A kind of polysubstituted aminobenzonitrile compound and preparation method thereof

Abstract

The present invention relates to a multi-substituted aminobenzonitrile compound and a preparation method thereof. The compound has the structural formula: wherein Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl. The method is specifically as follows: a polysubstituted aromatic amine compound, a first solvent, an oxidant and a desiccant are stirred, mixed and reacted; after monitoring by thin layer chromatography until the raw material completely disappears, the first solvent is dried and the solid is transferred to a pressure tube; under a protective gas atmosphere, a second solvent, a catalyst and a cyanation agent are added to the pressure tube, stirred, mixed and reacted; after the reaction is completed, the reaction is cooled to room temperature, and the crude product is purified to obtain a compound. Compared with the prior art, the present invention uses cheap and easily polysubstituted aromatic amine compounds as raw materials and tert-butyl isonitrile as a cyanation agent, thereby realizing a simple and efficient synthesis of polysubstituted aminobenzonitrile compounds with regional selectivity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a multi-substituted aminobenzonitrile compound and a preparation method thereof. Background Art

[0002] Polysubstituted aromatic amine compounds are a class of relatively important synthetic fragments or synthetic precursor compounds. Given that the cyano group has strong electron-withdrawing properties and its small spatial volume, it can penetrate into the target protein and interact with amino acid residues through hydrogen bonds, π-π bonds, etc. Polysubstituted aminobenzonitrile compounds have higher synthesis and application value and can significantly enhance the biological activity of the compound. Since the cyano group can be efficiently converted into amide, methylamine, aldehyde carbonyl, imine, and various nitrogen-containing heterocyclic fragments through simple synthetic means, polysubstituted aminobenzonitrile compounds have great application value in organic synthesis, biomedicine, and materials. For example: 5-amino-2-methylbenzonitrile is a key precursor in the synthesis of a class of high-efficiency triacene conjugated dyes used in sensitized solar cells (see reference: Chow, TJ et al. J. Mater. Chem., 2011, 21, 9523-9531); 5-amino-2-methoxybenzonitrile is a synthetic precursor of a class of xanthine oxidase inhibitors with micromolar efficiency (see reference: Meng, F.-H. et al. Chem. Biol. Drug Des., 2018, 91, 526-533); 4-amino-[1,1'-biphenyl]-2-carbonitrile can be used for the synthesis of fluorenone compounds, which are important precursors in the fields of medicine and materials (see reference: Hsieh J.-C. et al. Org. Lett., 2013, 15, 2742-2745). However, in the existing literature, there are not many reports on the synthesis of polysubstituted aminobenzonitrile compounds, and there are even fewer reports on the synthesis of polysubstituted aminobenzonitrile compounds using cheap and readily available polysubstituted aromatic amine compounds as raw materials.

[0003] The synthesis of traditional polysubstituted aminobenzonitrile compounds generally requires pre-nitration reaction of polysubstituted halogenated aromatic hydrocarbons, cyanation reaction, nitro reduction to amine and other processes (see reference: Khalafi-Nezhad, A. et al. Inorg. Chim. Acta, 2019, 494, 256-265). Most of the relevant synthesis documents inevitably use relatively toxic metal cyanides, such as zinc cyanide (see reference: Kung, PP et al. Bioorg. Med. Chem. Lett., 2008, 18, 6273-6278). At the same time, since the traditional method inevitably uses a large amount of nitric acid in the synthesis, there are many reaction steps, difficult post-reaction treatment, high cost, poor tolerance of functional groups, and residual metal cyanides that cause serious environmental pollution.

