A kind of electro-oxidation preparation method of Atalulun

Abstract

The invention relates to an electro-oxidation preparation method of ataluren shown in formula II. The preparation reaction is as follows: a halogenating reagent is selected from: NBS, NCS, DBDMH or DCDMH; the electro-oxidation is carried out in a single electrolytic cell, an anode working electrode and a cathode are installed, 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine (III), an organic solvent, an alkali and an electrolyte are used as an electrolyte, and electrolysis is carried out at a certain temperature and a constant voltage for a certain time to obtain 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole (VI) through electro-oxidation reaction; 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole is alcoholized in a hydrogen chloride methanol solution or a methanol sulfuric acid solution, and then hydrolyzed to obtain ataluren.

Description

Technical Field

[0001] The present invention relates to an electro-oxidation preparation method of Ataluren, a drug for treating Duchenne muscular dystrophy, wherein the key technology is the electro-oxidation reaction of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide. Background Art

[0002] Ataluren (Ⅱ), chemical name: 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid, is a small molecule oral drug developed by PTC, USA, for the treatment of Duchenne muscular dystrophy (DMD) and cystic fibrosis with nonsense mutations. It was launched in Europe in 2014.

[0003]

[0004] U.S. Patent [US2004204461A1] describes a method for preparing ataluren: 3-cyanobenzoic acid is reacted with iodomethane to generate methyl 3-cyanobenzoate; the latter is reacted with hydroxylamine to obtain methyl 3-(N-hydroxyamidino)benzoate; the latter is reacted with 2-fluorobenzoyl chloride to obtain methyl 3-[N-(2-fluorobenzoyloxy)amidino]benzoate; the latter is dehydrated and cyclized to obtain ataluren methyl ester Ia, which is hydrolyzed to obtain ataluren:

[0005]

[0006] The raw material 3-cyanobenzoic acid used in the preparation method is expensive, and methyl iodide is a highly toxic reagent and a controlled drug, which is not suitable for industrialization.

[0007] Gupt et al. [A metal-free tandem approach to prepare structurally diverse N-heterocycles: synthesis of 1,2,4-oxadiazoles and pyrimidinones. New Journal of Chemistry, 2014, 38(7): 3062-3070] selected 3-methylbenzamide hydrochloride to react with 2-fluorobenzoic acid to form 2-fluoro-N-(imino(3-methylphenyl)methyl)benzamide, which was then subjected to nucleophilic addition-deamination-intramolecular cyclization reaction to obtain 5-(2-fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole (Ⅰb). Ⅰb was oxidized with potassium permanganate to give ataluren II in a yield of 40%.

[0008]

[0009] Asad et al. [Iodine–induced Oxidative Cyclisation of N-Acyl Amidines: A Rapid Synthesis of 3, 5-Disubstituted-1,2,4-Oxadiazoles. Chemistry Select, 2016, 1(15): 4753-4757] synthesized 5-(2-fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole by iodine-induced oxidative cyclization of 2-fluoro-N-(imino(3-methylphenyl)methyl)benzamide, and then oxidized it to synthesize ataluren with a yield of 48%.

[0010]

[0011] The use of potassium permanganate oxidation produces serious waste, is not environmentally friendly, and is difficult to industrialize.

[0012] The Chinese invention patent [CN113735787A, published on December 3, 2021] describes an electro-oxidation preparation method of an intermediate (Ib) of Ataluren: N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamidine, which is electro-oxidized to obtain compound Ib.

[0013]

[0014] 5-(2-Fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole (Ib) is a key intermediate for the preparation of ataluren (II): Krasouskaya et al. [Synthesis of benzoic acids containing a 1,2,4-oxadiazolering. Russian Chemical Bulletin, 2015, 64(1):142-145] selected cobalt acetate as the catalysis, and 5-(2-fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole Ib can be oxidized by air to give ataluren II with a yield of 85%.

