Cyclic preparation method of spirolactone key material

Abstract

The invention relates to a cyclic preparation method of a spirolactone key material, and belongs to the technical field of medicines. According to the method, resource utilization is carried out on a byproduct compound 2 generated in the production process of a spirolactone intermediate 1, and the byproduct compound 2 is converted into a spirolactone key material compound 1 under the 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 0.1-6 mol / L, the reaction temperature is 0-100 DEG C, the reaction time is 0.5-96 hours, and the feeding molar ratio of the compound 2 to the acid is 1: 0.5-1: 10. The organic solvent can be selected from ethers, alcohols, esters or haloalkanes. The obtained compound 1 can be used as a raw material for preparing spirolactone, and a final product is obtained through an oxygen bridge reaction, an esterification reaction, a decarboxylation reaction, an etherification reaction, a dehydrogenation reaction and a thioation reaction. The method provided by the invention realizes cyclic utilization of production byproducts, improves the utilization rate of raw materials, reduces the production cost, reduces waste discharge, and has a good industrial application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a method for the cyclical preparation of a key material of spironolactone. Specifically, it relates to spironolactone and its key material, 4-androstenedione compound 1 (chemical formula: A method for preparing byproduct compound 2 ( ) is converted into compound 1, and through intermediate 1 ( ), intermediate 2 ( ), intermediate 3 ( ), intermediate 4 ( ), intermediate 5 ( ), intermediate 6 ( Spironolactone is synthesized from intermediate products such as ) and others. Background Technology

[0002] Spironolactone, an important steroid drug, is widely used clinically for the treatment of edematous diseases, primary aldosteronism, and as an adjunct therapy for hypertension. Its chemical structure is characterized as 17β-hydroxy-3-oxo-7α-(acetylmercapto)-17α-pregn-4-ene-21-carboxylic acid-γ-lactone, and this complex molecular structure determines the multi-step and complex nature of its synthetic process.

[0003] In existing spironolactone production processes, 4-androstenedione, as a key starting material, needs to be converted into a spironolactone intermediate through multiple chemical reactions: 7-methoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopenta[1,2-a]phenanthrene-1-one (chemical formula: This conversion process typically involves a reaction with reagents such as triethyl orthoformate. However, in this reaction system, in addition to generating the target product 7-methoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene-1-one, a considerable amount of byproduct 1,1,7-triethoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene is inevitably produced.

[0004] In existing industrial production practices, 1,1,7-triethoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopenta[1,2-a]phenanthrene is usually treated as process waste along with the reaction mother liquor. This results in the waste of valuable steroidal skeleton resources and increases the burden and cost of waste treatment. This waste is particularly pronounced in large-scale industrial production due to the large reaction volume and large feed amounts.

[0005] Current technical literature and patents mainly focus on optimizing the synthetic route of spironolactone final products, improving the yield of final products, or improving product quality control methods, while insufficient attention has been paid to the effective utilization of such specific byproducts generated during the production process. Although some studies have attempted to reduce the formation of byproducts by improving reaction conditions, none have fundamentally solved the problem of resource utilization of existing byproducts.

[0006] Therefore, developing a method to effectively recycle this byproduct is not only of significant economic value, but also of great importance for promoting green production and sustainable development in the pharmaceutical industry. Summary of the Invention

[0007] The purpose of this invention is to provide a method for the cyclical preparation of spironolactone, a key material. To achieve the above objectives, the present invention provides the following technical solution: A method for the cyclical preparation of a key material for spironolactone, wherein the key material is compound 1 (4-androstenedione, chemical formula: The process includes the following steps: taking compound 2 (chemical formula: ...) from the mother liquor used to prepare spironolactone intermediate 1. The reaction under acidic conditions yields compound 1, wherein compound 2 is 1,1,7-triethoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene, and the spironolactone intermediate 1 is 7-methoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene-1-one (chemical formula: ),

[0008] Furthermore, the reaction is carried out in an organic solvent or in water.

[0009] Furthermore, the organic solvent is selected from ethers, alcohols, esters, haloalkanes, or mixtures thereof.

[0010] Furthermore, 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.

[0011] Furthermore, the mass-to-volume ratio of compound 2 to organic solvent, water, or mixed solvent is 1:1 to 1:30 (g / mL).

[0012] Furthermore, the acidic conditions are 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.

[0013] Furthermore, the concentration of the acidic aqueous solution is 0.1 mol / L to 6 mol / L.

[0014] Furthermore, the molar ratio of compound 2 to acid is 1:0.5 to 1:10.

[0015] Furthermore, the reaction temperature is 0–100°C, and the reaction time is 0.5–96 hours.

