Synthesis method of dibenzo diazepine or oxazepine or thiazepine compounds

Abstract

The present invention discloses a method for the copper-catalyzed synthesis of dibenzo diazo- or oxa- or thia- heterocyclic compounds. The target product is synthesized by coupling an aromatic amine or an aromatic phenol or an aromatic thiol with an aromatic halide to construct an intermediate of diarylamine or diaryl ether or diaryl sulfide and then amination cyclization. Among them, the dibenzo diazo- / thia- heterocyclic compounds are obtained by a one-pot two-step method, which has low cost, mild reaction conditions, high chemoselectivity, high reaction yield and wide substrate adaptability.

Description

Technical Field:

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing dibenzo-diazepine or -oxazepine or -thiazepine compounds. Background Art:

[0002] The skeletons of dibenzo-diazepine or -oxazepine or -thiazepine compounds and their structural analogs widely exist in different kinds of drugs. Drugs with such skeletons have a wide range of pharmacological activities, including: anthelmintic, antibacterial, anticonvulsant, anticancer, antipyretic, anti-inflammatory, anxiolytic, antidepressant and other properties. Typical representatives include clozapine (A), quetiapine (B), loxapine (C), pirenzepine (D), nevirapine (E), etc.

[0003]

[0004] In 1964, the Schmutz group first synthesized dibenzo-diazepine drugs and their derivatives. Traditionally, dibenzo-diazepine compounds and their structural analogs are obtained through lactam or amide intermediates, and then the heterocyclic scaffold is functionalized to introduce substituents. (J. Comb. Chem. 2007, 9, 5, 773–782; J. Med. Chem. 2006, 49, 15, 4512–4516). This transformation usually requires harsh conditions, purification after each synthesis step, and the use of protecting groups. Most of the previously reported synthetic routes require the reduction of NO2 groups, and the functional group compatibility is limited, while the coupling of the substrate with two free NH2 groups results in a mixture of products. Transition metal-catalyzed methods have been used to synthesize these structures in recent years, and the Buchwald-Hartwig and Ullman / Goldberg C-N coupling methods may be the most useful methods.

[0005] The Buchwald research group developed a method for palladium-catalyzed synthesis of dibenzo-diazepine compounds in 2011 (J. Am. Chem. Soc. 2011, 133, 14228–14231). This method uses aromatic amines and aromatic halides as raw materials, and realizes C-N coupling through two-step palladium catalysis, amination of halides and intramolecular cyclization to synthesize dibenzo-diazepine compounds. However, the expensive palladium catalyst and various structurally complex phosphine ligands hinder its industrial production. Chinese Patent CN 103980212A discloses a method for copper-catalyzed synthesis of dibenzo-diazepine Methods for heterocyclic derivatives, however, these methods still rely on the pre-constructed dibenzamide structure. In 2022, Ma Jun'an et al. developed a method for the intramolecular reductive aminocarbonylation of 1-bromo-2-(2-nitrophenoxy)benzene and its structural analogues to synthesize dibenzoazepines (Org. Chem. Front., 2022, 9, 3869–3875). This method uses pre-constructed diaryl ethers and their structural analogues as raw materials, and is heated to 140-160 °C in the presence of a nickel catalyst, manganese, ligand, TMSCl, CO, etc. to synthesize the target product. However, this catalytic system requires pre-constructed intermediates, a large number of reaction reagents, and high-temperature conditions, and there is no obvious advantage compared with the traditional synthesis methods of dibenzoazepine compounds.

[0006] Therefore, there is a need to develop an efficient, concise, and general protocol for the synthesis of such compounds. Summary of the Invention:

[0007] The object of the present invention is to provide a method for the copper-catalyzed synthesis of dibenzo-diaza- or oxa- or thia- heterocyclic compounds, which constructs diarylamine or diaryl ether or diaryl sulfide intermediate products from aromatic amines or aromatic phenols or aromatic thiols and aromatic halides, and synthesizes the target product through amination cyclization, with low cost, mild reaction conditions, high chemoselectivity, high reaction yield, and wide substrate adaptability.

[0008] The present invention is achieved through the following technical solutions:

[0009] A method for the synthesis of dibenzo-diaza- or oxa- or thia-heterocyclic compounds, and the reaction equation is as follows:

[0010]

[0011] Wherein (Het)Ar-X is selected from R1 is I or Br or NH2; R2 is -OCH3 or -OCH2CH3 or phenyl or p-chlorophenyl; R3 is ortho-, meta-, or para-substituted, and is selected from any one of hydrogen, trifluoromethyl, methoxy, fluorine, chlorine, and methyl; R4 is O or phenyl or p-chlorophenyl; R5 is Br or Cl or NH2 or SH or OH; R6 is ortho-, meta-, or para-substituted, and is any one of hydrogen, trifluoromethyl, trifluoromethoxy, cyano, methoxy, fluorine, chlorine, and methyl; X is I or Br or Cl; Y is N or NH or S or O, and Z is N or NH.

[0012] Comprising the following steps:

[0013] Using aromatic amines, aromatic phenols, or aromatic thiols and aromatic halides as raw materials, a coupling reaction is carried out by heating in a solvent in the presence of a copper salt and a base to form diarylamine, diaryl ether, or diaryl sulfide intermediate products; then a ligand and an amine source are added, and under heating conditions, the diaryl ether intermediate products undergo an amination reaction under copper catalysis and spontaneously cyclize to form the target product.

[0014] Among them, the molar ratio of aromatic amines, aromatic phenols, or aromatic thiols, aromatic halides, copper salts, and bases is (1 - 5):1:(0.1 - 1):(1 - 5); the molar ratio of diaryl ether intermediate products, ligands, and amine sources is 1:0.01 - 0.5:1 - 5, and the concentration of the intermediate product is 0.5 - 5 mol / L.

