A method for synthesizing benzazepine compounds

Abstract

The present invention discloses a method for synthesizing benzazepine compounds; in a nitrogen atmosphere, a sulfonium salt in-situ generated from methyl trifluoromethanesulfonate and dimethyl sulfide is used as an activator, and undergoes a cyclization reaction with N,N-dibenzyl-3-phenylpropylamide compounds at 80 °C to generate benzazepine compounds; wherein methyl trifluoromethanesulfonate and dimethyl sulfide are activator precursors; the amide compounds include aryl amides, alkyl amides, heterocyclic amides, and amides with asymmetric functional groups connected to N; this method is a new method for synthesizing benzazepine compounds, without the participation of catalysts and additives, and the raw materials required are simple and easily available, the reaction conditions are mild, the operation is simple, the reaction yield is high, the substrate functional group compatibility is excellent, and it has high application value.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of organic intermediates, and particularly relates to a method for synthesizing benzazepine compounds. Background Art

[0002] Benzazepine compounds are a class of important heterocyclic organic compounds. Among them, the number of benzazepine heptacyclic compounds in nature is less than that of azole five-membered rings and azole six-membered rings. Most of them exist in the form of alkaloids and have excellent biological activities and medicinal values. Currently, many benzazepine compounds have been used clinically as drugs for treating the central nervous system, such as the antidepressant drug Anafranil, the antipsychotic drug Olanzapine, the antiepileptic drug Lorazepam, etc. Therefore, developing new synthetic methods for benzazepine compounds has important theoretical significance and practical value.

[0003] Currently, the methods for synthesizing benzazepine compounds are as follows:

[0004] Method 1: Starting from phenylpropanamide, reacting with paraformaldehyde through the Pictet-Spengler reaction, and finally obtaining benzazepine compounds through reduction.

[0005]

[0006] The limitation of this method is that it is prepared using paraformaldehyde as a raw material, which is highly harmful to the human body and the environment. Moreover, this substance is at risk of explosion when exposed to open flames, high heat, or contact with oxidants, which is not conducive to industrial production.

[0007] Method 2: Using tetralone and azoic acid through a ring-expansion reaction to obtain an inner amide, and then reducing it to obtain benzazepine compounds.

[0008]

[0009] The disadvantage of this method is that using tetralone and sodium azide as starting materials, tetralone is prone to form an explosive mixture with air, and sodium azide will even explode directly, presenting a relatively large safety hazard.

[0010] Method 3: Using a metal-catalyzed olefin metathesis reaction to prepare benzazepine compounds.

[0011]

[0012] The disadvantage of this method is that it uses a noble metal-catalyzed olefin metathesis reaction. The catalyst is expensive, the substrate scope is limited to a certain extent, and the industrial production cost is too high.

[0013] In summary, although there are various synthesis methods for benzazepine compounds at present, the synthesis strategy still faces problems such as harsh reaction conditions, the need for metal participation, high cost, and low generality. Summary of the Invention

[0014] Aiming at the above existing problems, the purpose of the present invention is to provide a synthesis method of benzazepine compounds with simple operation, good functional group tolerance, high reaction yield, and easy to be popularized in industrial production.

[0015] To achieve the above purpose, the technical scheme adopted by the present invention is as follows: A synthesis method of benzazepine compounds, and the synthesis method is as follows:

[0016]

[0017] Among them, the activator is a sulfonium salt in-situ generated from methyl trifluoromethanesulfonate and dimethyl sulfide;

[0018] Both R1 and R2 are substituents, and the substituents are selected from C1-C3 alkyl or silicon-based, 5-membered heteroaryl containing S heteroatom, C6-C 10 And aryl containing secondary substituents; the secondary substituents are selected from H, methyl, alkoxy, ester group, trifluoromethyl, isopropyl, tert-butyl, trimethylsilyl or halogen.

[0019] In the present invention, R1 is preferably aryl containing secondary substituents of C6-C 10 And the secondary substituents are selected from H, methyl, alkoxy, ester group, trifluoromethyl, trimethylsilyl or halogen.

