Electrochemical preparation of intermediates for linezolid and ataluren

Abstract

The present application relates to the preparation method of 3-phenyl-5-aryl-1,2,4-oxadiazole by electro-oxidation, and the preparation reaction is as follows: wherein R is selected from hydrogen, 4-fluoro, 4-chloro, 2-bromo, 4-tert-butyl, 3-methyl or 3,4-dimethyl; Ar is selected from phenyl, 2-thiophenyl, 2-fluorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-fluorophenyl or 4-methylphenyl. The preparation method of electro-oxidation is that (Z)-N'-hydroxy-N-(arylmethyl) benzamidine, organic solvent, base and electrolyte are used as electrolyte in a non-membrane electrolytic cell, and then constant voltage electrolysis is carried out at a certain temperature for a certain time, so that 3-phenyl-5-aryl-1,2,4-oxadiazole (I) is obtained by electro-oxidation reaction. The preparation method of electro-oxidation can be used for preparing line thiophene and ataluren.

Description

Technical Field

[0001] This invention relates to an electro-oxidative preparation method for the nematicide Tioxazafen and the intermediate of the drug Ataluren for treating Duchenne muscular dystrophy (DMD). Specifically, Tioxazafen is prepared by electro-oxidation of (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamidin, and 5-(2-fluorobenzyl)-3-hydroxy-3-methylbenzamidin is prepared by electro-oxidation of (Z)-N'-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamidin. Background Technology

[0002] Tioxazafen (Ia, chemical name: 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole) is a diazole nematicide synthesized by Monsanto. Monsanto developed tioxazafen in 2013. In 2015, Monsanto applied for joint review of tioxazafen under the North American Free Trade Agreement (NAFTA). On May 1, 2017, the U.S. Environmental Protection Agency (EPA) approved the registration of 82.5% tioxazafen technical grade and 45.9% (or 541 g / L) tioxazafen suspension concentrate. As a new active ingredient, its 10-year registration data protection right will expire on April 30, 2027. The EPA-approved tioxazafen suspension concentrate (NemaStrike) is used on three major crops: corn, soybeans, and cotton. Based on the EPA registration, NemaStrike has now been registered in 45 U.S. states and was launched in the 2018 planting season. Tioxazafen is an oxadiazole-based systemic broad-spectrum nematicide reported by Monsanto in 2013. It is primarily used for soil pest control and nematode treatment. Its novel mechanism of action demonstrates excellent efficacy against cyst nematodes, root-knot nematodes, and kidney-shaped nematodes. It provides a sustained effect at the crop root level for up to 75 days, thus controlling two generations of nematodes. Monsanto Technology LLC filed a patent application in China on August 13, 2008, for a composition of tioxazafen (CN201310342172), which has now expired.

[0003] Fosthiazate and fluensufone are nematicides with a thiazole ring structure, containing elements such as N, S, P, F, and Cl in their molecules. Their production processes generate waste gas and wastewater containing organic sulfur and organophosphorus compounds, causing significant environmental pollution. Imicyafos is a thiophosphate nematicide, also containing N, S, and P in its molecular structure. Its synthesis requires compounds such as dipropylsulfide and phosphorus trichloride, also having a significant environmental impact. Fosthiazate, on the other hand, does not contain phosphorus in its molecular structure. Its synthesis does not require odorous and polluting raw materials, achieving cleaner production. In the near future, fosthiazate is expected to replace thiazole, Imicyafos, and fluensufone as the primary nematicide.

[0004]

[0005] As a novel, broad-spectrum, systemic, non-fumigation nematicide for seed treatment, nematicide has a completely new mechanism of action. It exerts its efficacy by affecting the activity of nematode ribosomes, causing gene mutations in target nematodes. Nematicide exhibits excellent selectivity, affecting only harmful parasitic nematodes and being harmless to non-target nematodes. Due to the long retention time of nematicide suspension in plant roots, it can provide a residual effect of 75 days, thus effectively controlling two generations of nematodes. Nematicide can also enhance the vitality of crop roots, thereby significantly increasing crop yield [Zhang Mingming. Design, Synthesis, and Bioactivity Study of Novel Insecticides, Acaricides, and Plant Growth Regulators. Doctoral Dissertation, Qingdao University of Science and Technology, 2019].

[0006] Synthesis of linear thiophene (Ia): Liu Anchang et al. [Synthesis of novel nematicide Tioxazafen. Pesticides, 2014, 53(8): 561-563] reported a method using 2-thiophene carboxyl chloride and N-hydroxybenzomidine as raw materials, butyl acetate as solvent, and sodium hydroxide. The mixture was stirred at room temperature for 2 h, then refluxed for another 4 h to obtain linear thiophene with a yield of 86.3%. Among them, the yield of N-hydroxybenzomidine was 82.9%, and the yield of 2-thiophene carboxyl chloride was 88.5%. This process uses benzonitrile, which has high toxicity, and thionyl chloride, which has a strong irritating odor, polluting the environment and endangering the safety of laboratory personnel.

[0007]

[0008] Dahlb et al. [WO2006114400, 2006] described the synthesis of linear thiophene Ia using 2-thiopheneformyl chloride and N-hydroxybenzomidine as raw materials and pyridine as solvent under reflux. This method uses pyridine, which has a strong odor, as a solvent, causing serious environmental pollution.

[0009]

[0010] Deprez et al. [WO2013060744, 2013] described a method for synthesizing 1,2,4-oxadiazole compounds. This method uses high-boiling-point DMF as a solvent, and refluxes 2-thiopheneacetyl chloride and N-hydroxybenzamide to obtain linear thiophene. This process suffers from the problem of difficulty in recovering the DMF solvent.

[0011]

[0012] Miller et al. [WO 2014008257A1, 2014] provided a method for synthesizing N'-hydroxybenzomidine at 60 °C with a yield of 96.5%, using benzonitrile and hydroxylamine hydrochloride as raw materials and sodium hydroxide and methanol as solvent. Tetrabutylammonium aqueous solution, sodium hydroxide, and 2-thiophene carbonyl chloride were added to a 2-methyltetrahydrofuran solution of N'-hydroxybenzomidine, and the reaction was carried out at 70 °C to give linear thiophene with a yield of 95.0%.

[0013]

[0014] Kuram et al. [Copper-Catalyzed Direct Synthesis of 1,2,4‐Oxadiazoles from Amides and Organic Nitriles by Oxidative N–O Bond Formation. European Journal of Organic Chemistry, 2016, 2016(3): 438-442] described a method for synthesizing linear thiophene by constructing N–O bonds between thiophene formamide and benzonitrile using oxygen as an oxidant and copper as a catalyst, with a yield of 53%. This work used a metal catalyst, which is environmentally harmful.