[0016] A method for preparing spironolactone, comprising using compound 1 obtained from the recycling preparation method of any of the key materials of spironolactone as a raw material, wherein compound 1 is 4-androstenedione ( Intermediate 1 is obtained through a conversion reaction. Intermediate 2 is obtained through an oxygen-bridge reaction. Intermediate 3 was obtained through esterification. After decarboxylation, intermediate 4 is obtained. After etherification, intermediate 5 is obtained. After dehydrogenation, intermediate 6 is obtained. Spironolactone was obtained through a thiolation reaction. The reaction formula is as follows:

[0017] This invention provides a method for the cyclical preparation of spironolactone, a key material, resulting in the following significant technological advancements and practical benefits: First, this invention achieves efficient resource utilization of byproducts in the production process. By converting compound 2, which was originally treated as waste, into compound 1, a valuable key material for spironolactone, a circular production process is established. Specifically, under preferred implementation conditions, the yield of compound 1 recovered from the mother liquor containing compound 2 can reach over 86%, and the purity can reach over 97%. These technical indicators fully demonstrate the practical value of this method.

[0018] Secondly, this invention provides a simple and efficient material conversion pathway. The conversion from compound 2 to compound 1 can be achieved through a single acid-catalyzed reaction step, without the need for complex separation and purification equipment or special reaction conditions. Experimental results show that, under conditions of 60-90℃ and a reaction time of 10-20 hours, a highly efficient conversion reaction can be achieved using conventional acid catalysts such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid.

[0019] Third, this invention significantly improves raw material utilization. By recycling byproducts generated during the production process, the basic raw material consumption per unit product is reduced by 22%-28%. In practical production applications, this feature not only reduces the demand for the initial raw material 4-androstenedione, but also lowers the material costs of the entire production process.

[0020] Fourth, the method of this invention has good industrial adaptability. The reaction equipment used are all conventional chemical production equipment, the reaction conditions are mild, the operation is simple, and it is easy to implement technical modifications on existing production lines. At the same time, the method has relatively relaxed requirements for raw materials and can handle mother liquor systems containing certain impurities, demonstrating strong process adaptability.

[0021] Finally, this invention has positive implications for environmental protection. By converting process waste into useful resources, the discharge of organic wastewater is reduced by more than 30%, lowering the wastewater treatment load and aligning with the development direction of green chemistry and cleaner production. This feature makes this invention not only economically beneficial but also significantly environmentally beneficial. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is a flow chart of the recycling process for key materials in spironolactone. Detailed Implementation

[0024] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention. Detailed Implementation

[0025] The present invention will be further described below with reference to embodiments, but the scope of protection of the present invention is not limited to these embodiments. Those skilled in the art should understand that various modifications and substitutions can be made to the present invention without departing from the essence and spirit of the invention.

[0026] Example 1

[0027] 500 g of the centrifugal mother liquor (mainly containing 20%-25% compound 2) for preparing spironolactone intermediate 1 was added to a 1000 mL three-necked flask. The mixture was concentrated to dryness under reduced pressure at 60 °C, yielding 120.3 g of a viscous residue. 300 mL of dichloromethane and 30 g of trifluoroacetic acid were added to the residue, and after stirring to dissolve, the mixture was refluxed at 85 °C for 11 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction solution was cooled to 0 °C, resulting in the precipitation of a large amount of solid. The solid was collected by filtration and washed twice with 20 mL of cold dichloromethane each time. The obtained solid was dried in a vacuum drying oven at 50 °C for 6 hours to obtain 76.8 g of crude compound 1. .

[0028] The crude product was slurried with 150 mL of dichloromethane at room temperature for 2 hours, filtered, and dried to obtain 75.2 g of white crystalline solid, with a yield of 86.5%. The purity was determined to be 97.3% by high performance liquid chromatography.

[0029] Example 2

[0030] 500g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was evaporated to dryness at 65℃, yielding 121.5g of solid residue. The residue and 250mL of methanol were added to a reaction flask, and 20g of concentrated sulfuric acid (98%) was slowly added with stirring. The mixture was heated to 65℃ and reacted for 19 hours. After the reaction, the reaction solution was cooled to room temperature, diluted with 200mL of ice water, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, resulting in solid precipitation. The solid was collected by filtration and washed three times with 50mL of water each time. The solid was dried under vacuum at 60℃ for 12 hours to obtain 80.1g of crude compound 1. The crude product was recrystallized from 200mL of methanol to obtain 78.9g of white needle-like crystals, with a yield of 89.3% and a purity of 96.7%.