[0004] Patent CN110526832A discloses a method for preparing a polysubstituted alicyclic compound, wherein an aromatic high-valent iodine compound is activated by an activating agent, and then rearranged with an α-tin or silicon-substituted nitrile compound at -100 to -70°C to obtain an electrophilic dearomatization intermediate, which reacts with a nucleophilic reagent to obtain the polysubstituted alicyclic compound. However, although the patent introduces a cyano group, a highly toxic organic tin compound is used as a cyanation reagent, and ultra-low temperature conditions are used, so the safety and environmental friendliness of the reaction are poor, and the reaction conditions require high standards. Summary of the invention

[0005] The purpose of the present invention is to provide a polysubstituted aminobenzonitrile compound and a preparation method thereof in order to overcome at least one defect of the above-mentioned prior art. The present invention uses cheap and readily available polysubstituted aromatic amine compounds as raw materials and low-toxic tert-butyl isonitrile as a cyanation reagent to achieve a simple and efficient synthesis of polysubstituted aminobenzonitrile compounds with regional selectivity.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] One of the technical solutions of the present invention is to provide a multi-substituted aminobenzonitrile compound, the structural formula of which is:

[0008]

[0009] Among them, Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl.

[0010] One of the technical solutions of the present invention is to provide a method for preparing a polysubstituted aminobenzonitrile compound, the method comprising the following steps:

[0011] (1) stirring and mixing a polysubstituted aromatic amine compound, a first solvent, an oxidant, and a desiccant to react;

[0012] (2) after monitoring by thin layer chromatography (TLC) until the starting material completely disappears, the first solvent is dried and the solid is transferred to a thick-walled pressure-resistant tube;

[0013] (3) adding the second solvent, the catalyst and the cyanation reagent into the thick-walled pressure-resistant tube under a protective gas atmosphere, stirring and mixing and reacting;

[0014] (4) After the reaction is completed, the mixture is cooled to room temperature, and the crude product is directly purified without post-treatment to obtain the corresponding polysubstituted aminobenzonitrile compounds.

[0015] Using the easily available tert-butyl isocyanide as the cyanation reagent and a high-valent iodine reagent as the oxidant, cheap polysubstituted aromatic amine compounds are subjected to dearomatization-aromatization reaction. Under the premise of retaining the overall benzene ring structure and the substituents on the benzene ring, the corresponding polysubstituted aminobenzonitrile compounds are synthesized regioselectively.

[0016] Furthermore, the structural formula of the polysubstituted aromatic amine compound in step (1) is:

[0017]

[0018] Among them, Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl;

[0019] The first solvent is methanol or ethanol, the oxidant is a high-valent iodine reagent, the high-valent iodine reagent is iodosobenzene, diethyl iodobenzene or iodobenzene trifluoroacetate, and the desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate;

[0020] In step (3), the protective gas is nitrogen or argon, the second solvent is acetonitrile, benzonitrile, chlorobenzene or dimethyl sulfoxide, the catalyst is silver trifluoromethanesulfonate, silver tetrafluoroborate or silver trifluoroacetate, and the cyanation reagent is tert-butyl isonitrile.

[0021] Furthermore, in step (1), the molar ratio of the polysubstituted aromatic amine compound, the oxidant and the desiccant is (0.3-0.4):(0.36-0.40):(1.5-2.0), and the amount ratio of the polysubstituted aromatic amine compound and the first solvent is (0.3-0.4mmol):(2.0-3.0mL).

[0022] Furthermore, in step (1), the stirring speed is 400-500 rpm, the reaction temperature is 20-25° C., and the reaction time is 15-30 min.

[0023] As a preferred technical solution, in step (2), the first solvent is removed in vacuo at a certain temperature.

[0024] As a preferred technical solution, the temperature is 30-35°C, and the vacuum degree is 100-200 kPa.

[0025] Furthermore, in step (3), the molar ratio of the polysubstituted aromatic amine compound, the catalyst and the cyanation reagent is (0.3-0.4):(0.03-0.06):(1.5-1.6), and the amount ratio of the polysubstituted aromatic amine compound and the second solvent is (0.3-0.4mmol):(0.75-1.0mL).

[0026] Furthermore, in step (3), the stirring speed is 400-500 rpm, the reaction temperature is 85-120° C., and the reaction time is 18-24 h.

