Synthesis method of 7-thiodiaryl azepine ketone compound

Abstract

The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and particularly relates to a synthesis method of a 7-thiodiaryl azepine ketone compound, which comprises the following steps: by taking N-(2 '-iodine-[1, 1'-biphenyl])-N-methacrylamide as a raw material, carrying out 7-exo Heck reaction and sulfur-Michael addition reaction to obtain the 7-thiodiaryl azepine ketone compound. The efficient synthesis of a target compound is realized by a one-pot method under the catalysis of transition metal palladium and the promotion of alkali. The one-pot synthesis strategy developed by the research provides an efficient and practical method for synthesizing the 7-thiomethyl diaryl azepine ketone compound. The method not only improves the synthesis efficiency and reduces the cost, but also has excellent substrate applicability and functional group tolerance, adds new candidate molecules for a compound library in the field of medicinal chemistry, and has important scientific research significance and application value.

Description

Technical Field

[0001] The present invention belongs to the technical fields of chemical pharmaceuticals and fine chemical preparations, and particularly relates to a method for synthesizing 7-thiodiarylazepinone compounds. Background Art

[0002] Diarylazepinone compounds have attracted much attention in drug development due to their remarkable biological activities. The core structure of such molecules consists of a seven-membered lactam and sp 3 benzyl carbon, which is commonly found in various alkaloids, bioactive molecules, and drug molecules. For example, the Paullones series of compounds shown in chemical formula (a) exhibit antitumor activity as inhibitors of cyclin-dependent kinases; while LY41157 shown in chemical formula (b) is a clinical candidate drug for the treatment of Alzheimer's disease as an inhibitor of γ-secretase. Recent studies have pointed out that γ-secretase inhibitors can block the formation of the carcinogenic domain of Notch molecules and inhibit Notch activity, showing the potential to become new targeted therapeutic drugs. The potent γ-secretase inhibitor (GSI) RO4929097 shown in chemical formula (c) has proven to have a positive effect on patients with malignant melanoma in phase I clinical trials. Therefore, developing new methods for synthesizing diarylazepinone compounds and developing new diarylazepinone compound skeletons have important application values and practical significances. Currently, the methods for synthesizing such compounds mainly include strategies such as reductive amination-cyclization, C-H activation, and radical reactions.

[0003]

[0004] The exo Heck reaction is one of the most common and simple methods for synthesizing seven-membered rings. However, the sp 2 hybridized carbon-carbon double bond is obtained by β-H reductive elimination in the last step of the Heck reaction. Recently, Qiang Zhu and Shuang Luo's research group at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences reported a 7-exo cyclocarbonylation palladium-initiated Heck tandem reaction, generating a series of seven-membered dibenzolactam compounds, such as Equation (1). In this reaction, the insertion of CO is faster than the elimination of β-H. When using alcohol / phenol or aniline as a nucleophile, 7-acetate or 7-acetamide-substituted dibenzazepinone compounds are formed in good yields.

[0005] (1)

[0006] Subsequently, the research group reported a sulfur-Michael addition reaction of 7-methyleneenedibenzazepine compounds, synthesizing a series of thiodimethyldibenzazepine compounds, such as Equation (2).

[0007] (2)

[0008] Inspired by this, we designed to use N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide as a substrate, and through a one-pot procedure involving a 7-exo Heck reaction and a sulfur-Michael addition reaction, 7-thiomethyl diaryl azepinone compounds were prepared. In addition, the sulfur atom can form hydrogen-bond-like interactions with electron donors such as nitrogen, oxygen, or π systems to regulate the conformation and biological activity of the molecule, and this kind of interaction widely exists in natural products and drug molecules. Summary of the Invention

[0009] The technical problem to be solved by the present invention is: Based on the importance of 7-thiodyaryl azepinone compounds pointed out in the background art part and the limitations of current synthesis methods, the present invention provides a simple and rapid synthesis method for a new type of 7-thiodyaryl azepinone compounds.