[0015]

[0016] Naoki Ichinokawa et al. [CN107406437A, 2017] described the reaction of N'-hydroxybenzomidine with 2-thiophenecarboxaldehyde at 102 °C for 3 h with potassium hydroxide as base and tert-amyl alcohol as solvent to obtain linear thiophene with a yield of 96%.

[0017]

[0018] Wang et al. [Base-mediated one-pot synthesis of 1,2,4-oxadiazoles from nitriles, aldehydes and hydroxylamine hydrochloride without addition of extraoxidant. Organic & Biomolecular Chemistry, 2016, 14(41): 9814-9822] synthesized 3,5-disubstituted 1,2,4-oxadiazole compounds in a one-pot process using benzonitrile, aldehydes and hydroxylamine hydrochloride as raw materials, with a yield of 73%.

[0019]

[0020] Zhang Guangping et al. [Preparation of 2-thiophenecarboxylic acid, a key intermediate of the nematicide Tioxazafen. Fine Chemical Intermediates, 2020, 50(4): 18-20] prepared 2-thiophene ethyl ketone from thiophene and acetyl chloride, and then oxidized it with sodium hypochlorite to obtain 2-thiophenecarboxylic acid, a key intermediate of thiophene, with a yield of 87.84%.

[0021]

[0022] Vinaya et al. [One-pot synthesis of 3,5-diaryl substituted-1,2,4-oxadiazoles using gem-dibromomethylarenes. Canadian Journal of Chemistry, 2019, 97(9): 690-696] described a one-pot synthesis of 2-(dibromomethyl)thiophene with benzamide oxime, with a yield of 89%.

[0023]

[0024] Patrick et al. [Synthesis of 1,2,4-Oxadiazoles via DDQ-Mediated Oxidative Cyclization of Amidoximes. Synthesis: International Journal of Methods in Synthetic Organic Chemistry, 2016, 48(12): 1902-1909] described a method for preparing (Z)-N'-hydroxy-N-(thien-2-ylmethyl)benzamidin by reacting chlorobenzaldehyde oxime with thiophene-2-ylmethylamine, which is then oxidatively cyclized in 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to generate linear thiophene (Ia) in 52% yield. This method uses the highly toxic DDQ.

[0025]

[0026] Lade et al. [Oxidative cyclization of amidoximes and thiohydroximicacids: A facile and efficient strategy for accessing 3,5-disubstituted 1,2,4-oxadiazoles and 1,4,2-oxathiazoles. Tetrahedron Letters, 2017, 58(22): 2103-2108] describe a method for synthesizing 3,5-diphenyl-1,2,4-oxadiazoles from (Z)-N-benzyl-N'-hydroxybenzomidazine.

[0027]

[0028] Zhang et al. [Orthogonal aerobic conversion of N-benzyl amidoximes to 1, 2, 4-oxadiazoles or quinazolinones. Organic & biomolecular chemistry, 2013, 11(36): 6003-6007] used (Z)-N-benzyl-N'-hydroxybenzylamidine as a starting material, K3PO4, and DMF as solvents, and reacted at 60℃ and 1 atm oxygen for 5 h to obtain 3,5-diphenyl-1,2,4-oxadiazoles with a yield of 78%. The DMF used was difficult to recover.

[0029]

[0030] 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 in the United States for the treatment of nonsense mutation-induced Duchenne muscular dystrophy and cystic fibrosis. It was launched in Europe in 2014.

[0031]

[0032] 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole (Ib) is a key intermediate in the preparation of atalulone (II): Krasouskaya et al. [Synthesis of benzoic acids containing a 1,2,4-oxadiazole ring. Russian Chemical Bulletin, 2015, 64(1): 142-145] selected cobalt acetate as a catalyst, and 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole Ib was oxidized by air to atalulone II in 85% yield.

[0033]

[0034] 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] reacted 3-methylbenzamide hydrochloride with 2-fluorobenzoic acid to form 2-fluoro-N-(imino(3-tolyl)methyl)benzamide, which underwent nucleophilic addition-deamination-intramolecular cyclization to give 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole (Ib). Ib was then oxidized with potassium permanganate to synthesize atalulin II in 40% yield.

[0035]

[0036] Asad et al. [Iodine–induced Oxidative Cyclisation of N-Acyl Amidines: ARapid Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles. ChemistrySelect, 2016, 1(15): 4753-4757] synthesized 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazoles by iodine-induced oxidative cyclization of 2-fluoro-N-(imino(3-tolyl)methyl)benzamide, followed by oxidation to synthesize atalulone, with a yield of 48%.

[0037] Summary of the Invention

[0038] One objective of this invention is to provide an electro-oxidative preparation method for 3-phenyl-5-aryl-1,2,4-oxadiazole, as shown in chemical structural formula I, characterized by the following preparation reaction:

[0039]

[0040] Wherein, R is selected from: hydrogen, 4-fluoro, 4-chloro, 2-bromo, 4-tert-butyl, 3-methyl or 3,4-dimethyl; Ar is selected from: phenyl, 2-thienyl, 2-fluorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-fluorophenyl or 4-tolyl.

[0041] The electro-oxidation preparation method involves installing an anode working electrode and a cathode in a non-diaphragm electrolytic cell, using (Z)-N'-hydroxy-N-(arylmethyl)benzamidinium, an organic solvent, an alkali, and an electrolyte as the electrolyte, and electrolyzing at a constant voltage for a certain time at a certain temperature to obtain 3-phenyl-5-aryl-1,2,4-oxadiazole (I).

[0042] The working anode electrode of the electrolytic cell is selected from: carbon felt electrode, platinum mesh electrode, or graphite electrode; preferably: platinum mesh electrode; the working current density of the anode electrode is selected from: 11.0 mA / cm². 2 ~25.0mA / cm 2 The cathode of the electrolytic cell is selected from: platinum sheet electrode or carbon felt electrode; preferably: platinum sheet electrode.

[0043] The constant voltage is selected from 1.50 V to 4.50 V; the electrolysis temperature is selected from 15℃ to 55℃; and the electrolysis time is selected from 2 h to 8 h.

[0044] The organic solvent in the electrolyte is selected from: acetonitrile, acetone, methanol, methanol / water (volume ratio 10 / 1) or methanol / hexafluoroisopropanol (volume ratio 5 / 5). The base is selected from: potassium phosphate, potassium carbonate, sodium acetate, pyridine or triethylamine.

[0045] The electrolyte is selected from: tetrabutylammonium perchlorate, lithium perchlorate, ammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate or potassium hexafluorophosphate; the electrolyte concentration is selected from: 0.02mol / L to 0.1mol / L.

[0046] The concentration of (Z)-N'-hydroxy-N-(arylmethyl)benzamidin in the electrolyte is selected from 8 g / L to 30 g / L.