[0015] The aromatic halide is one or two of aromatic iodides or bromides.

[0016] The copper salt is selected from any one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper acetate, copper bromide, copper chloride, and copper sulfate.

[0017] The base is selected from any one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, and cesium carbonate.

[0018] The solvent is selected from any one or several of methanol, ethanol, diethylene glycol, ethylene glycol, polyethylene glycol 200, and polyethylene glycol 400.

[0019] Preferably, the ligand is selected from N-carbazolyl-1H-pyrrole-2-carboxamide.

[0020] The amine source is selected from any one or more of ammonia water, methanol solution of ammonia, cyclopropylamine, and ammonium chloride.

[0021] When the target product is a dibenzo diazepine type compound, the synthesis method includes the following one-pot two-step:

[0022] Using aromatic amines and aromatic iodides or bromides as raw materials, a coupling reaction is carried out by heating to 50 - 150 °C in the presence of a copper salt and a base to form intermediate products; among them, the molar ratio of aromatic iodides or bromides, aromatic amines, copper salts, and bases is 1:1 - 5:0.1 - 1:1 - 5;

[0023] In the reaction mixture of the previous step, a solvent, a ligand, and an amine source are added, and under heating conditions, the intermediate products are aminated at 60 - 130 °C and spontaneously cyclize to form the target product, where the molar ratio of the intermediate product, ligand, and amine source is 1:0.01 - 0.5:1 - 5, and the concentration of the intermediate product is 0.5 - 5 mol / L.

[0024] When the target product is dibenzooxazepine When synthesizing the compound of the class, the synthesis method includes the following two steps:

[0025] Using aromatic phenol and aromatic iodine or bromide as raw materials, dimethyl sulfoxide as the solvent, heating to 50 - 150 °C in the presence of copper(I) iodide, ligand 2-pyridinecarboxylic acid and base to carry out a coupling reaction to generate an intermediate product; wherein the molar ratio of aromatic iodine / bromide, aromatic phenol, copper(I) iodide, 2-pyridinecarboxylic acid, and base is 1:1 - 5:0.1 - 1:0.1 - 1:1 - 5, and the concentration of aromatic phenol is 0.5 - 5 mol / L;

[0026] Using the intermediate product obtained in the previous step as the raw material, in the presence of copper salt, ligand, amine source and base, heating at 60 - 130 °C, the intermediate product is aminated and spontaneously cyclized to generate the target product, wherein the molar ratio of intermediate product, copper salt, ligand, and amine source is 1:0.01 - 1:0.01 - 0.5:1 - 5, and the concentration of the intermediate product is 0.5 - 5 mol / L.

[0027] When the target product is a dibenzo[b,f][1,4]thiazepine class of compounds, the synthesis method includes the following one-pot two steps:

[0028] Using aromatic thiophenol and aromatic iodine or bromide as raw materials, adding a solvent, carrying out a coupling reaction at 20 - 120 °C in the presence of copper salt, ligand and base to generate an intermediate product; wherein the molar ratio of aromatic iodine / bromide, aromatic thiophenol, copper salt, ligand, and base is 1:1 - 5:0.01 - 1:0.01 - 0.5:1 - 5;

[0029] Adding an amine source to the reaction mixture in the previous step, heating at 80 - 150 °C, the intermediate product is aminated and spontaneously cyclized to generate the target product, wherein the molar ratio of intermediate product and amine source is 1:1 - 5.

[0030] The present invention also protects the application of dibenzo[b,f][1,4]diazepine or dibenzo[b,f][1,4]oxazepine or dibenzo[b,f][1,4]thiazepine class of compounds in pharmaceutical synthesis.

[0031] The advantages of the present invention are as follows: First, for dibenzo[b,f][1,4]diazepine / thiazepine compounds, there is no need to construct an intermediate product using an additional reaction system, reducing the intermediate separation and purification steps, simplifying the synthesis route, and saving production costs. Second, the reaction system has good substrate applicability, and the target product can be obtained in good to excellent yields for the amination cyclization of the intermediate products obtained by the coupling of aromatic amines / aromatic phenols / aromatic thiols and aromatic halides. Finally, using inexpensive and readily available copper catalysts, it is easier to realize the industrial production of this class of compounds compared with traditional palladium catalysis and nickel catalysis with harsh reaction conditions. Specific embodiments:

[0032] The following is a further description of the present invention, rather than a limitation of the present invention.

[0033] Example 1: Synthesis of 11-phenyl-5H-dibenzo[b,e][1,4]diazepine

[0034]

[0035] Add 256 mg (1.3 mmol) of 2-aminobenzophenone, 282 mg (1 mmol) of o-iodobromobenzene, 19 mg (0.1 mmol) of copper(I) iodide, and 276 mg (2 mmol) of potassium carbonate into a 10 mL reaction tube in sequence, seal it, and react at 50 °C for 24 h. After stopping the reaction, add 2 mL of diethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 340 mg of ammonia water (mass fraction 25%, 5 mmol), seal it, and react at 60 °C for 8 h. After stopping the reaction, add water, extract with ethyl acetate, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure, and purify by silica gel column chromatography to obtain 230 mg of 11-phenyl-5H-dibenzo[b,e][1,4]diazepine with a yield of 85%. 230 mg, yield 85%.

[0036] 1 H NMR (600 MHz, Chloroform-d) δ 7.74–7.69 (m, 2H), 7.46–7.38 (m, 3H), 7.33–7.27 (m, 2H), 7.07–6.99 (m, 3H), 6.93 (td, J = 7.5, 1.1 Hz, 1H), 6.78 (dd, J = 8.0, 1.1 Hz, 1H), 6.72–6.68 (m, 1H), 5.02 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.7, 154.5, 142.7, 141.2, 140.7, 132.3, 132.1, 130.0, 129.6, 128.6, 128.0, 127.5, 126.9, 124.2, 122.4, 119.8, 119.8.

