Preparation method of 3-oxo-4-androstene-17 beta-carboxylic acid

Abstract

The invention discloses a preparation method of 3-oxo-4-androstene-17 beta-carboxylic acid, and belongs to the technical field of medicine synthesis. According to the invention, pregnenolone is used as an initial raw material, and is oxidized by an oxidant in the presence of a catalyst to obtain 3-oxo-4-androstene-17 beta-carboxylic acid. The method is simple and convenient to operate, mild in reaction condition, low in cost, high in yield and suitable for industrial large-scale production, and has great significance in production of epristeride bulk drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for preparing 3-oxo-4-androstene-17β-carboxylic acid. Background Art

[0002] Epristeride, also known as epristeride, has a chemical name of 17β-(N-tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid. Its tablets were developed by our company and were first launched in China in 2003 as a Class I new drug. This product can form a ternary complex with 5α-reductase and nicotinamide adenine dinucleotide phosphate, thereby inhibiting the conversion of testosterone to dihydrotestosterone (DHT), reducing the DHT content in the patient's serum and prostate, and is clinically used to treat benign prostatic hyperplasia.

[0003] 3-Oxo-4-androstene-17β-carboxylic acid is the starting material for preparing the key intermediate of Aprelet in patent CN117946200A, and is also one of the intermediates of Aprelet, which is of great significance to the production of Aprelet API. Its structural formula is as follows:

[0004]

[0005] Existing literature reports on the preparation method of 3-oxo-4-androstene-17β-carboxylic acid, such as CN106632559 (published on May 10, 2017), which uses progesterone as a raw material and uses highly dangerous and toxic liquid bromine as a reaction reagent. The reaction conditions are harsh, the pollution is large, the production cost is high, and it is not suitable for actual production. Summary of the invention

[0006] The technical problem solved by the present invention is to provide a method for preparing 3-oxo-4-androstene-17β-carboxylic acid. The method uses cheaper pregnenolone as a starting material, has simple operation, mild reaction conditions, high yield, and is suitable for large-scale industrial production.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0008] A method for preparing 3-oxo-4-androstene-17β-carboxylic acid comprises the following steps:

[0009] Using pregnenolone as the starting material, 3-oxo-4-androstene-17β-carboxylic acid is obtained by oxidation with an oxidant under catalyst conditions;

[0010] The reaction formula is as follows:

[0011]

[0012] The oxidant is selected from any one of sodium hypochlorite or calcium hypochlorite.

[0013] The oxidation solvent is selected from any one or two of tetrahydrofuran, ethanol, dioxane, acetonitrile, isopropanol and methanol.

[0014] The oxidation reaction temperature is 0-25°C.

[0015] The heating time is 5 to 6 hours.

[0016] The mass ratio of pregnenolone to the organic solvent is 1:15-20.

[0017] The molar ratio of pregnenolone to the oxidant is 1:5-15.

[0018] The catalyst is 2,2,6,6-tetramethylpiperidinoxide.

[0019] The molar ratio of pregnenolone to the catalyst is 1:0.05-0.1.

[0020] Compared with the prior art, the present invention has the following advantages:

[0021] (1) The preparation method of the present invention is simple to operate, highly safe, has mild reaction conditions, low cost, high yield, and little pollution, and is suitable for large-scale industrial production, which is of great significance to the production of Aprelet raw materials.

[0022] (2) Compared with the prior art, the present invention overcomes the problems of high risk, high toxicity, harsh reaction conditions, high production cost and high pollution in the prior art, and provides a new technical solution that is more suitable for industrial production. DETAILED DESCRIPTION

[0023] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0024] Example 1

[0025] 0.005 mol of TEMPO solid was added to 500 mL of ethanol, stirred at room temperature to dissolve, 0.1 mol of pregnenolone was added, the temperature was lowered to 10°C, 500 mL of sodium hypochlorite solution (commercially available) with effective chlorine content of 13% to 16% was added dropwise, the temperature was raised to 25°C, and the reaction was kept warm for 5 hours. After the reaction was completed, 200 mL of 20% sodium sulfite solution was added and stirred for 15 minutes, most of the ethanol was evaporated under reduced pressure, 500 mL of ethyl acetate was added and stirred for 15 minutes, the liquid was separated, the aqueous layer was acidified to pH = 1-2 with concentrated hydrochloric acid, the temperature was lowered to 15°C, the solid was precipitated by stirring, filtered, and dried to obtain 25.3 g of 3-oxo-4-androstene-17β-carboxylic acid, with a molar yield of 80% and a purity of 95.3%.