[0047] Further preferred, the electrolyte is prepared by dissolving (Z)-N'-hydroxy-N-(arylmethyl)benzamidin 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.

[0048] The present invention further aims to provide 3-phenyl-5-aryl-1,2,4-oxadiazole of Formula I selected from:

[0049]

[0050] A second aspect of the present invention is to provide a novel method for preparing the nematicide nematicide thiophene (Ia), characterized by the preparation of an intermediate (Z)-N'-hydroxy-N-(thiophen-2-ylmethyl)benzamide by oximeting, chlorination, and substitution with thiophene-2-ylmethylamine of benzaldehyde, followed by electro-oxidation of (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamide to obtain thiophene. The preparation reaction is as follows:

[0051]

[0052] A third aspect of the present invention is to provide a novel method for preparing atalulone from a compound as shown in structural formula Ib, characterized in that 3-methylbenzaldehyde is selected and oxime-treated, chlorinated, and substituted with 2-fluorobenzylamine to prepare intermediate (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamide, which is then electro-oxidized to prepare compound Ib, which is subsequently oxidized to prepare atalulone (II). The preparation reaction is as follows:

[0053]

[0054] The beneficial technical effects of the invention are as follows:

[0055] (1) No toxic or dangerous oxidizing agents are needed in the oxidation reaction. "Electrons" are clean reaction reagents and are an important part of the development of "green pharmaceutical industry".

[0056] (2) Compared with traditional methods, electro-oxidation has the advantages of shorter reaction time, lower temperature and no use of toxic reagents.

[0057] (3) In industrial production, it simplifies the process, reduces production costs, and is safe and environmentally friendly, making it suitable for large-scale promotion and application. Detailed Implementation

[0058] The following examples are intended to illustrate the invention and not to further limit it.

[0059] Example 1

[0060] Preparation of linear thiophene (Ia)

[0061]

[0062] (1) Preparation of (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamidin

[0063] 0.53 g (5.0 mmol) benzaldehyde, 0.38 g (5.5 mmol) hydroxylamine hydrochloride, and 0.59 g (0.75 mmol) pyridine were dissolved in 20 mL of ethanol and stirred at room temperature for 2 h. The mixture was then acid-washed to obtain crude benzaldehyde oxime, which was directly used in the next reaction after solvent removal. Benzaldehyde oxime was dissolved in 10 mL of EtOH, and 1.0 g (7.5 mmol) N-chlorosuccinimide was added in five portions. The mixture was stirred for 4 h under nitrogen protection to obtain crude N-hydroxybenzoyl chloride. The crude N-hydroxybenzoyl chloride was added to a tetrahydrofuran solution containing 0.56 g (5.0 mmol) thiophene-2-ylmethylamine and 0.76 g (7.5 mmol) triethylamine. The mixture was stirred for 2 h under nitrogen protection and then at room temperature for 4 h. The solution was diluted with H2O and extracted with ethyl acetate (3 × 10⁻⁶). Wash with 20 mL of saturated saline solution, dry with anhydrous sodium sulfate, filter, remove solvent, and perform column chromatography (V). 乙酸乙酯 / 石油醚 0.967 g of white solid (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamide was obtained by separation (1 / 2), with a yield of 83.3% (based on benzaldehyde) and a melting point of 130~132℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.89 (s, 1H, OH), 7.40 (s, 5H, benzene ring), 7.33 (d, J = 4.8 Hz, 1H, thiophene ring), 6.91–6.88 (m, 1H, thiophene ring), 6.75 (s, 1H, thiophene ring), 6.31 (t, J = 6.8 Hz, 1H, NH), 4.31 (d, J = 6.8 Hz, 2H, CH₂); 13C NMR (101 MHz, DMSO-d6) δ: 154.70, 144.81, 132.75, 129.50, 128.63, 127.20, 125.05, 124.75, 42.28.

[0064] (2) Electro-oxidation preparation of linear thiophene Ia

[0065] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamidin as the raw material, platinum as the anode, carbon felt as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was then subjected to column chromatography (V... 乙酸乙酯 / 石油醚 0.092 g of white solid linear thiophene Ia was obtained by separation (1 / 16), with a yield of 80.7% and a melting point of 108-109 °C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 8.06 (d, J = 4.8 Hz, 1H, benzene ring), 8.02 (d, J = 4.8 Hz, 3H, benzene ring + thiophene ring), 7.58~7.51 (m, 3H, benzene ring + thiophene ring), 7.32 (t, J = 4.4 Hz, 1H, thiophene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 171.53, 168.56, 134.38, 133.15, 132.07, 129.62, 127.55, 126.38, 124.99.

[0066] Example 2 (Control Experiment 1)

[0067] Preparation of linear thiophene (Ia)

[0068]

[0069] 3-Phenyl-5-(2-thienyl)-1,2,4-oxadiazole was prepared according to the method described in the literature [Synthesis of 1,2,4-Oxadiazoles via DDQ-Mediated Oxidative Cyclization of Amidoximes. Synthesis: International Journal of Methods in Synthetic Organic Chemistry, 2016, 48(12): 1902-1909]. At room temperature, 0.05 g (0.22 mmol) (Z)-N'-hydroxy-N-(thien-2-ylmethyl)benzamide, 2.2 mL DMF, and 0.10 g (0.44 mmol) DDQ were added to a round-bottom flask, and the mixture was degassed with nitrogen for 5 min. The mixture was then heated to 150 °C and stirred for 30 min. The reaction mixture was cooled to room temperature, quenched with H2O, extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was purified by rapid chromatography (silica gel, hexane-EtOAc, 10-50%) to obtain 0.082 g of white solid 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, yield 53%, melting point 108-109℃.

[0070] Example 3

[0071] Preparation of Ataluluen II

[0072]

[0073] (1) Preparation of (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamidin

[0074] 0.60 g (5.0 mmol) of 3-methylbenzaldehyde, 0.38 g (5.5 mmol) of hydroxylamine hydrochloride, and 0.59 g (0.75 mmol) of pyridine were dissolved in 20 mL of ethanol and stirred at room temperature for 2 h. The mixture was then acid-washed to obtain crude benzaldehyde oxime, which was directly used in the next reaction after solvent removal. Benzaldehyde oxime was dissolved in 10 mL of EtOH, and 1.0 g (7.5 mmol) of N-chlorosuccinimide was added in five portions. The mixture was stirred under nitrogen for 4 h to obtain crude N-hydroxybenzoyl chloride. The crude N-hydroxybenzoyl chloride was added to a tetrahydrofuran solution containing 0.62 g (5.0 mmol) of (2-fluorophenyl)methylamine and 0.76 g (7.5 mmol) of triethylamine at 0 °C and stirred under nitrogen protection for 2 h. The mixture was then stirred at room temperature for 4 h, diluted with H2O, and extracted with ethyl acetate (3 × 10⁻⁶). Wash with 20 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and remove solvent to obtain the crude product; the crude product is then subjected to column chromatography (V... 乙酸乙酯 / 石油醚 0.942 g of white solid (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamide was obtained by separation (1 / 2), with a yield of 73.0% (based on 3-methylbenzaldehyde) and a melting point of 102-103 °C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.88 (d, J = 4.4 Hz, 1H, OH), 7.32 (t, J = 7.2 Hz, 1H, benzene ring), 7.21 ~ 7.27 (m, 2H, benzene ring), 7.15 ~ 7.21 (m, 2H, benzene ring), 7.12 (d, J = 7.2 Hz, 2H, benzene ring), 7.02 ~ 7.09 (m, 1H, benzene ring), 6.25 (t, J = 6.0 Hz, 1H, NH), 4.20 (d, J = 6.4 Hz, 2H, CH₂), 2.27 (s, 3H, CH₃); 13 C NMR (101 MHz, DMSO-d6) δ: 161.23, 158.81, 155.20, 137.83, 132.58, 130.10, 129.18, 128.53, 128.16, 125.58, 124.76, 115.38, 115.17, 21.36.

[0075] (2) Preparation of 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole (Ib)

[0076] In an electrolytic cell, using 0.13 g (0.5 mmol) (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was then subjected to column chromatography (V... 乙酸乙酯 / 石油醚 0.096 g of white solid 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole Ib was obtained by separation (1 / 16), with a yield of 75.59% and a melting point of 99~102℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 8.17 (dd, J = 13.6, 7.2 Hz, 1H, benzene ring), 7.85 (d, J = 8.8 Hz, 2H, benzene ring), 7.76 (dd, J = 13.6, 7.2 Hz, 1H, benzene ring), 7.49 ~ 7.53 (m, 1H, benzene ring), 7.42 ~ 7.49 (m, 2H, benzene ring), 7.40 (d, J = 7.2 Hz, 1H, benzene ring), 2.39 (s, 3H, CH3); 13 C NMR (101 MHz, DMSO-d6) δ: 172.80, 168.48, 161.69, 159.12, 139.10, 136.04, 132.75, 131.27, 12 9.58, 127.93, 126.35, 125.87, 124.73, 117.81, 117.60, 112.25, 21.32.

[0077] (3) Preparation of Atalulus II

[0078] Prepared according to the method described in the literature [Synthesis of benzoic acids containing a 1,2,4-oxadiazole ring. Russian Chemical Bulletin, 2015, 64(1): 142-145]: 0.33 g (1.3 mmol) of 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole, 0.23 g (1.3 mmol) of cobalt acetate, and 0.13 g (1.3 mmol) of sodium bromide were dissolved in 40 mL of glacial acetic acid. The solution was heated to 95°C and air was introduced. After reacting for 11 h, the solution was cooled to -20°C and filtered to obtain 0.313 g of atalulone II, with a yield of 85.0% and a melting point of 241-242°C.

[0079]

[0080] Example 4 (Control Experiment)

[0081] Preparation of 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole

[0082]

[0083] 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole was prepared according to the method described in the literature [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]. 0.38 g (1.5 mmol) of iodine and 0.41 g (3 mmol) of potassium carbonate were added to a round-bottom flask containing 0.26 g (1 mmol) of 2-fluoro-N-(imino(3-tolyl)methyl)benzamide and 5 mL of DMSO. The mixture was stirred at 100 °C for 3 h. After the reaction was complete, it was cooled to room temperature, quenched with 10 mL of 5% Na2S2O3, then 15 mL of brine was added, and the mixture was extracted with ethyl acetate (15 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent to give 0.220 g of 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole in 87% yield, with a melting point of 93–94 °C.

[0084] Example 5

[0085] Preparation of 3,5-diphenyl-1,2,4-oxadiazole

[0086]

[0087] (1) Preparation of (Z)-N-benzyl-N'-hydroxybenzamidin

[0088] Following the method in Example 1, the reaction was carried out for 12 hours, with a yield of 78.0% and a melting point of 114-115°C. 1¹H NMR (400 MHz, DMSO-d6) δ: 9.85 (d, J = 2.4 Hz, 1H, OH), 7.40 – 7.32 (m, 5H, benzene ring), 7.26 (t, J = 7.2 Hz, 2H, benzene ring), 7.19 (d, J = 6.8 Hz, 1H, benzene ring), 7.11 (d, J = 7.6 Hz, 2H, benzene ring), 6.30 (t, J = 7.2 Hz, 1H, NH), 4.15 (d, J = 6.8 Hz, 2H, CH₂); 13 C NMR (101 MHz, DMSO-d6) δ: 155.31, 141.41, 132.90, 129.41, 128.81 – 128.45, 127.03, 46.89.

[0089] (2) Preparation of 3,5-diphenyl-1,2,4-oxadiazole

[0090] In an electrolytic cell, using 0.11 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.092 g of a white solid, 3,5-diphenyl-1,2,4-oxadiazole, with a yield of 82.7% and a melting point of 109–111 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.20 (d, J = 7.2 Hz, 2H, benzene ring), 8.14 ~ 8.09 (m, 2H, benzene ring), 7.75 (t, J = 7.2 Hz, 1H, benzene ring), 7.68 (t, J = 7.6 Hz, 2H, benzene ring), 7.62 (d, J = 6.8 Hz, 3H, benzene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 175.89, 168.73, 133.83, 132.13, 130.03, 129.74, 128.38, 127.57, 126.61, 123.83.

[0091] Example 6

[0092] Preparation of 3-(4-fluorophenyl)-5-phenyl-1,2,4-oxadiazole

[0093]

[0094] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-4-fluorobenzomididine

[0095] Following the method in Example 1, the reaction was carried out for 12 hours, with a yield of 75.0% and a melting point of 90-92°C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.90 (s, 1H, OH), 7.41 – 7.34 (m, 2H, benzene ring), 7.26 (t, J = 6.8 Hz, 2H, benzene ring), 7.19 (dd, J = 8.8, 4.4 Hz, 3H, benzene ring), 7.11 (d, J = 7.2 Hz, 2H, benzene ring), 6.35 (t, J = 6.8 Hz, 1H, NH), 4.15 (d, J = 7.2 Hz, 2H, CH₂); 13 C NMR (101 MHz, DMSO-d6) δ: 164.06, 161.61, 154.44, 141.31, 130.71, 130.63, 129.36, 129.33, 128.67, 127.08, 127.01, 115.71, 115.49, 46.87.