[0027] As a preferred technical solution, in step (3), the thick-walled pressure-resistant pipe is placed in an oil bath for heating.

[0028] Furthermore, in step (4), purification is performed by silica gel column chromatography or recrystallization.

[0029] Furthermore, the silica gel column chromatography developing solvent is a mixed solvent of petroleum ether and ethyl acetate, or n-hexane and ethyl acetate, in a volume ratio of (5-15):1.

[0030] Furthermore, the recrystallization step is specifically as follows: taking n-hexane and ethyl acetate, or a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (50-60):1, heating to 60-70°C, and after the crude product is completely dissolved, standing and cooling to crystallize.

[0031] Compared with the prior art, the present invention has the following advantages:

[0032] (1) The present invention uses cheap and readily available polysubstituted aromatic amine compounds as raw materials and low-toxic, easy-to-operate liquid tert-butyl isocyanide as a cyanation reagent to achieve efficient synthesis of polysubstituted aminobenzonitrile compounds with regional selectivity;

[0033] (2) The method of the present invention is simple to operate, and column chromatography or recrystallization purification can be performed without post-treatment after the experiment;

[0034] (3) The polysubstituted aminobenzonitrile compounds synthesized by the method of the present invention have good development potential and application prospects in the fields of organic synthesis, biomedicine and materials. DETAILED DESCRIPTION

[0035] The present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and a specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0036] Unless otherwise specified, the equipment used in the following examples are all conventional equipment in the art; the reagents used are all commercially available products or prepared by conventional methods in the art unless otherwise specified. Anything not described in detail in the following examples can be achieved by conventional experimental means in the art.

[0037] A polysubstituted aminobenzonitrile compound, the compound structure is:

[0038]

[0039] Among them, Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl.

[0040] A method for preparing a polysubstituted aminobenzonitrile compound comprises the following steps:

[0041] (1) a polysubstituted aromatic amine compound, a high-valent iodine reagent and anhydrous sodium sulfate (Na2SO4) in a molar ratio of 0.3 mmol:0.36 mmol:5.0 mmol and 2 mL of methanol (MeOH) solvent are added into a 10 mL reaction bottle, wherein the high-valent iodine reagent is iodophenyl (PhIO) or diethyl iodophenyl (PIDA), and then stirred at 25°C and 500 rpm for 15-30 min;

[0042] (2) After monitoring by thin layer chromatography (TLC) until the starting material completely disappears, spin dry the methanol and transfer the solid to a 15 mL thick-walled pressure tube, and remove the methanol at 200 kPa vacuum at 30°C;

[0043] (3) 0.75 mL of acetonitrile (MeCN) was added to a thick-walled pressure tube, and silver trifluoromethanesulfonate (AgOTf) and tert-butyl isocyanate ( t BuNC) were added into thick-walled pressure-resistant tubes at a molar ratio of 0.03 mmol:1.5 mmol under nitrogen (N2) protection, and the thick-walled pressure-resistant tubes were placed in an oil bath at 85-120°C and stirred at 500 rpm for 18 h;

[0044] (4) After the reaction is completed, the product is cooled to room temperature and directly purified by silica gel column chromatography or recrystallization without post-treatment.

[0045] The reaction mechanism used in this embodiment is:

[0046]

[0047] Among them, Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl.