[0026] Example 2

[0027] 0.008 mol of TEMPO solid was added to 500 mL of tetrahydrofuran, and 50 mL of water was added. The mixture was stirred at room temperature until dissolved. 0.1 mol of pregnenolone was added, and the temperature was lowered to 10°C. 0.5 mol of calcium hypochlorite solid was added in batches, and the temperature was raised to 25°C. The mixture was kept warm for 5 hours. After the reaction was completed, 300 mL of 20% sodium sulfite solution was added and stirred for 15 minutes. Most of the tetrahydrofuran was evaporated under reduced pressure, and 500 mL of ethyl acetate was added and stirred for 15 minutes. The liquid was separated, and the aqueous layer was acidified to pH = 1-2 with concentrated hydrochloric acid, and the temperature was lowered to 15°C. The solid was precipitated by stirring, filtered, and dried to obtain 25.6 g of 3-oxo-4-androstene-17β-carboxylic acid, with a molar yield of 81% and a purity of 95.6%.

[0028] Example 3

[0029] 0.01 mol of TEMPO solid was added to 500 mL of dioxane, 60 mL of water was added, and the mixture was stirred at room temperature until dissolved. 0.1 mol of pregnenolone was added, the temperature was lowered to 10°C, 1 mol of calcium hypochlorite solid was added in batches, the temperature was raised to 25°C, and the mixture was kept warm for 6 hours. After the reaction was completed, 600 mL of 20% sodium sulfite solution was added and stirred for 15 minutes, most of the dioxane was evaporated under reduced pressure, 500 mL of ethyl acetate was added and stirred for 15 minutes, and the liquid was separated. The aqueous layer was acidified with concentrated sulfuric acid to pH = 1-2, the temperature was lowered to 15°C, the solid was precipitated by stirring, filtered, and dried to obtain 26.2 g of 3-oxo-4-androstene-17β-carboxylic acid, with a molar yield of 83% and a purity of 95.8%.

[0030] Example 4

[0031] 0.06 mol of TEMPO solid was added to 600 mL of acetonitrile, 50 mL of water was added, and the solution was dissolved by stirring at room temperature, 0.1 mol of pregnenolone was added, the temperature was lowered to 10°C, 1.5 mol of calcium hypochlorite solid was added in batches, the temperature was raised to 25°C, and the reaction was kept warm for 6 hours. After the reaction was completed, 900 mL of 20% sodium sulfite solution was added and stirred for 15 minutes, most of the acetonitrile was evaporated under reduced pressure, 500 mL of ethyl acetate was added and stirred for 15 minutes, and the liquid was separated. The water layer was acidified to pH = 1-2 with concentrated sulfuric acid, the temperature was lowered to 15°C, the solid was precipitated by stirring, filtered, and dried to obtain 22.1 g of 3-oxo-4-androstene-17β-carboxylic acid, with a molar yield of 70% and a purity of 95.1%.

[0032] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 3-oxo-4-androstene-17β-carboxylic acid, characterized in that: The following steps are involved: Using pregnenolone as the starting material, 3-oxo-4-androstene-17β-carboxylic acid is obtained by oxidation with an oxidant under catalyst conditions; The reaction formula is as follows:

2. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The oxidant is selected from any one of sodium hypochlorite or calcium hypochlorite.

3. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The oxidation solvent is selected from any one or two of tetrahydrofuran, ethanol, dioxane, acetonitrile, isopropanol and methanol.

4. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The oxidation reaction temperature is 0-25°C.

5. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The heating time is 5 to 6 hours.

6. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The mass ratio of pregnenolone to the organic solvent is 1:15-20.

7. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The molar ratio of pregnenolone to the oxidant is 1:5-15.

8. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The catalyst is 2,2,6,6-tetramethylpiperidinoxide.

9. The method for preparing 3-oxo-4-androstene-17β-carboxylic acid according to claim 1, characterized in that: The molar ratio of pregnenolone to the catalyst is 1:0.05-0.1.

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