Preparation method of spirolactone

Abstract

The invention provides a preparation method of spirolactone, and relates to the technical field of organic synthesis. The preparation method of spirolactone provided by the invention comprises the following steps: taking 4-androstene-3, 17-diketone as a raw material, carrying out nucleophilic addition reaction on the 4-androstene-3, 17-diketone and an organic zinc reagent 3-tert-butoxy-3-oxypropyl zinc bromide, then carrying out elimination-lactonization under the catalysis of trifluoroacetic acid, and completing lactonization while removing tert-butyl; then sequentially carrying out etherification reaction and oxidative dehydrogenation reaction to obtain canrenone, and finally carrying out addition reaction on canrenone and thioacetic acid to obtain spirolactone. The preparation method provided by the invention provides a novel construction method of 21-carboxylic acid-gamma-lactone, the method is good in specificity, the total mass yield of spirolactone is greater than 92%, and the total mass yield is high; moreover, the HPLC purity of the spirolactone prepared by the preparation method provided by the invention is greater than 99.7%, which is far higher than the purity of the spirolactone prepared by the existing process.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing spironolactone. Background Technology

[0002] Spironolactone, chemically named 17β-hydroxy-3-oxo-7α-(acetylthio)-17α-pregn-4-ene-21-carboxylic acid-γ-lactone (CAS No. 52-01-7), is an aldosterone receptor antagonist diuretic. Due to its combined effects of regulating water and electrolyte balance and anti-androgenic activity, it is widely used in the treatment of hypertension and heart failure. Currently, there are two main methods for preparing spironolactone: The first method uses dehydroepiandrosterone (DHEA) as a raw material, undergoing acetylene addition, Grignard carbon enrichment, carbon dioxide carboxylation, catalytic hydrogenation, and lactone formation to obtain a five-membered spirocyclic ring, followed by dehydrogenation and addition reactions. This synthetic method requires harsh reaction conditions, sophisticated equipment, is difficult to operate, involves many steps, and uses expensive reagents. Its overall yield is 18-40%, and its purity is approximately 98.5% (the overall yield is the product of the yields of each step, where the yield of each step = product / reactant × 100%). The second method uses androstenedione (such as 4-androsten-3,17-dione) as the starting material, and obtains a lactone compound through etherification, epoxidation, and lactone formation. This compound is then prepared via bromination, dehydrobromination, and addition reactions. This synthetic method uses a brominating agent during the bromination and debromination processes, which is environmentally unfriendly. Furthermore, the debromination is performed at high temperatures, resulting in numerous impurities. The overall yield is approximately 85%, and the purity is approximately 99.0%. Therefore, the overall yield of spironolactone obtained by the above methods is still relatively low. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to provide a method for preparing spironolactone, thereby improving the total yield of spironolactone.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing spironolactone, comprising the following steps: 4-Androsten-3,17-dione, 3-tert-butoxy-3-oxopropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent were mixed and subjected to a nucleophilic addition reaction followed by quenching to obtain tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate, trifluoroacetic acid, and lower chloroalkanes were mixed and subjected to an elimination-lactoneation reaction to obtain 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone, triethyl orthoformate, anhydrous ethanol and an organic acid catalyst were mixed and subjected to an etherification reaction to obtain 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone, substituted benzoquinone, and lower ketone were mixed and subjected to an oxidative dehydrogenation reaction to obtain 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, thioacetic acid, and a lower alcohol were mixed and subjected to an addition reaction to obtain spironolactone.

[0005] Preferably, the nucleophilic addition catalyst comprises zinc chloride and / or cerium chloride; The ether solvents include one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran, and diethyl ether; The molar ratio of 4-androsten-3,17-dione and 3-tert-butoxy-3-oxopropyl zinc bromide is 1:1~3; The mass ratio of the 4-androsten-3,17-dione to the nucleophilic addition catalyst is 1:0.05~0.3; The mass concentration of the 4-androsten-3,17-dione is 0.05~0.2 g / mL.

[0006] Preferably, the nucleophilic addition reaction is carried out at a temperature of -10 to 15°C for a time of 2 to 8 hours.