[0048] Embodiment 1:

[0049] A method for preparing N-(3-cyano-4-methylphenyl)-4-methylbenzenesulfonamide compound, the specific steps are as follows:

[0050] (1) 4-methyl-N-p-tolylbenzenesulfonamide (78.4 mg, 0.3 mmol), methanol solvent (2 mL), iodophenyl (79.2 mg, 0.36 mmol) and anhydrous sodium sulfate (213.1 mg, 1.5 mmol) were added to a 10 mL reaction bottle in sequence and stirred at 25 °C and 500 rpm for 15 min;

[0051] (2) Monitor by TLC until the reaction starting material disappears, spin dry the methanol solvent and transfer the solid to a 15 mL thick-walled pressure tube, and remove the methanol at 200 kPa vacuum at 30 °C;

[0052] (3) Under nitrogen protection, acetonitrile (0.75 mL), silver trifluoromethanesulfonate (7.7 mg, 0.03 mmol) and tert-butyl isocyanate (124.7 mg, 1.5 mmol) were added in sequence into a thick-walled pressure tube, and the mixture was stirred in an oil bath at 120° C. and 500 rpm for 18 h.

[0053] (4) After the reaction was completed, the mixture was cooled to room temperature and the crude product was directly purified by silica gel column chromatography without post-treatment. The developing solvent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a colorless solid (68.7 mg, yield 80%), namely N-(3-cyano-4-methylphenyl)-4-methylbenzenesulfonamide compound, with the structural formula:

[0054]

[0055] The melting point is 145-146℃.

[0056] The basic parameters of the compound are as follows:

[0057] IR(KBr,cm-1 ):3229,2232,1595,1653,1495,1470,1519,1360,1295,1211,1118,1079,1020,912,755,697,591,489;

[0058] 1 H NMR (400MHz, CDCl3): δ7.67 (dd, J=8.2, 4.5Hz, 2H), 7.45 (brs, 1H), 7.31-7.26 ( m,2H),7.23(t,J=1.9Hz,2H),7.18(d,J=8.4Hz,1H),2.45(s,3H),2.39(s,3H);

[0059] 13 C NMR (101MHz, CDCl3): δ144.62,138.93,135.54,135.06,131.44,130.05,127.31,126.04,124.72,117.46,113.57,21.69,19.95;

[0060] HRMS(ESI)m / z:calcd for C 15 H 15 N2O2S[M+H] + 286.0776, found 286.0773.

[0061] Embodiment 2:

[0062] A method for preparing an N-(3-cyano-4-methoxyphenyl)-4-methylbenzenesulfonamide compound is substantially the same as that in Example 1, except that the raw material is N-(4-methoxyphenyl)-4-methylbenzenesulfonamide (83.2 mg, 0.3 mmol), and a white solid (72.0 mg, yield 79%) is obtained, namely, N-(3-cyano-4-methoxyphenyl)-4-methylbenzenesulfonamide compound, having the structural formula:

[0063]

[0064] The melting point is 116-118℃.

[0065] The basic parameters of the compound are as follows:

[0066] 1H NMR (400MHz, CDCl3): δ7.81-7.40(m,2H),7.33(dd,J=9.0,2.7Hz,1H),7.26-7.21(m,2H ),7.19(d,J=2.7Hz,1H),7.12(s,1H),6.85(d,J=9.1Hz,1H),3.87(s,3H),2.38(s,3H);

[0067] 13 C NMR (101MHz, CDCl3): δ159.45,144.51,135.46,130.10,130.00,129.55,128.28,127.34,115.74,112.27,102.18,56.42,21.70.

[0068] Embodiment 3:

[0069] A method for preparing an N-(3-cyano-4,5-dimethylphenyl)-4-methylbenzenesulfonamide compound is substantially the same as that in Example 1, except that the raw material is N-(3,4-dimethylphenyl)-4-methylbenzenesulfonamide (82.6 mg, 0.3 mmol), and a colorless solid (64.0 mg, yield 72%) is obtained, namely, N-(3-cyano-4,5-dimethylphenyl)-4-methylbenzenesulfonamide compound, having the structural formula:

[0070]

[0071] The melting point is 155-156℃.