[0096] (2) Preparation of 3-(4-fluorophenyl)-5-phenyl-1,2,4-oxadiazole

[0097] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxy-4-fluorobenzamidinium as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.085 g of a white solid 3-(4-fluorophenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 70.8% and a melting point of 111–114 °C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 8.22 – 8.12 (m, 4H, benzene ring), 7.75 (t, J = 7.2 Hz, 1H, benzene ring), 7.67 (t, J = 7.6 Hz, 2H, benzene ring), 7.44 (t, J = 8.8 Hz, 2H, benzene ring); 13C NMR (101MHz, DMSO-d6) δ: 175.94, 167.91, 165.71, 163.23, 133.86, 130.15, 130.06, 130.02, 128.37, 123.74, 123.18, 117.01, 116.79.

[0098] Example 7

[0099] Preparation of 3-(4-chlorophenyl)-5-phenyl-1,2,4-oxadiazole

[0100]

[0101] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-4-chlorobenzamidin

[0102] Following the method in Example 1, the reaction was carried out for 12 hours, with a yield of 77.0% and a melting point of 117-119°C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.98 (s, 1H, OH), 7.42 (d, J = 8.4 Hz, 2H, benzene ring), 7.35 (d, J = 8.4 Hz, 2H, benzene ring), 7.26 (t, J = 7.2 Hz, 2H, benzene ring), 7.19 (d, J = 7.2 Hz, 1H, benzene ring), 7.11 (d, J = 7.2 Hz, 2H, benzene ring), 6.37 (t, J = 7.2 Hz, 1H, NH), 4.15 (d, J = 7.2 Hz, 2H, CH₂); 13 C NMR (101MHz, DMSO-d6) δ: 154.33, 141.26, 134.06, 131.82, 130.26, 128.75, 128.69, 127.10, 127.01, 46.88.

[0103] (2) Preparation of 3-(4-chlorophenyl)-5-phenyl-1,2,4-oxadiazole

[0104] In an electrolytic cell, using 0.13 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxy-4-chlorobenzamidin as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.095 g of a white solid 3-(4-chlorophenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 74.2% and a melting point of 104–106 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.19 (d, J = 7.2 Hz, 2H, benzene ring), 8.11 (d, J = 8.4 Hz, 2H, benzene ring), 7.75 (d, J = 7.2 Hz, 1H, benzene ring), 7.68 (dd, J = 7.7, 6.8 Hz, 4H, benzene ring); 13 CNMR (101 MHz, DMSO-d6) δ: 176.09, 167.95, 136.87, 133.95, 130.07, 129.94, 129.38, 128.42, 125.47, 123.71.

[0105] Example 8

[0106] Preparation of 3-(2-bromophenyl)-5-phenyl-1,2,4-oxadiazole

[0107]

[0108] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-2-bromobenzamide

[0109] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 82.0% and a melting point of 124-125°C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H, OH), 7.68–7.62 (m, 1H, benzene ring), 7.36–7.26 (m, 3H, benzene ring), 7.24 (t, J = 7.2 Hz, 2H, benzene ring), 7.20–7.10 (m, 2H, benzene ring), 7.07 (d, J = 7.2 Hz, 2H, benzene ring), 6.53 (t, J = 6.8 Hz, 1H, NH), 3.95 (d, J = 6.0 Hz, 2H, CH₂); 13C NMR (101 MHz, DMSO-d6) δ: 153.52, 141.04, 133.81, 132.90, 132.35, 131.28, 128.56, 127.78, 127.15, 123.48, 46.31.

[0110] (2) Preparation of 3-(2-bromophenyl)-5-phenyl-1,2,4-oxadiazole

[0111] In an electrolytic cell, using 0.15 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxy-2-bromobenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.090 g of a white solid 3-(2-bromophenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 60.0% and a melting point of 77–79 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.19 (d, J = 8.0 Hz, 2H, benzene ring), 8.03 (d, J = 8.0 Hz, 2H, benzene ring), 7.82 (d, J = 8.0 Hz, 2H, benzene ring), 7.75 (t, J = 8.0 Hz, 1H, benzene ring), 7.68 (t, J = 8.0 Hz, 2H, benzene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 176.11, 168.07, 133.93, 132.85, 130.05, 129.53, 128.42, 125.78, 123.71.

[0112] Example 9

[0113] Preparation of 3-(4-tert-butylphenyl)-5-phenyl-1,2,4-oxadiazole

[0114]

[0115] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-4-tert-butylbenzamide

[0116] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 68.0% and a melting point of 143~146℃. 1¹H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H, OH), 7.39 (d, J = 8.4 Hz, 2H, benzene ring), 7.28 (dd, J = 15.8, 8.4 Hz, 4H, benzene ring), 7.17 (dd, J = 21.6, 7.2 Hz, 3H, benzene ring), 6.20 (t, J = 7.2 Hz, 1H, NH), 4.17 (d, J = 7.2 Hz, 2H, CH₂), 1.27 (s, 9H, C₄H₹); 13 C NMR (101 MHz, DMSO-d6) δ: 155.24, 151.92, 141.47, 130.03, 128.68, 128.25, 127.01, 125.42, 46.94, 34.86, 31.49.

[0117] (2) Preparation of 3-(4-tert-butylphenyl)-5-phenyl-1,2,4-oxadiazole

[0118] In an electrolytic cell, using 0.14 g (0.5 mmol) of (Z)-N-benzyl-N'-hydroxy-4-tert-butylbenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) of K3PO4 and 0.34 g (0.1 M) of tetrabutylammonium perchlorate as the electrolytes, and 10 mL of MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.085 g of a colorless oily liquid 3-(4-tert-butylphenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 61.1%. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.16 (d, J = 7.2 Hz, 2H, benzene ring), 8.00 (d, J = 8.0 Hz, 2H, benzene ring), 7.71 (t, J = 6.8 Hz, 1H, benzene ring), 7.63 (t, J = 7.6 Hz, 2H, benzene ring), 7.56 (d, J = 8.4 Hz, 2H, benzene ring), 1.29 (s, 9H, CH₃); 13 C NMR (101 MHz, DMSO-d6) delta: 175.65, 168.60, 154.80, 133.64, 129.90, 128.28, 127.36, 126.37, 123.88, 35.11, 31.26.

[0119] Example 10

[0120] Preparation of 3-(3-methylphenyl)-5-phenyl-1,2,4-oxadiazole

[0121]

[0122] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-3-methylbenzamidin

[0123] Following the method in Example 1, the reaction was carried out for 12 hours, with a yield of 78.0% and a melting point of 107-109°C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H, OH), 7.25 (dd, J = 15.2, 7.6 Hz, 3H, benzene ring), 7.16 - 7.21 (m, 2H, benzene ring), 7.13 (d, J = 10.8 Hz, 4H, benzene ring), 6.25 (t, J = 6.8 Hz, 1H, NH), 4.14 (d, J = 7.2 Hz, 2H, CH₂), 2.27 (s, 3H, CH₃); 13 C NMR (101 MHz, DMSO-d6) δ: 155.41, 141.47, 137.78, 132.82, 130.02, 129.16, 128.57, 127.05, 125.69, 46.96, 21.38.

