Green Preparation Method of Key Intermediate of Telmisartan

Abstract

The present invention relates to an electrochemical preparation method of an anti - hypertensive drug telmisartan intermediate - 4 - methyl - 2 - propylbenzimidazole - 6 - carboxylate and bis - imidazole: 4 - butyramido - 3 - methylbenzoate is prepared into the telmisartan intermediate - 4 - methyl - 2 - propylbenzimidazole - 6 - carboxylate by an electro - oxidation method; 3 - methyl - 4 - nitrobenzonitrile is prepared into the telmisartan intermediate - bis - imidazole by an electrochemical method. In the electrochemical reaction, there is no need for toxic or dangerous oxidants or reductants, and "electrons" are clean reaction reagents, which is an important part of the development of "green pharmaceutical industry". During the electrochemical process, by changing the constant current density, the conversion rate and selectivity can be controlled; thus, telmisartan intermediates with high purity and high yield can be obtained.

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound, specifically a new method for preparing a key intermediate of telmisartan; in particular, an electrochemical preparation method for its key intermediates 4-methyl-2-propylbenzimidazole-6-carboxylate and bisimidazole. Background Art

[0002] In 2002, Brain et al. [An intramolecular palladium-catalysed aryl amination reaction to produce benzimidazoles. Tetrahedron Letters, 2002, 43(10):1893-1895] synthesized benzimidazole by N-arylation of o-bromophenyl amidine using palladium catalysis. Using tetrakis(triphenylphosphine)palladium as the catalyst, potassium carbonate and sodium tert-butoxide as the bases, the reaction was refluxed in toluene to obtain benzimidazole. In 2003, Brain et al. [An improved procedure for the synthesis of benzimidazoles, using palladium-catalyzed aryl-amination chemistry. The Journal of Organic Chemistry, 2003, 68(17):6814-6816] described that sodium hydroxide was used as the base, and aryl amination to synthesize benzimidazole was achieved under microwave conditions in a mixed system of water and dimethyl ether.

[0003]

[0004] Brasche et al. [C—H Functionalization / C-N Bond Formation: Copper-Catalyzed Synthesis of Benzimidazoles from Amidines. Angewandte Chemie International Edition, 2008, 47(10):1932-1934] described the preparation of benzimidazole compounds by copper-catalyzed amidines. Using copper acetate as the catalyst, acetic acid as the additive, DMSO as the solvent, and oxygen as the re-oxidant, the reaction was carried out at 100 °C to obtain benzimidazole compounds (the highest yield was 89%).

[0005]

[0006] Xiao et al. [Direct Imidation to Construct 1H-Benzo[d]imidazole through Pd II -Catalyzed C-H Activation Promoted by Thiourea. Chemistry-A European Journal, 2009, 15(30): 7292-7296] described the selection of tetramethylthiourea to improve the efficiency of benzimidazole synthesis from amidoxime. The N-arylbenzamidine formed by the reaction of aniline and benzonitrile was first synthesized into a palladium ring dimer under the catalysis of [PbCl 2 (PhCN) 2 . Tetramethylthiourea, copper acetate and oxygen were used as additives, and benzimidazole compounds were synthesized in N-methylpyrrolidone at 100 °C.

[0007]

[0008] Huang et al. [Synthesis of benzimidazoles by PIDA-promoted direct C(sp 2 )—H imidation of N-arylamidines. Chemistry–A European Journal, 2012, 18(44): 13964-13967] described the synthesis of benzimidazole derivatives from N-arylamidines. Using phenyliodine diacetate as an oxidant and cesium carbonate as an additive, 2-aryl / 2-alkylbenzimidazoles and 2-alkyl-fused benzimidazole compounds were synthesized in trifluoroethanol with high yields.

[0009]

[0010] Nguyen et al. [N-Chlorosuccinimide / sodium hydroxide-mediated synthesis of benzimidazoles from amidines under mild conditions. Heterocycles, 2012, 86(1): 555-563] described a one-pot method for the preparation of benzimidazole derivatives from N-arylamidines. Treatment of N-arylamidines with N-chlorosuccinimide produced N-aryl-N'-chloroamidines, which cyclized under the action of sodium hydroxide to obtain benzimidazole compounds with high yields.