[0020] In the present invention, R2 is preferably aryl containing secondary substituents of C6-C 10 And the secondary substituents are selected from H, methyl, trifluoromethyl or halogen.

[0021] Further preferably, R1 in the present invention is aryl containing methyl, aryl, aryl containing trifluoromethyl, aryl containing F or trimethylsilyl. Among them, the substituents in the aryl: methyl, trifluoromethyl and F are all para-substituted.

[0022] Further preferably, R2 in the present invention is aryl, aryl containing F or aryl containing trifluoromethyl; among them, the substituents in the aryl: methyl, F are all para-substituted.

[0023] The molar ratio of the activator: dimethyl(methylthio)sulfonium trifluoromethanesulfonate to the amide compound in the present invention is 1:1 to 1.5:1; preferably, the molar ratio of dimethyl(methylthio)sulfonium trifluoromethanesulfonate to the amide compound is 1.2:1. When the molar ratio is 1.2:1, the yield of the final product is high.

[0024] The reaction solvent of the present invention is preferably acetonitrile, and the molar concentration of the raw material amide compound in the reaction solvent is preferably 0.1 mmol / mL. The present invention uses a single organic solvent as the reaction system. If necessary, other organic solvents can be present in the system. However, considering the reaction efficiency and operational simplicity, it is preferably not to add other organic solvents, that is, a single organic solvent is used as the reaction system.

[0025] The reaction temperature of the present invention is 20 - 90 °C, preferably 80 °C; the reaction time is 8 - 18 h, preferably 12 h; the reaction temperature and reaction time of the present invention can be determined by those skilled in the art according to different reactants and can be determined by themselves according to actual needs.

[0026] After the reaction of the synthesis method of the present invention is completed, extraction is not required, and the benzazepine compound after purification is obtained through column chromatography separation.

[0027] The advantages of the present invention are as follows: The present invention uses a simple and easily available amide compound as the reaction substrate, undergoes a cyclization reaction with dimethyl(methylthio)sulfonium trifluoromethanesulfonate (activator), the reaction temperature is 80 °C, and benzazepine compounds are synthesized simply and efficiently under nitrogen conditions. Compared with other methods for synthesizing benzazepine compounds, the method of the present invention uses mild conditions, easily available raw materials, does not require the participation of metal catalysts, has low reaction costs, no safety hazards, and can be extended to industrial production.

[0028] The present invention can be widely applied to drug synthesis in industry and academia, and total synthesis of natural products, and has high application value. Description of the Drawings

[0029] Figure 1 1H NMR spectrum of 2-benzyl-4-methylthio-5-p-tolyl-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 1;

[0030] Figure 2 13C NMR spectrum of 2-benzyl-4-methylthio-5-p-tolyl-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 1;

[0031] Figure 3 1H NMR spectrum of methyl 4-(2-benzyl-4-methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzoate described in Example 7;

[0032] Figure 4 13C NMR spectrum of methyl 4-(2-benzyl-4-methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzoate described in Example 7;

[0033] Figure 5 1H NMR spectrum of 2-benzyl-5-(2-chlorophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 10;

[0034] Figure 6 13C NMR spectrum of 2-benzyl-5-(2-chlorophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 10;

[0035] Figure 7 1H NMR spectrum of 2-isopropyl-4-(methylthio)-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 11;

[0036] Figure 8 13C NMR spectrum of 2-isopropyl-4-(methylthio)-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one described in Example 11;

[0037] Figure 9 1H NMR spectrum of 4-(2-benzyl-4-(methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzonitrile described in Example 12;

[0038] Figure 10 13C NMR spectrum of 4-(2-benzyl-4-(methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzonitrile described in Example 12; Detailed implementation manners

[0039] The present invention will be further described in detail below in conjunction with the detailed implementation manners and the accompanying drawings;

[0040] In the present invention, the "amide compounds" have the meanings commonly understood by those skilled in the art, that is, amine compounds directly connected to acyl groups, and R1 is connected to the amide compounds through a C≡C bond, such as N,N-dibenzyl-3-(p-tolyl)propiolamide, N,N-dibenzyl-3-(m-tolyl)propanamide, N,N-dibenzyl-3-(2-chlorophenyl)propiolamide, N,N-dibenzyl-3-(thiophen-2-yl)propanamide and their various derivatives.