[0124] (2) Preparation of 3-(3-methylphenyl)-5-phenyl-1,2,4-oxadiazole

[0125] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxy-3-methylbenzamidinium as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.075 g of a white solid 3-(3-methylphenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 64.7% and a melting point of 87–89 °C. 1¹H NMR (400 MHz, DMSO-d⁶) δ: 8.19 (d, J = 8.0 Hz, 2H, benzene ring), 7.90 (d, J = 8.0 Hz, 2H, benzene ring), 7.75 (t, J = 6.0 Hz, 1H, benzene ring), 7.67 (t, J = 8.0 Hz, 2H, benzene ring), 7.41-7.52 (m, 2H, benzene ring), 2.42 (s, 3H, CH₃); 13 C NMR (101 MHz, DMSO-d6) δ: 175.77, 168.78, 139.09, 133.74, 132.70, 129.98, 129.57, 128.34, 127.95, 126.56, 124.72, 123.87, 21.35.

[0126] Example 11

[0127] Preparation of 3-(3,4-dimethylphenyl)-5-phenyl-1,2,4-oxadiazole

[0128]

[0129] (1) Preparation of (Z)-N-benzyl-N'-hydroxy-3,4-dimethylbenzamidin

[0130] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 64.0% and a melting point of 116~118℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.76 (s, 1H, OH), 7.27 (t, J = 7.2 Hz, 2H, benzene ring), 7.19 (d, J = 7.2 Hz, 1H, benzene ring), 7.12 (t, J = 8.8 Hz, 4H, benzene ring), 7.07 (d, J = 7.6 Hz, 1H, benzene ring), 6.20 (t, J = 6.8 Hz, 1H, NH), 4.15 (d, J = 6.8 Hz, 2H, CH₂), 2.20 (s, 3H, CH₃), 2.18 (s, 3H, CH₃); 13 C NMR (101MHz, DMSO-d6) δ: 155.40, 141.54, 137.56, 136.42, 130.35, 129.63, 128.65, 127.02, 125.96, 46.97, 19.71.

[0131] (2) Preparation of 3-(3,4-dimethylphenyl)-5-phenyl-1,2,4-oxadiazole

[0132] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-benzyl-N'-hydroxy-3,4-dimethylbenzamidin as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.095 g of a white solid 3-(3,4-dimethylphenyl)-5-phenyl-1,2,4-oxadiazole, with a yield of 76.0% and a melting point of 112–114 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.18 (d, J = 7.2 Hz, 2H, benzene ring), 7.87 (s, 1H, benzene ring), 7.81 (d, J = 8.0 Hz, 1H, benzene ring), 7.74 (t, J = 7.6 Hz, 1H, benzene ring), 7.67 (t, J = 7.6 Hz, 2H, benzene ring), 7.35 (d, J = 8.0 Hz, 1H, benzene ring), 2.33 (s, 3H, CH₃), 2.31 (s, 3H, CH₃); 13 C NMR (101 MHz, DMSO-d6) δ: 175.67, 168.78, 140.89, 137.81, 133.75, 130.74, 130.02, 128.35, 125.08, 124.12, 123.91, 19.86.

[0133] Example 12

[0134] Preparation of 5-(2-fluorophenyl)-3-phenyl-1,2,4-oxadiazole

[0135]

[0136] (1) Preparation of (Z)-N-(2-fluorobenzyl)-N'-hydroxybenzamide

[0137] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 83.0% and a melting point of 100~103℃. 1¹H NMR (400 MHz, DMSO-d6) δ: 9.99 – 9.90 (m, 1H, OH), 7.41 – 7.28 (m, 6H, benzene ring), 7.28 – 7.21 (m, 1H, benzene ring), 7.15 (t, J = 7.6 Hz, 1H, benzene ring), 7.05 (t, J = 9.4 Hz, 1H, benzene ring), 6.28 (d, J = 6.0 Hz, 1H, NH), 4.21 (d, J = 4.4 Hz, 2H, CH₂); 13 C NMR (101 MHz, DMSO-d6) δ: 1161.23, 158.80, 155.12, 132.66, 129.49, 129.17, 128.66, 128.46, 128.07, 124.76, 115.39, 115.18.

[0138] (2) Preparation of 5-(2-fluorophenyl)-3-phenyl-1,2,4-oxadiazole

[0139] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-(2-fluorobenzyl)-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.090 g of a white solid 5-(2-fluorophenyl)-3-phenyl-1,2,4-oxadiazole, with a yield of 75.0% and a melting point of 100–102 °C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 8.21 (s, 1H, benzene ring), 8.06 - 8.12 (m, 2H, benzene ring), 7.78 (d, J = 3.6 Hz, 1H, benzene ring), 7.45 - 7.64 (m, 5H, benzene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 172.90, 168.46, 161.71, 159.15, 136.11, 132.17, 131.32, 129.74, 127.59, 126.44, 125.92, 117.85, 117.65, 112.27.

[0140] Example 13

[0141] Preparation of 5-(4-fluorophenyl)-3-phenyl-1,2,4-oxadiazole

[0142]

[0143] (1) Preparation of (Z)-N-(4-fluorobenzyl)-N'-hydroxybenzamide

[0144] Following the method in Example 1, the reaction was carried out for 12 hours, with a yield of 80.0% and a melting point of 90-93°C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.86 (d, J = 2.8 Hz, 1H, OH), 7.35 (dd, J = 6.4, 5.6 Hz, 5H, benzene ring), 7.10 (dt, J = 19.2, 8.0 Hz, 4H, benzene ring), 6.34 (t, J = 6.7 Hz, 1H, NH), 4.12 (d, J = 6.9 Hz, 2H, CH₂); 13 CNMR (101 MHz, DMSO-d6) δ: 162.69, 160.28, 155.15, 137.57, 132.90, 129.41, 128.96, 128.58, 115.45, 115.24, 46.21.

[0145] (2) Preparation of 5-(4-fluorophenyl)-3-phenyl-1,2,4-oxadiazole

[0146] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-(4-fluorobenzyl)-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.085 g of a white solid 5-(4-fluorophenyl)-3-phenyl-1,2,4-oxadiazole, with a yield of 70.8% and a melting point of 108–110 °C. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 8.28 – 8.21 (m, 2H, benzene ring), 8.08 (d, J = 6.4 Hz, 2H, benzene ring), 7.60 (d, J = 6.8 Hz, 3H, benzene ring), 7.50 (t, J = 8.0 Hz, 2H, benzene ring); 13C NMR (101MHz, DMSO-d6) δ: 175.05, 168.74, 166.68, 164.17, 132.15, 131.29, 129.73, 127.57, 126.55, 120.57, 117.43, 117.21.