[0011]

[0012] At around 14:48 on March 21, 2019, the nitrification waste stored illegally for a long time in the old solid waste warehouse of Jiangsu Tianjiayi Chemical Co., Ltd. in Chenjiagang Chemical Industrial Park, Xiangshui County, Yancheng City, Jiangsu Province, continuously accumulated heat and increased in temperature, leading to spontaneous combustion, and the combustion triggered an explosion of the nitrification waste. The nitrification reaction of the telmisartan intermediate is dangerous. Workers in fine chemical and pharmaceutical chemistry are researching new processes for non-nitrified telmisartan.

[0013] Grenda et al. [Novel preparation of benzimidazoles from N-arylamidines. New Synthesis of Thiabendazole 1. The Journal of Organic Chemistry, 1965, 30(1): 259-261] selected sodium hypochlorite and sodium hydroxide to prepare benzimidazole compounds from N-aryl amidines.

[0014]

[0015] Luo Zhonghua et al. [Benzimidazole compounds and their preparation methods. CN201610373961.6, December 5, 2017] described the synthesis of the telmisartan intermediate - bisimidazole. 2-Methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline was dehydrated with butyramide to synthesize N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butyramidine, and the latter was oxidized and cyclized with sodium hypochlorite to obtain bisimidazole.

[0016]

[0017] Zhao Jianhong et al. [Org. Process Res. Dev. 2021, 25, 1022-1027; Synthesis method of telmisartan intermediate CN202110271180.7, June 25, 2021; Pharmaceutical intermediate compound and its preparation method and application, ZL202110266484.4, September 16, 2022] selected o-toluidine as the raw material and synthesized the telmisartan bisimidazole intermediate through amidation, formylation, cyclization, hydrolysis, amidination and oxidation, etc. Among them, AlCl 3 was used as a catalyst to synthesize N-(2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)phenyl)butyramidine (yield 95%), and the butyramidine was oxidized with calcium hypochlorite to obtain bisimidazole (yield 82%).

[0018]

[0019] Li Jing et al. [New synthetic route for key intermediate of telmisartan. Chinese Journal of Pharmaceuticals, 2020, 51(4): 487-489; Preparation method of an intermediate of telmisartan, ZL201811514781.0, Feb. 7, 2020] studied the synthesis of the key intermediate of telmisartan, 2-propyl-4-methyl-6-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazole: First, butyronitrile reacted with hydrochloric acid ethanol solution to obtain the hydrochloride of butyl iminoester, which was basified to obtain free butyl iminoester, and then reacted with 4-amino-3-methylbenzoic acid to obtain 4-butyramidinyl-3-methylbenzoic acid. The latter reacted with sodium hypochlorite and sodium hydroxide to obtain 2-propyl-4-methyl-1H-benzo[d]imidazole-6-carboxylic acid, which was dehydrated and condensed with N-methyl-o-phenylenediamine hydrochloride to form 2-propyl-4-methyl-6-(1-methyl-1H-benzo[d]imidazol-2-yl)-1H-benzo[d]imidazole, with an overall yield of 79%.

[0020]

[0021] Shandong Fuchang Pharmaceutical Co., Ltd., Shanghai Institute of Materia Medica, and Shanghai Tehua Pharmaceutical Technology Co., Ltd. [Compound based on benzimidazole-substituted nitrobenzene and its preparation method, CN201910807646.3, Mar. 5, 2021; Compound based on benzimidazole-substituted halogenophenyl butyramidine and its preparation method, CN201911023802.3, Apr. 27, 2021; Compound based on benzimidazole-substituted phenyl butyramide and its preparation method, 202010863046.1, published Mar. 5, 2021] selected 3-methyl-4-nitrobenzonitrile to obtain 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline; the latter was condensed with butyryl chloride, then reacted with triphosgene and methanol solution of ammonia, and finally chemically oxidized to obtain the double-imidazole intermediate of telmisartan:

[0022]

[0023] Xu Haichao et al. [Amidinyl radical formation through anodic N-H bond cleavage and its application in aromatic C-H bond functionalization. Angewandte Chemie International Edition, 2017, 56(2): 587-590] used tetrabutylammonium hexafluoroborate as the electrolyte, glassy carbon as the anode, and platinum sheet as the cathode. In methanol, under argon protection, it was refluxed, and the amidine compound was electrolyzed in a single-cell electrolytic cell in a constant-current manner to prepare nitrogen-containing heterocyclic compounds.