[0072] The basic parameters of the compound are as follows:

[0073] IR(KBr,cm -1 ):3214,2230,1610,1489,1393,1325,1162,1145,1091,1033,917,879,812,730,660,562,544;

[0074] 1 H NMR (400MHz, CDCl3): δ7.69(d,J=8.3Hz,2H),7.56(brs,1H),7.25(d,J=8.3Hz,2H),7.15(dd,J=16.4,2.1Hz,2H),2.38(s,3H),2.35(s,3H),2.21(s,3H);

[0075] 13C NMR (101MHz, CDCl3): δ144.50,139.60,137.38,135.67,134.92,130.01,127.31,127.16,122.04,118.12,113.62,21.67,20.30,17.47;

[0076] HRMS(ESI)m / z:calcd for C 16 H 17 O2N2S[M+H] + 301.1006, found 301.1005.

[0077] Embodiment 4:

[0078] A method for preparing an N-(3-cyano-4,5-dimethoxyphenyl)-4-methylbenzenesulfonamide compound is substantially the same as that in Example 1, except that the raw material is N-(3,4-dimethoxyphenyl)-4-methylbenzenesulfonamide (92.2 mg, 0.3 mmol), and a white solid (73.0 mg, yield 73%) is obtained, namely, an N-(3-cyano-4,5-dimethoxyphenyl)-4-methylbenzenesulfonamide compound, having the structural formula:

[0079]

[0080] The melting point is 130-131℃.

[0081] The basic parameters of the compound are as follows:

[0082] IR(KBr,cm -1 ):3243,2917,2233,1592,1490,1462,1428,1394,1325,1279,1162,1087,1012,929,571;

[0083] 1 H NMR (400MHz, CDCl3): δ7.66(d,J=8.2Hz,2H),7.41(s,1H),7.26(d,J=8.4Hz,2 H),6.99(d,J=2.5Hz,1H),6.71(s,1H),3.93(s,3H),3.80(s,3H),2.39(s,3H);

[0084] 13C NMR (101MHz, CDCl3): δ153.24,149.48,144.73,135.39,133.14,130.08,127.34,116.40,115.71,111.59,107.03,61.90,56.30,21.71;

[0085] HRMS(ESI)m / z:calcd for C 16 H 17 N2O4S[M+H] + 350.1169, found 350.1167.

[0086] Embodiment 5:

[0087] A method for preparing an N-(5-cyano-2,4-dimethylphenyl)-4-methylbenzenesulfonamide compound is substantially the same as that in Example 1, except that the raw material is N-(2,4-dimethylphenyl)-4-methylbenzenesulfonamide (82.6 mg, 0.3 mmol), and a colorless solid (48.0 mg, 55% yield) is obtained, namely, an N-(5-cyano-2,4-dimethylphenyl)-4-methylbenzenesulfonamide compound having the structural formula:

[0088]

[0089] The melting point is 200-201℃.

[0090] The basic parameters of the compound are as follows:

[0091] IR(KBr,cm -1 ):3288,2223,1504,1456,1402,1337,1295,1199,1166,1089,901,888,813,603,548,530;

[0092] 1 H NMR (400MHz, CDCl3): δ7.63 (d, J = 8.3Hz, 2H), 7.47 (s, 1H), 7.27 (s, 1H), 7.2 5(s,1H),7.05(s,1H),6.59(s,1H),2.44(s,3H),2.41(s,3H),2.07(s,3H);

[0093] 13C NMR (101MHz, CDCl3): δ144.51,139.75,137.50,136.28,133.03,132.90,130.00,127.95,127.24,117.62,111.17,21.69,19.95,18.13;

[0094] HRMS(ESI)m / z:calcd for C 16 H 17 N2O2S[M+H] + 301.1005, found 301.1005.

[0095] Embodiment 6:

[0096] A method for preparing a N-(4-cyano-5-methyl-[1,1'-biphenyl]-2-yl)-4-methylbenzenesulfonamide compound is basically the same as Example 1, except that the raw material is 4-methyl-N-(5-methyl-1,1'-biphenyl)-2-ylbenzenesulfonamide (101.3 mg, 0.3 mmol), and a colorless solid (89.4 mg, yield 82%) is obtained, namely, N-(4-cyano-5-methyl-[1,1'-biphenyl]-2-yl)-4-methylbenzenesulfonamide compound, the structural formula of which is:

[0097]

[0098] The melting point is 142-144℃.

