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CN-122011076-A - Preparation method of spirolactone

CN122011076ACN 122011076 ACN122011076 ACN 122011076ACN-122011076-A

Abstract

The invention provides a preparation method of spirolactone, and relates to the technical field of organic synthesis. The preparation method of spirolactone uses 4-androstene-3, 17 diketone as raw material, and makes nucleophilic addition reaction with organic zinc reagent 3-tert-butoxy-3-oxypropyl zinc bromide, then makes elimination-lactonization under the catalysis of trifluoroacetic acid, and at the same time makes lactonization be completed, then makes etherification reaction and oxidative dehydrogenation reaction in turn so as to obtain canrenone, and makes addition reaction with thioacetic acid so as to obtain spirolactone. The preparation method provided by the invention provides a novel construction method of 21-carboxylic acid-gamma-lactone, the method has good specificity, the total mass yield of spirolactone is more than 92%, the total mass yield is high, and the HPLC purity of spirolactone prepared by the preparation method provided by the invention is more than 99.7%, which is far higher than that of spirolactone prepared by the prior art.

Inventors

  • HU BIXIAN
  • LEI LINGZHI
  • WANG HONGFU
  • SHAO ZHENPING
  • CUI FENGFENG
  • LI JIE

Assignees

  • 浙江神洲药业有限公司

Dates

Publication Date
20260512
Application Date
20260130

Claims (10)

  1. 1. A method for preparing spirolactone, comprising the steps of: Mixing 4-androstene-3, 17 dione, 3-tert-butoxy-3-oxypropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent, performing nucleophilic addition reaction, and quenching to obtain 17 beta-hydroxy-3-oxopregna-4-en-17-propionic acid tert-butyl ester; Mixing the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester, trifluoroacetic acid and lower chloroalkane, and performing an elimination-lactonization reaction to obtain 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone; Mixing the 17 beta-hydroxy-3-oxo pregna-4-ene-21-carboxylic acid-gamma-lactone, triethyl orthoformate, absolute ethyl alcohol and an organic acid catalyst, and carrying out etherification reaction to obtain 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone; mixing the 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone, substituted benzoquinone and lower ketone, and performing oxidative dehydrogenation reaction to obtain 17 beta-hydroxy-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone; Mixing 17 beta-hydroxyl-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone, thioacetic acid and lower alcohol for addition reaction to obtain spirolactone.
  2. 2. The method of preparation according to claim 1, wherein the nucleophilic addition catalyst comprises zinc chloride and/or cerium chloride; the ether solvent comprises one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran and diethyl ether; The molar ratio of the 4-androstene-3, 17 dione to the 3-tert-butoxy-3-oxypropyl zinc bromide is 1:1-3; the mass ratio of the 4-androstene-3, 17 diketone to the nucleophilic addition catalyst is 1:0.05-0.3; The mass concentration of the 4-androstene-3, 17 diketone is 0.05-0.2 g/mL.
  3. 3. The preparation method according to claim 1 or2, wherein the nucleophilic addition reaction is carried out at a temperature of-10 to 15 ℃ for a time of 2 to 8 hours.
  4. 4. The method according to claim 1, wherein the lower chloroalkanes include one or more of dichloromethane, chloroform and 1, 2-dichloroethane; The mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester to the trifluoroacetic acid is 1:0.3-1.5; the mass concentration of the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester is 0.05-0.2 g/mL.
  5. 5. The method according to claim 1 or 4, wherein the temperature of the elimination-lactonization reaction is 10 to 30 ℃ for 1 to 5 hours.
  6. 6. The method of claim 1, wherein the organic acid catalyst comprises one or more of p-toluenesulfonic acid, benzenesulfonic acid and pyridine bromohydrogen salt; the mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone to the triethyl orthoformate is 1:0.5-3; the mass concentration of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone is 0.1-2 g/mL; The mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone to the organic acid catalyst is 1:0.01-0.1.
  7. 7. The method according to claim 1 or 6, wherein the etherification reaction is carried out at a temperature of 40 to 45 ℃ for a time of 1 to 3 hours.
  8. 8. The method of preparation according to claim 1, wherein the substituted benzoquinone comprises tetrachlorobenzoquinone and/or 2, 3-dichloro-5, 6-dicyanobenzoquinone; the lower ketone comprises acetone and/or butanone; The mass ratio of the 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone to the substituted benzoquinone is 1:0.6-3; the mass concentration of the 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone is 0.1-0.2 g/mL.
  9. 9. The method according to claim 1 or 8, wherein the oxidative dehydrogenation is carried out at a temperature of 20 to 45 ℃ for a time of 2 to 6 hours.
  10. 10. The production method according to claim 1, wherein the lower alcohol comprises one or more of methanol, ethanol, isopropanol and n-butanol; the mass ratio of the 17 beta-hydroxyl-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone to the thioacetic acid is 1:0.5-1; the mass concentration of the 17 beta-hydroxyl-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone is 0.1-0.2 g/mL; The addition reaction is carried out under the condition of reflux, and the time of the reflux is 2-5 h.