[0024] Summary of the Invention

[0025] One object of the present invention is to provide 4-butamidinyl-3-methylbenzoate shown by chemical structural formula Ⅳ:

[0026]

[0027] R is selected from: methyl, ethyl, benzyl, C3-C5 straight-chain alkyl or C3-C5 branched-chain alkyl.

[0028] Another object of the present invention is to provide a preparation method of 4-butamidinyl-3-methylbenzoate shown by formula Ⅳ, and the preparation reaction is as follows:

[0029]

[0030] R is selected from: methyl, ethyl, benzyl, C3-C5 straight-chain alkyl or C3-C5 branched-chain alkyl;

[0031] The molar ratio of the feed compounds Ⅲ: butyronitrile: aluminum trichloride = 1: 2-4: 1.5-3;

[0032] The preferred molar ratio of the feed is: the molar ratio of compound Ⅲ: butyronitrile: aluminum trichloride is selected from: 1: 4: 3; 1: 3.5: 3; 1: 3: 3 or 1: 4: 2.5;

[0033] A third object of the present invention is to provide an electrochemical preparation method of 4-methyl-2-propylbenzimidazole-6-carboxylate shown by chemical structural formula Ⅰ, and its preparation reaction is characterized as follows:

[0034]

[0035] R is selected from: hydrogen, methyl, ethyl, benzyl, C3-C5 straight-chain alkyl or C3-C5 branched-chain alkyl.

[0036] A third object of the present invention also provides an electrochemical preparation method of methyl 4-methyl-2-propylbenzimidazole-6-carboxylate shown by chemical structural formula Ⅰ-1, and its preparation reaction is characterized as follows:

[0037]

[0038] A third object of the present invention also provides an electrochemical preparation method of methyl 4-methyl-2-propylbenzimidazole-6-carboxylate shown by chemical structural formula Ⅰ-2, and its preparation reaction is characterized as follows:

[0039]

[0040] The fourth object of the present invention is to provide an electrochemical preparation method of bisimidazole shown by chemical structural formula A, which is characterized in that the preparation reaction is as follows:

[0041]

[0042] The electroreduction preparation method of the present invention is as follows:

[0043] In a divided electrolytic cell, an acidic solution of compound II or compound E and an organic solvent are used to form a cathode electrolyte; an acidic aqueous solution is used as an anode electrolyte; a cathode electrolytic product containing compound III or compound F is obtained through an electroreduction reaction.

[0044] Relative to the reference electrode, the voltage of the cathode working electrode is 1.00V to 2.50V; the current density of the cathode working electrode is between 25.0 mA / cm 2 and 250.0 mA / cm 2 ; the electrolysis temperature is between 15°C and 90°C.

[0045] After the electrolysis is complete, a cathode electrolytic product containing compound III or compound F is obtained.

[0046] Preferably, the reference electrode of the divided electrolytic cell is: a saturated potassium chloride calomel electrode.

[0047] The cathode of the divided electrolytic cell is: a brass electrode, a copper electrode, a titanium mesh electrode, nickel, lead, platinum or a graphite electrode.

[0048] The anode of the divided electrolytic cell is: a DSA electrode, a platinum mesh electrode or a titanium-based platinum electrode; wherein the DSA electrode is a metal oxide electrode with a titanium substrate, and the metal oxide is an oxide of titanium, manganese, cobalt, ruthenium or iridium.

[0049] The diaphragm of the divided electrolytic cell is: an HF-101 strong acid type cation exchange membrane.

[0050] The organic solvent in the cathode electrolyte is any one or more of tetrahydrofuran, ethyl acetate, C1-C5 straight-chain alcohols, C2-C5 branched-chain alcohols or acetonitrile.

[0051] Preferably, the concentration of compound II or compound E in the cathode electrolyte is between 3.0 g / L and 15.0 g / L.

