Method for preparing spirolactone intermediate canrenone

A technology of canrenone and intermediates, which is applied in the field of drug synthesis, can solve problems such as inconvenient operation, easy production of impurities, and impact on the quality of canrenone, and achieve the effects of reducing raw material costs, easy recycling, and reducing thermally degraded impurities

Active Publication Date: 2021-10-19
TIANJIN JINJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Among them, the decarboxylation reaction of intermediate 5 (lactone) to intermediate 6 (canrenone) needs to be carried out with toluene as a solvent at a high temperature above 120°C and under pressurized conditions, although the yield is relatively high and the reaction conditions are relatively high. It is mild, but still has the following defects: 1. The reaction temperature is above 120°C and the reaction takes a long time, which is easy to produce impurities and affect the quality of canrenone; 2. It needs to be carried out under pressure, resulting in relatively inconvenient operation

Method used

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  • Method for preparing spirolactone intermediate canrenone
  • Method for preparing spirolactone intermediate canrenone
  • Method for preparing spirolactone intermediate canrenone

Examples

Experimental program
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Effect test

Embodiment 1

[0020] A method for preparing spironolactone intermediate canrenone, comprising the following steps: dissolving 25g of lactone I in 500ml of toluene, adding 50ml of DMAC and 10g of poly-4-vinylpyridine, stirring and reacting at 80°C, and after 6 hours Add 300ml of water, stir and separate the water layer, filter the organic phase and concentrate under reduced pressure (absolute pressure less than 0.02MP, temperature less than 80°C) to a small volume (the amount of solvent is about 60-75ml), cool down and keep warm at 0-10°C After 2 hours, 17.8 g of solid were obtained after filtration. After testing: the melting point of the obtained product is 148-150°C (literature value 149-151°C), the molar yield is 80.40%, the product is determined to be canrenone by NMR detection, and its purity is 98.6% by HPLC detection.

Embodiment 2

[0022] A method for preparing spironolactone intermediate canrenone, comprising the following steps: dissolving 25 grams of lactone I in 250 ml of cyclohexane, adding 20 ml of NMP and 12.5 g of poly-4-vinylpyridine, and stirring at 50 ° C for reaction After 6 hours, add 200ml of water, separate the water layer after stirring, and concentrate under reduced pressure after filtering the organic phase (absolute pressure is less than 0.02MP, temperature is less than 50°C) to a small volume (solvent amount is about 60-75ml), cooling, 8 It was kept at -10°C for 2 hours, and 17.4 g of solid was obtained by filtration. After testing: the melting point of the obtained product is 150-151° C. (literature value 149-151° C.), the molar yield is 78.59%, the product is determined to be canrenone by NMR detection, and its purity is 98.8% by HPLC detection.

Embodiment 3

[0024] A method for preparing spironolactone intermediate canrenone, comprising the following steps: dissolving 20 grams of lactone I in 100 ml of methyl tetrahydrofuran, adding 4 ml of DMF and 1 g of poly-4-vinylpyridine, stirring at 65 ° C, Add 100ml of water after 6 hours, separate the water layer after stirring, filter the organic phase and concentrate under reduced pressure (absolute pressure less than 0.02MP, temperature less than 60°C) to a small volume (solvent amount is about 50-60ml), cool down, 0- It was kept at 10°C for 2 hours, and 15.2 g of solid was obtained by filtration. After testing: the melting point of the obtained product is 150-151° C. (literature value 149-151° C.), the molar yield is 85.82%, the product is determined to be canrenone by NMR detection, and its purity is 98.7% by HPLC detection.

[0025] The part characteristic hydrogen data of embodiment 1-3 gained product is as follows:

[0026]

[0027] 1 H NMR (400MHz, CDCl 3 )δ6.16-6.08(m,2H),5...

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Abstract

The invention provides a method for preparing spirolactone intermediate canrenone. The method comprises the following operation steps: a lactone substance (I) is dissolved in an organic solvent, a catalyst and an auxiliary agent are added, and the mixture is stirred at 50-80 DEG C to prepare the canrenone (II), wherein the organic solvent is at least one of cyclohexane, toluene or methyl tetrahydrofuran; the auxiliary agent is at least one of dimethyl formamide, N,N - dimethyl acetamide and N-methyl pyrrolidone; and the catalyst is poly-4-vinylpyridine. The reaction route is shown in the specification. Compared with the prior art, the method has the advantages that the reaction temperature is low, pressurization is not needed, the quality of canrenone can be improved, the energy consumption can be effectively reduced, and the production cost can be reduced.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for preparing spironolactone intermediate canrenone. Background technique [0002] Canrenone is a commonly used diuretic. It is a key intermediate of pritonone, drospirenone, etc. Its high-quality, efficient, simple and low-cost preparation process is of great significance to the synthesis of the above products. In the prior art, the mainstream process for producing canrenone and spironolactone is the technical solution disclosed in patent DE2404946: using androstenedione as raw material, after etherification, Corey epoxidation, dehydrogenation, lactone cyclization, and decarboxylation Canrenone is obtained, and spironolactone is obtained by addition of canrenone. [0003] Concrete reaction route is as follows: [0004] [0005] Among them, the decarboxylation reaction of intermediate 5 (lactone) to intermediate 6 (canrenone) needs to be carried out with tol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00
CPCC07J21/003
Inventor 只永润邵范武
Owner TIANJIN JINJIN PHARMA
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