A method for synthesizing bicalutamide

Abstract

The application discloses a kind of synthesis method of bicalutamide, belong to the technical field of preparation of organic compounds.The application uses N-(4-cyano-3-trifluoromethylphenyl) methyl acrylamide and N-(diphenylimine)-4-fluoro-benzenesulfonyl amide as starting material, carries out sulfonylation-peroxidation, obtains 2-tert-butyl peroxy-2-methyl-N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfone] propionamide;2-tert-butyl peroxy-2-methyl-N-[4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfone] propionamide is reduced, and bicalutamide is obtained.The method has the advantages of raw material, reaction condition is easy to obtain, warm, catalytic efficiency is high, and operation is simple.

Description

Technical Field

[0001] This invention relates to the field of organic compound preparation technology, and in particular to a method for synthesizing bicalutamide. Background Technology

[0002] Bicalutamide was developed by AstraZeneca in the UK. It was first launched in the UK in February 1995. It received FDA approval for marketing in the US in September 1995 and was approved for import and sale in China in 1999. Its brand name is Casodex. It is sold in more than 70 countries and markets. This drug is a novel nonsteroidal anti-androgen that blocks the action of androgens produced by the adrenal glands, inhibiting the binding or absorption of androgens, thus shrinking prostate tumors. Clinically, it is used to treat advanced prostate cancer, avoiding the adverse reactions caused by androgen therapy. Bicalutamide drugs are characterized by high specificity, good tolerability, long half-life, and convenient administration, and are widely used in the treatment of prostate cancer. The chemical name of bicalutamide is 2-hydroxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]propanamide, and its English name is N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-furophenyl)sulfonyl]-2-hydroxy-2-methyl-propanamide. The structural formula of bicalutamide is as follows:

[0003]

[0004] Bicalutamide has multiple synthetic routes, such as patents CN106831509A, JP200800749A, WO2007039127A1, and literature (Org. Biomol. Chem. 2021, 19, 446-456; Hecheng Huaxue, 2003, 11, 346-348; J.Med.Chem. 1988, 31, 885-887. uses thiols as reactants; CN109320442A, CN105541680A, WO2001028990A2, WO2012042532A1, CN102351762A, CN102321000A, and literature (Synthesis, 2022, 54, 2258-2266; J.Org.Chem. 2017, 82, 10628-10634; Zhongguo YikeDaxue Xuebao, 2005, 34, 518-519.) uses thioethers as reactants. However, thiols and thioethers usually have pungent odors and can cause significant pollution. Furthermore, most of the methods reported in the literature use the peroxyacid m-chloroperoxybenzoic acid as an oxidant. m-chlorobenzoic acid needs to be removed; if it cannot be effectively recovered, it will enter waste and cause secondary pollution. The oxidation reaction time is also long, lasting up to 16 hours, which is time-consuming. At the same time, the high explosiveness and high price of peroxyacid limit its industrial application. Patent WO2007013094A2 uses potassium permanganate to oxidize sulfides, and patent US2007027211A1 uses sodium perborate to oxidize sulfides. The resulting bicalutamide both have the problem of residual manganese and boron, which are not beneficial to the human body. Therefore, it is essential to develop a green, safe, and efficient new synthetic method for bicalutamide. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing bicalutamide to solve the above-mentioned problems existing in the prior art.

[0006] To achieve the above objectives, the present invention provides the following solution:

[0007] One of the technical solutions of the present invention is a method for synthesizing bicalutamide, comprising the following steps: using N-(4-cyano-3-trifluoromethylphenyl)methacrylamide and N-(diphenylimine)-4-fluoro-benzenesulfonamide as starting materials, performing a sulfonation-peroxidation reaction to obtain 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide; reducing the 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide to obtain bicalutamide.