[0052] The acidic aqueous solution serves as the electrolyte for the electroreduction reaction, and within this concentration range, the cathode electrolyte has appropriate conductivity.

[0053] Preferably, the acidic solution in the cathode electrolyte is selected from: a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution; the acidic solution is conducive to the supply and migration of protons.

[0054] Preferably, the anolyte is selected from: phosphoric acid solution or sulfuric acid solution. Acidic solutions are conducive to the supply and migration of protons.

[0055] Preferably, the liquid levels of the catholyte and the anolyte are at the same level.

[0056] The electrooxidation preparation method of the present invention is as follows:

[0057] The electrooxidation preparation method is carried out in a non-diaphragm electrolytic cell equipped with an anode working electrode and a cathode, using compound Ⅳ, compound C or compound G, an organic solvent, water, a base, and an electrolyte as the electrolyte solution; hydroxylamine as an additive, and electrooxidation to obtain compound Ⅰ, compound D or compound A.

[0058] The anode working electrode of the electrolytic cell is selected from: carbon felt electrode, platinum mesh electrode or graphite electrode; preferably: carbon felt electrode; the current density of the anode working electrode is selected from: 5 mA / cm 2 ~200 mA / cm 2 ; the cathode of the electrolytic cell is selected from: platinum mesh or nickel foam; preferably: platinum mesh.

[0059] The constant current is selected from: 10 mA to 400 mA; the electrolysis temperature is selected from: 15 °C to 65 °C; the electrolysis time is selected from: 1.5 h to 10.0 h;

[0060] The organic solvent in the electrolyte solution is selected from any one or more of: methanol, ethanol, propanol, butanol, acetonitrile, ethyl acetate, tetrahydrofuran or dioxane;

[0061] The base is selected from: sodium hydroxide, potassium hydroxide or the base self-generated during the electrolysis process; the concentration of the base is selected from: 0.01 mol / L to 0.1 mol / L.

[0062] The electrolyte is selected from one or two of: sodium chloride, potassium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride, triethylbenzylammonium chloride, trimethylbenzylammonium chloride or trioctylmethylammonium chloride; the electrolyte concentration is selected from: 0.02 mol / L to 0.1 mol / L;

[0063] The concentration of compound Ⅳ, compound C or compound G in the electrolyte solution is selected from: 8 g / L to 40 g / L.

[0064] The new method for preparing the telmisartan intermediate of the present invention is summarized as follows:

[0065]

[0066] The beneficial technical effects of the present invention are:

[0067] (1) In the electrochemical reaction, there is no need for toxic or dangerous oxidants or reductants. "Electrons" are clean reaction reagents and are an important part of the development of the "green pharmaceutical industry".

[0068] (2) In the electrochemical process, by changing the constant current density, the conversion rate and selectivity can be controlled, and high-purity and high-yield intermediates can be obtained.

[0069] (3) In industrial production, it simplifies the process flow, reduces production costs, is safe and environmentally friendly, and is suitable for large-scale promotion and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] APPENDIX Figure 1 Schematic structural diagram of a divided electrolytic cell DETAILED DESCRIPTION OF THE INVENTION

[0071] The following examples are intended to illustrate the present invention rather than further limit the present invention.

[0072] Example 1

[0073] Electroreduction preparation of methyl 3-methyl-4-aminobenzoate (Ⅲ-1)

[0074]

[0075] A divided electrolytic cell ( Figure 1 ), using a proton exchange membrane. A magnetic stir bar, 0.39 g of methyl 3-methyl-4-nitrobenzoate and 30 mL of methanol were added to the cathode (brass) electrolytic cell, stirred and dissolved, then 26 mL of deionized water and 4 mL of hydrochloric acid were added; in the anode (platinum mesh electrode) electrolytic cell, 60 mL of deionized water and 1.25 mL of sulfuric acid were added; a saturated calomel electrode was used as the reference electrode at the cathode, the current was controlled at 0.8 A, and stirred at 25 °C for 3.5 h; in the cathode electrolyte, potassium hydroxide solution was added to adjust to weak alkalinity, and then extracted with dichloromethane and rotary evaporated to obtain 0.32 g of methyl 3-methyl-4-aminobenzoate Ⅲ-1, mp. 115-116 °C, yield 97.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.55-7.52 (m, 2H, C 6 H 3 2,6-H), 6.60 (d, J = 8.4 Hz, 1H, C 6 H 3 5-H), 5.73 (s, 2H, NH 2 ), 3.73 (s, 3H, OCH 3 ), 2.07 (s, 3H, CH 3 ).

