WO2022083082A1

WO2022083082A1 - Method for preparing bicalutamide

Info

Publication number: WO2022083082A1
Application number: PCT/CN2021/088332
Authority: WO
Inventors: 唐保清; 张邦礼; 付志明; 付志雄; 刘洪生; 徐国平
Original assignee: 怀化宝华生物科技有限公司
Priority date: 2020-10-22
Filing date: 2021-04-20
Publication date: 2022-04-28
Also published as: CN112159372A

Abstract

The present invention provides a method for preparing bicalutamide intermediate 2, comprising the following steps: dissolving N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide in a lower fatty acid ester solvent, successively adding sodium percarbonate and acetic anhydride, stirring, heating, and performing an epoxidation reaction to obtain a reaction solution; filtering the reaction solution, washing the organic phase with a sodium thiosulfate solution, and recovering the solvent under reduced pressure; and adding petroleum ether, and carrying out cooling, crystallizing, filtering and drying to obtain the bicalutamide intermediate 2. The method for preparing bicalutamide intermediate 2 has mild reaction conditions, high reaction yield and high epoxidation efficiency, and the reaction solvent can be recycled.

Description

A kind of preparation method of bicalutamide

This application claims the priority of the Chinese patent application with the application number 202011138941.3 and the invention titled "A method for preparing bicalutamide", which was submitted to the China Patent Office on October 22, 2020, the entire contents of which are incorporated herein by reference Applying.

technical field

The invention relates to the technical field of biopharmaceuticals, in particular to a preparation method of a bicalutamide intermediate 2.

Background technique

Bicalutamide, chemical name: N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-methyl -2-Hydroxypropionamide. Bicalutamide was successfully developed by AstraZeneca in the United Kingdom. As a non-steroidal anti-androgen compound, it can feedback inhibit the secretion of gonadotropins from the anterior pituitary, and can reduce the production of androgen but has almost no androgenic activity. It is clinically used for treatment. Prostate cancer. Bicalutamide is currently the most widely used anti-androgen in the treatment of malignant prostate cancer due to its strong efficacy, convenient administration and few side effects.

In the related art, the document (Howard Tucker J.Med.Chem., 1988, 31, 954-959) discloses a method for synthesizing bicalutamide, which consists of 4-cyano-3-trifluoromethylaniline and 2-methylaniline Acryloyl chloride is acylated to obtain amide 1, 1 is oxidized by m-chloroperoxybenzoic acid to obtain epoxy compound 2, ring-opening is connected to p-fluorothiophenol to obtain 3, 3 is then oxidized by m-chloroperoxybenzoic acid to obtain bicalutamide 4 , the reaction formula is as follows:

In the synthesis method, m-chloroperoxybenzoic acid is used as an epoxidant, and the oxidant is prone to generate a large amount of solid waste, causing great environmental pollution, and the peroxyacid is explosive, unsafe to use, and has high requirements for safe production and operation. High; Dichloroethane is used as solvent, because of its high toxicity, it is difficult to remove residual products, which affects product quality.

SUMMARY OF THE INVENTION

The object of the present invention is to overcome the above-mentioned technical problems, and provide a kind of preparation method of bicalutamide intermediate 2 with mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.

In order to achieve the above object, the present invention provides a kind of preparation method of bicalutamide intermediate 2, comprises the steps:

Dissolve N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide in a lower fatty acid ester solvent, add sodium percarbonate and acetic anhydride successively, stir and heat, and carry out cyclization. The oxidation reaction obtains a reaction solution;

The reaction solution is filtered, the organic phase is washed with sodium thiosulfate solution, and the lower fatty acid ester solvent is recovered under reduced pressure;

After reclaiming the lower fatty acid ester solvent, adding petroleum ether for cooling crystallization, drying after filtration to obtain bicalutamide intermediate 2:

Preferably, the lower fatty acid ester is an ester of a fatty acid that is liquid at room temperature and has 2 to 6 carbon atoms.

Preferably, the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate.

Preferably, the lower fatty acid ester is ethyl acetate or ethyl formate.

Preferably, the reaction temperature of the epoxidation reaction is 10-50°C.

Preferably, the reaction temperature of the epoxidation reaction is 35-45°C.