[0010] The synthesis method of the novel 7-thiodyaryl azepinone compounds provided by the present invention is as follows: Add N-(2'-iodo-[1,1'-biphenyl])-N-substituted acrylamide, the catalyst palladium acetate, and the ligand triphenylphosphine into a reaction tube, add a magnetic stirrer, and displace the air in the tube with nitrogen for three times. Dissolve the base in organic solvent I to obtain a base solution, inject the base solution into the reaction tube, and carry out the reaction at 100 °C under stirring conditions, and monitor the reaction by thin-layer chromatography. For the subsequent reaction, dissolve benzenethiol in organic solvent II dichloromethane, inject it into the reaction tube, and stir and react at room temperature to 50 °C. After the reaction is completed, remove the organic solvent by distillation under reduced pressure, and separate the residue by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain 7-thiodyaryl azepinone compounds.

[0011] The structural general formula of the synthesized 7-thiodyaryl azepinone compounds is:

[0012]

[0013] Among them, R 1 is any one of common nitrogen protecting groups such as methyl, benzyl, and p-methoxybenzyl; R 2 is any one of hydrogen, methyl, methoxy, ester group, fluorine, chlorine, and nitro; R 3 is any one of methyl, methoxy, tert-butyl, ester group, fluorine, trifluoromethyl, chlorine, and nitro.

[0014] The above reaction process is summarized as the following reaction equation (3):

[0015] (3)

[0016] The general structural formula of N-(2'-iodo-[1,1'-biphenyl])-N-substituted acrylamide is as follows:

[0017]

[0018] Among them, R 1 is any one of common nitrogen protecting groups such as methyl, benzyl, p-methoxybenzyl, etc.; R 2 is any one of hydrogen, methyl, methoxy, ester group, fluorine, chlorine, nitro.

[0019] When R 1 is methyl and R 2 is hydrogen, the synthesis route of N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide is shown in reaction equation (4). o-Nitrobromobenzene and o-aminophenylboronic acid pinacol ester undergo Suzuki coupling and substitution reactions to form A. Under the action of hydrochloric acid, A undergoes diazotization reaction with sodium nitrite. Iodide ion undergoes substitution with the diazonium salt, eliminates nitrogen gas, and reacts with iodine to form B. Tin(II) chloride reduces the nitro group of B to an amino group to form C. Acryloyl chloride undergoes amidation reaction with C to form D. D then undergoes substitution reaction with iodomethane to obtain the product E.

[0020] (4)

[0021] The general structural formula of benzenethiol is as follows:

[0022]

[0023] Among them, R 3 is any one of methyl, methoxy, tert-butyl, ester group, fluorine, trifluoromethyl, chlorine, nitro.

[0024] For N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide, the molar ratio of the catalyst palladium acetate, ligand triphenylphosphine, Et3N and benzenethiol is 1:0.05:0.1:2.5:1.2.

[0025] The molar concentration of N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide in organic solvent I is 0.2 M.

[0026] Organic solvent I is preferably toluene, and organic solvent II is preferably dichloromethane; the volume ratio of organic solvent I to organic solvent II is 1:0.5 - 1.

[0027] The reaction time of the first step is 3 hours, and the reaction time of the second step is 12 hours.

[0028] Preferably, the reaction temperature of the second step is 50 °C.

[0029] In this study, an efficient one-pot synthesis strategy was successfully developed for the synthesis of novel 7-thiomethyl diaryl azepinone compounds with potential biological activities that have not been reported by other synthetic methods. This method uses N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide as a key intermediate, and through 7-exo Heck reaction and sulfur-Michael addition reaction, the efficient synthesis of the target compound is achieved under the catalysis of transition metal palladium and the promotion of a base. The reaction conditions are mild and the substrate applicability is good. Both benzenethiols with electron-donating functional groups and benzenethiols with electron-withdrawing functional groups can be well compatible with this reaction. This method not only improves the synthesis efficiency and reduces the cost, but also has excellent substrate applicability and functional group tolerance, adding new candidate molecules to the compound library in the field of medicinal chemistry, and has important scientific research significance and application value.