[0076] Example 2

[0077] Preparation of Methyl 4-(butanimidoyl)-3-methylbenzoate (IV-1)

[0078]

[0079] 1.65 g (10 mmol) of methyl 3-methyl-4-aminobenzoate and 4 mL of butyronitrile were added with 1.73 g (13 mmol) of AlCl 3 , the temperature was raised, and the mixture was stirred at 120 °C for 11 h. Ice water was added while it was still hot, and the mixture was stirred; the temperature was lowered, and saturated NaOH solution was slowly added dropwise to precipitate a solid. The pH was detected to be 14, and the solid was filtered by suction. The solid was washed several times with water; the solid was dissolved in dichloromethane, the flocculent insoluble matter was filtered off, the solvent was removed, and the obtained solid was washed with petroleum ether and filtered to obtain 1.46 g of pure white solid of methyl 4-(butanimidoyl)-3-methylbenzoate IV-1, with a yield of 62.4%, mp. 107 - 110 °C. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.74 (s, 1H, NH), 7.76 - 7.64 (m, 2H, C 6 H 3 ), 6.69 (d, J = 8.0 Hz, 1H, C 6 H 3 ), 3.85 (s, 1H, NH), 3.79 (s, 3H, CH 3 ), 2.12 (bs, 2H, CH 2 ), 2.06 (s, 3H, CH 3 ), 1.63 (bs, 2H, CH 2 ), 0.93 (bs, 3H, CH 3 ).

[0080] Example 3

[0081] Chemical Oxidation Preparation of Methyl 4-methyl-2-propylbenzimidazole-6-carboxylate (I-1)

[0082]

[0083] 0.23 g (1 mmol) of methyl 4-(butanimidoyl)-3-methylbenzoate and 5 mL of acetonitrile were slowly added dropwise with 2 g (2 mmol of NaClO) of 7.5% sodium hypochlorite solution at 20 °C. TLC was used for detection. The reaction was carried out for 40 min, and then 0.6 g (4 mmol of NaOH) of 30% sodium hydroxide solution was added dropwise and stirred for another 50 min. Sodium sulfite was used to quench sodium hypochlorite, and the mixture was extracted with dichloromethane (10 mL × 3), and column chromatography (V PE ∶V EA= 1:1) gave 0.13 g of methyl 4-methyl-2-propylbenzimidazole-6-carboxylate (I-1, yellow oil), with a yield of 56%. 1 HNMR (400 MHz, CDCl 3 ) δ: 10.34 (s, 1H, NH), 8.15 (s, 1H, C 6 H 2 ), 7.79 (s, 1H, C 6 H 2 ), 3.92 (s, 3H, CH 3 ), 2.96 (t, J = 7.2 Hz, 2H, CH 2 ), 2.57 (s, 3H, CH 3 ), 1.89 (t×q, J = 7.2 Hz, 2H, CH 2 ), 0.94 (t, J = 7.2 Hz, 3H, CH 3 ).

[0084] Example 4

[0085] Electrooxidative Preparation of Methyl 4-methyl-2-propylbenzimidazole-6-carboxylate (I-1)

[0086]

[0087] An electrolysis experiment was carried out using a single cell, with a platinum sheet (2×2 cm 2 ) as both the anode and cathode. 1.17 g (5.0 mmol) of methyl 4-butamidin-3-methylbenzoate was dissolved in 50 mL of acetonitrile, 150 mL of 4% sodium chloride solution was used as the electrolyte, 0.20 g of hydroxylamine was added, and the mixture was stirred at a constant current of 0.15 A at 20 °C for 6.0 h. TLC monitoring showed that the raw materials had basically reacted completely. It was extracted with ethyl acetate (100 mL×3), and column chromatography (V PE ∶V EA = 1:1) gave 1.10 g of methyl 4-methyl-2-propylbenzimidazole-6-carboxylate (yellow oil, I-1), with a yield of 95.0%. 1 H NMR (400 MHz, CDCl 3 ) δ: 10.34 (s, 1H, NH), 8.15 (s, 1H, C 6 H 2 ), 7.79 (s, 1H, C 6 H 2 ), 3.92 (s, 3H, CH 3 ), 2.96 (t, J = 7.2 Hz, 2H, CH 2 ), 2.57 (s, 3H, CH 3), 1.89 (dd, J = 14.4 Hz, J = 7.2 Hz, 2H, CH 2 ), 0.94 (t, J = 7.2 Hz, 3H, CH 3 ).