[0037] Example 2: Synthesis of 8-chloro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine

[0038]

[0039] ​​985 mg (5 mmol) of 2-aminobenzophenone, 317 mg (1 mmol) of 2-bromo-4-chloro-1-iodobenzene, 14 mg (0.1 mmol) of copper(I) iodide, and 1.1 g (5 mmol) of potassium phosphate were successively added to a 10 mL reaction tube, sealed, and reacted at 100 °C for 4 h. After the reaction was stopped, 1 mL of ethanol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added, sealed, and reacted at 100 °C for 3 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 8-chloro-11-phenyl-5H-dibenzo[b,e][1,4]diazepine 255 mg, with a yield of 84%.

[0040] 1 H NMR (600 MHz, Chloroform-d) δ 7.69 (d, J = 6.8 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.35–7.28 (m, 2H), 7.04–6.93 (m, 3H), 6.79 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 5.01 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 170.8, 154.2, 141.8, 141.4, 140.8, 132.4, 132.3, 130.4, 129.7, 129.1, 128.2, 128.0, 127.4, 126.4, 122.7, 120.6, 119.8.

[0041] Example 3: Synthesis of 5,11-dihydrobenzo[b][1,4]benzodiazepin -6-one

[0042]

[0043] 227 mg (1.5 mmol) of methyl anthranilate, 236 mg (1 mmol) of 1,2-dibromobenzene, 99 mg (1 mmol) of cuprous chloride, and 652 mg (2 mmol) of cesium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 12 h. After the reaction was stopped, 2 mL of methanol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 2 mL of a methanol solution of ammonia (2 M) were added, sealed, and reacted at 100 °C for 6 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 168 mg of 5,11-dihydrobenzo[b][1,4]benzodiazepin -6-one, with a yield of 80%.

[0044] 1 1H NMR (600 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.84 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 5.0 Hz, 2H), 6.95 (t, J = 7.7 Hz, 2H), 6.89 (q, J = 6.9 Hz, 2H). 13 13C NMR (150 MHz, DMSO) δ 168.4, 150.9, 140.4, 133.7, 132.6, 130.3, 124.9, 123.4, 123.2, 121.7, 121.2, 120.2, 119.5.

[0045] Example 4: Synthesis of 8-(trifluoromethoxy)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one

[0046]

[0047] 215 mg (1.3 mmol) of ethyl anthranilate, 367 mg (1 mmol) of 3-bromo-4-iodotrifluoromethoxybenzene, 40 mg (0.2 mmol) of copper(II) acetate, and 336 mg (3 mmol) of potassium tert-butoxide were successively added to a 10 mL reaction tube. The tube was sealed and reacted at 120 °C for 10 h. After the reaction was stopped, 0.5 mL of ethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 106 mg (2 mmol) of ammonium chloride were added. The tube was sealed again and reacted at 120 °C for 8 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. After separation and purification by silica gel column chromatography, 191 mg of 8-(trifluoromethoxy)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one was obtained with a yield of 65%.

[0048] 1 H NMR (600 MHz, Chloroform-d) δ 8.83 (s, 1H), 7.95 (dd, J = 7.9, 1.6 Hz, 1H), 7.35 (td, J = 7.6, 1.6 Hz, 1H), 7.04–7.00 (m, 1H), 6.91–6.85 (m, 2H), 6.81 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.50 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.1, 148.8, 145.3, 145.3, 137.8, 134.1, 133.1, 130.6, 123.0, 122.5, 122.5, 121.3, 120.5, 119.6, 119.2, 117.9, 117.6, 114.4.

[0049] Example 5: Synthesis of 8-chloro-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one

[0050]

[0051] 186 mg (1.1 mmol) of methyl 2-amino-5-fluorobenzoate, 317 mg (1 mmol) of 2-bromo-4-chloro-1-iodobenzene, 48 mg (0.3 mmol) of copper sulfate, and 384 mg (4 mmol) of sodium tert-butoxide were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 12 h. After the reaction was stopped, 2 mL of polyethylene glycol 200, 55 mg (0.2 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added, sealed, and reacted at 120 °C for 6 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 165 mg of 8-chloro-2-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one, with a yield of 63%.

[0052] 1 H NMR (600 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.98 (s, 1H), 7.39 (dd, J = 9.6, 3.1 Hz, 1H), 7.26 (td, J = 8.4, 3.2 Hz, 1H), 7.05–6.98 (m, 4H). 13 C NMR (150 MHz, DMSO) δ 165.9, 165.9, 156.8, 155.3, 145.8, 145.8, 138.4, 130.5, 125.8, 123.7, 123.3, 123.2, 120.5, 120.4, 120.4, 120.2, 120.1, 116.8, 116.7.

[0053] Example 6: Synthesis of 9-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one

[0054]

[0055] 227 mg (1.5 mmol) of methyl anthranilate, 297 mg (1 mmol) of 3-bromo-2-iodotoluene, 223 mg (1 mmol) of copper(II) bromide, and 112 mg (2 mmol) of potassium hydroxide were successively added to a 10 mL reaction tube. The tube was sealed and reacted at 130 °C for 12 h. After the reaction was stopped, 2 mL of polyethylene glycol 400, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added. The tube was sealed again and reacted at 100 °C for 8 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. The product was separated and purified by silica gel column chromatography to obtain 168 mg of 9-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, with a yield of 75%. -11-one 168 mg, yield 75%.