Description

Preparation method of spirolactone Technical Field The invention relates to the technical field of organic synthesis, in particular to a preparation method of spirolactone. Background Spironolactone, chemical name 17 beta-hydroxy-3-oxo-7 alpha- (acetylthio) -17 alpha-pregna-4-ene-21-carboxylic acid-gamma-lactone, CAS number 52-01-7, is an aldosterone receptor antagonist diuretic, and has both water salt metabolism regulation and antiandrogenic activity, and can be widely used in treatment of hypertension and heart failure. At present, the preparation method of spirolactone mainly comprises two steps, namely, taking dehydroepiandrosterone as a raw material, carrying out acetylene addition, grignard reaction carburetion, carbon dioxide carboxylation, catalytic hydrogenation and lactonization reaction to obtain five-membered spiro ring, and then carrying out dehydrogenation and addition reaction to obtain the spirolactone. The second is to use androstenedione (such as 4-androstene-3, 17 diketone) as initial raw material, obtain lactone compound through etherification, epoxidation and lactonization, and then obtain the product through bromination, dehydrobromination and addition reaction, the synthetic method uses brominating agent in the process of adding bromine and removing bromine, is not friendly to the environment, adopts Wen Tuoxiu high in removing bromine, has more impurities, has the total mass yield of about 85% and the purity of about 99.0%. It can be seen that the total yield of spirolactone obtained by the above preparation method is still low. Disclosure of Invention In view of the above, the present invention aims to provide a method for producing spirolactone, which improves the total yield of spirolactone. In order to achieve the above object, the present invention provides the following technical solutions: The invention provides a preparation method of spirolactone, which comprises the following steps: Mixing 4-androstene-3, 17 dione, 3-tert-butoxy-3-oxypropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent, performing nucleophilic addition reaction, and quenching to obtain 17 beta-hydroxy-3-oxopregna-4-en-17-propionic acid tert-butyl ester; Mixing the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester, trifluoroacetic acid and lower chloroalkane, and performing an elimination-lactonization reaction to obtain 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone; Mixing the 17 beta-hydroxy-3-oxo pregna-4-ene-21-carboxylic acid-gamma-lactone, triethyl orthoformate, absolute ethyl alcohol and an organic acid catalyst, and carrying out etherification reaction to obtain 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone; mixing the 17 beta-hydroxy-3-ethoxy-17 alpha-pregna-3, 5-diene-21-carboxylic acid-gamma-lactone, substituted benzoquinone and lower ketone, and performing oxidative dehydrogenation reaction to obtain 17 beta-hydroxy-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone; Mixing 17 beta-hydroxyl-17 alpha-pregna-4, 6-diene-3-ketone-21-carboxylic acid-gamma-lactone, thioacetic acid and lower alcohol for addition reaction to obtain spirolactone. Preferably, the nucleophilic addition catalyst comprises zinc chloride and/or cerium chloride; the ether solvent comprises one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran and diethyl ether; The molar ratio of the 4-androstene-3, 17 dione to the 3-tert-butoxy-3-oxypropyl zinc bromide is 1:1-3; the mass ratio of the 4-androstene-3, 17 diketone to the nucleophilic addition catalyst is 1:0.05-0.3; The mass concentration of the 4-androstene-3, 17 diketone is 0.05-0.2 g/mL. Preferably, the temperature of the nucleophilic addition reaction is-10-15 ℃ and the time is 2-8 hours. Preferably, the lower chloroalkanes include one or more of dichloromethane, chloroform and 1, 2-dichloroethane; The mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester to the trifluoroacetic acid is 1:0.3-1.5; the mass concentration of the 17 beta-hydroxy-3-oxopregna-4-ene-17-propionic acid tert-butyl ester is 0.05-0.2 g/mL. Preferably, the temperature of the elimination-lactonization reaction is 10-30 ℃ and the time is 1-5 h. Preferably, the organic acid catalyst comprises one or more of p-toluenesulfonic acid, benzenesulfonic acid and pyridine bromohydrogen salt; the mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone to the triethyl orthoformate is 1:0.5-3; the mass concentration of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone is 0.1-2 g/mL; The mass ratio of the 17 beta-hydroxy-3-oxopregna-4-ene-21-carboxylic acid-gamma-lactone to the organic acid catalyst is 1:0.01-0.1. Preferably, the etherification reaction is carried out at a temperature of 40-45 ℃ for 1-3 hours. Preferably, the substituted benzoquinone comprises tetrachlorobenzoquinone and/or 2, 3-dichloro-5, 6-dicyanob