[0041] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means well known in the art when necessary before use.

[0042] 1 H NMR and 1313C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform (CDCl3), and the reference was selected as: 1 1H NMR: CDCl3 was 7.26 ppm; 13 13C NMR: CHCl3 was 77.0 ppm.

[0043] Example 1: Synthesis of 2-Benzyl-4-(methylthio)-5-(p-tolyl)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0044] At room temperature, N,N-dibenzyl-3-(p-tolyl)propynamide (101.8 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 87.5 mg of the product, with a yield of 76%; its 1H NMR spectrum was as follows Figure 1 shown.

[0045] Product 2-Benzyl-4-(methylthio)-5-(p-tolyl)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.37–7.27 (m, 5H), 7.23–7.11 (m, 6H), 7.06–7.04 (m, 1H), 6.87–6.85 (m, 1H), 5.22 (d, J = 14.8 Hz, 1H), 4.54 (d, J = 14.8 Hz, 1H), 4.21 (d, J = 14.8 Hz, 1H), 3.96 (d, J = 14.4 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.3, 141.9, 138.8, 138.4, 137.7, 137.0, 136.9, 135.0, 130.9, 130.0, 129.1, 128.8, 128.2, 127.9, 127.90, 127.7, 126.5, 50.2, 49.3, 21.5, 17.6. Its 13C NMR spectrum was as follows Figure 2 shown.

[0046] Example 2: Synthesis of 2-Benzyl-5-(4-fluorophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0047] At room temperature, in a 25 mL Schlenk reaction tube that had been dried and repeatedly purged with nitrogen three times, N,N-dibenzyl-3-(4-fluorophenyl)propiolamide (103.1 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 78.3 mg of the product with a yield of 67%.

[0048] Product 2-benzyl-5-(4-fluorophenyl)-4-methylthio-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.39–7.29 (m, 5H), 7.23–7.19 (m, 4H), 7.14–7.07 (m, 3H), 6.85–6.83 (m, 1H), 5.22 (d, J = 14.8 Hz, 1H), 4.55 (d, J = 14.4 Hz, 1H), 4.25 (d, J = 14.8 Hz, 1H), 4.00 (d, J = 14.8 Hz, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.1, 163.8, 161.3 (d, J C-F = 249.4 Hz), 140.6, 138.5, 137.0, 136.9 (d, J C-F = 8.8 Hz), 136.5, 136.4 (d, J C-F = 3.4 Hz), 135.8, 132.0, 132.0 (d, J C-F = 8.3 Hz), 130.7, 128.8, 128.2, 128.1, 128.0, 127.7, 126.6, 115.5, 115.3 (d, J C-F = 21.7 Hz), 50.2, 49.4, 17.6. 19 F NMR (376 MHz, CDCl3) δ -112.58.

[0049] Example 3: Synthesis of 2-benzyl-5-(3,5-dimethylphenyl)-4-methylthio-1,2-dihydro-3H-benzo[c]azepin-3-one

[0050] At room temperature, N,N-dibenzyl-3-(3,5-dimethylphenyl)propiolamide (106.0 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 74.3 mg of the product, with a yield of 62%.

[0051] Product 2-benzyl-5-(3,5-dimethylphenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.35–7.28 (m, 5H), 7.20–7.18 (m, 2H), 7.08–7.03 (m, 2H), 6.89–6.87 (m, 3H), 5.24 (d, J = 15.2 Hz, 1H), 4.55 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 14.8 Hz, 1H), 3.97 (d, J = 14.4 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 164.2, 142.2, 140.4, 138.7, 137.9, 137.0, 136.8, 135.1, 130.9, 130.1, 128.8, 128.2, 127.9, 127.9, 127.7, 126.5, 50.2, 49.3, 21.4, 17.6.

[0052] Example 4: Synthesis of 2-benzyl-5-(4-methoxyphenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0053] At room temperature, N,N-dibenzyl-3-(4-methoxyphenyl)propiolamide (106.6 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 63.8 mg of the product, with a yield of 53%.