[0056] 1 H NMR (600 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.73 (s, 1H), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.35–7.31 (m, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.94–6.89 (m, 3H), 6.84–6.81 (m, 1H), 2.27 (s, 3H). 13 C NMR (150 MHz, DMSO) δ 167.8, 150.7, 142.2, 132.2, 131.1, 130.0, 127.7, 124.2, 124.2, 123.4, 120.5, 118.5, 117.3, 17.4.

[0057] Example 7: Synthesis of 8-chloro-4-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one -11-one

[0058]

[0059] 248 mg (1.5 mmol) of methyl 2-amino-3-methylbenzoate, 317 mg (1 mmol) of 2-bromo-4-chloro-1-iodobenzene, 67 mg (0.5 mmol) of copper(II) chloride, and 80 mg (2 mmol) of sodium hydroxide were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 18 h. After the reaction was stopped, 1 mL of ethylene glycol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added, sealed, and reacted at 100 °C for 8 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 180 mg of 8-chloro-4-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, with a yield of 70%. -11-one 180 mg, yield 70%.

[0060] Example 8: Synthesis of 7-fluoro-4-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one -11-one

[0061]

[0062] 248 mg (1.5 mmol) of methyl 2-amino-3-methylbenzoate, 301 mg (1 mmol) of 1-bromo-4-fluoro-2-iodobenzene, 67 mg (0.5 mmol) of copper(II) chloride, and 80 mg (2 mmol) of sodium hydroxide were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 18 h. After the reaction was stopped, 2 mL of a methanol solution of ammonia (2 M), 138 mg (0.5 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide were added, sealed, and reacted at 100 °C for 3 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 184 mg of 7-fluoro-4-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, with a yield of 76%. -11-one 184 mg, yield 76%.

[0063] 1 H NMR (600 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 6.99 (td, J = 10.1, 9.6, 4.2 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.81 (td, J = 8.4, 2.7 Hz, 1H), 2.35 (s, 3H). 1313C NMR (150 MHz, DMSO) δ 168.6, 160.1, 158.5, 148.0, 142.2, 142.2, 134.7, 130.2, 128.0, 128.0, 127.6, 125.4, 122.7, 122.6, 122.0, 110.3, 110.1, 109.2, 109.1, 18.4.

[0064] Example 9: Synthesis of 4,8 - dichloro - 5,10 - dihydro - 11H - dibenzo[b,e][1,4]diazepin - 11 - one

[0065]

[0066] 242 mg (1.3 mmol) of methyl 2 - amino - 3 - chlorobenzoate, 317 mg (1 mmol) of 2 - bromo - 4 - chloro - 1 - iodobenzene, 38 mg (0.2 mmol) of copper(I) iodide, and 212 mg (2 mmol) of sodium carbonate were successively added to a 10 mL reaction tube, which was sealed and reacted at 150 °C for 24 h. After the reaction was stopped, 1 mL of diethylene glycol, 138 mg (0.5 mmol) of N - carbazolyl - 1H - pyrrole - 2 - carboxamide, and 74 mg (1.3 mmol) of cyclopropylamine were added, and the tube was sealed and reacted at 110 °C for 4.5 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 189 mg of 4,8 - dichloro - 5,10 - dihydro - 11H - dibenzo[b,e][1,4]diazepin - 11 - one, with a yield of 68%.

[0067] 1 1H NMR (600 MHz, DMSO - d6) δ 10.06 (s, 1H), 8.16 (s, 1H), 7.62 (s, 1H), 7.42–7.38 (m, 1H), 6.99 (q, J = 8.7, 8.0 Hz, 4H). 13 13C NMR (150 MHz, DMSO) δ 166.8, 149.1, 138.5, 133.7, 131.7, 131.3, 127.0, 125.1, 124.7, 124.0, 121.6, 121.5, 121.1.

[0068] Example 10: Synthesis of 3 - methoxy - 5,10 - dihydro - 11H - dibenzo[b,e][1,4]diazepin - 11 - one

[0069] ​​​

[0070] 217 mg (1.2 mmol) of methyl 2-amino-4-methoxybenzoate, 236 mg (1 mmol) of 1,2-dibromobenzene, 38 mg of copper(I) iodide (0.2 mmol), and 212 mg (2 mmol) of sodium carbonate were successively added to a 10 mL reaction tube. The tube was sealed and reacted at 150 °C for 36 h. After the reaction was stopped, 1 mL of ethylene glycol, 14 mg (0.05 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 74 mg (1.3 mmol) of cyclopropylamine were added. The tube was sealed again and reacted at 110 °C for 6 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. The product was purified by silica gel column chromatography to obtain 173 mg of 3-methoxy-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one, with a yield of 72%.

[0071] 1 H NMR (600 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 6.98–6.85 (m, 4H), 6.54 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.7, 2.1 Hz, 1H), 3.76 (d, J = 1.0 Hz, 3H). 13 C NMR (150 MHz, DMSO) δ 167.9, 163.7, 152.1, 139.4, 134.6, 130.3, 124.7, 123.4, 121.5, 120.1, 115.3, 107.9, 103.3, 55.7.

[0072] Example 11: Synthesis of 3-(trifluoromethyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one

[0073]

[0074] 285 mg (1.3 mmol) of methyl 2-amino-4-(trifluoromethyl)benzoate, 236 mg (1 mmol) of 1,2-dibromobenzene, 38 mg of copper(I) iodide (0.2 mmol), and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube. The tube was sealed and reacted at 150 °C for 36 h. After the reaction was stopped, 1 mL of ethylene glycol, 14 mg (0.05 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 102 mg of aqueous ammonia solution (25% by mass, 1.5 mmol) were added. The tube was sealed again and reacted at 110 °C for 6 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. After purification by silica gel column chromatography, 222 mg of 3-(trifluoromethyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one was obtained with a yield of 80%.