[0008] Further, the sulfonation-peroxidation reaction using N-(4-cyano-3-trifluoromethylphenyl)methacrylamide and N-(diphenylimine)-4-fluorobenzenesulfonamide as starting materials includes: N-(4-cyano-3-trifluoromethylphenyl)methacrylamide, N-(diphenylimine)-4-fluorobenzenesulfonamide, an organic photocatalyst, and tert-butyl hydroperoxide (… t BuOOH) and solvent are mixed and subjected to ultraviolet light. The mixture undergoes sulfonation-peroxidation reaction under ultraviolet light excitation to obtain 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide (as a precursor of bicalutamide).

[0009] Furthermore, the structural formula of the N-(4-cyano-3-trifluoromethylphenyl)methacrylamide is as follows: The structural formula of the N-(diphenylimine)-4-fluoro-benzenesulfonamide is as follows: The structural formula of the 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide is as follows:

[0010] Furthermore, the sulfonation-peroxidation reaction refers to the sulfonation-peroxidation reaction of carbon-carbon double bonds, that is, the sulfonation-peroxidation reaction that occurs between the carbon-carbon double bonds in N-(4-cyano-3-trifluoromethylphenyl)methacrylamide and the carbon-carbon double bonds in N-(diphenylimine)-4-fluoro-benzenesulfonamide.

[0011] Further, the reduction of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide includes: mixing 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide, a hydrogen source, a catalyst, and a solvent, and heating to carry out a reduction reaction to obtain bicalutamide.

[0012] Furthermore, the reduction reaction refers to the reduction of the peroxy bond of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide.

[0013] Furthermore, the organic photocatalyst is 9-thioxanone; the solvent is acetonitrile (MeCN).

[0014] Furthermore, the application time of the ultraviolet light is 0.5 to 24 hours, preferably 2 hours, and the application time of the ultraviolet light is the time for the sulfonation-peroxidation reaction to proceed.

[0015] Furthermore, the ultraviolet light has a wavelength of 390 nm and an intensity of 10 W. The ultraviolet light is applied by irradiation with an ultraviolet lamp.

[0016] Furthermore, the sulfonation-peroxidation reaction is carried out at room temperature (20–30 °C).

[0017] Further, the molar ratio of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide to N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst, and tert-butyl hydroperoxide is 1.0:(2.0-5.0):0.05:5.0, preferably 1.0:2.0:0.05:5.0.

[0018] Furthermore, the tert-butyl hydrogen peroxide can be added either in the form of pure tert-butyl hydrogen peroxide or in the form of a tert-butyl hydrogen peroxide organic phase solution. When added in the form of a tert-butyl hydrogen peroxide organic phase solution, the tert-butyl hydrogen peroxide mentioned in the above molar ratio refers to the molar amount of tert-butyl hydrogen peroxide contained in the tert-butyl hydrogen peroxide organic phase solution.

[0019] Furthermore, the tert-butyl hydroperoxide organic phase solution is a tert-butyl hydroperoxide decane solution.

[0020] Furthermore, the concentration of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide in the solvent is 0.1M.

[0021] Further, the preparation method of the N-(diphenylimine)-4-fluoro-benzenesulfonamide is as follows: benzophenone... 4-Fluoro-benzenesulfonamide The solvent was mixed with triethylamine (NEt3) and titanium tetrachloride (TiCl4), and the mixture was heated under reflux to obtain N-(diphenylimine)-4-fluoro-benzenesulfonamide.

[0022] Furthermore, the solvent used in the preparation of N-(diphenylimine)-4-fluoro-benzenesulfonamide is dichloroethane.

[0023] Furthermore, the molar ratio of benzophenone to 4-fluoro-benzenesulfonamide, triethylamine, and titanium tetrachloride is 1.0:1.0:2.0:0.5.

[0024] Furthermore, the titanium tetrachloride is added under ice-water bath conditions, and the reflux reaction temperature is 90°C for 5 hours.

[0025] Furthermore, the hydrogen source is ammonium formate (NH4COOH); the catalyst is a palladium / carbon catalyst (Pd / C); and the solvent is methanol (MeOH).

[0026] Furthermore, the palladium / carbon catalyst is activated carbon supported on 5.0 wt% metallic palladium powder (i.e., the mass fraction of palladium powder in the palladium / carbon catalyst is 5.0 wt%), and the palladium / carbon catalyst is obtained by loading metallic palladium powder onto activated carbon.