[0015]

[0016] The Chinese invention patent [CN 106316885 B, 2019.2.12] describes the preparation method of Ataluren: isophthalonitrile is reacted with hydroxylamine to obtain 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine, which is acylated with 2-fluorobenzoyl chloride to obtain 3-[N-(2-fluorobenzoyloxy)amidino]benzonitrile, and 3-[N-(2-fluorobenzoyloxy)amidino]benzonitrile is subjected to dehydration cyclization and sulfuric acid-catalyzed hydrolysis to obtain Ataluren:

[0017]

[0018] The acylation reaction of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine with 2-fluorobenzoyl chloride has a selectivity problem: 3-[N-(2-fluorobenzoyloxy)amidino]benzonitrile can be obtained; the amino group on the amidino group can also undergo an acylation side reaction:

[0019] Summary of the invention

[0020] The purpose of the present invention is to provide 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine as shown in the chemical structural formula III:

[0021]

[0022] The second object of the present invention is to provide a method for preparing 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine as shown in the chemical structural formula III, characterized in that its preparation reaction is as follows:

[0023]

[0024] The halogenating agent is selected from: NBS, NCS, DBDMH or DCDMH.

[0025] Using 3-cyanobenzaldehyde, compound III is obtained through a three-step reaction of addition, halogenation and amidination in a one-pot method, and intermediates IV and V do not need to be separated.

[0026] The third object of the present invention is to provide an electro-oxidation of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine as shown in formula III, characterized in that 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine is electro-oxidized to prepare 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole as shown in formula VI, and the electro-oxidation reaction is as follows:

[0027]

[0028] The electro-oxidation is carried out in a single electrolytic cell with an anode working electrode and a cathode, 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine (III), an organic solvent, an alkali and an electrolyte as an electrolyte, at a certain temperature, constant voltage electrolysis for a certain period of time, and the electro-oxidation reaction obtains 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole (VI).

[0029] The anode working electrode of the electrolytic cell is selected from: carbon felt electrode, platinum mesh electrode or graphite electrode; preferably: platinum mesh electrode; the current density of the anode working electrode is selected from: 11.0 mA / cm 2 ~25.0mA / cm2 ; The cathode of the electrolytic cell is selected from: a platinum sheet electrode or a carbon felt electrode; preferably: a platinum sheet electrode.

[0030] The constant voltage is selected from: 1.50V to 4.50V; the electrolysis temperature is selected from: 15°C to 55°C; and the electrolysis time is selected from: 3.0h to 8.0h.

[0031] The organic solvent in the electrolyte is selected from: acetonitrile, acetone, methanol, ethanol, propanol or butanol; the base is selected from: one or two of: potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium carbonate, sodium acetate, pyridine or triethylamine.

[0032] The electrolyte is selected from: tetrabutylammonium perchlorate, lithium perchlorate, ammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate or potassium hexafluorophosphate; the electrolyte concentration is selected from: 0.02 mol / L-0.1 mol / L.

[0033] The concentration of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine (III) in the electrolyte is selected from: 8.0 g / L to 30 g / L.

[0034] More preferably, the electrolyte is prepared by dissolving 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine (III) in an organic solvent to obtain an organic solution, and mixing the organic solution with potassium phosphate at a molar ratio of 1:3 to obtain a mixed solution.

[0035] The fourth aspect of the present invention is to provide a method for preparing Ataluren (II) by electro-oxidation, characterized in that the preparation reaction of Ataluren is as follows:

[0036]

[0037] The halogenating agent is selected from: NBS, NCS, DBDMH or DCDMH; the electro-oxidation is carried out in a single electrolytic cell, equipped with an anode working electrode and a cathode, using 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamidine (III), an organic solvent, a base and an electrolyte as an electrolyte, at a certain temperature, constant voltage electrolysis for a certain time, and the electro-oxidation reaction obtains 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole (VI); the 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole shown in formula VI is alcoholized in a methanol solution of hydrogen chloride or a methanol sulfuric acid solution, and then hydrolyzed to obtain ataluren; wherein the hydrolysis is catalyzed by lithium hydroxide and carried out in tetrahydrofuran or dioxane. DETAILED DESCRIPTION

[0038] The following examples are intended to illustrate the present invention rather than to further limit the present invention.

