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Efficient preparation method of delta<9, 11>-canrenone

A high-efficiency technology for canrenone, applied in the field of high-efficiency Δ9,11-canrenone preparation, can solve the problems of increased impurity content, long process route, and reduced yield, and achieve low production cost, reduced process steps, and overall The effect of high quality and yield

Active Publication Date: 2020-12-11
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process route of this method is long and the process is cumbersome. Because it is fermented, sulfonated, and desulfonated after the formation of the 17-position lactone ring, the 17-position lactone ring will affect the fermentation, sulfonate, and desulfonate. Detrimental effects of ester reactions leading to increased impurity levels and lower yields

Method used

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  • Efficient preparation method of delta&lt;9, 11&gt;-canrenone
  • Efficient preparation method of delta&lt;9, 11&gt;-canrenone
  • Efficient preparation method of delta&lt;9, 11&gt;-canrenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0035] 1) Put 100ml of sulfuric acid solution with a mass concentration of 20% into a three-necked bottle, put in 10g of 9α-hydroxy-4-androstene-3,17dione, and keep warm at 60°C for reaction. Methane extraction, washing with water, concentration, water analysis, filtration, and drying to obtain Δ 9,11 -4-androstene-3,17dione 9.1 g.

[0036] 2) Put Δ 9,11 -4-androstene-3,17dione was put into 4.5ml of methanol, 3.5ml of trimethyl orthoformate and 0.09g of pyridine hydrochloride were added, and the temperature was kept at 20°C for reaction. After the reaction was completed, it was filtered and dried to obtain 3-methanol Oxy-androst-3,5,9(11)-trien-17-one 9.2 g.

[0037] 3) Put 1.2g sodium methoxide and 12.9g trimethylsulfonium iodide into the reaction bottle, 9.2g 3-methoxy-androst-3,5,9(11)-triene-17-one, put 92ml Dimethyl sulfoxide, keep warm at 0°C for reaction, after the reactio...

Embodiment 2

[0041] Example 2Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0042] 1) Put 20ml of sulfuric acid solution with a mass concentration of 80% into the three-necked bottle, cool down to 10°C, put in 10g of 9α-hydroxy-4-androstene-3,17dione, keep warm at 10°C for reaction, after the reaction is completed, water analysis , extracted with 200ml dichloromethane, washed with water, concentrated, water analyzed, filtered and dried to obtain Δ 9,11 -4-androstene-3,17dione 9.2 g.

[0043] 2) The 9.2gΔ 9,11 -4-androstene-3,17dione was put into 92ml of tetrahydrofuran, 16.2ml of pyrrolidine and 0.46g of pyridinium hydrobromide were added, and the temperature was kept at 50°C for reaction. After the reaction was completed, it was filtered and dried to obtain 3-pyrrolyl-androstene Ste-3,5,9(11)-trien-17-one 9.48 g.

[0044] 3) Put 5.36g of potassium ethylate and 10.05g of trimethylsulfonium bromide into the reaction bottle, 9.48g of 3-pyrrolyl-androst-3,5,...

Embodiment 3

[0048] Example 3Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0049] 1) Put 50ml of sulfuric acid solution with a mass concentration of 50% into a three-neck flask, put in 10g of 9α-hydroxy-4-androstene-3,17dione, and keep warm at 40°C for reaction. After the reaction is completed, analyze with water and extract with 100ml of toluene , washed with water, concentrated, hydrolyzed, filtered, and dried to obtain Δ 9,11 -4-androstene-3,17dione 9.0 g.

[0050] 2) Add 9.0gΔ 9,11 -4-Androstene-3,17-dione was put into 27ml tetrahydrofuran, added 26.4ml triethyl orthoformate, 0.9g p-toluenesulfonic acid, and kept at 40°C for reaction. After the reaction was completed, filtered and dried to obtain 3-ethyl Oxy-androst-3,5,9(11)-trien-17-one 9.0 g.

[0051] 3) Put 10.2g potassium tert-butoxide and 15.3g trimethylsulfonium chloride into the reaction flask, 9g 3-ethoxy-androst-3,5,9(11)-triene-17-one, put 27ml tetrahydrofuran, 27ml dimethyl sulfoxide, ke...

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Abstract

The invention discloses an efficient preparation method of delta<9, 11>-canrenone, and belongs to the technical field of preparation of intermediates of medicines. The method comprises the following steps of: by taking 9 alpha-hydroxyl-4-androstenedione as a raw material, firstly removing 9-site hydroxyl through dehydration reaction to generate delta<9, 11> double bonds, then protecting 3-site carbonyl, then performing epoxidation on 17-site carbonyl, condensing with malonic acid diester to form a lactone ring, and performing oxidative decarboxylation or decarboxylation oxidation reaction to obtain delta<9, 11>-canrenone. According to the method, the raw materials are cheap and easy to obtain, the cost is low, reaction products in all steps are easy to purify, the total mass yield of the final product is higher than 80%, and the method is high in operability, extremely high in commercial competitiveness, suitable for industrial large-scale production and good in economic benefit.

Description

technical field [0001] The invention relates to the technical field of preparation of intermediates of medicines, in particular to a high-efficiency Δ 9,11 - A process for the preparation of canrenone. Background technique [0002] Δ 9,11 -Canrenone is an important intermediate of eplerenone. Eplerenone is a new type of selective aldosterone receptor antagonist, which has stronger aldosterone antagonism than spironolactone, and has extremely low affinity for androgen and progesterone receptors , less adverse reactions, definite curative effect on the treatment of hypertension, heart failure and myocardial infarction, fewer adverse reactions, good tolerance, is a good substitute drug for spironolactone. Therefore, the research on Δ9,11-canrenone has also promoted the development of these fields. [0003] Existing Δ 9,11 The preparation process of -canrenone is mainly based on diketone as raw material, first synthesize canrenone, and then ferment the 11-position to form 11...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00
CPCC07J21/003
Inventor 黄橙橙邵振平王友富王荣王炳乾王洪福雷灵芝
Owner ZHEJIANG SHENZHOU PHARMA
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