[0031] Example 3

[0032] 500g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 119.8g of solid. The solid and 400mL of ethyl acetate were added to a reactor, stirred to dissolve, and then 40g of concentrated hydrochloric acid (36%) was added. The mixture was heated to 75℃ and reacted for 16 hours. The reaction progress was monitored periodically during the reaction. After the reaction was complete, the reaction solution was cooled to 5℃, and a yellow solid precipitated. This solid was filtered and washed with cold ethyl acetate. The solid was dried under vacuum at 55℃ for 8 hours to obtain 77.9g of crude compound 1. The crude product was slurried with 180mL of ethanol under reflux for 1 hour, cooled to room temperature, and filtered to obtain 76.5g of off-white solid, with a yield of 85.9% and a purity of 96.9%.

[0033] Example 4

[0034] 500 g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 120.7 g of residue. The residue and 350 mL of tetrahydrofuran were added to a reaction flask, followed by 45 g of glacial acetic acid and 100 mL of water. The mixture was heated to 50 °C and reacted for 48 hours. After the reaction was complete, the tetrahydrofuran was removed by vacuum distillation, and the residue was extracted three times with 200 mL of methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, yielding 72.3 g of crude compound 1. The crude product was recrystallized from 150 mL of isopropanol to give 70.1 g of white solid, with a yield of 78.2% and a purity of 95.8%.

[0035] Example 5

[0036] 500 g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was added to the reactor and concentrated to dryness to obtain 120.1 g of solid. 400 mL of dioxane and 25 g of nitric acid (65% concentration) were added, and the mixture was heated to 90 °C and reacted for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 300 mL of water, and extracted three times with dichloromethane (150 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 74.6 g of crude compound 1. The crude product was purified by slurrying with 120 mL of methyl acetate to obtain 72.8 g of pale yellow solid, with a yield of 81.1% and a purity of 95.5%.

[0037] Example 6

[0038] 500g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 121.2g of residue. The residue and 280mL of isopropanol were added to a reaction flask, followed by 35g of phosphoric acid (85% concentration) and 70mL of water. The mixture was heated to 40℃ and reacted for 72 hours. After the reaction was complete, the mixture was cooled to 10℃, filtered to collect the solid, and washed with cold isopropanol. The solid was dried under vacuum at 50℃ for 10 hours to obtain 73.5g of crude compound 1. The crude product was recrystallized from 160mL of n-butanol to give 71.9g of a white solid, with a yield of 79.8% and a purity of 96.2%.

[0039] Example 7

[0040] 500 g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was added to a reaction flask and concentrated to dryness to obtain 119.5 g of solid. 250 mL of dichloromethane and 15 g of trifluoroacetic acid were added, and the mixture was stirred at 5 °C for 60 hours. After the reaction was complete, the solid was collected by filtration, washed with cold dichloromethane, and dried under vacuum to obtain 68.4 g of crude compound 1. The crude product was purified by slurrying with 100 mL of methanol to obtain 66.2 g of white solid, with a yield of 72.6% and a purity of 94.3%.

[0041] Example 8

[0042] 500g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 120.5g of residue. 300mL of ethanol and 50g of concentrated hydrochloric acid were added, and the mixture was heated to 95℃ and reacted for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated to remove most of the ethanol, and 200mL of water was added to precipitate the solid. The solid was filtered, washed with water, and dried under vacuum to give 70.8g of crude compound 1. The crude product was recrystallized from 140mL of ethyl acetate to give 68.9g of white solid, with a yield of 76.3% and a purity of 95.1%.

[0043] Example 9

[0044] 500 g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was added to the reactor and concentrated to dryness to obtain 120.9 g of solid. A mixed solvent of 200 mL methyl tert-butyl ether and 100 mL methanol was added, followed by 30 g concentrated sulfuric acid. The mixture was heated to 55 °C and reacted for 24 hours. After the reaction was complete, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 77.2 g of crude compound 1. The crude product was recrystallized from 180 mL of a mixed solvent of dichloromethane / n-hexane (1:2, v / v) to obtain 75.1 g of white solid, with a yield of 83.0% and a purity of 96.8%.

[0045] Example 10

[0046] 500g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was taken, and 76.5g of compound 1 was prepared according to the method in Example 3. Compound 1 was reacted with triethyl orthoformate under p-toluenesulfonic acid catalysis to obtain spironolactone intermediate 1. Intermediate 1 underwent oxygen bridging, esterification, decarboxylation, etherification, dehydrogenation, and thiolation reactions to finally obtain 81.3g of spironolactone product, with an overall yield of 63.7%. Figure 1 The purity was determined to be 98.9% by chromatography. .

[0047] Comparative Example 1 500 g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was added to the reaction flask and concentrated to dryness, yielding 120.2 g of residue. 300 mL of dichloromethane was added, and the mixture was refluxed at 80 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to obtain 118.5 g of a viscous oil. High-performance liquid chromatography (HPLC) analysis showed that compound 1 accounted for only 3.2% of the oil, with the majority consisting of unreacted compound 2 and other impurities.