[0039] Example 1

[0040] Preparation of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide

[0041]

[0042] 10mmol 3-cyanobenzaldehyde, 11.0mmol hydroxylamine hydrochloride, 15.0mmol pyridine and 40mL ethanol were reacted at room temperature for 2h, and oxime was obtained after acid washing to remove pyridine. At room temperature, 7.5mmol N-chlorosuccinimide (NCS) was added to the N, N-dimethylformamide solution of oxime in portions; after the addition, the reaction solution was stirred at room temperature for 4h; at 0℃, 15mmol 2-fluorobenzylamine and 15mmol triethylamine were added dropwise to the reaction mixture, and the reaction solution was stirred at 0℃ for 2h and at room temperature for 4h. The reaction mixture was diluted with H2O, extracted with EtOAc (20mL×3), washed with brine, the organic phases were combined, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and flash column chromatography (V 石油醚 :V 乙酸乙酯 =2:1) ​​to give 2.22 g of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide, with a yield of 82.5% (calculated based on 3-cyanobenzaldehyde), mp 102-104°C. 1 H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H, OH), 7.85 (d, J = 7.6 Hz, 1H, Ar), 7.72 (s, 1H, Ar), 7.66 (d, J =7.9Hz,1H,Ar),7.57(t,J=7.8Hz,1H,Ar),7.33–7.23(m,2H,Ar),7.15(t,J=7.4Hz, 1H, Ar), 7.07–7.01 (m, 1H, Ar), 6.44 (t, J = 7.0 Hz, 1H, NH), 4.21 (d, J = 7.0 Hz, 2H, CH2).

[0043] Example 2

[0044] Electro-oxidation Preparation of 5-(2-Fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole

[0045]

[0046] In the electrolytic cell, add 1.35g (5.00mmol) 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide, 3.20g (15.0mmol) K3PO4, 3.40g (10.0mmol) n-Bu4NClO4 as electrolyte, 100mL acetonitrile as solvent, temperature is 30℃, platinum is used as cathode material, and electrolysis is carried out at constant potential of 3V for 4.0h under air atmosphere. After the reaction is completed, dichloromethane is extracted (3×100mL), the organic phase is combined, the organic phase is dried with anhydrous Na2SO4, filtered, vacuum rotary evaporated, column chromatography (V 石油醚 :V 乙酸乙酯 =16:1) to separate 1.14 g of white solid 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole, yield 85.9%, mp 109–111 °C; 1 H NMR (400MHz, DMSO-d6) δ: 8.40–8.32 (m, 2H, Ar), 8.20 (t, J=7.3 Hz, 1H, Ar), 8.07 (d, J=7.6Hz, 1H, Ar), 7.79 (t, J=7.5Hz, 2H, Ar), 7.56–7.45 (m, 2H, Ar); 13 C NMR (400MHz, DMSO-d6) δ: 173.38 (d, J = 4.2 Hz), 167.10, 160.46 (d, J = 258.3 Hz),136.38(d,J=8.9Hz),135.67,132.04,131.36,131.18,130.94,127.67,125 .97(d,J=3.6Hz),118.37,117.79(d,J=20.6Hz),113.05,112.01(d,J=11.3Hz); 19 F NMR (400MHz, DMSO-d6) δ: -109.22–-109.35.

[0047] Example 3

[0048] Electro-oxidation Preparation of 5-(2-Fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole

[0049]

[0050] In an electrolytic cell, add 1.35g (5.00mmol) 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide, 7.50mmol K3PO4, 7.50mmol K2HPO4, 3.40g (10.0mmol) n-Bu4NClO4 as electrolyte, 100mL acetonitrile as solvent, temperature is 30°C, platinum is the cathode material, and electrolysis is carried out at a constant potential of 3V for 4.0h under air atmosphere. After the reaction is completed, dichloromethane is extracted (3×100mL), the organic phases are combined, the organic phases are dried with anhydrous Na2SO4, filtered, vacuum rotary evaporated, and column chromatography (V 石油醚 :V 乙酸乙酯 =16:1) to separate 1.16 g of white solid 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole, yield 87.4%, mp 109–111 °C; 1 HNMR (400MHz, DMSO-d6) δ: 8.40–8.32 (m, 2H, Ar), 8.20 (t, J=7.3Hz, 1H, Ar), 8.07 (d, J=7.6Hz, 1H, Ar), 7.79 (t, J=7.5Hz, 2H, Ar), 7.56–7.45 (m, 2H, Ar); 13 C NMR (400MHz, DMSO-d6) δ: 173.38 (d, J=4.2Hz), 167.10, 160.46 (d, J= 258.3Hz),136.38(d,J=8.9Hz),135.67,132.04,131.36,131.18,130.94,127.67, 125.97(d,J=3.6Hz),118.37,117.79(d,J=20.6Hz),113.05,112.01(d,J=11.3Hz); 19 F NMR(400MHz, DMSO-d6)δ: -109.22–-109.35.

