Synthesis process of 5H-dibenzo [b, e] azepine-6, 11-diketone

Abstract

The invention relates to a synthesis method of 5H-dibenzo [b, e] azepine-6, 11-diketone. According to the method, a brand new intermediate is provided, 5H-dibenzo [b, e] azepine-6, 11-diketone is synthesized from the intermediate, raw materials in the method are cheap and easy to obtain, sodium azide in traditional synthesis is avoided, the reaction is green and safe, the product is unique, aftertreatment is simple and convenient, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a synthesis process of 5H-dibenzo[b,e]azepine-6,11-dione. Background Art

[0002] 5H-dibenzo[b, e]azepine-6, 11-dione is a benzazepine compound, belonging to a tricyclic compound containing a fused ring structure of two benzenes and a nitrogen-containing seven-membered heterocyclic ring in parallel. The compound has significant biological activity and is a key intermediate for many drugs in drug synthesis, and has important application value. For example, it can be used to synthesize drugs such as epinastine hydrochloride, parapine, etanercept, and mianserin.

[0003] The traditional method for synthesizing 5H-dibenzo[b, e]azepine-6, 11-dione is the anthraquinone method, which involves mixing concentrated sulfuric acid and dichloromethane, adding anthraquinone, and then adding sodium azide in batches to synthesize 5H-dibenzo[b, e]azepine-6, 11-dione through a Schmidt rearrangement reaction (patent document with publication number WO2007025938). The raw material sodium azide used in this method is easily hydrolyzed in water to form hydrazoic acid. In industrial production, hydrazoic acid reacts with certain metals (such as silver, gold, lead, copper, brass or solder) in the pipeline system to produce explosive metal azides, which are very likely to cause explosions in large-scale industrial production. At the same time, sodium azide is a highly toxic substance with a toxicity level comparable to that of cyanide. It decomposes itself to form nitrogen compounds, which damage the respiratory and nervous systems.

[0004] In summary, it is necessary to develop a new synthesis process for 5H-dibenzo[b, e]azepine-6, 11-dione to reduce the use and generation of harmful substances and meet the requirements of safety and green chemical processes. Summary of the invention

[0005] The purpose of the present invention is to provide a green synthesis process of 5H-dibenzo[b, e]azepine-6,11-dione in view of the deficiencies in the prior art.

[0006] In order to prepare 5H-dibenzo[b, e]azepine-6, 11-dione, the present invention first provides an intermediate compound, the structure of which is shown in the following formula: .

[0007] The present invention also provides a method for preparing 5H-dibenzo[b, e]azepine-6, 11-dione using the above compound. The reaction formula and preparation steps are as follows: .

[0008] 2-(2-Nitro-4, 5-dichlorobenzoyl)-benzoic acid was dechlorinated and reduced to give 2-aminobenzophenone-2-carboxylic acid, which was then amidated to give 5H-dibenzo[b, e]azepine-6, 11-dione.

[0009] Specifically, 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid is added to a solvent, and then a catalyst and an acid-binding agent are added, and then the reaction system is evacuated and filled with hydrogen. The reaction is carried out at a certain temperature for 6 to 36 hours, and the crude product is treated by alkali dissolution and acid precipitation to obtain 2-aminobenzophenone-2-carboxylic acid.

[0010] Some specific synthesis methods include dechlorination reduction of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid in the presence of an acid-binding agent and a catalyst in a solvent to obtain 2-aminobenzophenone-2-carboxylic acid.

[0011] The acid-binding agent used is any one or more of triethylamine, sodium hydroxide, ammonia water, and methanol ammonia; the catalyst is palladium carbon; and the solvent is any one or more of methanol, ethanol, isopropanol, tetrahydrofuran, and water.

[0012] Some specific synthesis methods, the mass ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the catalyst is 1:0.01~1.00, the molar ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the acid binding agent is 1:1~5, the reaction temperature is 0-60°C, and the reaction time is 6~36 h.

[0013] Some specific synthesis methods, the mass ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the catalyst is 1:0.02~0.5, the molar ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the acid binding agent is 1:1.5~5, and the reaction temperature is 10~40°C.

[0014] In some specific synthesis methods, the reaction temperature of the dechlorination reduction reaction is 20~35℃.