[0054] Product 2-benzyl-5-(4-methoxyphenyl)-4-methylthio-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.36–7.27 (m, 5H), 7.20–7.15 (m, 4H), 7.07–7.04 (m, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.88–6.85 (m, 1H), 5.21 (d, J = 14.8 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 15.2 Hz, 1H), 3.96 (d, J = 14.4 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4, 159.6, 141.5, 138.9, 137.0, 137.0, 134.8, 132.8, 131.6, 131.0, 128.8, 128.2, 127.9, 127.9, 127.7, 126.5, 113.6, 55.3, 50.2, 49.3, 17.7.

[0055] Example 5: Synthesis of 4-methylthio-5-phenyl-2-(4-trifluoromethyl)benzyl)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0056] At room temperature, N-benzyl-3-phenyl-N-(4-trifluoromethyl)benzylpropynamide (118.0 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 68.6 mg of the product with a yield of 52%.

[0057] Product 4-(methylthio)-5-phenyl-2-((4-(trifluoromethyl)benzyl)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H), 7.43–7.35 (m, 5H), 7.23–7.13 (m, 4H), 7.00–6.98 (m, 1H), 6.85–6.83 (m, 1H), 5.11 (d, J = 15.6 Hz, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.45 (d, J = 15.2 Hz, 1H), 3.94 (d, J = 14.4 Hz, 1H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.4, 142.2, 141.2, 140.45, 138.5, 136.7, 135.1, 131.0, 130.0, 128.5, 128.4, 128.3, 128.1, 128.0 (J C-F = 7.1 Hz) 126.4, 125.7, 125.6 (J C-F = 3.8 Hz) 50.8, 49.4, 17.6. 19 19F NMR (376 MHz, CDCl3) δ -62.49.

[0058] Example 6: Synthesis of 2-benzyl-4-(methylthio)-5-(m-tolyl)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0059] At room temperature, N,N-dibenzyl-3-(m-tolyl)propanamide (101.8 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After completion of the reaction, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 49 mg of the product, with a yield of 50%.

[0060] Product 2-benzyl-4-(methylthio)-5-(m-tolyl)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.37–7.28 (m, 6H), 7.21–7.16 (m, 3H), 7.07–7.05 (m, 3H), 6.87–6.85 (m, 1H), 5.23 (d, J = 14.8 Hz, 1H), 4.56 (d, J = 14.4 Hz, 1H), 4.23 (d, J = 15.2 Hz, 1H), 3.97 (d, J = 14.8 Hz, 1H), 2.36 (s, 6H) 13C NMR (101 MHz, CDCl3) δ 164.2, 142.0, 140.5, 138.7, 138.1, 137.0, 136.8, 135.3, 130.9, 130.6, 129.2, 128.8, 128.2, 127.9, 127.9, 127.7, 127.1, 126.5, 50.2, 49.3, 21.5, 17.6.

[0061] Example 7: Synthesis of Methyl 4-(2-benzyl-4-(methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzoate

[0062] At room temperature, methyl 4-(3-(dibenzylamino)-3-oxopropyl-1-yn-1-yl)benzoate (115.0 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After completion of the reaction, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to give 60.6 mg of the product with a yield of 47%; its 1H NMR spectrum is as Figure 3 shown.

[0063] Product methyl 4-(2-benzyl-4-(methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzoate: 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.36–7.28 (m, 7H), 7.19–7.16 (m, 2H), 7.06–7.04 (m, 1H), 6.78–6.76 (m, 1H), 5.19 (d, J = 15.2 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.24 (d, J = 14.8 Hz, 1H), 3.97 (d, J = 14.4 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.7, 163.9, 145.2, 140.6, 138.1, 137.0, 136.8, 136.2, 130.5, 130.2, 129.9, 129.7, 128.8, 128.2, 128.2, 128.1, 127.8, 126.7, 52.3, 50.2, 49.4, 17.5. Its 13C NMR spectrum is as shown in Figure 4 shown.

[0064] Example 8: Synthesis of 2-(4-fluorobenzyl)-4-(methylthio)-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one

[0065] At room temperature, N-benzyl-N-(4-fluorobenzyl)-3-phenylpropanamide (103.0 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After completion of the reaction, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 53.8 mg of the product, with a yield of 46%.