[0088] Example 5

[0089] Electrooxidative Preparation of Ethyl 4-Methyl-2-propylbenzimidazole-6-carboxylate (Ⅰ-2)

[0090]

[0091] (1) Prepare Ⅲ-2 according to the operation method of Example 1;

[0092] (2) Prepare Ⅳ-2 according to the operation method of Example 2;

[0093] (3) Prepare Ⅰ-2 according to the operation method of Example 4.

[0094] Preparation of Compound C in Example 6

[0095]

[0096] Prepared according to Example 5 in [CN201910807646.3]: 3-Methyl-4-nitrobenzonitrile (1.6 g, 10 mmol), anhydrous aluminum trichloride (2.7 g, 20 mmol), aniline (930 mg, 10 mmol) and toluene (20 mL) were refluxed for 10 h under nitrogen protection. After the reaction was cooled to room temperature, ice water was added to the reaction solution and stirred well. After separating and discarding the organic phase, the pH of the aqueous phase was adjusted to 11 - 12 with sodium hydroxide aqueous solution (about 10%). The precipitated solid was filtered, collected and dried thoroughly to obtain 1.8 g of light yellow solid compound C, with a yield of 71%. 1 H NMR (400 MHz, CDCl 3 ) δ: 2.66 (s, 3H, CH 3 ), 4.91 (brs, 2H, NH 2 ), 6.98 (d, J = 8 Hz, 1H, Ar-H), 7.09 - 7.12 (m, 1H, Ar-H), 7.36 - 7.40 (m, 2H, Ar-H), 7.78 (d, J = 8 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 8.01 (d, J = 8 Hz, 1H, Ar-H).

[0097] Example 7

[0098] Preparation of 2-(3-Methyl-4-nitrophenyl)-1H-benzo[d]imidazole (D)

[0099]

[0100] Prepared according to Example 5 in the method of [CN201910807646.3]: Compound C (1.28 g, 5 mmol) was added to acetonitrile (10 mL). Under an ice bath at 0 - 5 °C, N-chlorosuccinimide (800 mg, 6 mmol) was added, and the reaction was carried out for 1 h. An aqueous sodium hydroxide solution (1.0 g, dissolved in 5 mL of water) was added under an ice bath at 0 - 5 °C, and the mixture was stirred for 0.5 h under an ice bath at 0 - 5 °C. A solid precipitated out. Ethyl acetate (20 mL) was added for extraction, and the organic phase was concentrated to dryness to obtain 1.00 g of 2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole D, with a yield of 81%; 1 H NMR (400 MHz, DMSO-d 6 ) δ: 2.63 (s, 3H), 7.28 (m, 2H), 7.65 (m, 2H), 8.16 - 8.22 (m, 2H), 8.29 (s, 1H).

[0101] Example 8

[0102] Electro-oxidative preparation of 2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole (D)

[0103]

[0104] Prepared according to the operation method of Example 4: A single cell was used for the electrolysis experiment, and a platinum sheet (2×2 cm 2 ) was used as the anode and cathode. 1.27 g (5.0 mmol) of Compound C was dissolved in 60 mL of acetonitrile, 180 mL of 4% sodium chloride solution was used as the electrolyte, 0.20 g of hydroxylamine was added, and the mixture was stirred at a constant current of 0.10 A for 7.0 h at 25 °C. TLC monitoring showed that the raw materials had basically reacted completely. Ethyl acetate extraction was carried out 100 mL × 3, and column chromatography (V PE ∶V EA = 1∶1) gave 1.21 g of 2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole, with a yield of 95.6%. 1 HNMR (400 MHz, DMSO-d 6 ) δ: 2.64 (s, 3H, CH 3 ), 7.25 - 7.29 (m, 2H, C 6 H 4 ), 7.64 - 7.67 (m, 2H, C 6 H 4 ), 8.17 - 8.23 (m, 2H, C 6 H 3 2,6-H), 8.30 (d, J = 2.0 Hz, 1H, C 6 H3 2-H).