[0075] 1 H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.03–6.92 (m, 4H). 13 C NMR (150 MHz, DMSO) δ 167.1, 151.2, 139.4, 134.1, 133.6, 133.4, 133.2, 133.0, 129.8, 126.8, 126.4, 125.3, 125.0, 124.0, 123.2, 122.0, 121.4, 120.5, 117.1, 117.1, 117.1, 117.1, 116.2, 116.2, 116.1, 116.1.

[0076] Example 12: Synthesis of 8-methoxy-11-phenyl-5H-dibenzo[b,e][1,4]diazepine

[0077]

[0078] ​256 mg (1.3 mmol) of 2-aminobenzophenone, 313 mg (1 mmol) of 2-bromo-1-iodo-4-methoxybenzene, 19 mg (0.1 mmol) of copper(I) iodide, and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 120 °C for 4 h. After the reaction was stopped, 2 mL of ethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 340 mg of ammonia water (mass fraction 25%, 5 mmol) were added, sealed, and reacted at 80 °C for 3 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 8-methoxy-11-phenyl-5H-dibenzo[b,e][1,4]diazepine 258 mg, yield 86%.

[0079] 1 1H NMR (600 MHz, Chloroform-d) δ 7.71 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 7.0 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.00 (d, J = 7.7 Hz, 1H), 6.92 (dd, J = 13.8, 6.1 Hz, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 3.2 Hz, 2H), 4.91 (s, 1H), 3.78 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 170.3, 156.7, 155.2, 141.8, 141.3, 135.9, 132.3, 132.1, 130.1, 129.7, 128.0, 127.4, 122.3, 120.3, 119.6, 113.3, 112.5, 55.6.

[0080] Example 13: Synthesis of 11-phenyl-7-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine Synthesis

[0081]

[0082] 256 mg (1.3 mmol) of 2-aminobenzophenone, 351 mg (1 mmol) of 4-bromo-3-iodobenzotrifluoride, 19 mg (0.1 mmol) of cuprous iodide, and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 120 °C for 4 h. After stopping the reaction, 1 mL of diethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 340 mg of ammonia water (mass fraction 25%, 5 mmol) were added, sealed, and reacted at 90 °C for 3 h. After stopping the reaction, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 11-phenyl-7-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine 277 mg, yield 82%.

[0083] 1 H NMR (600 MHz, Chloroform-d) δ 7.73–7.69 (m, 2H), 7.50–7.44 (m, 1H), 7.42 (dd, J = 8.2, 6.7 Hz, 2H), 7.39–7.31 (m, 2H), 7.29 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (dd, J = 7.7, 1.6 Hz, 1H), 7.01–6.95 (m, 2H), 6.84–6.79 (m, 1H), 5.09 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 171.4, 153.9, 143.8, 143.0, 140.7, 132.5, 132.4, 130.6, 129.7, 128.8, 128.6, 128.4, 128.1, 127.5, 126.7, 124.9, 123.1, 122.9, 121.3, 121.1, 121.1, 121.1, 121.0, 120.0, 116.8, 116.8, 116.8, 116.7.

[0084] Example 14: Synthesis of 11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]diazepine

[0085]

[0086] ​302 mg (1.3 mmol) of 2-amino-4-chlorobenzophenone, 283 mg (1 mmol) of o-iodobromobenzene, 38 mg (0.2 mmol) of copper(I) iodide, and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 100 °C for 4 h. After the reaction was stopped, 1 mL of diethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 74 mg (1.3 mmol) of cyclopropylamine were added, sealed, and reacted at 90 °C for 3 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 11-(4-chlorophenyl)-5H-dibenzo[b,e][1,4]diazepine 252 mg, yield 83%.

[0087] 1 H NMR (600 MHz, Chloroform-d) δ 7.66 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.31 (td, J = 7.5, 1.8 Hz, 2H), 7.08–7.02 (m, 2H), 7.00–6.90 (m, 2H), 6.80 (d, J = 7.9 Hz, 1H), 6.74–6.69 (m, 1H), 5.07 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 168.4, 154.6, 142.6, 140.5, 139.5, 136.1, 132.2, 132.0, 130.9, 128.7, 128.2, 127.1, 127.1, 124.3, 122.6, 119.9, 119.8.

[0088] Example 15: Synthesis of 6-phenyl-11H-benzo[e]pyrido[3,2-b][1,4]diazepine Synthesis

[0089]

[0090] 256 mg (1.3 mmol) of 2-aminobenzophenone, 284 mg (1 mmol) of 3-bromo-2-iodopyridine, 19 mg (0.1 mmol) of cuprous iodide, and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 120 °C for 4 h. After stopping the reaction, 1 mL of diethylene glycol, 3 mg (0.01 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 340 mg of ammonia water (mass fraction 25%, 5 mmol) were added, sealed, and reacted at 90 °C for 3 h. After the reaction stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled under reduced pressure, and purified by silica gel column chromatography to obtain 6-phenyl-11H-benzo[e]pyrido[3,2-b][1,4]diazepine 211 mg, with a yield of 78%.

[0091] 1 H NMR (600 MHz, Chloroform-d) δ 7.94 (d, J = 4.1 Hz, 1H), 7.69 (d, J = 7.0 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.37–7.32 (m, 1H), 7.05–6.98 (m, 2H), 6.95 (t, J = 7.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 171.3, 153.2, 151.8, 144.5, 140.8, 136.9, 135.4, 132.6, 132.4, 130.4, 129.7, 128.1, 127.1, 122.5, 120.5, 120.0.