[0099] The basic parameters of the compound are as follows:

[0100] IR(KBr,cm -1 ):3292,2227,1597,1474,1384,1332,1260,1184,1165,1091,1032,955,871,824,765,667,546;

[0101] 1 H NMR (400MHz, CDCl3): δ7.89(d,J=8.5Hz,1H),7.45-7.35(m,5H),7.31(d,J=8.5Hz,1H) ,7.23(d,J=8.0Hz,2H),6.74(d,J=7.9Hz,2H),6.31(s,1H),2.52(s,3H),2.44(s,3H);

[0102] 13C NMR (101MHz, CDCl3): δ144.53,139.19,137.26,135.71,133.33,132.89,130.44, 129.89,129.68,129.59,129.04,127.27,125.79,116.49,114.28,21.72,20.54;

[0103] HRMS(ESI)m / z:calcd for C 21 H 19 N2O2S[M+H] + 363.1162, found 363.1158.

[0104] Embodiment 7:

[0105] A method for preparing a N-(5-cyano-6-methyl-1,1'-biphenyl)-3-yl)-4-methylbenzenesulfonamide compound is basically the same as Example 1, except that the raw material is 4-methyl-N-(6-methyl-1,1'-biphenyl)-3-ylbenzenesulfonamide (101.3 mg, 0.3 mmol), and a yellow liquid (92.4 mg, yield 90%) is obtained, namely, N-(5-cyano-6-methyl-1,1'-biphenyl)-3-yl)-4-methylbenzenesulfonamide compound, the structural formula of which is:

[0106]

[0107] The basic parameters of the compound are as follows:

[0108] IR(KBr,cm -1 ):3243,3061,2230,1699,1598,1464,1437,1368,1326,1185,1161,1090,975,704,665,558;

[0109] 1 H NMR (400MHz, CDCl3): δ7.72(d,J=8.4Hz,2H),7.50(s,1H)7.45-7.32(m,4H),7.28(d,J=8.0Hz,2H),7.18-7.11(m,3H),2.41(s,3H),2.34(s,3H);

[0110] 13C NMR (101MHz, CDCl3): δ144.65,144.55,139.25,136.37,135.60,134.99,130.08,129.15, 128.91,128.59,128.24,128.10,127.40,126.99,123.47,117.90,114.56,21.71,18.48;

[0111] HRMS(ESI)m / z:calcd for C 21 H 19 N2O2S[M+H] + 363.1162, found 363.1158.

[0112] Embodiment 8:

[0113] A method for preparing N-(3-cyano-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide compound is basically the same as Example 1, except that the raw materials are 4-methyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (116.2 mg, 0.3 mmol), iodophenyl diethyl ester (116.0 mg, 0.3 6mmol), step (1) reacting for 30min, step (3) 85°C oil bath, step (4) directly adding the crude product to a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 50:1 without post-treatment, heating to 65°C, standing and cooling to crystallize, to obtain a white solid (80.0mg, yield 60%), i.e., N-(3-cyano-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)-4-methylbenzenesulfonamide compound, the structural formula is:

[0114]

[0115] The melting point is 218-220℃.

[0116] The basic parameters of the compound are as follows:

[0117] IR(KBr,cm -1 ):3227,3063,2980,2929,2229,1592,1451,1347,1224,1157,1091,1032,987,902,848,813,676,551;

[0118] 1H NMR (400MHz, C2D6SO): δ10.42(s,1H),7.60(d,J=8.3Hz,2H),7.55(d,J=2.6Hz,1H),7 .44(d,J=2.5Hz,1H),7.32(d,J=8.0Hz,2H),2.49(s,3H),2.30(s,3H),1.24(s,12H);

[0119] 13 C NMR (101MHz, C2D6SO): δ144.22,143.38,136.63,136.13,131.91,130.39,127.31,125.67,118.26,113.74,84.69,25.10,21.49,19.72;

[0120] HRMS(ESI)m / z:calcd for C 21 H 26 BN2O4S[M+H] + 413.1701, found 413.1699.