[0007] Preferably, the lower chlorinated alkanes include one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane; The mass ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to trifluoroacetic acid is 1:0.3~1.5; The mass concentration of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate is 0.05~0.2 g / mL.

[0008] Preferably, the elimination-lactoneation reaction is carried out at a temperature of 10~30℃ for 1~5h.

[0009] Preferably, the organic acid catalyst includes one or more of p-toluenesulfonic acid, benzenesulfonic acid, and pyridine hydrobromide; The mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to triethyl orthoformate is 1:0.5~3; The mass concentration of the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone is 0.1~2 g / mL; The mass ratio of the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to the organic acid catalyst is 1:0.01~0.1.

[0010] Preferably, the etherification reaction is carried out at a temperature of 40-45°C for 1-3 hours.

[0011] Preferably, the substituted benzoquinones include tetrachlorobenzoquinone and / or 2,3-dichloro-5,6-dicyanobenzoquinone; The lower ketones include acetone and / or butanone; The mass ratio of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to the substituted benzoquinone is 1:0.6~3; The mass concentration of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone is 0.1~0.2 g / mL.

[0012] Preferably, the temperature of the oxidative dehydrogenation reaction is 20~45℃ and the time is 2~6h.

[0013] Preferably, the lower alcohol includes one or more of methanol, ethanol, isopropanol and n-butanol; The mass ratio of 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone to thioacetic acid is 1:0.5~1; The mass concentration of the 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone is 0.1~0.2 g / mL; The addition reaction is carried out under reflux conditions; the reflux time is 2 to 5 hours.

[0014] The method for preparing spironolactone provided by this invention uses 4-androsten-3,17-dione as a raw material, which undergoes a nucleophilic addition reaction with the organozinc reagent 3-tert-butoxy-3-oxopropyl zinc bromide. Then, elimination-lactolation is carried out under the catalysis of trifluoroacetic acid, simultaneously removing the tert-butyl group and completing the lactone reaction. In this process, the organozinc reagent and the nucleophilic addition catalyst work together to selectively generate the 17β-hydroxy intermediate, avoiding the formation of the 17α-hydroxy isomer. Trifluoroacetic acid effectively removes the tert-butyl group and, under the strongly acidic conditions of trifluoroacetic acid, readily forms the lactone ring, improving the specificity of the method. Subsequently, etherification and oxidative dehydrogenation reactions are performed sequentially to obtain 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone (canrenone), which is finally added to thioacetic acid to obtain spironolactone. The preparation method provided by this invention offers a novel method for constructing 21-carboxylic acid-γ-lactone. The method exhibits high specificity, with a total mass yield of spironolactone >92%, demonstrating a high overall mass yield. Furthermore, the HPLC (liquid chromatography) purity of the spironolactone prepared by the method provided by this invention is >99.7%, which is significantly higher than the purity of spironolactone prepared by existing processes.

[0015] Furthermore, the preparation method provided by this invention has milder reaction conditions compared to traditional processes, and does not require special equipment for preparation; moreover, the preparation method provided by this invention is simple to operate, low in cost, and suitable for industrial production. Attached Figure Description

[0016] Figure 1 The liquid chromatogram of spironolactone obtained in Example 1; Figure 2 The liquid chromatogram of spironolactone obtained in Example 2 is shown. Detailed Implementation

[0017] This invention provides a method for preparing spironolactone, comprising the following steps: 4-Androsten-3,17-dione, 3-tert-butoxy-3-oxopropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent were mixed and subjected to a nucleophilic addition reaction followed by quenching to obtain tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate, trifluoroacetic acid, and lower chloroalkanes were mixed and subjected to an elimination-lactoneation reaction to obtain 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone, triethyl orthoformate, anhydrous ethanol and an organic acid catalyst were mixed and subjected to an etherification reaction to obtain 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone, substituted benzoquinone, and lower ketone were mixed and subjected to an oxidative dehydrogenation reaction to obtain 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, thioacetic acid, and a lower alcohol were mixed and subjected to an addition reaction to obtain spironolactone.

[0018] Unless otherwise specified, the materials and equipment used in this invention are all commercially available products in the field.