[0027] Further, the molar ratio of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide to ammonium formate and catalyst is 1.0:(2.0-3.0):0.1, preferably 1.0:3.0:0.1. The molar amount of catalyst refers to the molar amount of palladium powder in the palladium / carbon catalyst.

[0028] Furthermore, the concentration of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide in the solvent is 0.1M.

[0029] Furthermore, the reduction reaction is carried out at a temperature of 50°C for a time of 0.5–12 h.

[0030] Furthermore, the reduction reaction is preferably carried out over a period of 3 hours.

[0031] The present invention discloses the following technical effects:

[0032] (1) This invention uses N-(4-cyano-3-trifluoromethylphenyl)methacrylamide and N-(diphenylimine)-4-fluoro-benzenesulfonamide as starting materials, and performs a sulfonation-peroxidation reaction to obtain 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide; the 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide is then reduced to obtain bicalutamide. This invention can prepare bicalutamide in only two steps, which has the advantages of readily available raw materials and simple operation.

[0033] (2) In the preparation of the bicaloamine precursor, the present invention does not require the use of thiols with irritating odors or metal catalysts, and the reaction can be carried out by photocatalysis, resulting in high reaction efficiency. The palladium / carbon catalyst used in the reduction process is a recyclable catalyst, which helps to reduce environmental pollution and can also effectively recover and reuse the rare metal palladium.

[0034] (3) The synthesis method of the present invention also has the advantages of mild reaction conditions (sulfonation-peroxidation reaction can be carried out efficiently under light and room temperature conditions, and reduction reaction can be carried out efficiently at a low heating temperature), high reaction yield (up to 80%), high catalytic efficiency (the light reaction only takes 2 hours and the reduction process only takes 3 hours to obtain the final product bicalutamide), and green and environmentally friendly (the catalyst and reaction solvent can be recycled). Attached Figure Description

[0035] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0036] Figure 1 The 1H NMR spectrum of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide prepared in Example 1;

[0037] Figure 2 The carbon NMR spectrum of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide prepared in Example 1;

[0038] Figure 3 The nuclear magnetic resonance fluorine spectrum of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide prepared in Example 1;

[0039] Figure 4 The 1H NMR spectrum of bicalutamide prepared in Example 1;

[0040] Figure 5 The carbon NMR spectrum of bicalutamide prepared in Example 1;

[0041] Figure 6 The NMR fluorine spectrum of bicalutamide prepared in Example 1 is shown. Detailed Implementation

[0042] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0043] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0044] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0045] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This application specification and embodiments are merely exemplary.

[0046] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0047] This invention provides a method for synthesizing bicalutamide, specifically comprising the following steps:

[0048] N-(4-cyano-3-trifluoromethylphenyl)methacrylamide, N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst (9-thioxanone), and tert-butyl hydroperoxide ( tThe molar ratio of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide to N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst, and tert-butyl hydroperoxide is 1.0:(2.0-5.0):0.05:5.0, preferably 1.0:2.0:0.05:5.0; N-(4-cyano-3-trifluoromethylphenyl)methacrylamide in solvent (The molar ratio of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide to N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst, and tert-butyl hydroperoxide is 1.0:(2.0-5.0):0.05:5.0; N-(4-cyano-3-trifluoromethylphenyl)methacrylamide in solvent (The molar ratio of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide to N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst, and tert-butyl hydroperoxide is 1.0:(2.0-5.0):0.05:5.0, preferably 1.0:2.0: ...) The concentration of the reagent is 0.1M), and ultraviolet light (wavelength 390nm, intensity 10W) ​​is applied to excite the reaction, and a sulfonation-peroxidation reaction is carried out under ultraviolet light excitation (reaction time is 0.5-24h, preferably 2h, the reaction is carried out at room temperature) to obtain 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide (as a precursor of bicalutamide); A mixture of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide, hydrogen source (ammonium formate), catalyst (palladium / carbon catalyst, 5.0 wt% activated carbon supported on metallic palladium powder), and solvent (methanol) (2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide and ammonium formate) The molar ratio of the catalyst is 1.0:(2.0~3.0):0.1, preferably 1.0:3.0:0.1; the concentration of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide in the solvent is 0.1M, and the reaction is carried out by heating (reaction temperature is 50℃; time is 0.5~12h, preferably 3h) to obtain bicalutamide.