[0015] Some specific synthesis methods, the solvent for the amidation ring-closing reaction is one or more of xylene, benzene, o-dichlorobenzene, concentrated sulfuric acid, polyphosphoric acid, and hydrochloric acid aqueous solution, the reaction temperature is 50~200°C, and the reaction time is 2~24h.

[0016] In some specific synthesis methods, the reaction temperature of the amidation ring-closing reaction is 80~200℃.

[0017] The present invention also provides a method for preparing 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid: 2-(3, 4-dichlorobenzoyl)-benzoic acid obtained by Friedel-Crafts acylation reaction of phthalic anhydride and o-dichlorobenzene is subjected to nitration reaction to obtain 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid.

[0018] Specifically, the solvent for the Friedel-Crafts acylation reaction is any one or more of dichloromethane, chloroform, benzene, toluene, chlorobenzene, and o-dichlorobenzene.

[0019] Specifically, the Friedel-Crafts acylation reaction catalyst is any one or more of AlCl3, FeCl3, SnCl4, BF3, TiCl4, ZnCl2, HF, H2SO4, and H3PO4.

[0020] Specifically, the nitrating agent for the nitration reaction is any one or more of concentrated nitric acid, fuming nitric acid, and a mixed acid of concentrated nitric acid and concentrated sulfuric acid.

[0021] Specifically, the molar ratio of phthalic anhydride to the catalyst is 1:0.5-4, the reaction temperature of the Friedel-Crafts acylation reaction is 25-125° C., and the reaction time is 2-10 h.

[0022] Specifically, the molar ratio of 2-(3, 4-dichlorobenzoyl)-benzoic acid to the nitrating agent is 1:1-3, the reaction temperature is -10-80°C, and the reaction time is 5-30h.

[0023] Specifically, the molar ratio of 2-(3, 4-dichlorobenzoyl)-benzoic acid to the nitrating agent is 1:1-3, the reaction temperature is -10-40°C, and the reaction time is 5-30h.

[0024] Specifically, the molar ratio of 2-(3, 4-dichlorobenzoyl)-benzoic acid to the nitrating agent is 1:1-3, the reaction temperature is -10-20°C, and the reaction time is 5-30h.

[0025] Specifically, the nitrating agent of the present invention is a mixed acid of concentrated nitric acid and concentrated sulfuric acid.

[0026] Specifically, the nitrating agent of the present invention is a mixed acid of 98% sulfuric acid:98% nitric acid in a mass ratio of 1:3.

[0027] The specific post-treatment method of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid is to quench the reaction solution and then filter it, and the filter cake is slurried by a solvent to remove other by-products in the reaction. The solvent used for slurrying is any one or more of dichloromethane, petroleum ether, methanol, ethyl acetate, tetrahydrofuran, acetone, chloroform, and 1,2-dichloroethane.

[0028] The synthesis process of 5H-dibenzo[b, e]azepine-6, 11-dione adopted in the present invention has the following advantages compared with the traditional process: An intermediate with a completely new structure is provided, and 5H-dibenzo[b, e]azepine-6,11-dione is prepared by using the intermediate, thereby avoiding the use of sodium azide in traditional synthesis, reducing the risk of the reaction, and reducing the pollution to the environment and the requirements for production equipment. Since 5H-dibenzo[b, e]azepine-6,11-dione is an asymmetric structure, the traditional Schmidt rearrangement reaction cannot effectively control the position of the amino group in the lactam, and a large number of by-products with different amino positions will be generated, while the synthesis process of the present invention can selectively control the amino position. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the H NMR spectrum of compound 1.

[0030] Figure 2 is the H NMR spectrum of compound 2.

[0031] Figure 3 is the carbon NMR spectrum of compound 2.

[0032] Figure 4 is the mass spectrum of compound 2.

[0033] Figure 5 is the H NMR spectrum of compound 3.

[0034] Figure 6 is the carbon NMR spectrum of compound 3.

[0035] Figure 7 This is the H NMR spectrum of 5H-dibenzo[b, e]azepine-6, 11-dione.