[0019] The preparation route of spironolactone in this invention is shown in Route 1: Route 1.

[0020] In this invention, 4-androsten-3,17-dione (4-AD, compound 1), 3-tert-butoxy-3-oxopropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent are mixed and subjected to a nucleophilic addition reaction followed by quenching to obtain tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate (compound 2).

[0021] In this invention, the molar ratio of 4-androsten-3,17-dione and 3-tert-butoxy-3-oxopropyl zinc bromide can be 1:1 to 3, specifically 1:1, 1:1.5, 1:2, 1:2.5, or 1:3; the nucleophilic addition catalyst can include zinc chloride and / or cerium chloride; the mass ratio of 4-androsten-3,17-dione to the nucleophilic addition catalyst can be 1:0.05 to 0.3, specifically 1:0.05, 1:0.1, 1:0.15, or 1:0.2. The ratio of the ether solvent to the volume of the ether solvent can be 1:0.25 or 1:0.3; the ether solvent may include one or more of tetrahydrofuran, 2-methyltetrahydrofuran and diethyl ether; the mass concentration of the 4-androsten-3,17-dione (i.e., the mass ratio of the 4-androsten-3,17-dione to the volume ratio of the ether solvent) can be 0.05~0.2 g / mL, specifically 0.05 g / mL, 0.1 g / mL, 0.12 g / mL, 0.15 g / mL, 0.18 g / mL or 0.2 g / mL.

[0022] In this invention, mixing 4-androsten-3,17-dione, 3-tert-butoxy-3-oxopropyl zinc bromide, a nucleophilic addition catalyst, and an ether solvent may include the following steps: 3-tert-butoxy-3-oxypropyl zinc bromide is first mixed with a first ether solvent to obtain a 3-tert-butoxy-3-oxypropyl zinc bromide solution; The 4-androsten-3,17-dione and the second ether solvent are mixed in a second mixture, and then mixed in a third mixture with the 3-tert-butoxy-3-oxopropyl zinc bromide solution and the nucleophilic addition catalyst.

[0023] In this invention, the first and second ether solvents can independently include one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and diethyl ether; the concentration of the 3-tert-butoxy-3-oxopropyl zinc bromide solution can be 0.5~1 mol / L, specifically 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, 0.9 mol / L, or 1 mol / L. This invention does not specifically limit the conditions for the first, second, and third mixing processes, as long as the raw materials are completely mixed.

[0024] In this invention, the temperature of the nucleophilic addition reaction can be -10 to 15°C, specifically -10°C, -5°C, 0°C, 5°C, 10°C, or 15°C; the time of the nucleophilic addition reaction can be 2 to 8 hours, specifically 2 hours, 4 hours, 5 hours, 6 hours, or 8 hours; the nucleophilic addition reaction can be carried out under a protective atmosphere, specifically nitrogen and / or argon.

[0025] In this invention, the quenching reagent used can be a saturated ammonium chloride aqueous solution. This invention, by quenching the reaction solution obtained from the nucleophilic addition reaction, avoids side reactions during post-processing, thereby improving the yield and purity of the intermediate product and the subsequently obtained spironolactone.

[0026] After quenching, the present invention may further include separating the quenched solution obtained from the quenching process, concentrating the resulting organic phase sequentially to obtain a concentrated solution; performing solid-liquid separation on the concentrated solution, and drying the resulting solid to obtain the tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The present invention does not specifically limit the methods of separation, concentration, solid-liquid separation, and drying; conventional methods in the art can be used. In the present invention, separation may specifically be static separation; concentration may specifically be vacuum distillation; solid-liquid separation may specifically be filtration; and drying may specifically be oven drying. The present invention does not specifically limit the conditions for concentration, as long as the organic phase is concentrated to the point where no solvent evaporates.

[0027] After obtaining tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate, the present invention mixes the tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate, trifluoroacetic acid, and lower chloroalkanes and carries out an elimination-lactoneation reaction to obtain 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone (compound 3).