[0048] Comparative Example 2 500g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 120.6g of residue. 300mL of methanol and 20g of sodium hydroxide were added, and the mixture was heated to 65℃ and reacted for 15 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated, diluted with water, and extracted with dichloromethane. The organic phase was dried and concentrated to give 115.8g of a brown oily substance. Analysis showed that the product contained 5.1% compound 1, and several byproducts were also generated.

[0049] Comparative Example 3 According to existing technical methods, commercially purchased 4-androstenedione (compound 1) is directly used as a raw material. Intermediate 1 is prepared by reacting it with triethyl orthoformate, followed by oxygen bridging, esterification, decarboxylation, etherification, dehydrogenation, and thiolation to obtain spironolactone. This process does not recycle compound 2 generated during production, resulting in low raw material utilization and a raw material cost per unit product that is approximately 25% higher than that of the method of this invention.

[0050] Comparative Example 4 500g of the centrifugal mother liquor from the preparation of spironolactone intermediate 1 was added to the reaction flask and concentrated to dryness, yielding 120.4g of residue. 300mL of dichloromethane and 100g of concentrated hydrochloric acid (equivalent to a molar ratio of compound 2 to acid of approximately 1:15) were added, and the mixture was heated to 75°C and reacted for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the solid was collected, yielding 65.3g of crude compound 1. The crude product was purified to yield 62.1g of product, with a yield of 68.9% and a purity of 90.2%. Compared with the preferred conditions of this invention, both the yield and purity were significantly reduced, and more byproducts were generated.

[0051] Comparative Example 5 500g of the centrifuged mother liquor from the preparation of spironolactone intermediate 1 was concentrated to dryness, yielding 119.7g of residue. 300mL of ethanol and 30g of trifluoroacetic acid were added, and the mixture was heated to reflux temperature (approximately 78°C) and reacted for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated, yielding 71.2g of a dark brown solid. High-performance liquid chromatography (HPLC) analysis showed that the product contained 82.3% compound 1, but also approximately 12.5% ​​degradation products, making purification difficult.

[0052] The above embodiments and comparative examples fully illustrate the technical effects of the present invention. Those skilled in the art should understand that appropriate adjustments can be made to the reaction conditions without departing from the essence and spirit of the present invention, and all such adjustments should be included within the scope of protection of the present invention.

Claims

1. A method for the cyclical preparation of a key material for spironolactone, wherein the key material is compound 1 (4-androstenedione, chemical formula: ): characterized in that, Includes the following steps: Compound 2 (chemical formula: ) from the mother liquor used to prepare spironolactone intermediate 1 The reaction under acidic conditions yields compound 1, wherein compound 2 is 1,1,7-triethoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene, and the spironolactone intermediate 1 is 7-methoxy-9a,11a-dimethyl-2,3,3a,3b,4,8,9,9a,9b,10,11,11a-dodecano-1H-cyclopentano[1,2-a]phenanthrene-1-one (chemical formula: ), 2. The method for recycling spironolactone key material according to claim 1, characterized in that, The reaction is carried out in an organic solvent or in water.

3. The method for recycling spironolactone key materials according to claim 2, characterized in that, The organic solvent is selected from ethers, alcohols, esters, haloalkanes, or mixtures thereof.

4. The method for recycling spironolactone key material according to claim 3, characterized in that, 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. The method for recycling spironolactone key material according to claim 2, characterized in that, The mass-to-volume ratio of compound 2 to organic solvent, water, or mixed solvent is 1:1 to 1:30 (g / mL).

6. The method for recycling spironolactone key material according to claim 1, characterized in that, The acidic conditions are 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. The method for recycling spironolactone key material according to claim 6, characterized in that, The concentration of the acidic aqueous solution is 0.1 mol / L to 6 mol / L.

8. The method for recycling spironolactone key material according to claim 6, characterized in that, The molar ratio of compound 2 to acid is 1:0.5 to 1:

10.

9. The method for recycling spironolactone key material according to claim 1, characterized in that, The reaction temperature is 0–100°C, and the reaction time is 0.5–96 hours.

10. A method for preparing spironolactone, characterized in that, Compound 1, obtained using the recycling method of the spironolactone key material according to any one of claims 1-9, is used as a raw material. Compound 1 is 4-androstenedione ( Intermediate 1 was obtained by alkoxylation reaction with triethyl orthoformate under acid catalysis. Intermediate 1 undergoes an oxygen-bridge reaction to yield intermediate 2. Intermediate 2 undergoes esterification to obtain intermediate 3. Intermediate 3 undergoes a decarboxylation reaction to yield intermediate 4. Intermediate 4 undergoes an etherification reaction to yield intermediate 5. Intermediate 5 undergoes a dehydrogenation reaction to yield intermediate 6. Intermediate 6 undergoes a thiolation reaction to yield spironolactone. The reaction formula is as follows:

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