NL2030589B1 - Preparation method of bicalutamide - Google Patents

Abstract

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

Description

PREPARATION METHOD OF BICALUTAMIDE

TECHNICAL FIELD

[01] The present disclosure relates to the technical field of biological pharmacy, and more particularly to a method for preparing a Bicalutamide intermediate 2.

BACKGROUND ART

[02] The chemical name of Bicalutamide is N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-methyl-2-hydroxypropionamide. Bicalutamide is successfully researched and developed by AstraZeneca Company of British. Bicalutamide can be used for feedback inhibition of pituitary anterior lobe secretion gonadotropin as a non-steroidal anti-androgen compound, can reduce generation of androgen but hardly has androgen activity, and is clinically used for treating prostatic cancer. Bicalutamide is an anti-androgen malignant prostatic cancer treatment drug which is most clinically applied at present due to strong drug effect, convenience in administration and few side effects.

[03] In related technologies, the literature (Howard Tucker J. Med. Chem., 1988, 31, 954-959) discloses a synthesis method of Bicalutamide. The method comprises the following steps: acylating 4-cyano-3-trifluoromethyl phenylamine and 2-methacryloyl chloride to obtain amide 1; oxidizing 1 with metachloroperbenzoic acid to obtain an epoxy compound 2; carrying out ring opening and connecting fluorothiophenol to obtain 3; and oxidizing 3 with metachloroperbenzoic acid to obtain Bicalutamide 4, wherein the reaction formula is as follows:

KR .

HN Nen A Felon MES mm ® sd oe | ee 8 | en

No NÀ mie ke eo! Foc 2 3 2

[04] ©

[05] In the synthetic method, metachloroperbenzoic acid is used as an epoxidation agent, the epoxidation agent easily generates a large amount of solid waste, which causes great environmental pollution, and peroxy acid has explosiveness and is unsafe to use, so there are high requirements on safe production operation. Dichloroethane is used as a solvent, which has high the toxicity, and its residual products are difficult to remove, which influences the product quality.

SUMMARY

[06] The present disclosure aims to overcome the above technical problems and provides a method for preparing a bicalutamide intermediate 2, which is mild in reaction condition, high in reaction yield and high in epoxidation efficiency and can recycle a reaction solvent.

[07] In order to achieve the above object, the present disclosure provides a method for preparing a bicalutamide intermediate 2. The preparation method comprises the following steps:

[08] dissolving N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction solution;

[09] filtering the reaction solution, washing an organic phase with a sodium thiosulfate solution, and recovering the lower fatty acid ester solvent under reduced pressure; and

[10] after recovering the lower fatty acid ester solvent, adding petroleum ether, cooling, crystallizing, filtering, and drying to obtain the bicalutamide intermediate 2: 0

NE J AN

3

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[11] 2 12] Preferably, the lower fatty acid ester is ester of fatty acid which is liquid at normal temperature and has 2 to 6 carbon atoms.

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

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

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

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

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

[18] Preferably, the molar ratio of sodium percarbonate to acetic anhydride is 1: (0.3-0.8).

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

[20] Compared with the prior art, the method for preparing the bicalutamide intermediate 2 has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[21] The technical solution of the present disclosure will be described clearly and completely below in conjunction with the embodiments. Obviously, embodiments described are only a part of embodiments of the present disclosure, and are not all of embodiments thereof. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present disclosure without creative efforts shall fall within the protection scope of the present disclosure.

[22] The present disclosure provides a method for preparing a bicalutamide intermediate 2, comprising the following steps:

[23] dissolving N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction solution;

[24] filtering the reaction solution, washing an organic phase with a sodium thiosulfate solution, and recovering the lower fatty acid ester solvent under reduced pressure; and

[25] after recovering the lower fatty acid ester solvent, adding petroleum ether, cooling, crystallizing, filtering, and drying to obtain the bicalutamide intermediate 2:

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[27] A preparation method provided by the present disclosure comprises the following steps: by taking N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (an intermediate 1) as a raw material, sodium percarbonate as an oxygen source and lower fatty acid ester as a solvent, carrying out epoxidation on the intermediate 1 at the reaction temperature of 10-50°C to generate an intermediate 2, wherein the reaction formula is as follows: 7 gS EEN STN, AD

AN een DE, OR GR SIF VAN

YY Nn # ECH,COhO à x f ’

GO CF Fall 3

[28] 1 2

[29] The lower fatty acid ester is an ester of 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;

[30] The epoxidation reaction is 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.