[0049] The preparation method of N-(diphenylimine)-4-fluoro-benzenesulfonamide is as follows: benzophenone, 4-fluoro-benzenesulfonamide and solvent (dichloroethane) are mixed, and then triethylamine and titanium tetrachloride are added (the molar ratio of benzophenone to 4-fluoro-benzenesulfonamide, triethylamine and titanium tetrachloride is 1.0:1.0:2.0:0.5). The mixture is heated to reflux for 5 h (reflux temperature is 90℃) to obtain N-(diphenylimine)-4-fluoro-benzenesulfonamide.

[0050] The synthetic reaction formula for N-(diphenylimine)-4-fluoro-benzenesulfonamide is as follows:

[0051]

[0052] The present invention will be further described below with reference to specific embodiments.

[0053] The preparation method of N-(diphenylimine)-4-fluoro-benzenesulfonamide used in the following examples is as follows: 901 mg (5 mmol) of benzophenone and 875 mg (5 mmol) of 4-fluoro-benzenesulfonamide were dissolved in 20 mL of dichloroethane, 1389 μL (10 mmol) of triethylamine was added, and 2.5 mL (2.5 mmol) of 1 M titanium tetrachloride solution was added under ice-water bath. The mixture was refluxed at 90 °C for 5 hours to obtain N-(diphenylimine)-4-fluoro-benzenesulfonamide.

[0054] All other raw materials and reagents used in the following examples are commercially available products.

[0055] The palladium / carbon catalyst used in the following examples is activated carbon supported on 5.0 wt% metallic palladium powder.

[0056] The general formula (overall reaction process) for the synthesis of bicalutamide in the following examples is as follows:

[0057]

[0058] Example 1

[0059] A method for synthesizing bicalutamide, comprising the following steps:

[0060] (1) Take 260.0 mg (1.0 mmol) of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide, 715.0 mg (2.0 mmol) of N-(diphenylimine)-4-fluoro-benzenesulfonamide and 10.0 mg (0.05 mmol) of 9-thioxanthone and dissolve them in 10.0 mL of acetonitrile. Add 910.0 μL of decane solution of tert-butyl hydroperoxide (concentration of 5.5 M, containing 5 mmol of tert-butyl photohydrogen peroxide) and irradiate with a UV lamp for 2 h (wavelength of 390 nm, intensity of 10 W). Under UV excitation, carry out sulfonation-peroxidation reaction. After the reaction is completed, 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide by column chromatography.

[0061] (2) 502.0 mg (1.0 mmol) of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide, 200.0 mg (0.1 mmol) of palladium / carbon catalyst, and 195.0 mg (3.0 mmol) of ammonium formate were dissolved in 10.0 mL of methanol and heated at 50 °C for 3 h for reduction reaction. After the reaction was completed, 344 mg of bicalutamide was obtained by column chromatography (the yield was calculated to be 80%).

[0062] The 1H NMR spectrum, 1C NMR spectrum, and 1N NMR spectrum of the 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide obtained in step (1) of this embodiment are shown below. Figure 1-3 As shown, the characteristics are as follows:

[0063] 1 H NMR(400MHz, CDCl3)δ8.82(s,1H),8.02(s,1H),7.96-7.92(m,2H)7.82(s,2H),7.27-7 .21(m,2H),3.92(d,J=14.6Hz,1H),3.72(d,J=14.6Hz,1H),1.73(s,3H),1.34(s,9H).