[0028] In this invention, the mass ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to trifluoroacetic acid can be 1:0.3~1.5, specifically 1:0.3, 1:0.5, 1:0.8, 1:1, 1:1.2 or 1:1.5; the lower chloroalkane can include one or more of dichloromethane, trichloromethane and 1,2-dichloroethane; the 17β-hydroxy- The mass concentration of tert-butyl 3-oxopregn-4-ene-17-propionate (i.e., the mass ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to the volume ratio of the lower chloroalkanes) can be 0.05~0.2 g / mL, specifically 0.05 g / mL, 0.1 g / mL, 0.12 g / mL, 0.15 g / mL, 0.18 g / mL or 0.2 g / mL.

[0029] In this invention, the temperature of the elimination-lactoneation reaction can be 10~30℃, specifically 10℃, 15℃, 20℃, 25℃ or 30℃; the time of the elimination-lactoneation reaction can be 1~5h, specifically 1h, 2h, 3h, 4h or 5h.

[0030] In this invention, the reactions that occur during the elimination-lactoneation process are specifically shown in route 2: Route 2.

[0031] During the elimination-lactolation reaction, compound 2 undergoes an elimination reaction to eliminate the tert-butyl group, forming intermediate compound 7; compound 7 undergoes lactolation to form compound 3, and the elimination and lactolation reactions occur simultaneously.

[0032] After completing the elimination-lactoneation reaction, the present invention may further include neutralizing the reaction solution obtained from the elimination-lactoneation reaction to a pH value of 6.5-7.5, followed by liquid-liquid separation. The resulting organic phase is then concentrated, crystallized, subjected to solid-liquid separation, and dried to obtain the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. In the present invention, the pH value of the neutralized solution can be 6.5-7.5, specifically 6.5, 6.8, 6.9, 7.0, 7.1, or 7.5; the base used for neutralization can be an inorganic base, specifically one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide; the inorganic base can be used in the form of a saturated aqueous solution of an inorganic base. The present invention does not specifically limit the method of liquid-liquid separation; any conventional liquid-liquid separation method in the art can be used, specifically, static liquid-liquid separation. The present invention does not specifically limit the method of concentration; any conventional concentration method in the art can be used, specifically, vacuum distillation. In this invention, the crystallization reagent used for crystallization may include lower alcohols; the lower alcohol may be one or more of ethanol, methanol, isopropanol, and n-propanol; this invention does not have a special limitation on the amount of the crystallization reagent, and conventional amounts in the art can be used. This invention does not have a special limitation on the method of solid-liquid separation, and conventional solid-liquid separation methods in the art can be used, specifically filtration. This invention does not have a special limitation on the method of drying, and conventional drying methods in the art can be used, specifically drying. This invention uses lower alcohols to crystallize the concentrated reaction solution. During the crystallization process, 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone precipitates from the lower alcohol in crystal form, while impurities dissolve in the lower alcohol. Further purification is achieved by removing the lower alcohol containing dissolved impurities through solid-liquid separation, thereby improving the purity of the intermediate product obtained.

[0033] After obtaining 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone, the present invention mixes the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone, triethyl orthoformate, anhydrous ethanol and an organic acid catalyst, and carries out an etherification reaction to obtain 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone (compound 4).

[0034] In this invention, the mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to triethyl orthoformate can be 1:0.5~3, specifically 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, or 1:3; the mass concentration of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone (i.e., the ratio of the mass of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to the volume of anhydrous ethanol) can be 0.1~2g. The concentration of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone can be 0.1 g / mL, 0.5 g / mL, 1 g / mL, 1.5 g / mL, or 2 g / mL. The organic acid catalyst can include one or more of p-toluenesulfonic acid, benzenesulfonic acid, and pyridine hydrobromide. The mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to the organic acid catalyst can be 1:0.01~0.1, specifically 1:0.01, 1:0.03, 1:0.05, 1:0.07, 1:0.09, or 1:0.1. In this invention, anhydrous ethanol is used simultaneously as both the reaction substrate and the required anhydrous organic solvent. During the etherification reaction, anhydrous ethanol participates in the reaction to form an ethyl ether group.