[0066] Product 2-(4-fluorobenzyl)-4-methylthio-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.42–7.40 (m, 3H), 7.25–7.16 (m, 6H), 7.03–6.98 (m, 3H), 6.84–6.82 (m, 1H), 5.05 (d, J = 15.2 Hz, 1H), 4.56 (d, J = 14.8 Hz, 1H), 4.32 (d, J = 14.8 Hz, 1H), 3.95 (d, J = 14.4 Hz, 1H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.2, 141.9, 140.5, 138.6, 136.9, 135.3, 130.9, 130.0, 129.9, 129.9, 128.42, 128.4, 128.0, 127.9 (J C-F = 2.5 Hz) 126.4, 115.7, 115.5 (J C-F = 21.6 Hz), 50.4, 48.9, 17.6. 19 F NMR (376 MHz, CDCl3) δ -114.67.

[0067] Example 9: Synthesis of 2-benzyl-5-(3-bromophenyl)-4-methylthio-1,2-dihydro-3H-benzo[c]azepin-3-one

[0068] At room temperature, N,N-dibenzyl-3-(3-bromophenyl)propiolamide (121.3 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 60.8 mg of the product, with a yield of 45%.

[0069] Product 2-benzyl-5-(3-bromophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34–7.28 (m, 7H), 7.21–7.18 (m, 3H), 7.06–7.04 (m, 1H), 6.84–6.81 (m, 1H), 5.19 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.23 (d, J = 15.2 Hz, 1H), 3.96 (d, J = 14.8 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.8, 142.4, 140.0, 138.1, 136.9, 136.8, 136.3, 132.8, 131.4, 130.6, 129.9, 128.8, 128.2, 128.2, 128.1, 127.7, 126.7, 122.5, 50.2, 49.4, 17.5.

[0070] Example 10: Synthesis of 2-benzyl-5-(2-chlorophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0071] At room temperature, N,N-dibenzyl-3-(2-chlorophenyl)propynamide (108.0 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 50.0 mg of the product with a yield of 41%. Its 1H NMR spectrum is as Figure 5 shown.

[0072] Product 2-benzyl-5-(2-chlorophenyl)-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.57–7.55 (m, 1H), 7.43–7.31 (m, 8H), 7.19–7.16 (m, 2H), 7.07–7.05 (m, 1H), 6.85–6.83 (m, 1H), 5.23 (d, J = 14.8 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.24 (d, J = 15.2 Hz, 1H), 3.98 (d, J = 14.8 Hz, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.6, 139.5, 138.7, 137.0, 136.9, 136.8, 132.6, 131.6, 130.3, 129.8, 128.8, 128.6, 128.2, 128.0, 128.0, 127.7, 126.7, 50.2, 49.5, 17.3; The carbon NMR spectrum is as shown in Figure 6 shown.

[0073] Example 11: Synthesis of 2-isopropyl-4-(methylthio)-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one

[0074] At room temperature, N-benzyl-N-isopropyl-3-phenylpropanamide (83.2 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 38.8 mg of the product, with a yield of 40%. The 1H NMR spectrum is as shown in Figure 7 shown.

[0075] Product 2-isopropyl-4-methylthio-5-phenyl-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.42–7.37 (m, 3H), 7.32–7.30 (m, 1H), 7.24–7.14 (m, 4H), 6.82–6.80 (m, 1H), 4.95–4.88 (m, 1H), 4.38 (d, J = 14.8 Hz, 1H), 4.24 (d, J = 14.8 Hz, 1H), 2.25 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.4, 141.3, 140.8, 138.9, 138.7, 136.0, 130.8, 130.1, 128.3, 128.3, 127.9, 127.7, 126.7, 45.7, 45.1, 21.2, 21.1, 17.5; Its carbon NMR spectrum is as shown in Figure 8 shown below.

[0076] Example 12: Synthesis of 4-(2-benzyl-4-methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzonitrile

[0077] At room temperature, N,N-dibenzyl-3-(4-cyanophenyl)propiolamide (105.1 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 47.6 mg of the product, with a yield of 40%; Its 1H NMR spectrum is as shown in Figure 9 shown below.