[0064] 13 C NMR (100Hz, CDCl3) δ 170.4, 166.3 (d, J = 263.0Hz), 141.5, 137.1, 137.0, 135.9, 134.1 (q, J = 33.5Hz), 130.7 (d, J = 9. 8Hz), 122.1 (q, J = 135.6Hz), 121.5, 117.5 (q, J = 4.9Hz), 116.6 (d, J, 22.5Hz), 115.5, 104.8, 84.3, 82.5, 60.8, 26.5.

[0065] 19 F NMR(377MHz, CDCl3)δ-62.2(3F),-103.1(1F).

[0066] HRMS(ESI)m / z:[M+Na + ]Calcd for C 22 H 22 F2N2O5SNa:525.1083,Found:525.1067.

[0067] The proton, carbon, and fluorine NMR spectra of the bicalutamide obtained in step (2) of this embodiment are as follows: Figure 4-6 As shown, the characteristics are as follows:

[0068] 1H NMR (400MHz, DMSO-d6): δ10.39(s,1H),8.44(d,J=1.8Hz,1H),8.22(dd,J=8.6,1.8Hz,1H),8.10(d,J=8.8Hz,1H) ,7.95-7.91(m,2H),7.40-7.35(m,2H),6.41(s,1H),3.95(d,J=14.8Hz,1H),3.72(d,J=14.8Hz,1H),1.41(s,3H).

[0069] 13 C NMR (100MHz, DMSO-d6): δ174.2, 165.5 (d, J = 253.3Hz), 143.6, 137.6 (d, J = 2.8Hz), 136.7, 132.0 (d, J = 31.9Hz), 131.9 (d,J=9.2Hz),124.3(q,J=272.0Hz),123.3,118.0(q,J=5.5Hz),116.5(d,J=22.6Hz),116.3,102.4,73.6,63.9,27.6.

[0070] 19 F NMR(377MHz,DMSO-d6)δ-61.1(3F),-105.6(1F).

[0071] The above-mentioned proton, carbon, and fluorine NMR spectra correspond to the known spectra of bicalutamide, proving the successful synthesis of bicalutamide.

[0072] Example 2

[0073] Same as Example 1, except that the amount of ammonium formate used in step (2) was 130.0 mg (2.0 mmol), and after the reaction was completed, column chromatography was used to separate 301 mg of bicalutamide (the yield was calculated to be 70%).

[0074] The proton, carbon, and fluorine NMR spectra of the bicalutamide prepared in this embodiment are consistent with those of Example 1.

[0075] Example 3

[0076] Same as Example 1, except that the amount of N-(diphenylimine)-4-fluoro-benzenesulfonamide used in step (1) was 1787.5 mg (5.0 mmol). In this example, 311 mg of bicalutamide was finally obtained (the yield was calculated to be 72%).

[0077] The proton, carbon, and fluorine NMR spectra of the bicalutamide prepared in this embodiment are consistent with those of Example 1.

[0078] Comparative Example 1

[0079] Same as Example 1, except that the amount of N-(diphenylimine)-4-fluoro-benzenesulfonamide used in step (1) was 357.5 mg (1.0 mmol), and the comparative example finally obtained 198 mg of bicalutamide (the yield was calculated to be 46%).

[0080] The NMR spectra of the bicalutamide prepared in this comparative example, including the proton NMR spectrum, carbon NMR spectrum, and fluorine NMR spectrum, are consistent with those of Example 1.

[0081] Comparative Example 2

[0082] Same as Example 1, except that the amount of tert-butyl hydroperoxide decane solution used in step (1) was 182.0 μL (containing 1 mmol of tert-butyl hydroperoxide). The comparative example finally obtained 43 mg of bicalutamide (the yield was calculated to be 10%).

[0083] The NMR spectra of the bicalutamide prepared in this comparative example, including the proton NMR spectrum, carbon NMR spectrum, and fluorine NMR spectrum, are consistent with those of Example 1.

[0084] Comparative Example 3

[0085] Same as Example 1, except that the amount of tert-butyl hydroperoxide decane solution used in step (1) was 546.0 μL (containing 3 mmol of tert-butyl hydroperoxide). The comparative example finally obtained 95 mg of bicalutamide (the yield was calculated to be 22%).