[31] Sodium percarbonate is an inorganic compound, is white powder, has the effective oxygen content of 12-13% and is insoluble in an organic solvent. The mechanism of epoxidation reaction is as follows: firstly, sodium percarbonate and acetic anhydride react to generate an organic peroxide intermediate, and then the organic peroxide intermediate reacts with N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide to generate an epoxy compound. The essence of the method is as follows: sodium percarbonate and acetic anhydride react to prepare epoxidation reagents such as peroxy-acetic anhydride, etc, and the epoxidation reagents react with

N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide while acting in the reaction process, so the defects that organic peroxides are unstable and easy to decompose are avoided, the reaction is stable, and the operation is safe.

[32] The epoxidation reaction of sodium percarbonate and acetic anhydride is a solid-liquid two-phase reaction, and in order to ensure the reaction to be complete, the molar ratio of N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide to sodium 5 percarbonate is 1: (1.1-1.5).

[33] Acetic anhydride reacts with sodium percarbonate to form peroxy-acetic anhydride, and peroxy-acetic anhydride is reduced into acetic anhydride after transferring oxygen atoms to N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide. Therefore, acetic anhydride can be recycled. In order to accelerate the reaction speed, the molar ratio of sodium percarbonate to acetic anhydride is 1: (0.3-0.8) during actual operation.

[34] Example 1

[35] To a 500-mL three-necked flask, 150 mL of ethyl acetate, sodium percarbonate (18.84 g, 0.12 mol) and N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (25.4 g, 0.10 mol) were added, stirred; acetic anhydride (7.14 g, 0.07 mol) was added dropwise at 35-40 °C; the temperature was slowly increased to 45°C after adding dropwise; stirring was carried out for 5 h; the reaction process was tracked by TLC (thin layer chromatography); after reaction, the mixture was cooled to room temperature, and the reaction system was filtered; the organic layer was washed once by using a sodium thiosulfate solution and then was washed twice by using saturated brine; rotary evaporation was carried out under a reduced pressure to recover ethyl acetate; 80 mL of petroleum ether was added after the ethyl acetate was recovered, and then stirring, cooling, crystallizing, filtering and drying were carried out to obtain 24.6 g of bicalutamide intermediate 2 white solid, wherein the yield was 91.1%.

[36] Example 2

[37] To a 500-mL three-necked flask, 180 mL of methyl formate, sodium percarbonate (23.55 g, 0.15 mol) and N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (25.4 g, 0.10 mol) were added, stirred; acetic anhydride (7.65 g, 0.075 mol) was added dropwise at 35-40 °C; the temperature was slowly increased to 50°C after adding dropwise; stirring was carried out for 5 h; the reaction process was tracked by

TLC (thin layer chromatography), after reaction, the mixture was cooled to room temperature, and the reaction system was filtered; the organic layer was washed once by using a sodium thiosulfate solution and then was washed twice by using saturated brine; rotary evaporation was carried out under a reduced pressure to recover methyl formate;

100 mL of petroleum ether was added after the methyl formate was recovered; and then stirring, cooling, crystallizing, filtering and drying were carried out to obtain 24.92 g of bicalutamide intermediate 2 white solid, wherein the yield was 92.3%.

[38] Example 3

[39] To a 500-mL three-necked flask, 200 mL of methyl acetate, sodium percarbonate (21.98 g, 0.14 mol) and N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (25.4 g, 0.10 mol) were added, stirred; acetic anhydride (8.16 g, 0.08 mol) was added dropwise at 30-35°C; the temperature was slowly increased to 45°C after adding dropwise; stirring was carried out for 8 h; the reaction process was tracked by TLC (thin layer chromatography), after reaction, the mixture was cooled to room temperature, and the reaction system was filtered; the organic layer was washed once by using a sodium thiosulfate solution and then was washed twice by using saturated brine; rotary evaporation was carried out under a reduced pressure to recover methyl acetate; 85 mL of petroleum ether was added after the methyl acetate was recovered; and then stirring, cooling, crystallizing, filtering and drying were carried out to obtain 25.2 g of bicalutamide intermediate 2 white solid, wherein the yield was 93.3%.