[0030] The beneficial effects of the present invention are as follows: Using N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide as a substrate, with palladium acetate as a catalyst, at a reaction temperature of 100 °C, an intermediate with high activity is generated. Subsequently, a 7-exo Heck reaction occurs with the double bond in the molecule to form a product containing a carbon-carbon double bond. The benzenethiol forms a sulfur anion under the action of a base, and a sulfur-Michael addition reaction is carried out on the olefin product generated by the 7-exo Heck reaction under the reaction condition of 50 °C, and finally a product of 7-thiomethyl diaryl azepinone compounds is obtained. The synthesized compounds may have unique chemical structures and diverse biological activities, and can be used in multiple drug development fields such as anti-tumor, anti-inflammatory, and anti-depressant, and have the potential to become candidate molecules for new drug research and development. Detailed implementation manners

[0031] Now, the present invention will be further described in conjunction with specific embodiments. The following embodiments are intended to illustrate the present invention rather than further limit the present invention.

[0032] The N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide used in the present invention was prepared with reference to relevant literature (reference: Huaanzi Hu, Yan Peng, Ting Yu, Sidi Cheng, Shuang Luo, Qiang Zhu. Palladium-Catalyzed Enantioselective 7-exo-Trig Carbopalladation / Carbonylation: Cascade Reactions To Achieve Atropisomeric Dibenzo[b,d]azepin-6-ones[J]. Org. Lett. 2021, 23, 3636-3640). The palladium acetate catalyst, triphenylphosphine ligand, Et3N and various benzenethiols were directly used after being purchased from the market. Solvents such as toluene and DCM were purified and refined.

[0033] Example 1

[0034]

[0035] Add N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide 1a (36.3 g, 0.1 mmol), the catalyst palladium acetate (1.12 g, 0.005 mmol), and the ligand triphenylphosphine (2.62 g, 0.01 mmol) into a reaction tube. Add a magnetic stir bar and displace the air in the tube with nitrogen three times. Weigh Et3N (34.7 μL) and dissolve it in toluene (0.5 mL), then inject it into the reaction tube. React at 100 °C for 3 hours under stirring conditions, and monitor the reaction by thin-layer chromatography. For the subsequent reaction, weigh p-toluenethiol (13.66 g, 0.12 mmol) and dissolve it in dichloromethane (DCM) (0.5 mL), then inject it into the reaction tube. Stir at 50 °C for 12 hours. After the reaction is completed, remove the organic solvents by distillation under reduced pressure. The residue is separated by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain the 7-thiomethyl diaryl azepinone compound 2a, a colorless oil, 29.4 mg, with a yield of 82%. 1 H NMR (300 MHz, Chloroform-d) δ 7.61–7.51 (m, 2H), 7.49–7.39 (m, 3H), 7.38–7.28 (m, 3H), 7.20 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 3.96–3.80 (m, 1H), 3.59–3.48 (m, 2H), 3.33 (s, 3H), 2.25 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 170.93, 141.29, 137.07, 136.75, 136.57, 133.64, 132.41, 130.78, 129.90, 129.68, 128.67, 128.48, 127.39, 125.43, 123.80, 122.55, 45.81, 36.18, 32.58, 21.02.

[0036] Example 2

[0037]

[0038] Add N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide 1a (36.3 g, 0.1 mmol), palladium acetate catalyst (1.12 g, 0.005 mmol), ligand triphenylphosphine (2.62 g, 0.01 mmol), and K2CO3 (34.5 mg, 0.25 mmol) into a reaction tube. Add a magnetic stir bar and displace the air in the tube with nitrogen three times. Inject 0.5 mL of toluene as the solvent into the reaction tube. Place the reaction tube in a heating magnetic stirrer at 100 °C and stir for 3 hours. Weigh 4-methylbenzenethiol (13.66 g, 0.12 mmol), dissolve it in 0.5 mL of dichloromethane (DCM), then inject it into the reaction tube and stir at room temperature for 12 hours. After the reaction is completed, remove the organic solvents by distillation under reduced pressure. The residue is separated by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent, and the 7-thiomethyl diaryl azepinone compound 2a is not obtained.