[0051] Example 4

[0052] Electro-oxidation Preparation of 5-(2-Fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole

[0053]

[0054] In an electrolytic cell, add 1.35g (5.00mmol) 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide, 7.50mmol Na3PO4, 7.50mmol Na2HPO4, 3.40g (10.0mmol) n-Bu4NClO4 as electrolyte, 100mL acetonitrile as solvent, temperature is 30°C, platinum is used as cathode and anode materials, and electrolysis is carried out at a constant potential of 3V for 4.0h under air atmosphere. After the reaction is completed, dichloromethane is extracted (3×100mL), the organic phases are combined, the organic phases are dried with anhydrous Na2SO4, filtered, vacuum rotary evaporated, and column chromatography (V 石油醚 :V 乙酸乙酯 =16:1) to separate 1.15 g of white solid 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole, yield 86.7%, mp 109–111 °C; 1 HNMR (400MHz, DMSO-d6) δ: 8.40–8.32 (m, 2H, Ar), 8.20 (t, J=7.3Hz, 1H, Ar), 8.07 (d, J=7.6Hz, 1H, Ar), 7.79 (t, J=7.5Hz, 2H, Ar), 7.56 – 7.45 (m, 2H, Ar); 13 C NMR (400MHz, DMSO-d6) δ: 173.38 (d, J = 4.2Hz), 167.10, 160.46 (d, J=258.3Hz),136.38(d,J=8.9Hz),135.67,132.04,131.36,131.18,130.94,127.67 ,125.97(d,J=3.6Hz),118.37,117.79(d,J=20.6Hz),113.05,112.01(d,J=11.3Hz); 19 F NMR(400MHz, DMSO-d6)δ: -109.22–-109.35.

[0055] Example 5

[0056] Preparation of Ataluren

[0057]

[0058] Dry hydrogen chloride was introduced into 200 ml of methanol solution at 0-5°C until saturated. 200 ml of saturated hydrogen chloride methanol solution and 5.00 mmol of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole were stirred at 25°C for 20 h. After the reaction was completed, water was added to precipitate a white solid. 1.29 g of white solid 3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl)benzoic acid methyl ester Ia was obtained by suction filtration. The yield was 86.6%, and the mp was 133-135°C. 1 H NMR (400MHz, DMSO-d6) δ: 8.61 (s, 1H, Ar), 8.34 (d, J = 8.0 Hz,1H,Ar),8.25(td,J=7.6,1.6Hz,1H,Ar),8.18(d,J=8.0Hz,1H,Ar),7.85–7.75(m,2H,Ar),7.60–7.47(m,2H,Ar),3.94(s,3H,OCH3).

[0059] Hydrolysis was carried out according to the method of the literature [Li S, Wan P, Ai J, et al. Palladium-Catalyzed, Silver-Assisted Direct C-5–H Arylation of 3-Substituted 1,2,4-Oxadiazoles under Microwave Irradiation. Advanced Synthesis & Catalysis, 2017, 359(5):772–778]: 3.40 mmol 3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl)benzoic acid methyl ester in 50.0 mL tetrahydrofuran solution and 6.80 mmol LiOH in 50.0 mL aqueous solution, stirred at 65°C for 10 h; the solvent was removed under reduced pressure, and the obtained residue was acidified with 1 M HCl aqueous solution in an ice bath, and a white solid precipitated. After filtration and drying, 800 mg of white solid Atalulun was obtained, with a yield of 82.8%, and mp of 238-240°C; 1 H NMR(400MHz,DMSO-d6)δ:13.24(s, 1H,COOH),8.58(s,1H,Ar),8.25–8.12(m,3H,Ar),7.81–7.65(m,2H,Ar),7.52–7.45(m,2H, Ar); 13C NMR (400MHz, DMSO-d6) δ: 173.12 (d, J = 4.2Hz), 167.42 (d, J = 84.0Hz), 161.72, 159.15,136.22,132.68,132.36,131.47,131.34,130.19,128.24,126.79,125.89(d,J=3.5Hz),117.73(d,J=20.6Hz),112.12(d,J=11.2Hz); 19 F NMR(400MHz,DMSO-d6)δ: -109.32.