[40] Example 4

[41] To a 500-mL three-necked flask, 180 mL of ethyl acetate, sodium percarbonate (20.4g, 0.13mol) and N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (25.4 g, 0.10 mol) were added, stirred; acetic anhydride (6.12 g, 0.06 mol) was added dropwise at 35-40 °C; after adding dropwise; stirring was carried out for 8 h at a temperature of 40-45°C; the reaction process was tracked by TLC ; after reaction, the mixture was cooled to room temperature, and the reaction system was filtered; the organic layer was washed once by using a sodium thiosulfate solution and then was washed twice by using saturated brine; rotary evaporation was carried out under a reduced pressure to recover ethyl acetate; 100 mL of petroleum ether was added after the ethyl acetate was recovered, and then stirring, cooling, crystallizing, filtering and drying were carried out to obtain 24.78 g of bicalutamide intermediate 2 white solid, wherein the yield was 91.8%.

[42] Example 5

[43] To a 500-mL three-necked flask, 200 mL of ethyl formate, sodium percarbonate (21.98 g, 0.14 mol) and N-[4-cyano-3-(trifluoromethyl) phenyl]-2-methacrylamide (25.4 g, 0.10 mol) were added, stirred; acetic anhydride (10.2 g, 0.10 mol) was added dropwise at 30-35°C; the temperature was slowly increased to 40-45°C after adding dropwise, stirring was carried out for 10 h; the reaction process was tracked by TLC; after reaction, the mixture was cooled to room temperature, and the reaction system was filtered; the organic layer was washed once by using a sodium thiosulfate solution and then was washed twice by using saturated brine; rotary evaporation was carried out under a reduced pressure to recover ethyl formate; 100 mL of petroleum ether was added after the ethyl formate was recovered, and then stirring, cooling, crystallizing, filtering and drying were carried out to obtain 25.36 g of bicalutamide intermediate 2 white solid, wherein the yield was 93.9%.

[44] Based on the above examples 1 to 5, the yield for the method for preparing a

Bicalutamide intermediate 2 provided in the present disclosure could reach more than 91%.

[45] Compared with the related technologies, the method for preparing a

Bicalutamide intermediate 2 provided in the present disclosure has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency, and recyclable reaction solvents.

[46] The above descriptions are merely the preferred embodiments of the present disclosure. It should be noted that for those of ordinary skill in the art, several improvements can be made without departing from the principle of the present disclosure, and these improvements shall also fall within the scope of protection of the present disclosure.

Claims (10)

Conclusions A process for preparing a bicalutamide intermediate, comprising the steps of: dissolving N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide in a lower fatty acid ester solvent, adding sodium percarbonate and acid anhydride sequentially, stirring and heating and conducting epoxidation reaction to obtain a reaction solution; filtering the reaction solution, washing an organic phase with a sodium thiosulfate solution and recovering the lower fatty acid ester solvent under reduced pressure; and after recovering the lower fatty acid ester solvent, adding petroleum ether, cooling, crystallizing, filtering and drying to obtain the bicalutamide intermediate 2: ans { $ } Fil > » ‘ The method according to claim 1, wherein the lower fatty acid ester is ester of fatty acid which is liquid at normal temperature and has 2-6 carbon atoms. The method of claim 2, wherein the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate. The method of claim 3, wherein the lower fatty acid ester is ethyl acetate or ethyl formate. The method according to claim 1, wherein the reaction temperature of epoxidation reaction is 10-50°C. The method according to claim 5, wherein the reaction temperature of epoxidation reaction is 35-45°C. The method of claim 1, wherein the molar ratio of N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methacrylamide to sodium percarbonate is 1:(1.1-1.5). The method according to claim 1 or 7, wherein the molar ratio of sodium percarbonate to acid anhydride is 1: (0.3-0.8) 1s. The method according to claim 1, 5 or 6, wherein the reaction time of epoxidation reaction is 1-12 hours. The method of claim 1, wherein the organic phase is washed with sodium thiosulfate solution and then washed with saturated brine.