Preferably, the molar ratio of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide and sodium percarbonate is 1:(1.1～1.5).

Preferably, the molar ratio of the sodium percarbonate and acetic anhydride is 1:(0.3～0.8).

Preferably, the reaction time of the epoxidation reaction is 1-12 h.

Compared with the related art, the preparation method of the bicalutamide intermediate 2 provided by the present invention has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The present invention provides a preparation method of bicalutamide intermediate 2, comprising the following steps:

The preparation method provided by the present invention uses N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide (intermediate 1) as a raw material, uses sodium percarbonate as an oxygen source, and uses The lower fatty acid ester is used as a solvent, and the intermediate 1 is epoxidized to generate the intermediate 2 at a reaction temperature of 10 to 50 ° C. The reaction formula is as follows:

The lower fatty acid ester is an ester of a fatty acid which is liquid at normal temperature and has 2 to 6 carbon atoms. Preferably, the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate. Further, the lower fatty acid ester is ethyl acetate or ethyl formate.

The epoxidation reaction is an endothermic reaction, and the reaction temperature is 10-50°C. Preferably, the reaction temperature of the epoxidation reaction is 35-45° C., and the reaction time is 1-12 h.

Sodium percarbonate is an inorganic compound, white powder, its content of available oxygen is 12-13%, it is insoluble in organic solvent. The mechanism of the epoxidation reaction is: first, sodium percarbonate and acetic anhydride generate an organic peroxy compound intermediate, and then react with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropene. The amide reacts to form an epoxy compound. The essence of this method is to prepare epoxidation reagents such as peroxyacetic anhydride through the action of sodium percarbonate and acetic anhydride, which react with N-[4-cyano-3-(trifluoromethyl)benzene during the reaction process base]-2-methacrylamide reaction, avoiding the weakness of unstable and easy decomposition of organic peroxy compounds, stable reaction and safe operation.

The epoxidation reaction of sodium percarbonate and acetic anhydride is a solid-liquid two-phase reaction. In order to ensure complete reaction, the N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide The molar ratio with sodium percarbonate is 1:(1.1～1.5).

The role of acetic anhydride is to react with sodium percarbonate to form peracetic anhydride, which itself reacts with N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide. After the transfer of the oxygen atom, it is reduced to acetic anhydride. Therefore, acetic anhydride can be recycled. In order to speed up the reaction, in actual operation, the molar ratio of the sodium percarbonate and acetic anhydride is 1:(0.3-0.8).

Example 1

In a 500mL three-neck flask, add 150mL of ethyl acetate, sodium percarbonate (18.84g, 0.12mol), N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide ( 25.4g, 0.10mol), stirred, at 35～40℃, add dropwise acetic anhydride (7.14g, 0.07mol), after the dropwise addition, slowly heat up to 45℃, stir for 5h, TLC (thin layer chromatography) tracking The reaction process, after the reaction was completed, cooled to room temperature, the reaction system was filtered, the organic layer was washed once with sodium thiosulfate solution, and then twice with saturated brine, and the ethyl acetate was recovered by rotary evaporation under reduced pressure. 80 mL of petroleum ether was stirred and cooled for crystallization, filtered and dried to obtain 24.6 g of bicalutamide intermediate 2 as a white solid with a yield of 91.1%.

Embodiment 2

In a 500mL three-neck flask, add 180mL of methyl formate, sodium percarbonate (23.55g, 0.15mol), N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide ( 25.4g, 0.10mol), stir, at 35～40℃, add acetic anhydride (7.65g, 0.075mol) dropwise, after the dropwise addition, slowly heat up to 50℃, stir for 6h, TLC tracks the reaction progress, the reaction is complete After cooling to room temperature, the reaction system was filtered, the organic layer was washed once with sodium thiosulfate solution, and then twice with saturated brine, and methyl formate was recovered by rotary evaporation under reduced pressure. After recovering methyl formate, 100 mL of petroleum ether was added, and stirred. Crystallization by cooling, filtration, and drying to obtain bicalutamide intermediate 2 as a white solid 24.92 g with a yield of 92.3%.