[0035] In this invention, the temperature of the etherification reaction can be 40~45℃, specifically 40℃, 41℃, 42℃, 43℃, 44℃ or 45℃; the time of the etherification reaction can be 1~3h, specifically 1h, 2h or 3h.

[0036] After completing the etherification reaction, the present invention may further include cooling the reaction solution obtained from the etherification reaction to 0-10°C, performing solid-liquid separation, and then drying to obtain the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The present invention does not specifically limit the method of solid-liquid separation; any conventional solid-liquid separation method in the art can be used, specifically filtration. The present invention also does not specifically limit the method of drying; any conventional drying method in the art can be used, specifically baking.

[0037] After obtaining 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone, the present invention mixes the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone, substituted benzoquinone, and a lower ketone, and performs an oxidative dehydrogenation reaction to obtain 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone (compound 5).

[0038] In this invention, the substituted benzoquinone may include tetrachlorobenzoquinone and / or 2,3-dichloro-5,6-dicyanobenzoquinone; the mass ratio of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to the substituted benzoquinone may be 1:0.6~3, specifically 1:0.6, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3; the lower ketone may include acetone and / or butanone; the 17β- The mass concentration of hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone (i.e., the mass ratio of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to the volume ratio of the lower ketone) can be 0.1~0.2 g / mL, specifically 0.1 g / mL, 0.2 g / mL, 0.4 g / mL, 0.6 g / mL, 0.8 g / mL or 2 g / mL.

[0039] In this invention, the temperature of the oxidative dehydrogenation reaction can be 20~45℃, specifically 20℃, 25℃, 30℃, 35℃, 40℃ or 45℃; the time of the oxidative dehydrogenation reaction can be 2~6, specifically 2h, 3h, 4h, 5h or 6h.

[0040] After completing the oxidative dehydrogenation reaction, the present invention may further include subjecting the reaction solution obtained from the oxidative dehydrogenation reaction to a first solid-liquid separation, concentrating the filtrate, and then sequentially crystallizing and undergoing a second solid-liquid separation, followed by drying the solid to obtain the 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The present invention does not specifically limit the methods of the first and second solid-liquid separations; conventional solid-liquid separation methods in the art can be used, specifically filtration. In the present invention, the crystallization reagent used for crystallization may include low-boiling-point acetate ester organic solvents; specifically, the low-boiling-point acetate ester organic solvents may be one or more of ethyl acetate, isopropyl acetate, n-propyl acetate, and methyl acetate; the present invention does not specifically limit the amount of the crystallization reagent used; conventional amounts in the art can be used. The present invention does not specifically limit the method of concentration; conventional concentration methods in the art can be used, specifically vacuum distillation. The present invention does not specifically limit the method of drying; conventional drying methods in the art can be used, specifically oven drying.

[0041] After obtaining 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, the present invention mixes the 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, thioacetic acid and a lower alcohol (denoted as the first lower alcohol) and carries out an addition reaction to obtain spironolactone (compound 6).

[0042] In this invention, the mass ratio of 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone to thioacetic acid is 1:0.5~1, specifically 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1; the first lower alcohol may include one or more of methanol, ethanol, isopropanol and n-butanol; the 17β-hydroxy-17α-pregn- The mass concentration of 17β-dien-3-one-21-carboxylic acid-γ-lactone (i.e., the mass ratio of the 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone to the volume ratio of the first lower alcohol) can be 0.1~0.2 g / mL, specifically 0.1 g / mL, 0.2 g / mL, 0.4 g / mL, 0.6 g / mL, 0.8 g / mL or 2 g / mL.

[0043] In this invention, the addition reaction can be carried out under reflux conditions, and the reflux temperature can be specifically the boiling point of the lower alcohol; the reflux time can be 2 to 5 hours, specifically 2 hours, 3 hours, 4 hours or 5 hours.