[0078] Product 4-(2-benzyl-4-methylthio)-3-oxo-2,3-dihydro-1H-benzo[c]azepin-5-yl)benzonitrile: 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.35–7.27 (m, 7H), 7.20–7.19 (m, 2H), 7.07–7.05 (m, 1H), 6.75–6.72 (m, 1H), 5.16 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.8 Hz, 1H), 3.99 (d, J = 14.8 Hz, 1H), 2.37 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.6, 145.2, 139.5, 137.7, 137.1, 136.9, 136.7, 132.2, 130.9, 130.3, 128.8, 128.4, 128.3, 128.2, 127.8, 126.9, 118.6, 112.1, 50.2, 49.5, 17.5; The carbon NMR spectrum is as Figure 10 shown.

[0079] Example 13: Synthesis of 2-benzyl-4-methylthio-5-thiophen-2-yl-1,2-dihydro-3H-benzo[c]azepin-3-one

[0080] At room temperature, N,N-dibenzyl-3-(thiophen-2-yl)propylamide (99.4 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a 25 mL Schlenk reaction tube that had been dried and purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 40.8 mg of the product, with a yield of 36%.

[0081] Product 2-benzyl-4-(methylthio)-5-(thiophen-2-yl)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 4.8 Hz, 1H), 7.36–7.30 (m, 3H), 7.27–7.25 (m, 3H), 7.23–7.20 (m, 2H), 7.12–7.03 (m, 3H), 5.19 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.18 (d, J = 15.2 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.0, 141.2, 138.4, 137.2, 136.8, 136.8, 133.9, 131.1, 130.8, 128.8, 128.3, 128.2, 127.9, 127.8, 127.7, 126.7, 126.5, 50.1, 49.3, 17.7。

[0082] Example 14: Synthesis of 4-(methylthio)-5-phenyl-2-((trimethylsilyl)methyl)-1,2-dihydro-3H-benzo[c]azepin-3-oneAt room temperature, N-benzyl-3-phenyl-N-((trimethylsilyl)methyl)prop-2-ynamide (96.5 mg, 0.30 mmol), dimethyl(methylthio)sulfonium trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After the reaction was completed, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to obtain 37.5 mg of the product, with a yield of 34%.

[0083] Product 4-(methylthio)-5-phenyl-2-((trimethylsilyl)methyl)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.43–7.39 (m, 3H), 7.29–7.19 (m, 5H), 6.86 (d, J = 7.8 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H), 3.94 (d, J = 14.4 Hz, 1H), 3.55 (d, J = 15.2 Hz, 1H), 2.61 (d, J = 15.2 Hz, 1H), 2.31 (s, 3H), 0.14 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 162.9, 140.9, 140.7, 138.8, 136.6, 136.0, 130.9, 130.1, 128.3, 128.3, 128.0, 127.8, 126.5, 53.8, 39.0, 17.6, -1.40.。

[0084] Example 15: Synthesis of 2-benzyl-5-ethyl-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one

[0085] At room temperature, N,N-dibenzylpent-2-yne (83.2 mg, 0.30 mmol), dimethyl(methylsulfonium) trifluoromethanesulfonate (93.0 mg, 0.36 mmol), and acetonitrile (3 mL) were successively added to a dry 25 mL Schlenk reaction tube that had been repeatedly purged with nitrogen three times. The reaction was carried out at 80 °C for 12 hours. After completion of the reaction, the crude product was obtained by filtration and rotary evaporation, and further purified by column chromatography to give 32.0 mg of the product with a yield of 33%.

[0086] Product 2-benzyl-5-ethyl-4-(methylthio)-1,2-dihydro-3H-benzo[c]azepin-3-one: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.6 Hz, 1H), 7.36–7.28 (m, 4H), 7.25–7.17 (m, 3H), 7.01 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 14.4 Hz, 1H), 4.12 (d, J = 14.8 Hz, 1H), 3.80 (d, J = 14.0 Hz, 1H), 2.97–2.79 (m, 2H), 2.45 (s, 3H), 1.11–1.08 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 164.3, 144.3, 137.8, 137.1, 133.0, 128.7, 128.2, 127.7, 127.6, 127.4, 126.8, 50.1, 49.1, 28.4, 17.0, 13.1.