[0147] Example 14

[0148] Preparation of 5-(4-chlorophenyl)-3-phenyl-1,2,4-oxadiazole

[0149]

[0150] (1) Preparation of (Z)-N-(4-chlorobenzyl)-N'-hydroxybenzamide

[0151] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 82.0% and a melting point of 110~112℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.87 (s, 1H, OH), 7.36 (d, J = 6.8 Hz, 3H, benzene ring), 7.31 (d, J = 8.0 Hz, 4H, benzene ring), 7.12 (d, J = 8.4 Hz, 2H, benzene ring), 6.40 (t, J = 6.8 Hz, 1H, NH), 4.14 (d, J = 7.2 Hz, 2H, CH₂);

[0152] (2) Preparation of 5-(4-chlorophenyl)-3-phenyl-1,2,4-oxadiazole

[0153] In an electrolytic cell, using 0.13 g (0.5 mmol) (Z)-N-(4-chlorobenzyl)-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.100 g of a white solid 5-(4-chlorophenyl)-3-phenyl-1,2,4-oxadiazole, with a yield of 78.1% and a melting point of 125–127 °C. 1¹H NMR (400 MHz, DMSO-d⁶) δ: 8.18 (d, J = 8.4 Hz, 2H, benzene ring), 8.08 (d, J = 6.0 Hz, 2H, benzene ring), 7.72 (d, J = 8.8 Hz, 2H, benzene ring), 7.61 (t, J = 5.6 Hz, 3H, benzene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 175.05, 168.79, 138.68, 132.18, 130.20, 129.74, 127.57, 126.48, 122.70.

[0154] Example 15

[0155] Preparation of 5-(2-bromophenyl)-3-phenyl-1,2,4-oxadiazole

[0156]

[0157] (1) Preparation of (Z)-N-(2-bromobenzyl)-N'-hydroxybenzamide

[0158] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 75.0% and a melting point of 110~112℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.84 (d, J = 2.4 Hz, 1H, OH), 7.42 (d, J = 8.4 Hz, 2H, benzene ring), 7.27 - 7.37 (m, 5H, benzene ring), 7.04 (d, J = 8.0 Hz, 2H, benzene ring), 6.38 (t, J = 6.8 Hz, 1H, NH), 4.09 (d, J = 7.2 Hz, 2H, CH₂); 13 C NMR (101 MHz, DMSO-d6) δ: 155.05, 140.98, 132.82, 131.49, 129.35, 128.58, 120.03, 46.27.

[0159] (2) Preparation of 5-(2-bromophenyl)-3-phenyl-1,2,4-oxadiazole

[0160] In an electrolytic cell, using 0.15 g (0.5 mmol) (Z)-N-(2-bromobenzyl)-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.105 g of a white solid 5-(2-bromophenyl)-3-phenyl-1,2,4-oxadiazole, with a yield of 70.0% and a melting point of 60–62 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.08 (t, J = 8.4 Hz, 4H, benzene ring), 7.86 (d, J = 8.4 Hz, 2H, benzene ring), 7.60 (q, J = 6.0 Hz, 3H, benzene ring); 13 C NMR (101 MHz, DMSO-d6) δ: 175.18, 168.80, 133.14, 132.19, 130.27, 129.74, 127.65, 126.48, 123.03.

[0161] Example 16

[0162] Preparation of 5-(4-methylphenyl)-3-phenyl-1,2,4-oxadiazole

[0163]

[0164] (1) Preparation of (Z)-N-(4-methylbenzyl)-N'-hydroxybenzamide

[0165] Following the method of Example 1, the reaction was carried out for 12 h, with a yield of 78.0% and a melting point of 101~103℃. 1 ¹H NMR (400 MHz, DMSO-d6) δ: 9.84 (s, 1H, OH), 7.36 (s, 5H, benzene ring), 7.06 (d, J = 8.0 Hz, 2H, benzene ring), 7.00 (d, J = 8.0 Hz, 2H, benzene ring), 6.21 (t, J = 6.8 Hz, 1H, NH), 4.10 (d, J = 6.8 Hz, 2H, CH₂), 2.24 (s, 3H, CH₃); 13C NMR (101 MHz, DMSO-d6) δ: 155.34, 138.31, 136.08, 132.95, 129.31, 128.58, 127.01, 46.70, 21.10.

[0166] (2) Preparation of 5-(4-methylphenyl)-3-phenyl-1,2,4-oxadiazole

[0167] In an electrolytic cell, using 0.12 g (0.5 mmol) (Z)-N-(4-methylbenzyl)-N'-hydroxybenzamide as the raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g (1.5 mmol) K3PO4 and 0.34 g (0.1 M) tetrabutylammonium perchlorate as the electrolytes, and 10 mL MeOH as the solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The solution was extracted with ethyl acetate (3 × 20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dissolved to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether ratio 1 / 16) to obtain 0.075 g of a white solid 5-(4-methylphenyl)-3-phenyl-1,2,4-oxadiazole, with a yield of 64.7% and a melting point of 113–115 °C. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ: 8.09 (dd, J = 7.6, 3.2 Hz, 4H, benzene ring), 7.61 (d, J = 7.2 Hz, 3H, benzene ring), 7.48 (d, J = 8.0 Hz, 2H, benzene ring), 2.44 (s, 3H, benzene ring); 13 C NMR (101MHz, DMSO-d6) δ: 175.98, 168.67, 144.28, 132.08, 130.59, 129.72, 128.36, 127.56, 126.71, 121.14, 21.73.

[0168] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the specification and drawings should be considered illustrative rather than restrictive.

Claims

1. A method for the electro-oxidative preparation of 3-phenyl-5-aryl-1,2,4-oxadiazole as shown in Formula I, characterized in that... Its preparation reaction is as follows: Wherein, R is selected from: hydrogen, 4-fluoro, 4-chloro, 2-bromo, 4-tert-butyl, 3-methyl or 3,4-dimethyl; Ar is selected from: phenyl, 2-thienyl, 2-fluorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-fluorophenyl or 4-tolyl; The electro-oxidation preparation method involves installing an anode working electrode and a cathode in a non-diaphragm electrolytic cell, using (Z)-N'-hydroxy-N-(arylmethyl)benzamide, an organic solvent, an alkali, and an electrolyte as the electrolyte. Electrolysis is performed at a constant voltage for a certain time at a specific temperature to obtain 3-phenyl-5-aryl-1,2,4-oxadiazole (I). The organic solvent is selected from acetonitrile, methanol, methanol / water (volume ratio 10 / 1), or methanol / hexafluoroisopropanol (volume ratio 5 / 5). The alkali is selected from potassium phosphate, potassium carbonate, sodium acetate, or triethylamine.