[0036] Figure 8 This is the carbon NMR spectrum of 5H-dibenzo[b, e]azepine-6, 11-dione. DETAILED DESCRIPTION

[0037] The present invention is further described in detail below in conjunction with the examples, but the present invention is not limited to the following examples. The following specific example synthesis route is as follows: . Embodiment 1:

[0038] Add 250 mL of o-dichlorobenzene to a 500 mL four-necked flask, and add 140 g of anhydrous aluminum chloride at room temperature. Slowly drip 10.1 g of triethylamine using a constant pressure dropping funnel, raise the temperature to 80 °C under constant stirring, and react for 1 h. Add 59.24 g of phthalic anhydride, react for 6 h, cool the red-black liquid in the flask to room temperature, slowly pour it into 1 L of 10% hydrochloric acid ice water solution while stirring to quench the reaction, stir to completely hydrolyze the aluminum chloride, filter to obtain a yellow solid, pour it into 1 L of 5% hydrochloric acid solution at 80 °C and stir for 30 min, and recover the filtrate for reuse. Filter and wash the obtained yellow filter cake with water, filter under reduced pressure to obtain a light yellow filter cake, and dry it at 60 °C to obtain compound 1, 110.3 g of light yellow dry solid, and the yield is 93.4%. Compound 1 prepared in this example was identified by nuclear magnetic resonance (such as Figure 1 The NMR instrument model is Bruker ARX400. Embodiment 2:

[0039] Add 25 mL of o-dichlorobenzene to a 50 mL four-necked flask, and add 2.8 g of anhydrous aluminum chloride at room temperature. Slowly drip 1.01 g of triethylamine using a constant pressure dropping funnel, heat to 80 °C under constant stirring, and react for 1 h. Add 5.92 g of phthalic anhydride, react for 6 h, cool the red-black liquid in the flask to room temperature, slowly pour into 100 mL of 10% hydrochloric acid ice water solution while stirring to quench the reaction, stir to completely hydrolyze the aluminum chloride, filter to obtain a yellow solid, pour into 100 mL of 5% hydrochloric acid solution at 80 °C and stir for 30 min, and recover the filtrate for reuse. Filter by suction, wash the obtained yellow filter cake with water, and filter under reduced pressure to obtain a light yellow filter cake, which is dried at 60 °C to obtain compound 1, 2.54 g of light yellow dry solid, and the yield is 21.5%. Embodiment 3:

[0040] Add 25 mL of o-dichlorobenzene to a 50 mL four-necked flask, and add 11.2 g of anhydrous aluminum chloride at room temperature. Slowly drip 1.01 g of triethylamine using a constant pressure dropping funnel, heat to 80 °C under constant stirring, and react for 1 h. Add 5.92 g of phthalic anhydride, react for 6 h, cool the red-black liquid in the flask to room temperature, slowly pour into 100 mL of 10% hydrochloric acid ice water solution while stirring to quench the reaction, stir to completely hydrolyze the aluminum chloride, filter to obtain a yellow solid, pour into 100 mL of 5% hydrochloric acid solution at 80 °C and stir for 30 min, and recover the filtrate for reuse. Filter by suction, wash the obtained yellow filter cake with water, and filter under reduced pressure to obtain a light yellow filter cake, which is dried at 60 °C to obtain compound 1, 10.1 g of light yellow dry solid, and the yield is 85.6%. Embodiment 4:

[0041] Add 25 mL of o-dichlorobenzene to a 50 mL four-necked flask, and add 22.4 g of anhydrous aluminum chloride at room temperature. Slowly drip 1.01 g of triethylamine using a constant pressure dropping funnel, heat to 80 °C under constant stirring, and react for 1 h. Add 5.92 g of phthalic anhydride, react for 6 h, cool the red-black liquid in the flask to room temperature, slowly pour into 100 mL of 10% hydrochloric acid ice water solution while stirring to quench the reaction, stir to completely hydrolyze the aluminum chloride, filter to obtain a yellow solid, pour into 100 mL of 5% hydrochloric acid solution at 80 °C and stir for 30 min, and recover the filtrate for reuse. Filter by suction, wash the obtained yellow filter cake with water, and filter under reduced pressure to obtain a light yellow filter cake, which is dried at 60 °C to obtain compound 1, 10.5 g of light yellow dry solid, and the yield is 89.02%. Embodiment 5:

[0042] Add 47 g of 98% concentrated sulfuric acid to a 50 mL two-necked flask, and place it in an ice-water bath and stir to cool. Add 10.8 g of compound 1 to the reaction flask and stir. After the temperature in the flask drops, slowly drip in mixed acid (98% sulfuric acid, concentrated sulfuric acid: fuming nitric acid = 1:3, 2.88 g fuming nitric acid and 0.96 g concentrated sulfuric acid). After dripping, react in an ice-water bath for 22 h. Pour the reaction solution into a dropping funnel and drip in 200 mL of water to dilute the acid, and an off-white solid will precipitate. Stir to fully disperse the solid. Filter, and rinse the solid repeatedly with clean water until the washing liquid is weakly acidic. Filter, dry the solid to obtain an off-white powdery crude product. Add the crude product to a 250 mL two-necked flask, add 50 mL of dichloroethane, reflux and stir in an oil bath for 1 h, cool to room temperature, filter, and dry the filter cake at 60 ° C to obtain 8 g of compound 2 with a yield of 64.3%. Compound 2 prepared in this example was identified by NMR and mass spectrometry (eg Figure 2 , 3 , 4) NMR instrument model BrukerARX400, mass spectrometer model AB Sciex 5800 MALDI-TOF / TOF TM instrument. Embodiment 6:

[0043] Add 47 g of 98% concentrated sulfuric acid to a 50 mL two-necked flask, and place it in an ice-water bath to stir and cool. Add 10.8 g of compound 1 to the reaction flask and stir. After the temperature in the flask drops, slowly drip in mixed acid (98% sulfuric acid: concentrated sulfuric acid: fuming nitric acid = 1:3, 2.4 g fuming nitric acid and 0.8 g concentrated sulfuric acid). After dripping, react in an ice-water bath for 22 h. Pour the reaction solution into a dropping funnel and drip in 200 mL of water to dilute the acid. Heat is released and an off-white solid precipitates. Stir to fully disperse the solid. Filter, rinse the solid repeatedly with clean water until the washing liquid is weakly acidic. Filter, dry the solid to obtain an off-white powdery crude product. Add the crude product to a 250 mL two-necked flask, add 50 mL of dichloroethane, reflux and stir in an oil bath for 1 h, cool to room temperature, filter, and dry the filter cake at 60 ° C to obtain 7.2 g of compound 2 with a yield of 57.9%. Embodiment 7:

[0044] Add 47 g of 98% concentrated sulfuric acid to a 50 mL two-necked flask, and place it in an ice-water bath to stir and cool. Add 10.8 g of compound 1 to the reaction flask and stir. After the temperature in the flask drops, slowly drip in mixed acid (98% sulfuric acid concentrated sulfuric acid: fuming nitric acid, 4.8 g fuming nitric acid and 1.6 g concentrated sulfuric acid). After dripping, react in an ice-water bath for 22 h. Pour the reaction solution into a dropping funnel and drip in 200 mL of water to dilute the acid. Heat is released and an off-white solid precipitates. Stir to fully disperse the solid. Filter, rinse the solid repeatedly with clean water until the washing liquid is weakly acidic. Filter, dry the solid to obtain an off-white powdery crude product. Add the crude product to a 250 mL two-necked flask, add 50 mL of dichloroethane, reflux and stir in an oil bath for 1 h, cool to room temperature, filter, and dry the filter cake at 60 ° C to obtain 4.57 g of compound 2 with a yield of 36.7%. Embodiment 8:

[0045] Add 47 g of 98% concentrated sulfuric acid to a 50 mL two-necked flask and place it in an ice-water bath to stir and cool. Add 10.8 g of compound 1 to the reaction flask and stir. After the temperature in the flask drops, slowly drip in mixed acid (98% sulfuric acid: concentrated sulfuric acid: fuming nitric acid = 1:3, 7.2 g fuming nitric acid and 2.4 g concentrated sulfuric acid). After dripping, react in an ice-water bath for 22 h. Pour the reaction solution into a dropping funnel and drip in 200 mL of water to dilute the acid. Heat is released and an off-white solid precipitates. Stir to fully disperse the solid. Filter and rinse the solid repeatedly with clean water until the washing liquid is weakly acidic. Filter and dry the solid to obtain an off-white powdery crude product. Add the crude product to a 250 mL two-necked flask, add 50 mL of dichloroethane, place in an oil bath and reflux and stir for 1 h, cool to room temperature, filter, and dry the filter cake at 60 ° C to obtain 1.8 g of compound 2 with a yield of 14.5%. Embodiment 9:

[0046] In a 50 mL flask, add 500 mg of compound 2, 30 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at room temperature, and the reaction stops after 12 h. The reaction solution is filtered under reduced pressure, and the filtrate is spin-dried to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, the solution is dropped into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrated with 0.1 mol / L sodium hydroxide solution to a pH of 4. Filter to obtain a yellow solid, and dry it in vacuum at 60 ° C to obtain 282 mg of compound 2 with a yield of 79.5%. Compound 3 prepared in this example was identified by nuclear magnetic resonance (such as Figure 5 and 6 The NMR instrument model is Bruker ARX400.