[0092] Example 16: Synthesis of 5,12-dihydro-13H-benzo[e]naphtho[2,3-b][1,4]diazepin -13-one

[0093]

[0094] 266 mg (1.2 mmol) of 2-amino-3-bromonaphthalene, 262 mg (1 mmol) of methyl 2-iodobenzoate, 190 mg of copper(I) iodide (1 mmol), and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 30 h. After the reaction was stopped, 1 mL of ethylene glycol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 102 mg of aqueous ammonia solution (25% by mass, 1.5 mmol) were added, sealed, and reacted at 110 °C for 6 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 179 mg of 5,12-dihydro-13H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-one, with a yield of 69%. -13-one 179 mg, yield 69%.

[0095] 1 H NMR (600 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.30 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.45 (s, 2H), 7.43–7.37 (m, 1H), 7.32 (dt, J = 21.2, 7.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H). 13 C NMR (150 MHz, DMSO) δ 167.0, 148.5, 139.3, 132.8, 131.5, 130.1, 130.1, 129.3, 126.1, 125.5, 124.7, 124.0, 121.9, 120.4, 118.8, 117.0, 114.4.

[0096] Example 17: Synthesis of 4H-benzo[e]thieno[3,4-b][1,4]diazepin-9(10H)-one

[0097]

[0098] 227 mg (1.5 mmol) of methyl anthranilate, 242 mg (1 mmol) of 3,4-dibromothiophene, 30 mg (0.3 mmol) of cuprous chloride, and 112 mg (2 mmol) of potassium hydroxide were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 20 h. After the reaction was stopped, 2 mL of ethylene glycol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added, sealed, and reacted at 100 °C for 8 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 147 mg of 4H-benzo[e]thieno[3,4-b][1,4]diazepin-9(10H)-one, with a yield of 68%.

[0099] 1 H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.32 (s, 1H), 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.31 (ddd, J = 8.1, 7.1, 1.7 Hz, 1H), 6.90–6.82 (m, 2H), 6.65 (d, J = 3.7 Hz, 1H), 6.51 (d, J = 3.7 Hz, 1H). 13 C NMR (150 MHz, DMSO) δ 166.0, 148.0, 139.9, 133.7, 133.3, 131.3, 121.5, 120.6, 118.8, 108.7, 104.9.

[0100] Example 18: Synthesis of Benzo[6,7][1,4]diazepino[3,2,1-hi]indol-5(4H)-one

[0101]

[0102] 255 mg (1.3 mmol) of 7-bromoindole, 262 mg (1 mmol) of methyl 2-iodobenzoate, 38 mg (0.2 mmol) of cuprous iodide, and 276 mg (2 mmol) of potassium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 150 °C for 18 h. After the reaction was stopped, 2 mL of ethylene glycol, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 114 mg (2 mmol) of cyclopropylamine were added, sealed, and reacted at 100 °C for 8 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 164 mg of benzo[6,7][1,4]diazepino[3,2,1-hi]indol-5(4H)-one, with a yield of 70%.

[0103] 1 1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.08 (dd, J = 19.5, 5.8 Hz, 2H), 7.53 (s, 2H), 7.15 (p, J = 3.5 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.95 (t, J = 7.7 Hz, 1H), 6.71 (dd, J = 15.5, 5.5 Hz, 2H). 13 13C NMR (150 MHz, DMSO) δ 165.2, 139.9, 135.1, 134.9, 132.6, 129.0, 127.1, 126.5, 124.2, 123.3, 122.7, 120.3, 115.4, 111.4, 107.8.

[0104] Example 19: Synthesis of 2-chlorodibenzo[b,f][1,4]oxazin-11(10H)-one -11(10H)-one synthesis

[0105]

[0106] 296 mg (1 mmol) of methyl 2-iodo-5-chlorobenzoate, 173 mg (1 mmol) of o-bromophenol, 2 mL of dimethyl sulfoxide, 38 mg (0.2 mmol) of copper(I) iodide, 424 mg (2 mmol) of potassium phosphate, and 25 mg (0.2 mmol) of picolinic acid were successively added to a 10 mL reaction tube, sealed, and reacted at 120 °C for 24 h. After stopping the reaction, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. After purification by silica gel column chromatography, 239 mg of methyl 2-(2-bromophenoxy)-5-chlorobenzoate was obtained with a yield of 70%.

[0107] 1 1H NMR (600 MHz, Chloroform-d) δ 7.92 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (dd, J = 8.8, 2.6 Hz, 1H), 7.28–7.22 (m, 1H), 7.02 (td, J = 7.7, 1.5 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 164.7, 154.3, 153.7, 134.0, 133.5, 131.8, 128.9, 128.7, 125.1, 123.8, 121.2, 119.3, 114.2, 52.5.

[0108] 342 mg (1 mmol) of the intermediate, 19 mg (0.1 mmol) of cuprous iodide, 424 mg (2 mmol) of potassium phosphate, 28 mg (0.1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, 114 mg (2 mmol) of cyclopropylamine, and 2 mL of ethylene glycol were successively added to a 10 mL reaction tube, sealed, and reacted at 100 °C for 8 h. After the reaction stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled under reduced pressure, and purified by silica gel column chromatography to obtain 198 mg of 2-chlorodibenzo[b,f][1,4]oxa -11(10H)-one, with a yield of 81%.

[0109] 1 H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 8.7, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24–7.13 (m, 3H). 13 C NMR (150 MHz, DMSO) δ 163.9, 157.0, 149.6, 133.5, 130.2, 130.0, 128.9, 126.8, 125.6, 124.9, 122.2, 121.2, 120.8.

[0110] Example 20: Synthesis of 10,11-dihydrodibenzo[b,f][1,4]oxa-11-one

[0111]

[0112] 215 mg (1 mmol) of methyl 2-bromobenzoate, 643 mg (5 mmol) of o-chlorophenol, 2 mL of dimethyl sulfoxide, 38 mg (0.2 mmol) of cuprous iodide, 424 mg (2 mmol) of potassium phosphate, and 25 mg (0.2 mmol) of 2-pyridinecarboxylic acid were successively added to a 10 mL reaction tube, sealed, and reacted at 130 °C for 24 h. After the reaction stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was distilled under reduced pressure, and purified by silica gel column chromatography to obtain 197 mg of methyl 2-(2-chlorophenoxy)benzoate, with a yield of 75%.