2. The method for preparing 3-phenyl-5-aryl-1,2,4-oxadiazole by electrooxidation as described in claim 1, characterized in that, The working anode electrode of the electrolytic cell is selected from: carbon felt electrode, platinum mesh electrode, or graphite electrode; the working current density of the anode electrode is selected from: 11.0 mA / cm². 2 ~25.0mA / cm 2 The cathode of the electrolytic cell is selected from platinum mesh electrode or carbon felt electrode.

3. The method for preparing 3-phenyl-5-aryl-1,2,4-oxadiazole by electrooxidation as described in claim 1, characterized in that, The constant voltage is selected from 0.50 V to 1.50 V; the electrolysis temperature is selected from 15℃ to 55℃; and the electrolysis time is selected from 2h to 8h.

4. The method for preparing 3-phenyl-5-aryl-1,2,4-oxadiazole by electrooxidation as described in claim 1, characterized in that, The electrolyte is selected from: tetrabutylammonium perchlorate, lithium perchlorate, ammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate or potassium hexafluorophosphate; the electrolyte concentration is selected from: 0.02mol / L to 0.1mol / L.

5. The method for preparing 3-phenyl-5-aryl-1,2,4-oxadiazole by electrooxidation as described in claim 1, characterized in that, The concentration of (Z)-N'-hydroxy-N-(arylmethyl)benzamide in the electrolyte is selected from 8 g / L to 30 g / L; the electrolyte is prepared by dissolving (Z)-N'-hydroxy-N-(arylmethyl)benzamide 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.

6. The preparation method according to claim 1, wherein the 3-phenyl-5-aryl-1,2,4-oxadiazole shown in Formula I is selected from:

7. A novel method for preparing the nematicide thiophene shown in Formula Ia, characterized in that... Benzaldehyde was oximated, chlorinated, and reacted with thiophene-2-ylmethylamine to prepare the intermediate (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamide. (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamide was then electro-oxidized to prepare the linear thiophene shown in Formula Ia. The preparation reaction is as follows: The specific steps are as follows: (1) 0.53 g benzaldehyde, 0.38 g hydroxylamine hydrochloride, and 0.59 g pyridine were dissolved in 20 mL ethanol and stirred at room temperature for 2 h. After acid washing, crude benzaldehyde oxime was obtained and directly used in the next step of the reaction after solvent removal. Benzaldehyde oxime was dissolved in 10 mL EtOH and 1.0 g N-chlorosuccinimide was added in five portions. The mixture was stirred for 4 h under nitrogen protection to obtain crude N-hydroxybenzoyl chloride. Crude N-hydroxybenzoyl chloride was added to a tetrahydrofuran solution of 0.56 g thiophene-2-ylmethylamine and 0.76 g triethylamine at 0 °C. The mixture was stirred for 2 h under nitrogen protection and then stirred at room temperature for 4 h. The mixture was diluted with H2O, extracted three times with 20 mL ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and solvent removed. The mixture was then subjected to V... 乙酸乙酯 / 石油醚 0.967 g of white solid (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamidin was obtained by 1 / 2 solvent column chromatography, with a yield of 83.3% and a melting point of 130-132 °C. (2) In an electrolytic cell, using 0.12 g (Z)-N'-hydroxy-N-(thiophene-2-ylmethyl)benzamidin as raw material, platinum as the anode, carbon felt as the cathode, 0.32 g K3PO4 and 0.34 g tetrabutylammonium perchlorate as electrolytes, and 10 mL MeOH as solvent, electrolysis was performed at a constant voltage of 3 V for 2 h at room temperature. The product was extracted three times with 20 mL ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and desolventized to obtain the crude product. The crude product was then subjected to V 乙酸乙酯 / 石油醚 0.092 g of the white solid linear thiophene shown in Formula Ia was obtained by 1 / 16 solvent column chromatography, with a yield of 80.7% and a melting point of 108-109 °C.

8. A novel method for preparing atalulene as shown in structural formula II, characterized in that... The intermediate (Z)-N-(2-fluorobenzaldehyde) was prepared by oximation, chlorination, and reaction with 2-fluorobenzylamine. (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzylamine was then electro-oxidized to give the compound shown in formula Ib. The latter was further oxidized to give atalulone shown in formula II. The preparation reactions are as follows: The specific steps are as follows: (1) 0.60 g 3-methylbenzaldehyde, 0.38 g hydroxylamine hydrochloride, and 0.59 g pyridine were dissolved in 20 mL ethanol and stirred at room temperature for 2 h. After acid washing, crude benzaldehyde oxime was obtained and directly used in the next step of the reaction after solvent removal. Benzaldehyde oxime was dissolved in 10 mL EtOH and 1.0 g N-chlorosuccinimide was added in five portions. The mixture was stirred under nitrogen for 4 h to obtain crude N-hydroxybenzoyl chloride. Crude N-hydroxybenzoyl chloride was added dropwise to a tetrahydrofuran solution of 0.62 g 2-fluorobenzylamine and 0.76 g triethylamine at 0 °C and stirred under nitrogen protection for 2 h. The mixture was stirred at room temperature for 4 h, diluted with H2O, extracted three times with 20 mL ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and solvent removed to obtain the crude product. The crude product was subjected to V 乙酸乙酯 / 石油醚 0.942 g of white solid (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamide was obtained by 1 / 2 solvent column chromatography, with a yield of 73.0% and a melting point of 102-103 °C. (2) In an electrolytic cell, using 0.13 g (Z)-N-(2-fluorobenzyl)-N'-hydroxy-3-methylbenzamidinium as raw material, a platinum mesh as the anode and a platinum sheet as the cathode, 0.32 g K3PO4 and 0.34 g tetrabutylammonium perchlorate as electrolytes, and 10 mL MeOH as solvent, electrolysis was performed at a constant voltage of 3 V at room temperature for 2 h. The product was extracted three times with 20 mL ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and desolventized to obtain the crude product. The crude product was then subjected to V 乙酸乙酯 / 石油醚 0.096 g of the white solid 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole, as shown in Formula Ib, was obtained by 1 / 16 solvent column chromatography with a yield of 75.6% and a melting point of 99-102 °C. (3) Dissolve 0.33 g of 5-(2-fluorophenyl)-3-(3-tolyl)-1,2,4-oxadiazole, 0.23 g of cobalt acetate and 0.13 g of sodium bromide in 40 mL of glacial acetic acid; purge air at 95°C and react for 11 h, cool to -20°C, and filter to obtain 0.313 g of atalulene as shown in Formula II, with a yield of 85.0% and a melting point of 241~242°C.

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