[0105] Example 9

[0106] Preparation of 1-methyl-2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole (E)

[0107]

[0108] Prepared according to Example 1 in the method of [CN201910807646.3]: Compound D (506 mg, 2 mmol), dimethyl sulfate (277 mg, 2.2 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added to acetone (10 mL) at room temperature and stirred evenly; refluxed for 2 h, the reaction was concentrated, most of the solvent was recovered, then water (20 mL) was added, the precipitated solid was collected and dried thoroughly to obtain 507 mg of 1-methyl-2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole (pale yellow solid, E), with a yield of 95%.

[0109] Example 10

[0110] Preparation of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (F)

[0111]

[0112] Prepared according to Example 6 in the method of [CN201910807646.3]: Compound E (300 mg) was added to tetrahydrofuran (20 mL) and stirred until dissolved and clarified, then Raney Ni (30 mg) and ammonia water (35%, 6 mL) were added, and the reaction was stirred at room temperature in an atmospheric hydrogen atmosphere for 4 h. After the reaction was completed, it was filtered, the filter residue was washed with a small amount of dichloromethane / ethanol (total 30 mL, 1 / 1) mixed solvent, the organic phase was washed once with saturated brine, most of the solvent was recovered by concentration, ethanol (10 mL) and hydrochloric acid (6N, 10 mL) were added and stirred well to form a salt, after concentrating to remove water, it was slurried in ethanol to obtain 269 mg of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (yellow solid, F), with a yield of 90%; 1 H NMR (400 MHz, DMSO-d 6 ) δ: 2.18 (s, 3H), 4.05 (s, 3H), 6.16 (brs, 2H), 6.87 (d, J = 8 Hz, 1H), 7.56~7.65 (m, 4H), 7.79 (d, J = 8 Hz, 1H), 7.96 (d, J = 4 Hz, 1H).

[0113] Example 11

[0114] Electroreductive Preparation of 2-Methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (F)

[0115]

[0116] Prepared according to the operation method of Example 1: Divided electrolytic cell ( Figure 1 ), using a proton exchange membrane. Add a magnetic stir bar, 0.267 g of compound E and 30 mL of methanol to the cathode (brass) electrolytic cell, stir to dissolve, then add 26 mL of deionized water and 4 mL of hydrochloric acid; in the anode (platinum mesh electrode) electrolytic cell, add 60 mL of deionized water and 1.25 mL of sulfuric acid; use a saturated calomel electrode as the reference electrode at the cathode, control the current at 0.8 A, stir at 25 °C for 5.0 h; in the cathode electrolyte, adjust to weak alkalinity with potassium hydroxide solution, then extract with dichloromethane and rotary evaporate to obtain 0.225 g of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline (F), with a yield of 95.0%.

[0117] Example 12

[0118] Preparation of N-(2-Methyl-4-(1-methyl-1H-benzoimidazol-2-yl)phenyl)butyramidine (G)

[0119]

[0120] Prepared according to the method of [Organic Process Research & Development, 2021, 25(4): 1022 - 1027, experimental part of the annex material]: 2-Methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline, 3 equivalents of aluminum chloride and butyronitrile at 135 - 140 °C, react for 3 h to obtain N-(2-Methyl-4-(1-methyl-1H-benzoimidazol-2-yl)phenyl)butyramidine, with a yield of 95%.

[0121] Example 13

[0122] Electrooxidative Preparation of Bisimidazole (A)

[0123]

[0124] Prepared according to the operation method of Example 4: Use a single cell for electrolysis experiment, platinum sheet (2×2 cm 2 ) as the anode and cathode electrodes. Dissolve 1.53 g (5.0 mmol) of compound G in 80 mL of acetonitrile, use 160 mL of 4% sodium chloride solution as the electrolyte, 0.20 g of hydroxylamine, stir at a constant current of 0.12 A at 25 °C for 8.0 h, monitor by TLC until the raw materials are basically completely reacted, extract with ethyl acetate 100 mL × 3, column chromatography (VPE ∶V EA = 1∶1) to obtain 1.42 g of bisimidazole (A) with a yield of 93.3%.