[0047] Embodiment 10: Add 500 mg of compound 2, 10 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at room temperature, and stop the reaction after 12 hours of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Filter to obtain a yellow solid, dry it under vacuum at 60 ° C, and obtain 145 mg of compound 3 with a yield of 40.9%.

[0048] Embodiment 11: Add 500 mg of compound 2, 100 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace the hydrogen. Stir at room temperature, and stop the reaction after 12 hours of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Dry at 60 °C in vacuum. Obtain 288 mg of compound 3 with a yield of 81.2%.

[0049] Embodiment 12: Add 500 mg of compound 2, 200 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace the hydrogen. Stir at room temperature, and stop the reaction after 12 hours of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Dry at 60 °C in vacuum. Obtain 292 mg of compound 3 with a yield of 82.3%.

[0050] Embodiment 13: Add 500 mg of compound 2, 30 mg of palladium carbon, 357 mg of triethylamine and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at room temperature, and stop the reaction after 12 h of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Dry at 60 °C in vacuum. Obtain 257 mg of compound 3 with a yield of 72.4%.

[0051] Embodiment 14: Add 500 mg of compound 2, 30 mg of palladium carbon, 0.5 mL of methanol ammonia and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at room temperature, and stop the reaction after 12 h of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Dry at 60 °C in vacuum. Obtain 98 mg of compound 3 with a yield of 27.7%.

[0052] Embodiment 15: Add 500 mg of compound 2, 30 mg of palladium carbon, 140 mg of sodium hydroxide and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at room temperature, and stop the reaction after 12 hours of reaction. Filter the reaction solution under reduced pressure, and then spin dry the filtrate to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, drop the solution into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrate with 0.1 mol / L sodium hydroxide solution to a pH of 4. Dry at 60 °C in vacuum. 112 mg of compound 3 was obtained with a yield of 31.6%.

[0053] Embodiment 16: Add 500 mg of compound 2, 30 mg of palladium carbon, 0.25 mL of saturated ammonia and 5 mL of isopropanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace the hydrogen. Stir at room temperature, and the reaction stops after 12 h of reaction. The reaction solution is filtered under reduced pressure, and the filtrate is dried to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, the solution is dropped into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrated with 0.1 mol / L sodium hydroxide solution to a pH of 4. Filter to obtain a yellow solid, and dry it at 60 ° C in vacuum. 268 mg of compound 3 is obtained with a yield of 75.5%.

[0054] Embodiment 17: Add 500 mg of compound 2, 30 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol to a 50 mL flask. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at 60 ° C, and the reaction stops after 12 h of reaction. The reaction solution is filtered under reduced pressure, and the filtrate is dried to obtain a yellow-green solid. After adding 71 mg of sodium hydroxide and 20 mL of water to dissolve the yellow-green solid, the solution is dropped into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrated with 0.1 mol / L sodium hydroxide solution to a pH of 4. Filter to obtain a yellow solid, and dry it at 60 ° C in vacuum. 58 mg of compound 3 is obtained with a yield of 15.8%.

[0055] Embodiment 18: In a 50 mL flask, add 500 mg of compound 2, 30 mg of palladium carbon, 0.25 mL of saturated ammonia water and 5 mL of methanol. Connect the reaction device to a hydrogen balloon, and then discharge the gas in the device to replace hydrogen. Stir at 0 ° C, and the reaction stops after 12 h of reaction. The reaction solution is filtered under reduced pressure, 71 mg of sodium hydroxide and 20 mL of water are added to dissolve the yellow-green solid, and the solution is dropped into 2 mL of 36.5% hydrochloric acid to precipitate a large amount of yellow solid, and then back-titrated with 0.1 mol / L sodium hydroxide solution to pH 4. Filter to obtain a yellow solid, and dry it at 60 ° C in vacuum. 94 mg of compound 3 is obtained with a yield of 26.5%.

