JPS634560B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention discloses 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene, which is a highly effective therapeutic antialdosterone diuretic.
The present invention relates to an industrial method for producing 21-carboxylic acid γ-lactone (hereinafter abbreviated as spironolactone). More specifically, the present invention provides 17-hydroxy-3
-Oxo-17α-Pregnar-4,6-Diene-21
-Provides a method for producing highly pure spironolactone in high yield from carboxylic acid γ-lactone using extremely simple operations. Spironolactone is usually 17-hydroxy-3-oxo-17α
-Pregnar-4,6-diene-21-carboxylic acid
It is produced by heating and reacting γ-lactone with a large excess of thioacetic acid. At that time, approximately 25% of therapeutically inactive 7β-acetylthio derivatives are produced as by-products.
Therapeutically active spironolactone, the 7α-acetylthio derivative, is obtained in only about 70% yield. Furthermore, according to Japanese Patent Application Laid-Open No. 46-4020, if methanol is used as a solvent, a 7α-acetylthio derivative can be obtained with a yield of about 90%.
However, according to the inventors' experiments, this method
In addition to 7α-acetylthio derivatives and 7β-acetylthio derivatives, 8-10% of by-products are produced,
7α-acetylthio derivatives cannot be obtained in yields higher than 90%. Furthermore, the reason why it is not preferred to use methanol as a solvent is that the stability of therapeutically active 7α-acetylthio derivatives is very poor in this solvent. For example, after dissolving the 7α-acetylthio derivative in methanol and heating it to methanol reflux temperature for 9 hours, the recovery rate of the 7α-acetylthio derivative is only 35%. The purpose of the present invention is to suppress the production of by-products other than 7α-acetylthio derivatives and 7β-acetylthio derivatives, and further increase the production ratio of 7α-acetylthio derivatives to 7β-acetylthio derivatives, thereby producing highly pure spironolactone.
The objective is to provide a method for producing with high yield. Therefore, this purpose is to
Oxo-17α-pregnar-4,6-diene-21-
When producing spironolactone by adding thioacetic acid to carboxylic acid γ-lactone, by using N-methyl-2-pyrrolidone or N,N-dimethylformamide as a solvent and by crystallizing and separating the reaction product. achieved. The present invention will be explained in detail below. Therapeutically useful spironolactone is obtained by reacting 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone with thioacetic acid in a solvent. The solvent used in the method of the invention is N-methyl-2-pyrrolidone or N,N-dimethylacetamide. Of course, both may be used together.
The amount of solvent used is 1 to 10 ml, preferably 3 to 6 ml per g, based on the weight of the raw steroid.
It is. The amount of thioacetic acid used is 1.1 to 20 times the mole, preferably 1.5 to 7 times the mole of the raw material steroid. The reaction temperature is 10-120°C, preferably 30-100°C, more preferably 50-85°C. The addition reaction may also be carried out in the presence of a catalytic amount of an acid stronger than thioacetic acid, if desired. The advantage of using N-methyl-2-pyrrolidone or N,N-dimethylacetamide as the reaction solvent is that, in addition to obtaining high yields of therapeutically active 7α-acylthio derivatives, the desired 7- The aim is to suppress the production of by-products other than acetylthio derivatives to almost no extent. A 7-acetylthio derivative is a mixture of a 7α-acetylthio derivative and a 7β-acetylthio derivative, and the therapeutically active 7α-acetylthio derivative can be easily separated and purified from this mixture by a simple purification method such as recrystallization. Therapeutically inactive 7β-acetylthio derivatives can be easily converted to 7α-acetylthio derivatives in high yields and can also be easily converted to 4,6-diene-3-oxosteroids in high yields by treatment with alkali. It is possible. Therefore, not producing any by-products other than the 7-acetylthio derivative increases the yield of the 7α-acetylthio derivative,