[0044] After the addition reaction is completed, the present invention further includes cooling the reaction solution obtained from the addition reaction to -5~5℃ for solid-liquid separation, and then drying the resulting solid after crystallization to obtain the spironolactone. In the present invention, the final cooling temperature can be -5~5℃, specifically -5℃, -2℃, 0℃, 3℃, or 5℃. The present invention does not specifically limit the method of solid-liquid separation; conventional solid-liquid separation methods in the art can be used, specifically filtration. In the present invention, the crystallization reagent used for crystallization can include a second lower alcohol; the second lower alcohol can be one or more of ethanol, methanol, isopropanol, and n-propanol; the present invention does not specifically limit the amount of the crystallization reagent; conventional amounts in the art can be used. The present invention does not specifically limit the drying method; conventional drying methods in the art can be used, specifically baking.

[0045] To further illustrate the present invention, the solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0046] Example 1 Under nitrogen protection, 30 g of 4-androsten-3,17-dione and zinc chloride were dissolved in tetrahydrofuran at a mass ratio of 10:1. A 1 mol / L solution of 3-tert-butoxy-3-oxopropyl zinc bromide in tetrahydrofuran was then added, and the reaction was carried out at 0 °C for 4 h. After the reaction was complete, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution, separated, and the resulting organic phase was concentrated, filtered, and dried to obtain 41.5 g of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The mass ratio of 4-androsten-3,17-dione to the volume of tetrahydrofuran was 3 g:50 mL; the mass ratio of 4-androsten-3,17-dione to the volume of the 3-tert-butoxy-3-oxopropyl zinc bromide solution in tetrahydrofuran was 3 g:16 mL.

[0047] 40g of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate was mixed with dichloromethane at a mass-to-volume ratio of 1g:10mL, and then trifluoroacetic acid was added. The mixture was subjected to an elimination-lactoneation reaction at 15°C for 3 hours. After the reaction was complete, the resulting reaction solution was neutralized to pH 7.0 with saturated sodium bicarbonate aqueous solution. The mixture was separated, and the resulting organic phase was concentrated, crystallized with ethanol, filtered, and the resulting solid was dried to obtain 31.6g of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. The mass-to-volume ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to trifluoroacetic acid was 1g:0.3mL.

[0048] 30g of the obtained 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone was mixed with anhydrous ethanol at a mass-to-volume ratio of 3g:5mL. Triethyl orthoformate and p-toluenesulfonic acid were then added, and the mixture was subjected to an etherification reaction at 40℃ for 2 hours. After the reaction was completed, the resulting reaction solution was cooled to 0-10℃ and filtered. The resulting solid was dried to obtain 31.5g of 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to the volume of triethyl orthoformate was 3g:5mL; the mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to p-toluenesulfonic acid was 30:0.5.

[0049] 30g of the obtained 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone was mixed with acetone at a mass-to-volume ratio of 3g:18mL, and then tetrachlorobenzoquinone was added. The mixture was subjected to an oxidative dehydrogenation reaction at 25°C for 4 hours. After the reaction was complete, the resulting reaction solution was filtered, the filtrate was concentrated, crystallized with ethyl acetate, and then filtered again. The resulting solid was dried to obtain 26.3g of 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The mass ratio of 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to tetrachlorobenzoquinone was 3:2.

[0050] 25g of 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, methanol, and thioacetic acid were mixed at a mass-volume ratio of 25g:125mL:13mL and subjected to an addition reaction. After reflux for 5 hours, the resulting reaction solution was cooled to 0°C, filtered, and the resulting solid was purified by methanol crystallization and dried to obtain 25.1g of spironolactone. The mass yield of the single-step addition reaction was 100.4%, and the total mass yield of spironolactone was 101%.

[0051] The 1H NMR spectrum of the spironolactone prepared in Example 1 is as follows: 1 H NMR (500MHz, CDCl3, ppm): δ5.69(s,1H) ,3.96(m,1H) ,2.82(m,1H) ,2.55-2.49(m,2H) ,2.43(m,1H) ,2.41(m,1H) ,2.37(m,2H) ,2.32(s,3H) ,2.22(m,1H) ,2.04(m,1H) ,1.99(m,1H) ,1.91(m,1H) ,1.81(m,1H) ,1.71(m,1H) ,1.65(m,1H) ,1.56(m,2H) ,1.46(m,1H) ,1.39(m,2H) ,1.29(m,1H) ,1.21(s,3H) ,1.01(m,1H) ,0.97(s,3H).