[0060] Example 6

[0061] Preparation of Ataluren

[0062]

[0063] (1) Dry hydrogen chloride was introduced into 200 ml of methanol solution at 0-5°C until saturation. 200 ml of saturated hydrogen chloride methanol solution and 5.00 mmol of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole were stirred at 25°C for 20 h. After the reaction was completed, water was added to precipitate a white solid. After filtration, 1.29 g of white solid 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester Ia was obtained. The yield was 86.6%, and the mp was 133-135°C.

[0064] (2) Hydrolysis according to the method of Example 9 in the Chinese invention patent [CN202110345947.6, 2021.6.29]: At 25°C, 30 mL of 1,4-dioxane and 2.98 g (10 mmol) of 3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl) methyl benzoate were added to the reaction bottle, and then 20 mL of an aqueous solution containing 0.84 g (20 mmol) of lithium hydroxide was dripped into the above reaction solution. The dripping was completed within 0.5 h, and the mixture was stirred at 15-20°C for 8 h (TLC monitoring). Water was added to adjust the pH to 2, and a large amount of white solid precipitated. The mixture was filtered through a Buchner funnel and the filter cake was washed with a small amount of water. 2.79 g of Atalulun was obtained by vacuum drying with a yield of 98.0% and an mp of 238-240°C. 1 H NMR(400MHz,DMSO-d6)δ:13.24(s,1H,COOH),8.58(s,1H,Ar),8.25–8.12(m,3H,Ar),7.81–7.65(m,2H,Ar),7.52–7.45(m,2H,Ar); 13CNMR (400MHz, DMSO-d6) δ: 173.12 (d, J = 4.2Hz), 167.42 (d, J = 84.0Hz), 161.72, 159.15, 136.22, 132.68, 132.36, 131.47, 131.34, 130.19, 128.24, 126.79, 125.89 (d, J = 3.5Hz), 117.73 (d, J = 20.6Hz), 112.12 (d, J = 11.2Hz); 19 F NMR (400MHz, DMSO-d6)δ: -109.32.

[0065] Example 7

[0066] Preparation of Ataluren

[0067]

[0068] (1) 20 g of methanol, 1.0 mmol of sulfuric acid and 0.5 mmol of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole were refluxed and stirred for 4 h. After the reaction was completed, 1.30 g of white solid 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid methyl ester Ia was obtained after post-treatment. The yield was 87.2%, and the mp was 133-135°C.

[0069] Hydrolyze according to the method in the literature [Neil G. Armstead et al. Method for preparing 1,2,4-oxadiazolebenzoic acid. CN101535284B. 2014.12.10]: 2.98g 3-[5-(2-fluorophenyl)-[1,2,4]-oxadiazole-3-yl]benzoic acid methyl ester, 8.94mL tert-butyl alcohol and 1.75g 25.1% sodium hydroxide aqueous solution; 63-67℃, stir for 0.5h, 68-72℃, stir for 3h; add 4.06g sulfuric acid (13.9%) to acidify under stirring, stir for another 0.5h at 68-72℃, filter; wash the filter cake with 14.2g 38-42℃ hot tert-butyl alcohol aqueous solution and 65-70℃ 3×15mL hot water respectively; dry in vacuum for 26h to obtain 2.11g Atalulun, yield 74.2%, mp 238-240℃; 1 HNMR(400MHz,DMSO-d6)δ:13.24(s,1H,COOH),8.58(s,1H,Ar),8.25–8.12(m,3H,Ar),7.81–7.65(m,2H,Ar),7.52–7.45(m,2H,Ar); 13C NMR (400MHz, DMSO-d6) δ: 173.12 (d, J = 4.2Hz), 167.42 (d, J = 84.0Hz), 161.72, 159.15, 136.22, 132.68, 132.36 ,131.47,131.34,130.19,128.24,126.79,125.89(d,J=3.5Hz),117.73(d,J=20.6Hz),112.12(d,J=11.2Hz); 19 F NMR(400MHz,DMSO-d6)δ: -109.32.

[0070] Example 8 (verification experiment)

[0071] Hydrolysis of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole

[0072] Patent [CN 106316885 B, 2019.2.12] Example 1 Preparation method: Add 13.3g 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole (0.05mol), 133mL acetic acid, 10mL water into a 250mL flask, add 20mL concentrated sulfuric acid dropwise, heat to 100°C, keep warm for 5 hours, HPLC shows that the raw materials are completely reacted, continue to react for 2 hours, the reaction is completed, cool to 20°C, keep warm and stir for 3 hours, filter, wash the filter cake with acetone, drain, and vacuum dry at 60°C for 12h to obtain 13.5g white solid with a yield of 95%.

