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A kind of synthetic method of spironolactone intermediate canrenone

A synthesis method and a technology for intermediates, applied in the field of chemical synthesis, can solve the problems of harsh reaction conditions, high equipment requirements, lengthy steps, etc., and achieve the effects of stable method, good selectivity and low cost.

Active Publication Date: 2016-08-24
ZHEJIANG SHENZHOU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, due to the rapid rise in the price of saponin (diene), it has brought great pressure to the production of related products
[0003] On the other hand, when the existing preparation methods construct the 21,17-carboxylide spiro ring structure, most of the reaction conditions are harsh, the steps are tedious, the requirements for equipment are high, and the reagents used are expensive and the overall yield is low , and the cost is high (refer to: Compilation of National API Production Process [M], 1979:997-999; DE2404947[P]; US4129564[P]; US4472310[P]; EP1903051(A2)[P])

Method used

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  • A kind of synthetic method of spironolactone intermediate canrenone
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  • A kind of synthetic method of spironolactone intermediate canrenone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Alkynylation reaction

[0029] The reaction formula is as follows:

[0030]

[0031] Under the protection of nitrogen, add 28g of pre-crushed potassium hydroxide to the three-necked flask, add 200mL of solvent tetrahydrofuran and 10g of 4AD(I), stir evenly, control the temperature at 15-20°C, add 12mL of propynyl alcohol dropwise, and the dropwise addition time is about 0.5 hour, then the temperature was controlled at 15-20°C, and the reaction was carried out for about 6 hours, monitored by TLC until the reaction was complete. Add about 9 mL of hydrochloric acid aqueous solution (concentration about 2N) dropwise to the reaction solution, adjust the pH value to neutral, concentrate under reduced pressure, add 100 mL of water for water analysis, let stand for 0.5 hours, filter, and dry at 60°C for 24 hours to obtain 11.5 g of the compound (II), the mass yield is about 115%. Embodiment 2: Alkynylation reaction

Embodiment 2

[0032] Under the protection of nitrogen, add 25g of pre-crushed sodium hydroxide to the three-necked flask, add 200mL of solvent 2-methyltetrahydrofuran and 10g of 4AD(I), stir evenly, control the temperature at 15-20°C, add dropwise 12mL of propynyl alcohol, The dropwise addition time was about 0.5 hour, and then the temperature was controlled at 15-20°C, and the reaction was carried out for about 10 hours, monitored by TLC until the reaction was complete. Add about 12mL hydrochloric acid aqueous solution (concentration 2N) dropwise to the reaction solution, adjust the pH value to neutral, add 100mL water for water analysis after concentration under reduced pressure, let stand for 0.5 hour, filter, and dry at 60°C for 24 hours to obtain 10.8g compound ( II), the mass yield is about 108%.

Embodiment 3

[0033] Embodiment 3: hydrogenation reaction

[0034] The reaction formula is as follows:

[0035]

[0036] Under the protection of nitrogen, add 10g of compound (II) and 200mL of ethanol to a three-neck flask, add 1g of activated carbon loaded with 5% palladium carbon, pass in hydrogen, and react at 20-30°C for about 5 hours. After the reaction is complete, stop the ventilation, filter, and the filtrate Concentrate under reduced pressure to nearly dryness, add 50 mL of water for water analysis, filter, and dry at 60°C to obtain 9.3 g of compound (III); the mass yield is about 93%.

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Abstract

The invention relates to a synthesis method of a chemical medicine, and concretely relates to a synthesis method of a spironolactone intermediate canrenone. The method comprises the following steps: carrying out an ethynylation reaction on a compound I 4-androstenedione (4AD), hydrogenating, carrying out an oxidation cyclization reaction, and carrying out a bromization and debromination reaction to obtain the compound V canrenone, and the above reaction route is shown in the specification. A synthesis method of the structure of an important 21,17-carboxy lactone spiro ring adopted in the invention is different from previous process modes, and is concise and efficient. The method has the characteristics of high yield, good selectivity, low cost, mild reactions, suitableness for industrialization, stability and easy realization.

Description

technical field [0001] The invention relates to a method for synthesizing chemical drugs, in particular to a method for synthesizing spironolactone intermediate canrenone. Background technique [0002] Canrenone, chemically named 17β-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid-γ-lactone, is a commonly used diuretic and is also a synthetic aldosterone An important intermediate of the receptor antagonist spironolactone. Canrenone can also be widely used in the preparation of important steroid raw materials such as eplerenone and other cardiovascular disease drugs. Canrenone has two important pharmacodynamic structures: 21,17-carboxylide spiro structure and 4,6-dien-3-one structure. Some existing preparation techniques (refer to: "Simple and efficient synthesis method of canrenone", "Chinese Modern Applied Pharmacy"; "Improved synthesis process of eplerenone intermediate canrenone", "Chinese Journal of Medicinal Chemistry" ) mostly uses dehydroepiandrosterone or de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J21/00
CPCC07J21/003
Inventor 王荣
Owner ZHEJIANG SHENZHOU PHARMA
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