[0039] Example 3

[0040]

[0041] Add N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide 1a (36.3 g, 0.1 mmol), palladium acetate (1.12 g, 0.005 mmol) as the catalyst, triphenylphosphine (2.62 g, 0.01 mmol) as the ligand, and K2CO3 (16.56 mg, 0.12 mmol) into the reaction tube. Add a magnetic stir bar and displace the air in the tube with nitrogen three times. Inject 0.5 mL of toluene into the reaction tube as the solvent. Place the reaction tube in a heating magnetic stirrer at 100 °C and stir for 3 hours. Weigh p-toluenethiol (13.66 g, 0.12 mmol) and dissolve triethylamine (Et3N) (34.7 μL) in 0.5 mL of dichloromethane (DCM), then inject it into the reaction tube and stir at room temperature for 12 hours. After the reaction is completed, remove the organic solvents by distillation under reduced pressure. The residue is separated by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain the 7-thiomethyl diaryl azepinone compound 2a, a colorless oil, 20.1 mg, with a yield of 56%.

[0042] Example 4

[0043]

[0044] Add N-(2'-iodo-[1,1'-biphenyl])-N-methylacrylamide 1a (36.3 g, 0.1 mmol), palladium acetate (1.12 g, 0.005 mmol) as the catalyst, triphenylphosphine (2.62 g, 0.01 mmol) as the ligand, and K2CO3 (16.56 mg, 0.12 mmol) into the reaction tube. Add a magnetic stir bar and displace the air in the tube with nitrogen three times. Inject 0.5 mL of toluene into the reaction tube as the solvent. Place the reaction tube in a heating magnetic stirrer at 100 °C and stir for 3 hours. Weigh p-toluenethiol (13.66 g, 0.12 mmol) and dissolve triethylamine (Et3N) (34.7 μL) in 0.5 mL of dichloromethane (DCM), then inject it into the reaction tube and stir at 50 °C for 12 hours. After the reaction is completed, remove the organic solvents by distillation under reduced pressure. The residue is separated by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain the 7-thiomethyl diaryl azepinone compound 2a, a colorless oil, 23.7 mg, with a yield of 66%.

[0045] Example 5

[0046]

[0047] Add N-(2’-iodo-[1,1’-biphenyl])-N-methylacrylamide 1a (36.3 g, 0.1 mmol), palladium acetate catalyst (1.12 g, 0.005 mmol), ligand triphenylphosphine (2.62 g, 0.01 mmol), K2CO3 (16.56 mg, 0.12 mmol) into the reaction tube. Add a magnetic stir bar and displace the air in the tube with nitrogen three times. Inject 0.5 mL of DMF into the reaction tube as the solvent. Place the reaction tube in a heating magnetic stirrer at 100 °C and stir for 3 hours. Weigh p-toluenethiol (13.66 g, 0.12 mmol) and triethylamine (Et3N) (34.7 μL), dissolve them in 0.5 mL of dichloromethane (DCM), then inject into the reaction tube and stir at 50 °C for 12 hours. After the reaction is completed, remove the organic solvents by distillation under reduced pressure. The residue is separated by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain 7-thiomethyl diaryl azepinone compound 2a, a colorless oil, 10.0 mg, with a yield of 28%.

[0048] Example 6

[0049] Referring to the method of Reference Example 1, change the solvent volume of DCM to 0.25 mL to obtain 7-thiomethyl diaryl azepinone compound 2a, a colorless oil, 24.8 mg, with a yield of 69%.

[0050] Example 7

[0051]

[0052] Add p-methoxythiophenol (16.82 g, 0.12 mmol) into the reaction tube to replace p-methylthiophenol in Example 1, and refer to the method of Example 1 for the rest to obtain 7-thiomethyl diaryl azepinone compound 2b, a colorless oil, 37.1 mg, with a yield of 99%. 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 7.7 Hz, 2H), 7.50–7.28 (m, 6H), 7.29–7.23 (m, 2H), 6.71 (d, J = 8.7 Hz, 2H), 3.90–3.76 (m, 1H), 3.73 (s, 3H), 3.54–3.39 (m, 2H), 3.33 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 170.92, 159.17, 141.33, 137.15, 136.73, 134.12, 129.86, 128.64, 128.39, 127.32, 126.06, 125.39, 123.81, 122.52, 114.49, 99.99, 55.32, 45.76, 36.13, 33.90.

