Method for safely preparing epristeride in one step

Abstract

The invention discloses a method for safely preparing epristeride in one step, and belongs to the technical field of medicine synthesis. The method comprises the following steps: taking 3-bromo-N-(1, 1-trimethyl ethyl) androstane-3, 5-diene-17beta-formamide as an initial raw material, carrying out carboxylation reaction on an alcohol solvent through a catalyst under an alkaline condition, then adding water to carry out hydrolysis reaction, and acidifying to obtain epristeride. The method is simple and convenient to operate, short in route, mild in reaction condition, high in yield, particularly high in safety and suitable for industrial mass production, and has great significance in production of epristeride raw material medicines.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for safely preparing aprelet in one step. Background Art

[0002] Epristeride, also known as elisteride, 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 (approval certificate number: National Medicine Certificate X19990154). 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. The structural formula of epristeride is as follows:

[0003]

[0004] In most of the reported literature on the preparation of Aprelet, such as CN102002085 (publication date: 2011.04.06) and CN107513093 (publication date: 2017.12.26), carbon monoxide is used to form the key carboxylation reaction of Aprelet via a bistriphenylphosphine palladium dichloride catalyst. It is known that carbon monoxide is a highly dangerous, toxic, flammable, explosive, poisonous and difficult to control gas. The operation is complicated in actual production and use, which brings many uncertainties and seriously affects production safety. Summary of the invention

[0005] The technical problem solved by the invention is to provide a one-step safe method for preparing aprelet, which has the advantages of simple operation, mild reaction conditions, high yield and high safety, and is suitable for large-scale industrial production.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0007] A one-step safe method for preparing Aprelet comprises the following steps:

[0008] Using 3-bromo-N-(1,1-dimethylethyl)androstane-3,5-diene-17β-carboxamide as the starting material, an alcohol solvent is subjected to a carboxylation reaction in the presence of a catalyst under alkaline conditions, and then water is added to carry out a hydrolysis reaction, and after acidification, Aprelet is obtained;

[0009] The reaction formula is as follows:

[0010]

[0011] The base is selected from any one of sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; and the reagent participating in the carboxylation reaction is chloroform.

[0012] The alcohol solvent is selected from any one of methanol, ethanol and isopropanol.

[0013] The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the alcohol is 1:6-12.

[0014] The molar ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the base is 1:10-20.

[0015] The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to chloroform is 1:1.5-2.5.

[0016] The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the catalyst is 1:0.05-0.15.

[0017] The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to water is 1:10-14.

[0018] The carboxylation reaction temperature is 60-68° C., and the heating time is 5-8 hours.

[0019] The temperature for dropping chloroform is 20-30°C; the temperature for hydrolysis is 20-40°C, and the reaction time is 6-10h.

[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, has mild reaction conditions, low cost, high yield, and especially high safety, and is suitable for large-scale industrial production, which is of great significance to the production of Aprelet API.

[0022] (2) Compared with the prior art, the present invention overcomes the problems of the prior art such as high risk, high toxicity, flammability, explosion and poisoning, and complex preparation and operation, and provides a new technical solution that is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the NMR spectrum of Aplilate prepared in Example 2;

[0024] Figure 2 This is the liquid phase spectrum of Aplilate prepared in Example 2. DETAILED DESCRIPTION

[0025] 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.

[0026] The calculation formula for calculating the molar yield of Aiplete in the following examples is as follows:

[0027]

[0028] Example 1

[0029] Add 30 g of solid sodium hydroxide to 300 g of ethanol, stir at room temperature until dissolved, and after the system temperature drops to room temperature, add 30 g of 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide and 1.5 g of bistriphenylphosphine palladium dichloride, control the temperature to 20-30°C, add 45 g of chloroform dropwise, and keep the temperature for reaction for 30 minutes after the addition is completed, then raise the temperature to 60-68°C and keep the temperature for reaction for 7-8 hours. After the reaction, cool to 20-40°C, filter, add 300g of water to the filtrate, maintain the temperature at 20-40°C, react for 8-10h, concentrate under reduced pressure to remove methanol, add 240g of ethyl acetate, adjust pH to 1-2 with 5mol / L hydrochloric acid aqueous solution, separate the liquids, extract the aqueous phase with 240g of ethyl acetate again, combine the organic phases, wash the organic phases with 300g of purified water 3 times, concentrate under reduced pressure to remove 360g of ethyl acetate, a large amount of solid precipitates, cool to -10-0°C, freeze for 8-12h, filter, and dry to obtain 22g of white solid Aeplet, with a molar yield of 80%.

