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CN-121991152-A - Cyclic preparation method of spirolactone key material

CN121991152ACN 121991152 ACN121991152 ACN 121991152ACN-121991152-A

Abstract

The invention relates to a cyclic preparation method of spirolactone key materials, and belongs to the technical field of medicines. The method is used for recycling the byproduct compound 2 generated in the production process of the spirolactone intermediate 1, and the byproduct compound is converted into the spirolactone key material compound 1 under an acidic condition. The reaction is carried out in an organic solvent or an aqueous medium, the acidic aqueous solution is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, nitric acid or phosphoric acid, the concentration range is 0.1-6mol/L, the reaction temperature is 0-100 ℃, the reaction time is 0.5-96 hours, and the feeding mole ratio of the compound 2 to the acid is 1:0.5-1:10. The organic solvent may be selected from ethers, alcohols, esters or haloalkanes. The obtained compound 1 can be used as a raw material for preparing spirolactone, and the final product is obtained through oxygen bridge reaction, esterification reaction, decarboxylation reaction, etherification reaction, dehydrogenation reaction and thio reaction. The invention realizes the recycling of the byproducts, improves the utilization rate of raw materials, reduces the production cost, reduces the emission of waste, and has good industrial application prospect.

Inventors

  • ZHOU WENXIANG
  • XU HUIHUI
  • CHEN ZHONGPING
  • HUANG ZHENGFU
  • PU JIN

Assignees

  • 浙江朗华制药有限公司

Dates

Publication Date
20260508
Application Date
20260127

Claims (10)

  1. 1. A cyclic preparation method of spirolactone key materials, wherein the key materials are compound 1 (4-androstenedione, chemical formula: ) The method is characterized by comprising the following steps: from the preparation of spirolactone intermediate 1 compound 2 in the mother liquor (formula: ) Reacting under acidic conditions to obtain a compound 1, wherein the compound 2 is 1,1,7-triethoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthrene, the spirolactone intermediate 1 is 7-methoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthren-1-one (formula: ),
  2. 2. The cyclic preparation process of spirolactone key material of claim 1, wherein said reaction is carried out in an organic solvent or water.
  3. 3. The cyclic preparation method of spirolactone key materials according to claim 2, wherein said organic solvent is selected from ethers, alcohols, esters, haloalkanes or mixtures thereof.
  4. 4. The method for the cyclic preparation of spirolactone key materials according to claim 3, wherein the ethers are selected from methyl tert-butyl ether, tetrahydrofuran, dioxane or isopropyl ether, the alcohols are selected from methanol, ethanol, isopropanol or n-butanol, the esters are selected from ethyl acetate, isopropyl acetate or methyl acetate, and the haloalkanes are selected from dichloromethane or dichloroethane.
  5. 5. The cyclic preparation method of spirolactone key materials according to claim 2, wherein the mass-volume ratio of the compound 2 to the organic solvent or water or mixed solvent is 1:1-1:30 (g/mL).
  6. 6. The cyclic preparation process of spirolactone key material of claim 1, wherein said acidic condition is provided by an acidic aqueous solution which is an aqueous solution of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, nitric acid or phosphoric acid.
  7. 7. The cyclic preparation method of spirolactone key materials of claim 6, wherein the concentration of the acidic aqueous solution is 0.1mol/L to 6mol/L.
  8. 8. The cyclic preparation method of spirolactone key materials of claim 6, wherein the feeding molar ratio of the compound 2 to the acid is 1:0.5-1:10.
  9. 9. The cyclic preparation method of spirolactone key materials according to claim 1, wherein the reaction temperature is 0-100 ℃ and the reaction time is 0.5-96 hours.
  10. 10. A process for preparing spirolactone, which comprises using compound 1 obtained by the cyclic preparation of spirolactone key material as claimed in any one of claims 1 to 9 as raw material, wherein compound 1 is 4-androstenedione @ ) The intermediate is obtained through alkoxylation reaction with triethyl orthoformate under the catalysis of acid ) Intermediate 1 is subjected to oxygen bridge reaction to obtain intermediate 2 # ) The intermediate 3 is obtained by the esterification reaction of the intermediate 2 ) The intermediate 3 is subjected to decarboxylation reaction to obtain an intermediate 4 # ) Intermediate 4 is subjected to etherification reaction to obtain intermediate 5 # ) The intermediate 5 is dehydrogenated to obtain an intermediate 6% ) Intermediate 6 is subject to thio reaction to obtain spirolactone @ ) The reaction formula is as follows:

Description

Cyclic preparation method of spirolactone key material Technical Field The invention relates to the technical field of medicines, in particular to a cyclic preparation method of spirolactone key materials. Specifically, the spirolactone and a key material 4-androstenedione compound 1 (chemical formula: ) The process involves reacting a by-product compound 2 [ ], with ) Is converted into the compound 1 and passes through the intermediate 1) Intermediate 2%) Intermediate 3%) Intermediate 4%) Intermediate 5%) Intermediate 6%) And synthesizing spirolactone from the intermediate product. Background Spironolactone (Spironolactone) is used as an important steroid medicine and is widely applied to the auxiliary treatment of edema diseases, primary aldosteronism and hypertension clinically. The chemical structure of the catalyst is characterized by 17 beta-hydroxy-3-oxo-7 alpha- (acetylmercapto) -17 alpha-pregna-4-ene-21-carboxylic acid-gamma-lactone, and the complex molecular structure determines the multi-step nature and the complexity of the synthesis process. In the existing spirolactone production process, 4-androstenedione is used as a key starting material, and needs to be converted into a spirolactone intermediate, namely 7-methoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthren-1-one (chemical formula: ). This conversion process usually involves a reaction with a reagent such as triethyl orthoformate, however, in this reaction system, in addition to the target product 7-methoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthren-1-one, it is also unavoidable that a considerable amount of by-product 1,1,7-triethoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthrene is produced. In existing industrial production practice 1,1,7-triethoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthrene is generally treated as process waste together with the reaction mother liquor. This results in waste of valuable steroid skeleton resources on the one hand and increases the burden and cost of three-waste treatment on the other hand. Especially in large-scale industrial production, the waste phenomenon is obvious due to large reaction volume and large feeding amount. Current technical literature and patents focus primarily on optimizing the synthetic route of spirolactone end products, increasing the end product yields, or improving the product quality control methods, while not paying sufficient attention to the efficient use of such specific byproducts generated during production. Although some studies have attempted to reduce the formation of by-products by improving the reaction conditions, none have fundamentally solved the problem of recycling of the existing by-products. Therefore, the development of a method capable of effectively recycling the byproducts has remarkable economic value and has important significance for promoting green production and sustainable development of the pharmaceutical industry. Disclosure of Invention The invention aims to provide a cyclic preparation method of spirolactone key materials, In order to achieve the above object, the present invention provides the following technical solutions: a cyclic preparation method of spirolactone key materials, wherein the key materials are compound 1 (4-androstenedione, chemical formula: ) The method comprises the following steps: from the preparation of spirolactone intermediate 1 compound 2 in the mother liquor (formula: ) Reacting under acidic conditions to obtain a compound 1, wherein the compound 2 is 1,1,7-triethoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthrene, the spirolactone intermediate 1 is 7-methoxy-9 a,11 a-dimethyl-2, 3a,3b,4,8, 9a,9b,10,11 a-dodecahydro-1H-cyclopenta [1,2-a ] phenanthren-1-one (formula: ), further, the reaction is carried out under organic solvent or water conditions. Further, the organic solvent is selected from ethers, alcohols, esters, haloalkanes or mixtures thereof. Further, the ethers are selected from methyl tertiary butyl ether, tetrahydrofuran, dioxane or isopropyl ether, the alcohols are selected from methanol, ethanol, isopropanol or n-butanol, the esters are selected from ethyl acetate, isopropyl acetate or methyl acetate, and the haloalkanes are selected from dichloromethane or dichloroethane. Further, the mass volume ratio of the compound 2 to the organic solvent or water or mixed solvent is 1:1-1:30 (g/mL). Further, the acidic condition is provided by an acidic aqueous solution which is an aqueous solution of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, nitric acid or phosphoric acid. Further, the concentration of the acidic aqueous solution is 0.1mol/L to 6mol/L. Further, the feeding molar ratio of the compound 2 to the acid is 1:0.5-1:10. Further, the reaction te