[0113] 11H NMR (600 MHz, Chloroform-d) δ 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.51–7.41 (m, 2H), 7.19 (dt, J = 15.8, 7.7 Hz, 2H), 7.05 (t, J = 7.7 Hz, 1H), 6.87 (dd, J = 46.5, 8.2 Hz, 2H), 3.82 (d, J = 1.5 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.0, 155.6, 153.1, 133.7, 132.1, 130.7, 127.9, 125.0, 124.3, 123.8, 122.7, 120.1, 119.2, 52.2。

[0114] 262 mg (1 mmol) of the intermediate, 190 mg (1 mmol) of cuprous iodide, 276 mg (2 mmol) of potassium carbonate, 275 mg (1 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, 114 mg (2 mmol) of cyclopropylamine, and 2 mL of ethylene glycol were successively added to a 10 mL reaction tube, sealed, and reacted at 100 °C for 24 h. After the reaction stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 10,11-dihydrodibenzo[b,f][1,4]oxazin-11-one with a yield of 79%.

[0115] 1 1H NMR (600 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.82–7.75 (m, 1H), 7.61 (dt, J = 8.6, 4.2 Hz, 1H), 7.33 (tdd, J = 13.0, 8.2, 4.8 Hz, 3H), 7.18 (d, J = 4.6 Hz, 2H), 7.15–7.10 (m, 1H). 13 13C NMR (150 MHz, DMSO) δ 166.3, 159.4, 150.9, 134.9, 131.9, 131.6, 126.4, 126.2, 125.9, 125.7, 122.1, 121.8, 121.1.

[0116] Example 21: Synthesis of dibenzo[b,f][1,4]thiazepin-11-[10H]one -11-[10H]one synthesis

[0117]

[0118] 215 mg (1 mmol) of methyl 2-bromobenzoate, 227 mg (1.2 mmol) of o-bromothiophenol, 2 mL of ethylene glycol, 38 mg (0.2 mmol) of cuprous iodide, 276 mg (2 mmol) of potassium carbonate, and 55 mg (0.2 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide were successively added to a 10 mL reaction tube, sealed, and reacted at 20 °C for 18 h. After the reaction was stopped, 114 mg (2 mmol) of cyclopropylamine was added, sealed, and reacted at 80 °C for 36 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain dibenzo[b,f][1,4]thiazepine -11-[10H]one, 148 mg, yield 65%.

[0119] 1 H NMR (600 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 18.1, 7.7 Hz, 2H), 7.46 (dt, J = 23.9, 7.5 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, DMSO) δ 168.9, 140.4, 138.3, 136.8, 133.0, 132.5, 131.9, 131.8, 130.3, 129.4, 129.4, 125.9, 123.7.

[0120] Example 22: Synthesis of 2-chlorodibenzo[b,f][1,4]thiazepine -11-[10H]one

[0121]

[0122] 296 mg (1 mmol) of methyl 2-iodo-5-chlorobenzoate, 227 mg (1.2 mmol) of o-bromothiophenol, 2 mL of ethylene glycol, 38 mg (0.2 mmol) of cuprous iodide, 276 mg (2 mmol) of potassium carbonate, and 55 mg (0.2 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide were successively added to a 10 mL reaction tube, sealed, and reacted at 120 °C for 2 h. After the reaction was stopped, 114 mg (2 mmol) of cyclopropylamine was added, sealed, and reacted at 150 °C for 12 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 2-chlorodibenzo[b,f][1,4]thiazepine -11-[10H]Ketone 183 mg, yield 70%.

[0123] 1 H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.67 (s, 1H), 7.60–7.51 (m, 3H), 7.39 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H). 13 C NMR (150 MHz, DMSO) δ 167.5, 140.1, 139.9, 135.8, 134.2, 133.7, 133.1, 132.2, 131.2, 130.6, 129.1, 126.1, 123.9.

[0124] Example 23: Synthesis of 8-cyano-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one

[0125]

[0126] 196 mg (1.3 mmol) of methyl 2-aminobenzoate, 308 mg (1 mmol) of 2-bromo-4-cyano-1-iodobenzene, 38 mg of copper(I) iodide (0.2 mmol), and 212 mg (2 mmol) of sodium carbonate were successively added to a 10 mL reaction tube, sealed, and reacted at 130 °C for 20 h. After the reaction was stopped, 1 mL of diethylene glycol, 138 mg (0.5 mmol) of N-carbazolyl-1H-pyrrole-2-carboxamide, and 340 mg of ammonia water (25% by mass, 5 mmol) were added, sealed, and reacted at 110 °C for 5 h. After the reaction was stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 160 mg of 8-cyano-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin -11-one, yield 68%.

[0127] 1 H NMR (600 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.45 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.29 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H). 1313C NMR (150 MHz, DMSO) δ 167.5, 148.5, 144.4, 134.3, 132.9, 130.4, 129.1, 124.7, 122.3, 121.8, 120.7, 119.8, 119.3, 104.7.

[0128] Application: Synthesis of Quetiapine

[0129]

[0130] The target product dibenzo[b,f][1,4]thiazepin-11-[10H]one (227 mg, 1 mmol) obtained in Example 21, 168 mg (1.1 mmol) of phosphorus oxychloride, 61 mg (0.5 mmol) of N,N-dimethylaniline, and 5 mL of toluene were successively added to a 10 mL reaction tube, sealed, and reacted at 110 °C for 8 h. After stopping the reaction, the reaction solution was directly evaporated to dryness, and the residue was placed in a 10 mL flask. Then, 191 mg (1.1 mmol) of 2-[2-(1-piperazinyl)ethoxy]ethanol and 5 mL of xylene were added, and the mixture was refluxed for 5 h. After the reaction stopped, water was added, and the mixture was extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography to obtain 249 mg of quetiapine with a yield of 65%.