[0030] Example 2

[0031] Add 30 g of potassium hydroxide solid to 270 g of methanol, stir at room temperature to dissolve, after the system temperature drops to room temperature, add 30 g of 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide and 3 g of bistriphenylphosphine palladium dichloride, control the temperature to 20-30°C, add 60 g of chloroform dropwise, keep the temperature for reaction for 30 min after the addition is completed, then raise the temperature to 60-68°C and keep the temperature for reaction for 5-6 h. After the reaction, cool to 20-40°C, filter, add 330g of water to the filtrate, keep the temperature at 20-40°C, react for 6-7h, concentrate under reduced pressure to remove methanol, add 300g of ethyl acetate, adjust pH to 1-2 with 5mol / L hydrochloric acid aqueous solution, separate the liquids, extract the aqueous phase with 300g of ethyl acetate again, combine the organic phases, wash the organic phases with 330g of purified water 3 times, concentrate under reduced pressure to remove 500g of ethyl acetate, a large amount of solid precipitates, cool to -10-0°C, freeze for 8-12h, filter, dry, and obtain 23g of white solid Apelite with a molar yield of 83%. The NMR spectrum and liquid spectrum of the prepared Apelite are as follows Figure 1 and 2 shown.

[0032] Example 3

[0033] Add 230 g of cesium carbonate solid to 360 g of isopropanol and stir at room temperature for 30 min. After the system temperature drops to room temperature, add 30 g of 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide and 4.5 g of bistriphenylphosphine palladium dichloride. Control the temperature to 20-30°C, drop 75 g of chloroform, and keep the temperature for reaction for 30 min after the dropwise addition. Then raise the temperature to 60-68°C and keep the temperature for reaction for 7-8 h. After the reaction, cool to 20-40°C, filter, add 400g of water to the filtrate, maintain the temperature at 20-40°C, react for 7-8h, concentrate under reduced pressure to remove methanol, add 280g of ethyl acetate, adjust pH to 1-2 with 2mol / L hydrochloric acid aqueous solution, separate the liquids, extract the aqueous phase with 320g of ethyl acetate again, combine the organic phases, wash the organic phases with 400g of purified water 3 times, concentrate under reduced pressure to remove 490g of ethyl acetate, a large amount of solid precipitates, cool to -10-0°C, freeze for 8-12h, filter, and dry to obtain 23.5g of white solid Apelite with a molar yield of 85%.

[0034] Example 4

[0035] Add 50 g of potassium carbonate solid to 180 g of methanol, stir at room temperature to dissolve, after the system temperature drops to room temperature, add 30 g of 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide and 3 g of bistriphenylphosphine palladium dichloride, control the temperature to 20-30°C, add 60 g of chloroform dropwise, keep the temperature for reaction for 30 min after the addition is completed, then raise the temperature to 60-68°C and keep the temperature for reaction for 5-6 h. After the reaction, cool to 20-40°C, filter, add 360g of water to the filtrate, maintain the temperature at 20-40°C, react for 6-7h, concentrate under reduced pressure to remove methanol, add 300g of ethyl acetate, adjust pH to 1-2 with 5mol / L aqueous hydrochloric acid solution, separate the liquids, extract the aqueous phase with 300g of ethyl acetate again, combine the organic phases, wash the organic phases with 330g of purified water 3 times, concentrate under reduced pressure to remove 500g of ethyl acetate, a large amount of solid precipitates, cool to -10-0°C, freeze for 8-12h, filter, and dry to obtain 20g of white solid Aeplet, with a molar yield of 73%.

[0036] 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 one-step safe method for preparing aiplete, characterized in that: The following steps are involved: Using 3-bromo-N-(1,1-dimethylethyl)androstane-3,5-diene-17β-carboxamide as the starting material, an alcohol solvent is subjected to a carboxylation reaction in the presence of a catalyst under alkaline conditions, and then water is added to carry out a hydrolysis reaction, and after acidification, Aprelet is obtained; The reaction formula is as follows:

2. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The base is selected from any one of sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; and the reagent participating in the carboxylation reaction is chloroform.

3. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The alcohol solvent is selected from any one of methanol, ethanol and isopropanol.

4. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the alcohol is 1:6-12.

5. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The molar ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the base is 1:10-20.

6. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to chloroform is 1:1.5-2.

5.

7. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to the catalyst is 1:0.05-0.

15.

8. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The mass ratio of the 3-bromo-N-(1,1-dimethylethyl)androsta-3,5-diene-17β-carboxamide to water is 1:10-14.

9. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The carboxylation reaction temperature is 60-68° C., and the heating time is 5-8 hours.

10. The one-step safe preparation method of Aprelet according to claim 1, characterized in that: The temperature for dropping chloroform is 20-30°C; the temperature for hydrolysis is 20-40°C, and the reaction time is 6-10h.

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