[0053] Example 8

[0054]

[0055] 4-tert-Butylbenzenethiol (19.95 g, 0.12 mmol) was added to the reaction tube to replace p-methylbenzenethiol in Example 1, and the remaining methods were referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2c, a colorless oil, 39.7 mg, with a yield of 99%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 7.6 Hz, 2H), 7.30 (ddt, J = 39.9, 19.3, 7.4 Hz, 6H), 7.14 (q, J = 8.3 Hz, 4H), 3.80 (td, J = 11.1, 6.4 Hz, 1H), 3.52–3.42 (m, 2H), 3.26 (s, 3H), 1.16 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.95, 149.82, 141.31, 137.07, 136.75, 133.66, 132.37, 130.58, 129.86, 128.65, 128.62, 128.43, 127.36, 125.92, 125.39, 123.81, 122.54, 45.77, 36.13, 34.44, 32.37, 31.23.

[0056] Example 9

[0057]

[0058] 4-(Trifluoromethyl)benzenethiol (21.38 g, 0.12 mmol) was added to the reaction tube to replace p-methylbenzenethiol in Example 1, and the remaining methods were referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2d, a colorless oil, 36.7 mg, with a yield of 89%. 11H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 7.6 Hz, 2H), 7.45 (dt, J = 10.5, 7.2 Hz, 5H), 7.34 (q, J = 8.1, 7.7 Hz, 5H), 4.03–3.92 (m, 1H), 3.72–3.64 (m, 1H), 3.62–3.54 (m, 1H), 3.35 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.62, 141.99, 141.10, 136.71, 136.50, 133.45, 129.92, 128.85, 128.77, 128.68, 127.75, 127.65, 127.59 (q, J = 31.3 Hz), 125.68 (q, J = 4.04 Hz), 125.65, 124.02 (q, J = 290.88 Hz), 123.57, 122.58, 45.49, 36.29, 30.49.

[0059] Example 10

[0060]

[0061] p-Fluorothiophenol (15.37 g, 0.12 mmol) was added to the reaction tube to replace p-methylthiophenol in Example 1, and the remaining methods were referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2e, a colorless oil, 36.0 mg, with a yield of 99%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 7.5 Hz, 2H), 7.35 (dq, J = 23.1, 7.9 Hz, 4H), 7.22 (dt, J = 16.2, 7.3 Hz, 4H), 6.81 (t, J = 8.5 Hz, 2H), 3.80 (dd, J = 14.1, 10.4 Hz, 1H), 3.50–3.39 (m, 2H), 3.26 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.76, 162.01 (d, J = 248.46 Hz), 141.25, 136.89, 136.71, 133.59, 133.25 (d, J = 8.08 Hz), 130.91, 129.87, 128.70 (d, J = 4.04 Hz), 128.48, 127.45, 125.51, 123.69, 122.51, 115.97 (d, J = 22.22 Hz), 45.72, 36.15, 33.20.

[0062] Example 11

[0063]

[0064] p-Chlorothiophenol (17.35 g, 0.12 mmol) was added to the reaction tube to replace p-methylthiophenol in Example 1, and the remaining method was referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2f, a colorless oil, 10.6 mg, with a yield of 28%. 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 7.6 Hz, 2H), 7.45 (dq, J = 14.6, 7.7, 7.3 Hz, 3H), 7.34 (dd, J = 14.0, 6.7 Hz, 3H), 7.25–7.14 (m, 4H), 3.90 (dq, J = 13.4, 6.5 Hz, 1H), 3.60

[0065] –3.50 (m, 2H), 3.34 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 170.72, 141.17, 136.73, 136.70, 134.75, 133.51, 131.14, 129.90, 129.01, 128.78, 128.71, 128.57, 127.53, 125.57, 123.64, 122.55, 45.63, 36.23, 31.54.

[0066] Example 12

[0067]

[0068] p-Bromothiophenol (22.69 g, 0.12 mmol) was added to the reaction tube to replace p-methylthiophenol in Example 1, and the remaining method was referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2g, a colorless oil, 30.0 mg, with a yield of 71%. 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 7.6 Hz, 2H), 7.44 (dq, J = 14.3, 7.4 Hz, 3H), 7.38–7.28 (m, 5H), 7.15 (d, J = 8.5 Hz, 2H), 3.94–3.86 (m, 1H), 3.61–3.50 (m, 2H), 3.33 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 170.70, 141.15, 136.71, 135.50, 133.50, 131.92, 131.21, 129.91, 128.80, 128.72, 128.58, 127.54, 125.59, 123.64, 122.55, 120.15, 45.63, 36.24, 31.82.