Embodiment 3

In a 500mL three-neck flask, add 200mL of methyl acetate, sodium percarbonate (21.98g, 0.14mol), N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide ( 25.4g, 0.10mol), stir, at 30～35℃, add acetic anhydride (8.16g, 0.08mol) dropwise, after the dropwise addition, slowly heat up to 45℃, stir for 8h, TLC tracks the reaction progress, the reaction is complete After cooling to room temperature, the reaction system was filtered, the organic layer was washed once with sodium thiosulfate solution, and then twice with saturated brine, and methyl acetate was recovered by rotary evaporation under reduced pressure. After recovering methyl acetate, 85 mL of petroleum ether was added, and stirred. Crystallization by cooling, filtration, and drying to obtain bicalutamide intermediate 2, 25.2 g of a white solid, with a yield of 93.3%.

Embodiment 4

In a 500mL three-neck flask, add 180mL of ethyl acetate, sodium percarbonate (20.4g, 0.13mol), N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide ( 25.4g, 0.10mol), stir, at 35～40℃, add dropwise acetic anhydride (6.12g, 0.06mol), after the dropwise addition, stir at 40～45℃ for 8h, follow the reaction progress by TLC, the reaction is complete After cooling to room temperature, the reaction system was filtered, the organic layer was washed once with sodium thiosulfate solution, and then twice with saturated brine, and ethyl acetate was recovered by rotary evaporation under reduced pressure. After recovering ethyl acetate, 100 mL of petroleum ether was added, and the mixture was stirred. It was crystallized by cooling, filtered and dried to obtain 24.78 g of bicalutamide intermediate 2 as a white solid with a yield of 91.8%.

Embodiment 5

In a 500mL three-neck flask, add 200mL of ethyl formate, sodium percarbonate (21.98g, 0.14mol), N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide ( 25.4g, 0.10mol), stir, at 30～35℃, add acetic anhydride (10.2g, 0.10mol) dropwise, after the dropwise addition, heat up to 40～45℃ and stir for 10h, TLC tracks the reaction progress, the reaction is complete After cooling to room temperature, the reaction system was filtered, the organic layer was washed once with sodium thiosulfate solution, and then twice with saturated brine, and ethyl formate was recovered by rotary evaporation under reduced pressure. After recovering ethyl formate, 100 mL of petroleum ether was added and stirred. It was crystallized by cooling, filtered and dried to obtain 25.36 g of bicalutamide intermediate 2 as a white solid with a yield of 93.9%.

In combination with Example 1 and Example 5, it can be seen that the yield in the preparation method of the bicalutamide intermediate 2 provided by the present invention can reach more than 91%.

The above are only the embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, improvements can be made without departing from the inventive concept of the present invention, but these belong to the present invention. scope of protection.

Claims

A kind of preparation method of bicalutamide intermediate, is characterized in that, comprises the steps:

Dissolve N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide in a lower fatty acid ester solvent, add sodium percarbonate and acetic anhydride successively, stir and heat, and carry out cyclization. The oxidation reaction obtains a reaction solution;

The reaction solution is filtered, the organic phase is washed with sodium thiosulfate solution, and the lower fatty acid ester solvent is recovered under reduced pressure;

After reclaiming the lower fatty acid ester solvent, adding petroleum ether for cooling crystallization, drying after filtration to obtain bicalutamide intermediate 2:
The preparation method according to claim 1, wherein the lower fatty acid ester is an ester of a fatty acid that is liquid at normal temperature and has 2 to 6 carbon atoms.
The preparation method according to claim 2, wherein the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate.
The preparation method according to claim 3, wherein the lower fatty acid ester is ethyl acetate or ethyl formate.
The preparation method according to claim 1, wherein the reaction temperature of the epoxidation reaction is 10-50°C.
The preparation method according to claim 5, wherein the reaction temperature of the epoxidation reaction is 35-45°C.
The preparation method according to claim 1, wherein the molar ratio of the N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide and sodium percarbonate is 1: (1.1 to 1.5).
The preparation method according to claim 1 or 7, wherein the molar ratio of the sodium percarbonate and acetic anhydride is 1:(0.3～0.8).
The preparation method according to claim 1, 5 or 6, wherein the reaction time of the epoxidation reaction is 1-12 h.
The preparation method according to claim 1, characterized in that, after the organic phase is washed with sodium thiosulfate solution, washed with saturated brine.