[0052] The 1H NMR spectrum results show that the product obtained in Example 1 is spironolactone.

[0053] The detection of spironolactone was performed according to the high-performance liquid chromatography (HPLC) method specified in the currently effective European Pharmacopoeia EP11.0. The HPLC conditions were as follows: the chromatographic column was an RP column. 18 Chromatographic column (reversed phase C) 18 chromatographic column), specifications are The mobile phase was 3 μm; the mobile phase was water:acetonitrile:methanol:tetrahydrofuran = 540:15:425:20; the mobile phase flow rate was 1 mL / min; the detection wavelength was 254 nm; and the elution method was isocratic elution.

[0054] The liquid chromatogram of spironolactone obtained in Example 1 is shown below. Figure 1 As shown in Table 1, the peak information of the liquid chromatography is as follows.

[0055] Table 1. Liquid chromatography peak information of spironolactone in Example 1

[0056] Depend on Figure 1 As shown in Table 1, the HPLC purity of the spironolactone obtained in Example 1 is 99.802%, which is high.

[0057] Example 2 Under nitrogen protection, 30 g of 4-androsten-3,17-dione and zinc chloride were dissolved in tetrahydrofuran at a mass ratio of 6:1. A 0.5 mol / L solution of 3-tert-butoxy-3-oxopropyl zinc bromide in tetrahydrofuran was then added, and the reaction was carried out at 5 °C for 5 h. After the reaction was complete, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution, separated, and the resulting organic phase was concentrated, filtered, and dried to obtain 40.8 g of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The mass ratio of 4-androsten-3,17-dione to the volume of tetrahydrofuran was 3 g:20 mL; the mass ratio of 4-androsten-3,17-dione to the volume of the 3-tert-butoxy-3-oxopropyl zinc bromide solution in tetrahydrofuran was 3 g:50 mL.

[0058] 40g of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate was mixed with dichloromethane at a mass-to-volume ratio of 4g:20mL, and then trifluoroacetic acid was added. The mixture was subjected to an elimination-lactoneation reaction at 25°C for 4 hours. After the reaction was complete, the resulting reaction solution was neutralized to pH 6.9 with saturated sodium bicarbonate aqueous solution. The mixture was separated, and the resulting organic phase was concentrated, crystallized with ethanol, filtered, and the resulting solid was dried to obtain 31.3g of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. The mass-to-volume ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to trifluoroacetic acid was 1g:0.5mL.

[0059] 30g of the obtained 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone was mixed with anhydrous ethanol at a mass-to-volume ratio of 3g:10mL. Triethyl orthoformate and p-toluenesulfonic acid were then added, and the mixture was subjected to an etherification reaction at 45℃ for 3 hours. After the reaction was completed, the mixture was filtered, and the resulting solid was dried to obtain 30.5g of 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to triethyl orthoformate was 3g:10mL; the mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to p-toluenesulfonic acid was 30:1.

[0060] 30g of the obtained 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone was mixed with acetone at a mass-to-volume ratio of 1g:10mL, and then tetrachlorobenzoquinone was added. The mixture was subjected to an oxidative dehydrogenation reaction at 35℃ for 5 hours. After the reaction was complete, the resulting reaction solution was filtered, the filtrate was concentrated, crystallized with ethyl acetate, and then filtered again. The resulting solid was dried to obtain 26g of 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The mass ratio of 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to tetrachlorobenzoquinone was 1:1.

[0061] 25g of the obtained 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, methanol, and thioacetic acid were mixed at a mass-volume ratio of 25g:180mL:18mL and subjected to an addition reaction. After reflux for 4 hours, the resulting reaction solution was cooled to 0℃, filtered, and the resulting solid was purified by methanol crystallization and dried to obtain 24.8g of spironolactone. The mass yield of the single-step addition reaction was 99.2%, and the total mass yield was 93.1%.

[0062] The spironolactone prepared in Example 2 was analyzed by liquid chromatography under the same conditions as in Example 1. The liquid chromatogram of the spironolactone prepared in Example 2 is shown below. Figure 2 As shown in the figure, the liquid chromatography peak information is shown in Table 2.