[0125] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it is obvious that various modifications and variations can still be made without departing from the spirit and scope of the present invention. Therefore, the specification should be regarded as illustrative rather than restrictive.

Claims

1. Electrochemical preparation method of the bisimidazole shown in formula A characterized in that its preparation reaction is as follows: The specific operation is as follows: (1) 1.6 g of 3-methyl-4-nitrobenzonitrile, 2.7 g of anhydrous aluminum trichloride, 930 mg of aniline and 20 mL of toluene are refluxed for 10 h under nitrogen protection; after the reaction is cooled to room temperature, ice water is added to the reaction solution and stirred well. After separating and discarding the organic phase, 10% sodium hydroxide aqueous solution is added to the aqueous phase to adjust the pH to 11-12. The precipitated solid is filtered, collected and dried thoroughly to obtain 1.8 g of a light yellow solid compound C, with a yield of 71%; (2) Use a single slot for the electrolysis experiment and select 2×2 cm 2 platinum sheets as the cathode and anode; 1.27 g of compound C was dissolved in 60 mL of acetonitrile, 180 mL of 4% sodium chloride solution was used as the electrolyte, 0.20 g of hydroxylamine, and stirred at a constant current of 0.10 A at 25 °C for 7.0 h. The reaction of the raw materials was monitored by TLC to be complete, and extracted with ethyl acetate three times with 100 mL each. Select V PE ∶V EA = 1∶1 petroleum ether / ethyl acetate column chromatography to obtain 1.21 g of 2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole shown in formula D, with a yield of 95.6%; (3) 506 mg of compound D, 277 mg of dimethyl sulfate and 414 mg of potassium carbonate are added to 10 mL of acetone at room temperature and stirred evenly; reflux for 2 h, concentrate the reaction, recover most of the solvent, then add 20 mL of water, collect the precipitated solid and dry it thoroughly to obtain 507 mg of a light yellow solid of 1-methyl-2-(3-methyl-4-nitrophenyl)-1H-benzo[d]imidazole shown in formula E, with a yield of 95%; (4) Select a divided electrolytic cell and use a proton exchange membrane; add a magnetic stirrer, 0.267 g of compound E and 30 mL of methanol to the electrolytic cell equipped with a brass cathode, stir to dissolve, then add 26 mL of deionized water and 4 mL of hydrochloric acid; in the electrolytic cell equipped with a platinum mesh anode, add 60 mL of deionized water and 1.25 mL of sulfuric acid; use a saturated calomel electrode as the reference electrode at the cathode, control the current at 0.8 A, stir at 25 °C for 5.0 h; in the cathode electrolyte, add potassium hydroxide solution to adjust to weakly alkaline, then extract with dichloromethane and rotary evaporate to obtain 0.225 g of 2-methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline shown in formula F, with a yield of 95.0%; (5) 2-Methyl-4-(1-methyl-1H-benzo[d]imidazol-2-yl)aniline shown in formula F, 3 equivalents of aluminum chloride and butyronitrile are reacted at 135-140 °C for 3 h to obtain N-(2-methyl-4-(1-methyl-1H-benzoimidazol-2-yl)phenyl)butyramidine shown in formula G, with a yield of 95%; (6) Use a single cell for the electrolysis experiment and select 2×2 cm 2 platinum sheets as the cathode and anode; 1.53 g of compound G was dissolved in 80 mL of acetonitrile. 160 mL of 4% sodium chloride solution was used as the electrolyte, along with 0.20 g of hydroxylamine. Stirring was carried out at a constant current of 0.12 A at 25 °C for 8.0 h. The reaction of the raw materials was monitored by TLC and found to be complete. Extraction was performed with ethyl acetate (100 mL × 3). Selecting V PE ∶V EA = 1∶1, column chromatography with petroleum ether / ethyl acetate gave 1.42 g of the bisimidazole shown in formula A, with a yield of 93.3%.

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