[0121] In this embodiment, a simple and easily available polysubstituted aromatic amine compound is used as a raw material, and a low-toxic and easy-to-operate tert-butyl isonitrile is used as a cyanation reagent to synthesize the corresponding polysubstituted aminobenzonitrile compound. The method has the advantages of simple reaction operation, no need for post-reaction treatment, and cheap and readily available raw materials, and has great development potential and application prospects in the fields of organic synthesis, biomedicine and materials.

[0122] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a polysubstituted aminobenzonitrile compound, characterized in that: The structural formula of the polysubstituted aminobenzonitrile compound is: Among them, Ts is p-toluenesulfonyl, R 1 is methyl or methoxy, R 2 is hydrogen, methyl, phenyl, methoxy or bipinacol borate, R 3 is hydrogen, methyl or phenyl; The method comprises the following steps: (1) stirring and mixing a polysubstituted aromatic amine compound, a first solvent, an oxidant, and a desiccant to react; (2) After monitoring by thin layer chromatography until the raw material completely disappears, the first solvent is dried and the solid is transferred to a pressure tube; (3) under a protective gas atmosphere, adding a second solvent, a catalyst and a cyanation reagent into a pressure-resistant tube, stirring and mixing and reacting; (4) cooling to room temperature after the reaction is completed, and purifying the crude product to obtain a polysubstituted aminobenzonitrile compound; The structural formula of the polysubstituted aromatic amine compound in step (1) is: Wherein, the substituents are the same as those of the polysubstituted aminobenzonitrile compounds; The oxidant is a high-valent iodine reagent, and the high-valent iodine reagent is iodosobenzene, diethyl iodobenzene or iodobenzene trifluoroacetate; In step (3), the catalyst is silver trifluoromethanesulfonate, silver tetrafluoroborate or silver trifluoroacetate, and the cyanation reagent is tert-butyl isocyanide.

2. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (1), the first solvent is methanol or ethanol, and the desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate; In step (3), the protective gas is nitrogen or argon, and the second solvent is acetonitrile, benzonitrile, chlorobenzene or dimethyl sulfoxide.

3. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (1), the molar ratio of the polysubstituted aromatic amine compound, the oxidant and the desiccant is (0.3-0.4):(0.36-0.40):(1.5-2.0), and the amount ratio of the polysubstituted aromatic amine compound and the first solvent is (0.3-0.4mmol):(2.0-3.0mL).

4. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (1), the stirring speed is 400-500 rpm, the reaction temperature is 20-25° C., and the reaction time is 15-30 min.

5. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (3), the molar ratio of the polysubstituted aromatic amine compound, the catalyst and the cyanation reagent is (0.3-0.4):(0.03-0.06):(1.5-1.6), and the amount ratio of the polysubstituted aromatic amine compound and the second solvent is (0.3-0.4mmol):(0.75-1.0mL).

6. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (3), the stirring speed is 400-500 rpm, the reaction temperature is 85-120° C., and the reaction time is 18-24 h.

7. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 1, characterized in that: In step (4), purification is performed by silica gel column chromatography or recrystallization.

8. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 7, characterized in that: The silica gel column chromatography developing agent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (5-15):1, or normal hexane and ethyl acetate.

9. The method for preparing a polysubstituted aminobenzonitrile compound according to claim 7, characterized in that: The recrystallization step is specifically as follows: taking n-hexane and ethyl acetate, or a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (50-60):1, heating to 60-70°C, and after the crude product is completely dissolved, standing and cooling to crystallize.

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