[0063] Table 2. Liquid chromatography peak information of spironolactone in Example 2.

[0064] Depend on Figure 2 As shown in Table 2, the HPLC purity of the spironolactone obtained in Example 2 is 99.744%, which is high.

[0065] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing spironolactone, characterized in that, Includes the following steps: 4-Androsten-3,17-dione, 3-tert-butoxy-3-oxopropyl zinc bromide, a nucleophilic addition catalyst and an ether solvent were mixed and subjected to a nucleophilic addition reaction followed by quenching to obtain tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate. The tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate, trifluoroacetic acid, and lower chloroalkanes were mixed and subjected to an elimination-lactoneation reaction to obtain 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone, triethyl orthoformate, anhydrous ethanol and an organic acid catalyst were mixed and subjected to an etherification reaction to obtain 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone. The 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone, substituted benzoquinone, and lower ketone were mixed and subjected to an oxidative dehydrogenation reaction to obtain 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone. The 17β-hydroxy-17α-pregn-4,6-dien-3-one-21-carboxylic acid-γ-lactone, thioacetic acid, and a lower alcohol were mixed and subjected to an addition reaction to obtain spironolactone.

2. The preparation method according to claim 1, characterized in that, The nucleophilic addition catalyst includes zinc chloride and / or cerium chloride; The ether solvents include one or more of tetrahydrofuran, 2-methyl-tetrahydrofuran, and diethyl ether; The molar ratio of 4-androsten-3,17-dione and 3-tert-butoxy-3-oxopropyl zinc bromide is 1:1~3; The mass ratio of the 4-androsten-3,17-dione to the nucleophilic addition catalyst is 1:0.05~0.3; The mass concentration of the 4-androsten-3,17-dione is 0.05~0.2 g / mL.

3. The preparation method according to claim 1 or 2, characterized in that, The nucleophilic addition reaction is carried out at a temperature of -10 to 15°C for 2 to 8 hours.

4. The preparation method according to claim 1, characterized in that, The lower chloroalkanes include one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane; The mass ratio of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate to trifluoroacetic acid is 1:0.3~1.5; The mass concentration of tert-butyl 17β-hydroxy-3-oxopregn-4-ene-17-propionate is 0.05~0.2 g / mL.

5. The preparation method according to claim 1 or 4, characterized in that, The elimination-lactoneation reaction is carried out at a temperature of 10~30℃ for 1~5h.

6. The preparation method according to claim 1, characterized in that, The organic acid catalyst includes one or more of p-toluenesulfonic acid, benzenesulfonic acid, and pyridine hydrobromide; The mass ratio of 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to triethyl orthoformate is 1:0.5~3; The mass concentration of the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone is 0.1~2 g / mL; The mass ratio of the 17β-hydroxy-3-oxopregn-4-ene-21-carboxylic acid-γ-lactone to the organic acid catalyst is 1:0.01~0.

1.

7. The preparation method according to claim 1 or 6, characterized in that, The etherification reaction is carried out at a temperature of 40-45°C for 1-3 hours.

8. The preparation method according to claim 1, characterized in that, The substituted benzoquinones include tetrachlorobenzoquinone and / or 2,3-dichloro-5,6-dicyanobenzoquinone; The lower ketones include acetone and / or butanone; The mass ratio of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone to the substituted benzoquinone is 1:0.6~3; The mass concentration of the 17β-hydroxy-3-ethoxy-17α-pregn-3,5-diene-21-carboxylic acid-γ-lactone is 0.1~0.2 g / mL.

9. The preparation method according to claim 1 or 8, characterized in that, The oxidative dehydrogenation reaction is carried out at a temperature of 20-45°C for 2-6 hours.

10. The preparation method according to claim 1, characterized in that, The lower alcohols include one or more of methanol, ethanol, isopropanol, and n-butanol; The mass ratio of 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone to thioacetic acid is 1:0.5~1; The mass concentration of the 17β-hydroxy-17α-pregn-4,6-diene-3-one-21-carboxylic acid-γ-lactone is 0.1~0.2 g / mL; The addition reaction is carried out under reflux conditions; the reflux time is 2 to 5 hours.

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