Furthermore, it has a great economic effect in increasing the purification efficiency of 7α-acetylthio derivatives. Furthermore, in the solvent used in the method of the present invention, the 7α-acetylthio derivative is extremely stable even when reacted for a long time. In the method of the present invention, spironolactone is isolated from the reaction mixture by a crystallization separation method. Thereby, highly pure spironolactone can be easily obtained from the reaction mixture. Usually, after adding an appropriate amount of water or water and a polar solvent to the reaction mixture, it is cooled and then filtered to separate the precipitated spironolactone. As is clear from the Examples described below, the spironolactone thus obtained usually has a purity of 95% or more. This shows that the solvent used in the method of the present invention is not only excellent as a solvent for addition reactions, but also has excellent effects as a purification solvent. One of the preferred embodiments of the present invention is to use crude, low-purity 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone as a raw material. The addition reaction again proceeds in the same way as when using high purity raw materials, the reaction products are formed in almost theoretical yields and the relative proportions of isomers are also good. Most of the accompanying impurities remain in the solvent used as reaction medium. If the starting material is contaminated with large amounts of impurities and the purity of the product does not pass the prescribed specifications,
The product obtained can be purified by simple solvent treatment. The present invention will be explained in more detail below using Examples and Reference Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof. Example 1 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone 1.111 g (3.263 mmole, purity 99.78%), N-methyl-2-pyrrolidone 3.33 ml and p - Heat 47 mg of toluenesulfonic acid monohydrate to 60°C under nitrogen atmosphere. Add 0.67 ml of thioacetic acid to this and stir for 8.5 hours. Next, 3.3 ml of water heated to 60°C is slowly added to the resulting reaction mixture. After the addition is complete, the mixture is slowly cooled to 25° C. over 1.5 hours with continued stirring. During this time, the acetylthio derivative precipitates out as crystals from the mixed solution. It is then filtered and the crystals are washed twice with 6 ml of water. The obtained crystals are dried under reduced pressure at 70°C until a constant weight is reached. The dry crystal weight was 1.259 g. Analysis of this crystal revealed that the content of spironolactone was 96.5%. Melting point: 195.0°C to 198.9°C Example 2 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone 1.005 g (2.951 mmole), N-methyl-2-pyrrolidone 3 ml and 46 mg of p-toluenesulfonic acid monohydrate is heated to 80° C. under nitrogen atmosphere. Add 0.6 ml of thioacetic acid to this and stir for 2 hours. Next, 3 ml of N-methyl-2-pyrrolidone is added at 80°C. Subsequently, 6 ml of water are added dropwise over a period of 25 minutes.
After dropping, slowly cool to 30°C over 1 hour. During this time, the acetylthio derivative precipitates out as crystals from the mixed solution. Next, a mixture of 6.6 ml of methanol and 6 ml of water was added dropwise over 25 minutes at 30°C. After the addition is complete, stir at 30°C for an additional hour. The crystals are then filtered and washed twice with 5 ml of an equal volume mixture of methanol and water. The obtained crystals are dried under reduced pressure at 70°C. The dry crystal weight was 1.043 g.
Analysis of this crystal revealed that the spironolactone content was 97.6%. Melting point: 204.7-206.7℃ Example 3 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone 1.004g (purity 99.86% 2.944mmole), N-methyl-2-pyrrolidone 3 ml and 45 mg of p-toluenesulfonic acid monohydrate are heated to 80° C. under nitrogen atmosphere. Add 0.6 ml of thioacetic acid to this and stir for 2 hours.
Next, 1 ml of acetic acid was added at 80°C, and then 3 ml of water was added dropwise over 10 minutes. After dropping, it takes 1 hour and 20 minutes to reach 30℃.
Cool slowly until During this time, the acetylthio derivative is precipitated from the mixed solution. Then at 30℃, methanol 3.3
ml and 3 ml of water was added dropwise over 6 minutes. After the addition is complete, stir at 30°C for an additional hour. The crystals are then filtered and washed twice with 5 ml of an equal volume mixture of methanol and water. The obtained crystals are dried under reduced pressure at 70°C. The dry crystal weight was 0.931 g.
Analysis of this crystal revealed that the spironolactone content was 99.8%. Melting point: 203.8-205.6°C Example 4 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone 1.003 g, N-methyl-2-pyrrolidone 3 ml and p-toluenesulfonic acid Heat 43 ml of the monohydrate to 60° C. under nitrogen atmosphere. here thioacetic acid 0.6
ml and conduct the addition reaction under stirring at 60°C, and monitor changes in the raw materials and products over time. The results are shown in Table 1 below.