[0087]

[0088]

[0089]

[0090] Table 1 Results Table of Examples

[0091] As can be seen from Examples 1-15, the method of the present invention starts from various cheap and readily available amide compounds, uses a sulfonium salt (dimethyl(methylthio)sulfonium trifluoromethanesulfonate) in situ generated from commercially available methyl trifluoromethanesulfonate and dimethyl sulfide as an activator, reacts, and reacts at 80 °C under nitrogen conditions to obtain benzazepine compounds. This method has good tolerance to aryl amide compounds, alkyl amide compounds, and heterocyclic amide compounds, and is a general synthesis method for benzazepine compounds with mild conditions and simple operation.

[0092] Example 16: Optimization of the reaction system

[0093] In this example, both R1 and R2 are aryl groups; under the same experimental conditions, comparative experiments were carried out on the type of solvent, reaction temperature, and dosage ratio, and the results are shown as follows:

[0094]

[0095]

[0096] Table 2 Optimization of the reaction system

[0097] Standard conditions: 1 0.3 mmol (1.0 equivalent); solvent: 3.0 mL; the yield is the isolated yield; DCE = 1,2-dichloroethane, DCM = dichloromethane, MeCN = acetonitrile; eq: equivalent; rt: room temperature.

[0098] It should be noted that the above are only the preferred embodiments of the present invention, and are not used to limit the protection scope of the present invention. Any combination or equivalent transformation made on the basis of the above embodiments belongs to the protection scope of the present invention.

Claims

1. A method for synthesizing benzazepine compounds, characterized in that, The synthesis method is as follows: Amide compound, activator, benzazepine compound Among them, the activator is a sulfonium salt in-situ generated from methyl trifluoromethanesulfonate and dimethyl sulfide; R1 and R2 are both substituents, and the substituents are selected from C1-C3 alkyl groups, 5-membered heteroaryl groups containing S heteroatoms, aryl groups having a secondary substituent and containing C6-C 10 aryl groups; The secondary substituent is selected from H, methyl, trifluoromethyl, isopropyl, tert-butyl, trimethylsilyl or halogen.

2. The synthesis method of the benzazepine compound according to claim 1, characterized in that, The said R1 is selected from aryl groups having C6-C 10 and having a secondary substituent; the secondary substituent is selected from H, methyl, trifluoromethyl, trimethylsilyl or halogen.

3. The synthesis method of the benzazepine compound according to claim 1, characterized in that, The aforementioned R2 is selected from aryl groups having 6 to 10 and containing a secondary substituent; the secondary substituent is selected from H, methyl, trifluoromethyl or halogen.

4. The synthesis method of the benzazepine compound according to claim 1, characterized in that, The said R1 is selected from aryl containing methyl, aryl, aryl containing trifluoromethyl, aryl containing F or trimethylsilyl; the said R2 is selected from aryl, aryl containing F or aryl containing trifluoromethyl.

5. The method for synthesizing benzazepine compounds according to claim 1, characterized in that, The molar ratio of dimethyl(methylthio)sulfonium trifluoromethanesulfonate to the amide compound is 1~1.5:

1.

6. The synthesis method of the benzazepine compound according to claim 5, characterized in that, The molar ratio of dimethyl(methylthio)sulfonium trifluoromethanesulfonate and the amide compound is 1.2:

1.

7. The method for synthesizing benzazepine compounds according to claim 6, characterized in that, In the said method, the reaction solvent is acetonitrile; the molar concentration of the amide compound in the reaction solvent is 0.1 mmol / mL.

8. The method for synthesizing benzazepine compounds according to claim 1, characterized in that, The reaction temperature of the said method is 20~90 °C; the reaction time is 8~18 h.

9. The synthetic method of the benzazepine compound according to claim 1, characterized in that, In the said method, after the reaction is completed, column chromatography separation is carried out to obtain the refined benzazepine compound.

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