[0131] 1 1H NMR (600 MHz, Chloroform-d) δ 7.47 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 (td, J = 15.8, 14.9, 8.3 Hz, 3H), 7.13 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 5.05 (s, 1H), 3.89–3.28 (m, 10H), 2.74–2.53 (m, 6H). 13 13C NMR (150 MHz, CDCl3) δ 160.1, 148.4, 139.5, 133.6, 131.8, 131.7, 130.5, 128.7, 128.5, 127.9, 127.5, 124.9, 122.5, 72.0, 66.9, 61.4, 57.3, 52.4, 52.4.

Claims

1. Synthesis method of dibenzo-diazine or oxazine or thiazine compounds, characterized in that The reaction equation is as follows: ​ wherein (Het)Ar-X is selected from R1 is I or Br or NH2; R2 is -OCH3 or -OCH2CH3 or phenyl or p-chlorophenyl; R3 is selected from any one of hydrogen, trifluoromethyl, methoxy, fluorine, chlorine, and methyl; R4 is O or phenyl or p-chlorophenyl; R5 is Br or Cl or NH2 or SH or OH; R6 is selected from any one of hydrogen, trifluoromethyl, trifluoromethoxy, cyano, methoxy, fluorine, chlorine, and methyl; X is I or Br or Cl; Y is N or NH or S or O, and Z is N or NH; It includes the following steps: Using an aromatic amine, aromatic phenol or aromatic thiol and an aromatic halide as raw materials, heating in a solvent in the presence of a copper salt and a base to carry out a coupling reaction to generate a diarylamine, diaryl ether or diaryl sulfide intermediate; then adding a ligand and an amine source, and under heating conditions, the diaryl ether intermediate undergoes an amination reaction under the catalysis of a copper salt and spontaneously cyclizes to form the target product; the copper salt is selected from any one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper acetate, copper bromide, copper chloride, copper sulfate; the amine source is selected from any one or more of ammonia water, methanol solution of ammonia, cyclopropylamine, ammonium chloride; the ligand is selected from N-carbazolyl-1H-pyrrole-2-carboxamide.

2. The method according to claim 1, wherein The molar ratio of the aromatic amine, aromatic phenol or aromatic thiol, aromatic halide, copper salt and base is (1-5):1:(0.1-1):(1-5); the molar ratio of the diaryl ether intermediate, ligand, and amine source is 1:0.01-0.5:1-5, and the concentration of the intermediate is 0.5-5 mol / L.

3. The method according to claim 1, wherein The aromatic halide is one or two of aromatic iodide or bromide.

4. The method according to claim 1, characterized in that The base is selected from any one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate; the solvent is selected from any one or several of methanol, ethanol, diethylene glycol, ethylene glycol, polyethylene glycol 200, polyethylene glycol 400.

5. The method according to claim 1, characterized in that, When the target product is a dibenzo diazepine compound, the synthesis method includes the following one-pot two-step: Using aromatic amine and aromatic iodine or bromide as raw materials, heating to 50-150 °C in the presence of copper salt and base for a coupling reaction to generate an intermediate product; wherein, the molar ratio of aromatic iodine or bromide, aromatic amine, copper salt, and base is 1:1-5:0.1-1:1-5; adding a solvent, a ligand, and an amine source to the reaction mixture of the previous step, and under heating conditions, the intermediate product is aminated at 60-130 °C and spontaneously cyclizes to form the target product, wherein the molar ratio of the intermediate product, the ligand, and the amine source is 1:0.01-0.5:1-5, and the concentration of the intermediate product is 0.5-5 mol / L.

6. The method according to claim 1, characterized in that, When the target product is a dibenzooxazepine compound, the synthesis method comprises the following two steps: Using aromatic phenol and aromatic iodine or bromide as raw materials, dimethyl sulfoxide as the solvent, heating to 50 - 150 °C in the presence of copper(I) iodide, ligand 2-pyridinecarboxylic acid and a base to carry out a coupling reaction to generate an intermediate product; wherein the molar ratio of aromatic iodine / bromide, aromatic phenol, copper(I) iodide, 2-pyridinecarboxylic acid, and base is 1:1 - 5:0.1 - 1:0.1 - 1:1 - 5, and the concentration of aromatic phenol is 0.5 - 5 mol / L; Using the intermediate product obtained in the previous step as the raw material, in the presence of a copper salt, ligand, amine source and base, heating to 60 - 130 °C to aminate the intermediate product and then spontaneously cyclize to form the target product, wherein the molar ratio of the intermediate product, copper salt, ligand, and amine source is 1:0.01 - 1:0.01 - 0.5:1 - 5, and the concentration of the intermediate product is 0.5 - 5 mol / L.

7. The method according to claim 1, wherein When the target product is a dibenzothiazepine compound, the synthesis method includes the following one-pot two-step: using aromatic thiophenol and aromatic iodine or bromide as raw materials, adding a solvent, and carrying out a coupling reaction at 20-120 °C in the presence of a copper salt, a ligand and a base to generate an intermediate product; wherein the molar ratio of the aromatic iodine / bromide, aromatic thiophenol, copper salt, ligand, and base is 1:1-5:0.01-1:0.01-0.5:1-5; adding an amine source to the reaction mixture of the previous step, and after aminating the intermediate product at 80-150 °C under heating conditions, spontaneously cyclizing to generate the target product, wherein the molar ratio of the intermediate product to the amine source is 1:1-5.

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