[0073] In the verification experiment, it was found that 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole was hydrolyzed to obtain 3-[5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl]benzamide:

[0074]

[0075] 420mg 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole (1.6mmol), 10mL acetic acid and 1mL water, add 10mL concentrated sulfuric acid dropwise, heat to 100℃, keep warm for 5h, TLC shows that the raw material reacts completely, continue to react for 2h, cool to 20℃ after the reaction is completed, keep warm and stir for 3h, filter, wash the filter cake with acetone, drain, and vacuum dry at 60℃ for 12h to obtain 440mg white solid. The product is confirmed to be 3-[5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl]benzamide by structure: 1HNMR (400MHz, DMSO-d6) δ: 8.59 (s, 1H, Ar), 8.27–8.19 (m, 2H, Ar), 8.11 (d, J = 7.6Hz, 1H, Ar), 7.79 (d, J=5.6Hz, 1H, Ar), 7.68 (t, J=8.0Hz, 1H, Ar), 7.61–7.44 (m, 2H, Ar), 7.14 (s, 2H, CONH2).

[0076] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it is apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the description should be regarded as illustrative rather than restrictive.

Claims

1. A method for preparing Ataluren by electro-oxidation as shown in structural formula II, characterized in that The preparation reaction of Ataluren is as follows: The specific operations are as follows: (1) 10 mmol 3-cyanobenzaldehyde, 11.0 mmol hydroxylamine hydrochloride, 15.0 mmol pyridine and 40 mL ethanol were selected, reacted at room temperature for 2 h, and oxime was obtained after acid washing to remove pyridine; 7.5 mmol N-chlorosuccinimide was added to the N,N-dimethylformamide solution of oxime at room temperature in portions; after the addition, the reaction solution was stirred at room temperature for 4 h; 15 mmol 2-fluorobenzylamine and 15 mmol triethylamine were added dropwise to the reaction mixture at 0°C, and the reaction solution was stirred at 0°C for 2 h and at room temperature for 4 h; the reaction mixture was diluted with H2O, extracted with 20 mL ethyl acetate 3 times, washed with brine, the organic phases were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure, and V was selected. 石油醚 :V 乙酸乙酯 =2:1 solvent rapid column chromatography purification, to obtain 2.22g of 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide represented by formula III, with a yield of 82.5%; (2) In an electrolytic cell, 1.35 g 3-cyano-N-(2-fluorobenzyl)-N'-hydroxybenzamide, 7.50 mmol K3PO4, 7.50 mmol K2HPO4, and 3.40 g n-Bu4NClO4 were added as electrolyte, 100 mL acetonitrile was used as solvent, the temperature was 30°C, platinum was used as cathode and anode materials, and electrolysis was carried out at a constant potential of 3 V for 4.0 h under air atmosphere; after the reaction was completed, the reaction was extracted 3 times with 100 mL dichloromethane, the organic phases were combined, the organic phases were dried with anhydrous Na2SO4, filtered, and evaporated under reduced pressure, and V was selected. 石油醚 :V 乙酸乙酯 =16:1 solvent column chromatography to obtain 1.16 g of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole as a white solid represented by Formula VI, with a yield of 87.4%; (3) Dry hydrogen chloride was introduced into 200 ml of methanol solution at 0-5°C until saturated, and 200 ml of saturated hydrogen chloride methanol solution and 5.00 mmol of 5-(2-fluorophenyl)-3-(3-cyanophenyl)-1,2,4-oxadiazole were stirred at 25°C for 20 h. After the reaction was completed, water was added to precipitate a white solid, which was filtered to obtain 1.29 g of methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazole-3-yl)benzoate as a white solid represented by formula Ia, with a yield of 86.6%; (4) At 25°C, 30 mL of 1,4-dioxane and 2.98 g of methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate were added to the reaction flask. Subsequently, 20 mL of an aqueous solution containing 0.84 g of lithium hydroxide was dripped into the reaction solution within 0.5 h. The mixture was stirred at 15-20°C for 8 h. The mixture was monitored by TLC. Water was added to adjust the pH to 2. A large amount of white solid precipitated. The solid was filtered through a Buchner funnel and the filter cake was washed with a small amount of water. The solid was dried under vacuum to obtain 2.79 g of atarulun represented by Formula II with a yield of 98.0%.

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