...

Embodiment 2

[0049] One, preparation formula II compound

[0050] As described in Example 1.

[0051] 2. Compound of formula III: 3β, 5β-dihydroxy-6β, 7β, 15β, 16β-dimethylene-5β-androsta-21, 17-carboxylide-21-formic acid

[0052] Dissolve 12g of sodium ethoxide in 100mL of absolute ethanol, heat to 30-35°C, add 22mL of condensing agent monoethyl malonate, raise the temperature to an internal temperature of 35-40°C, stir for 10 minutes, then add 10g of the compound of formula II , heated to reflux, reflux reaction for 3 hours, TLC monitored the completion of the reaction, cooled to room temperature, filtered, adjusted the pH of the filtrate to 6-7, crystallized in ice water, filtered, and dried to obtain 11.1 grams of the compound of formula III: 3β, 5β -Dihydroxy-6β, 7β, 15β, 16β-dimethylene-5β-androst-21,17-carboxylactone-21-carboxylic acid.

[0053] TLC monitoring conditions are: cyclohexane: ethyl acetate = 1:2.

[0054] 3. Compound of formula IV: 6β, 7β, 15β, 16β-dimethylene-5β-hyd...

Embodiment 3

[0063] One, preparation formula II compound

[0064] As described in Example 1.

[0065] 2. Compound of formula III: 3β, 5β-dihydroxy-6β, 7β, 15β, 16β-dimethylene-5β-androsta-21, 17-carboxylate-21-sodium formate

[0066] Dissolve 12g of sodium ethoxide in 100mL of absolute ethanol, heat to 30-35°C, add 33g of condensing agent ethyl malonate sodium salt, raise the temperature to an internal temperature of 35-40°C, stir for 10 minutes, then add 10g of formula II Compound, heated to reflux, reflux reaction for 3 hours, TLC monitored the completion of the reaction, cooled to room temperature, filtered, adjusted the pH of the filtrate to 6-7, crystallized in ice water, filtered, and dried to obtain 12 grams of oil: 3β, 5β -dihydroxy-6β, 7β, 15β, 16β-dimethylene-5β-androst-21,17-carboxylactone-21-carboxylic acid; the resulting oil was dissolved in 120 mL of methanol and cooled to -5 ~0°C, add 1.5g sodium methoxide, stir at -5~0°C for 2 hours, suction filter and dry to obtain 10.5g...

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PUM

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Abstract

The invention discloses a drospirenone intermediate and a preparation method thereof, and an application thereof in preparation of drospirenone. The intermediate has a chemical structural general formula as shown in the specification, R in the general formula is H, Li, Na, K, 1 / 2Mg, 1 / 2Ca, NH4, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2 or CH(CH3)3; the preparation of the intermediate comprises the step (3) or the steps (2) to (3) or the steps (1) to (3) in a synthetic route as follows: adding the drospirenone intermediate to an organic solvent which is mutually soluble to water, and water; heating to reflux, cooling to room temperature after reflux reaction is ended; devitrifying from ice water; and filtering and drying to prepare the drospirenone. A heavy metal reagent and a poisonous reagent are not used again in preparation of the intermediate, and the process of preparing the drospirenone by using the intermediate; and the preparation process is simple and feasible.

Description

technical field [0001] The invention relates to a drospirenone intermediate, a preparation method thereof and an application thereof in the preparation of drospirenone, belonging to the technical field of medicinal chemistry. Background technique [0002] The chemical name of drospirenone is 6β, 7β, 15β, 16β-dimethylene-3-oxo-17α-pregna-4-ene-21,17-carboxylate, which is a kind of highly effective and less side effect Steroidal contraceptives, with anti-mineralocorticoid and anti-androgen effects, are currently one of the most important contraceptives. [0003] German Schering AG (Schering AG) reported the drospirenone compound patent for the first time in German patent DE2652761, but the raw material of the first step of introducing the side chain at the 17th position of this method is very expensive and the cost is high. German Schering company reported another synthetic route in European patent EP0075189, and its synthetic route is as follows: [0004] [0005] This r...

Claims

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Application Information

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IPC IPC(8): C07D307/94
Inventor 安晓霞黄成军毛锋旺
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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