【table】

[Table] In the following, these symbols represent the same meaning. It is clearly seen that the 7β-acetylthio derivative is converted to the 7α-acetylthio derivative. Example 5 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid 1.005 g of γ-lactone and 3 ml of N-methyl-2-pyrrolidone are heated to 60° C. under a nitrogen atmosphere. Add 0.6 ml of thioacetic acid to this, perform the addition reaction at 60°C with stirring,
Similar to Example 4, the changes over time of the raw materials and products are followed. The results are shown in Table 2 below.

[Table] It is clearly seen that the 7β-acetylthio derivative is converted to the 7α-acetylthio derivative. Example 6 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone 1.016 g, N,N-dimethylacetamide 3 ml
and 45 mg of p-toluenesulfonic acid monohydrate,
Heat to 60 °C under nitrogen atmosphere. Thioacetic acid here
Add 0.6ml and carry out the addition reaction at 60°C with stirring.
Track the evolution of raw materials and products over time. The results are shown in Table 3 below.

[Table] Clearly, 7β-acetylthio derivatives are 7α-
It can be seen that it is converted to an acetylthio derivative. Reference example 1 496 mg of spironolactone was added with N- under a nitrogen atmosphere.
The mixture to which 1.5 ml of methyl-2-pyrrolidone was added was heated and stirred at 60°C for 9 hours. Thereafter, this mixed solution was cooled and analyzed by high performance liquid chromatography, and as a result, the recovery rate of spironolactone was 98.3%. In addition, 17-hydroxy-3
-Oxo-17α-pregnar-4.6-diene-21-carboxylic acid γ-lactone was produced at a ratio of 0.8% to the spironolactone charged. Reference example 2 497 mg of spironolactone was added with N- under a nitrogen atmosphere.
A mixture of 1.5 ml of methylpyrrolidone, 0.3 ml of thioacetic acid, and 22 mg of p-toluenesulfonic acid monohydrate was heated and stirred at 60° C. for 9 hours. After that, this mixture was cooled and analyzed by high performance liquid chromatography, and the recovery rate of spironolactone was found to be
It was 95.7%. In addition, 7β-isomer and 17-hydroxy-3-oxo-17α-pregnane-4,6-
Diene-21-carboxylic acid γ-lactone was produced in proportions of 4.8% and 0.3 mol%, respectively, based on the spironolactone charged. Reference example 3 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone 1.827g (4.39 mmole), 7β-acetylthio-17-hydroxy-3-oxo-17α
- Pregn-4-ene-21-carboxylic acid γ-lactone 1.3507 g (3.24 mmole) and 17-hydroxy-3-oxo-17α-pregn-4,6-diene-21-carboxylic acid γ-lactone 0.0949 g
(0.28 mmole) in 312 ml of methanol, 1N
-Add 19ml of NaOH and stir at 40℃ for 3 hours.
After the reaction, add an aqueous hydrochloric acid solution to neutralize. After distilling off the methanol, extraction is performed with benzene and the benzene solution is concentrated to obtain 2.7190 g of crystals.
When analyzed by liquid chromatography, 17-hydroxy-3-oxo-17α-pregnane-4,6-
Diene-21-carboxylic acid γ-lactone is 2.4091
g (7.06 mmole, recovery rate 89.3 mol%). Reference example 4 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid 15 ml of methanol was added to 5.00 g (14.7 mmole) of γ-lactone, and then 3.00 g of thioacetic acid was added for 2.0 hours. react. The relationship between reaction temperature and product composition is shown in Table 4 below, and it can be seen that the formation of about 10% by-products of unknown structure cannot be avoided.

[Table] Reference Example 5 A mixture of 998 mg of spironolactone and 2 ml of methanol under a nitrogen atmosphere was heated and stirred at methanol reflux temperature for 9 hours. Thereafter, this mixed solution was cooled and analyzed by high performance liquid chromatography, and as a result, the recovery rate of spironolactone was 35.1%. In addition, 17-hydroxy-3-oxo-
17α-Pregnar-4,6-diene-21-carboxylic acid Produced at a ratio of 33.9 mol% to spironolactone charged with γ-lactone. No 7β-isomer was detected. Reference Example 6 A mixture of 984 mg of spironolactone, 2 ml of methanol, and 6.4 ml of thioacetic acid was heated and stirred at methanol reflux temperature for 9 hours. Next, after cooling this mixture, analysis using high performance liquid chromatography revealed that the recovery rate of spironolactone was
It was 68.9%. In addition to this, 17-hydroxy-3-
Oxo-17α-pregnar-4,6-diene-21-
Carboxylic acid γ-lactone was produced at a rate of 4.1 mol% based on the spironolactone charged. 7β
- No isomers were detected.

Claims (1)

[Claims] 1 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone is added with thioacetic acid to form 7α-acetylthio-17-hydroxy-3- When producing oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone, use N-methyl-2-pyrrolidone or N,N-dimethylacetamide as a solvent and crystallize the reaction product. A method for producing the above-mentioned substance, which comprises separating the substance. 2. In the method for producing 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone according to claim 1, a catalytic amount of an acid stronger than thioacetic acid is used. A method characterized by adding thioacetic acid in the presence of. 3. In the method for producing 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone according to claim 1, crude 17-lactone is used as a starting material.
Hydroxy-3-oxo-17α-pregna-4,
A method characterized by using 6-diene-21-carboxylic acid γ-lactone. 4 In the method for producing 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone described in claim 1, water or A method characterized by adding water and a polar solvent to crystallize and separate the reaction product. 5 In the method for producing 7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone described in claim 4, the polar solvent is N-methyl -2-
A method characterized in that it is at least one selected from the group consisting of pyrrolidone, N,N-dimethylacetamide, methanol, ethanol, tetrahydrofuran, dioxane, and acetic acid.