[0086] The NMR spectra of the bicalutamide prepared in this comparative example, including the proton NMR spectrum, carbon NMR spectrum, and fluorine NMR spectrum, are consistent with those of Example 1.

[0087] Comparative Example 4

[0088] Same as Example 1, except that the temperature of the reduction reaction in step (2) is 30°C. The comparative example finally yielded 215 mg of bicalutamide (the yield was calculated to be 50%).

[0089] The NMR spectra of the bicalutamide prepared in this comparative example, including the proton NMR spectrum, carbon NMR spectrum, and fluorine NMR spectrum, are consistent with those of Example 1.

[0090] Comparative Example 5

[0091] Same as Example 1, except that the temperature of the reduction reaction in step (2) is 70°C. The comparative example finally yielded 172 mg of bicalutamide (the yield was calculated to be 40%).

[0092] The proton, carbon, and fluorine NMR spectra of the bicalutamide prepared in this comparative example are consistent with those of Example 1.

[0093] Comparative Example 6

[0094] Same as Example 1, except that the solvent used in step (1) is acetone. This comparative example finally yielded 258 mg of bicalutamide (the calculated yield was 60%).

[0095] The proton, carbon, and fluorine NMR spectra of the bicalutamide prepared in this comparative example are consistent with those of Example 1.

[0096] Comparative Example 7

[0097] Same as Example 1, except that the solvent used in step (2) is acetone. This comparative example finally yielded 22 mg of bicalutamide (the calculated yield was 5%).

[0098] The proton, carbon, and fluorine NMR spectra of the bicalutamide prepared in this comparative example are consistent with those of Example 1.

[0099] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing bicalutamide, characterized in that, The process includes the following steps: mixing N-(4-cyano-3-trifluoromethylphenyl)methacrylamide, N-(diphenylimine)-4-fluoro-benzenesulfonamide, an organic photocatalyst, tert-butyl hydrogen peroxide, and a solvent, applying ultraviolet light, and performing a sulfonation-peroxidation reaction under ultraviolet light excitation to obtain 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide; and reducing the 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide to obtain bicalutamide.

2. The method for synthesizing bicalutamide as described in claim 1, characterized in that, The reduction of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide includes: mixing 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide, a hydrogen source, a catalyst, and a solvent, and heating to carry out a reduction reaction to obtain bicalutamide.

3. The method for synthesizing bicalutamide as described in claim 1, characterized in that, The organic photocatalyst is 9-thioxanone; the solvent is acetonitrile.

4. The method for synthesizing bicalutamide as described in claim 1, characterized in that, The ultraviolet light is applied for 0.5 to 24 hours.

5. The method for synthesizing bicalutamide as described in claim 1, characterized in that, The molar ratio of N-(4-cyano-3-trifluoromethylphenyl)methacrylamide to N-(diphenylimine)-4-fluoro-benzenesulfonamide, organic photocatalyst, and tert-butyl hydroperoxide is 1.0:(2.0~5.0):0.05:5.

0.

6. A method for synthesizing bicalutamide as described in claim 1, characterized in that, The preparation method of N-(diphenylimine)-4-fluoro-benzenesulfonamide is as follows: benzophenone, 4-fluoro-benzenesulfonamide and solvent are mixed, then triethylamine and titanium tetrachloride are added, and the mixture is heated to undergo a reflux reaction to obtain N-(diphenylimine)-4-fluoro-benzenesulfonamide.

7. The method for synthesizing bicalutamide as described in claim 2, characterized in that, The hydrogen source is ammonium formate; the catalyst is a palladium / carbon catalyst; and the solvent is methanol.

8. The method for synthesizing bicalutamide as described in claim 7, characterized in that, The molar ratio of 2-tert-butylperoxy-2-methyl-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonethio]propionamide to ammonium formate and catalyst is 1.0:(2.0~3.0):0.

1.

9. The method for synthesizing bicalutamide as described in claim 2, characterized in that, The reduction reaction was carried out at a temperature of 50°C for a time of 0.5 to 12 hours.

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