[0069] Example 13

[0070]

[0071] o-Toluenethiol (14.90 g, 0.12 mmol) was added to the reaction tube to replace p-methylbenzenethiol in Example 1, and the remaining methods were referred to Example 1 to obtain 7-thiomethyl diaryl azepinone compound 2h, a colorless oil, 30.1 mg, yield 84%. 1 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 7.7 Hz, 2H), 7.43–7.32 (m, 3H), 7.32–7.17 (m, 4H), 7.04–6.94 (m, 3H), 3.85–3.74 (m, 1H), 3.52–3.43 (m, 2H), 3.26 (s, 3H), 2.21 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.93, 141.23, 138.29, 136.98, 136.72, 135.46, 133.60, 130.08, 129.90, 129.19, 128.70, 128.50, 127.43, 126.45, 126.18, 125.49, 123.80, 122.56, 45.59, 36.21, 31.08, 20.44.

[0072] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing 7-thiodiarylazepinone compounds, characterized in that, The synthesis method is as follows: Add N-(2'-iodo-[1,1'-biphenyl])-N-substituted acrylamide, palladium catalyst, phosphine ligand into a reaction tube, and displace with nitrogen; dissolve the base in organic solvent I to obtain a base solution, inject the base solution into the reaction tube, and carry out stirring reaction I until the reaction is complete; dissolve benzenethiol in organic solvent II to obtain a benzenethiol solution, inject the benzenethiol solution into the reaction tube, and carry out stirring reaction II to obtain 7-thiobisarylazepinone compounds. The structural formula of the N-(2’-iodo-[1,1’-biphenyl])-N-substituted acrylamide is as follows: ; The structural formula of the benzenethiol is ; The structural formula of the 7-thiodiarylazepinone compound is ; Among them, R 1 is a nitrogen protecting group, and the nitrogen protecting group is any one of methyl, benzyl, and p-methoxybenzyl; R 2 is any one of hydrogen, methyl, methoxy, ester group, fluorine, chlorine, and nitro; R 3 is any one of methyl, methoxy, tert-butyl, ester group, fluorine, trifluoromethyl, chlorine, and nitro.

2. The synthesis method of the 7-thiodiarylazepinone compounds according to claim 1, characterized in that, The molar ratio of the N-(2'-iodo-[1,1'-biphenyl])-N-substituted acrylamide, palladium catalyst, phosphine ligand, base and benzenethiol is 1:0.05:0.1:2.5:1.

2.

3. The method for synthesizing 7-thiodiarylazepinone compounds according to claim 1 or 2, characterized in that, The palladium catalyst is palladium acetate, the phosphine ligand is triphenylphosphine, the base is triethylamine, the organic solvent I is toluene, and the organic solvent II is dichloromethane.

4. The synthesis method of the 7-thiodiarylazepinone compound according to claim 1, characterized in that, The molar concentration of the N-(2'-iodo-[1,1'-biphenyl])-N-substituted acrylamide in the organic solvent I is 0.2 mol / L.

5. The synthesis method of the 7-thiodiarylazepinone compound according to claim 1, characterized in that, The volume ratio of the organic solvent I to the organic solvent II is 1:0.5 - 1.

6. The synthesis method of the 7-thiodiarylazepinone compound according to claim 1, characterized in that, The reaction temperature of the stirring reaction I is 100 °C, and the reaction time is 3 hours.

7. The synthesis method of 7-thiodiarylazepinone compounds according to claim 1, characterized in that, The reaction temperature of the stirring reaction II is from room temperature to 50 °C, and the reaction time is 12 hours.

8. The synthetic method of 7-thiodiarylazepinone compounds according to claim 1, characterized in that, The synthesis method further includes: after the reaction is completed, remove the organic solvent by vacuum distillation, and purify the residue by silica gel column chromatography using petroleum ether and ethyl acetate as eluents.

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