[0056] Embodiment 19: First, 24.1 g of compound 3 and 400 mL of water were added to a flask, and then 9.2 mL of 36.5% concentrated hydrochloric acid was added. The mixture was reacted under reflux for 4 h. After the reaction was completed, the mixture was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 22.0 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 98.7%. The 5H-dibenzo[b, e]azepine-6, 11-dione prepared in this example was identified by nuclear magnetic resonance (such as Figure 7 and 8 The NMR instrument model is Bruker ARX400.

[0057] Embodiment 20: First, 24.1 g of compound 3 and 400 mL of water were added into a flask, and then 4.6 mL of 36.5% concentrated hydrochloric acid was added. The reaction was carried out under reflux for 4 h. After the reaction was completed, it was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 9.7 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 43.5%.

[0058] Embodiment 21: First, 24.1 g of compound 3 and 400 mL of water were added into a flask, and then 13.8 mL of 36.5% concentrated hydrochloric acid was added. The reaction was carried out under reflux for 4 h. After the reaction was completed, it was filtered while hot, the filter cake was washed with water until it was neutral, and dried to obtain 18.3 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 82.1%.

[0059] Embodiment 22: First, 24.1 g of compound 3 and 400 mL of water were added into a flask, and then 18.4 mL of 36.5% concentrated hydrochloric acid was added. The reaction was carried out under reflux for 4 h. After the reaction was completed, it was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 15.6 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 69.9%.

[0060] Embodiment 23: First, 24.1 g of compound 3 and 400 mL of water were added into a flask, and then 9.2 mL of 36.5% concentrated hydrochloric acid was added. The reaction was carried out at 50 °C for 4 h. After the reaction was completed, it was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 8.7 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 39.0%.

[0061] Embodiment 24: First, 24.1 g of compound 3 and 400 mL of water were added into a flask, and then 9.2 mL of 36.5% concentrated hydrochloric acid was added. The reaction was carried out at 80 °C for 4 h. After the reaction was completed, it was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 17.6 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 78.9%.

[0062] Embodiment 25: 24.1 g of compound 3 was added to a flask and reacted under reflux conditions in 400 mL of xylene for 4 h. The mixture was filtered while hot, the filter cake was washed with water until neutral, and dried to obtain 19.34 g of the product 5H-dibenzo[b, e]azepine-6, 11-dione with a yield of 86.7%.

Claims

1. A compound of the formula: 。 2. A method for synthesizing 5H-dibenzo[b, e]azepine-6,11-dione, characterized in that: Using the compound described in claim 1 as a raw material, the reaction formula and reaction steps are as follows: ； 2-(2-Nitro-4, 5-dichlorobenzoyl)-benzoic acid was dechlorinated and reduced to give 2-aminobenzophenone-2-carboxylic acid, which was then amidated to give 5H-dibenzo[b, e]azepine-6, 11-dione.

3. The synthesis method according to claim 2, characterized in that In a solvent, 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid is dechlorinated and reduced in the presence of an acid-binding agent and a catalyst to obtain 2-aminobenzophenone-2-carboxylic acid; The acid-binding agent used is any one or more of triethylamine, sodium hydroxide, ammonia water, and methanol ammonia; the catalyst is palladium carbon; and the solvent is any one or more of methanol, ethanol, isopropanol, tetrahydrofuran, and water.

4. The synthesis method according to claim 3, characterized in that The mass ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the catalyst is 1:0.01-1.0, the molar ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the acid-binding agent is 1:1-5, the reaction temperature is 0-60°C, and the reaction time is 6-36 h.

5. The synthesis method according to claim 4, characterized in that The mass ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the catalyst is 1:0.02~0.40, the molar ratio of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid to the acid binding agent is 1:1.5~5, and the reaction temperature is 20~40°C.

6. The synthesis method according to claim 2, characterized in that The solvent for the amidation ring-closing reaction is one or more of xylene, benzene, o-dichlorobenzene, concentrated sulfuric acid, polyphosphoric acid, and hydrochloric acid aqueous solution. The reaction temperature is 50-200° C. and the reaction time is 2-24 hours.

7. The synthesis method according to claim 6, characterized in that The reaction temperature of the amidation ring-closing reaction is 80~200℃.

8. The synthesis method according to any one of claims 2 to 7, characterized in that: The preparation method of 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid is as follows: Phthalic anhydride and o-dichlorobenzene are reacted to obtain 2-(3, 4-dichlorobenzoyl)-benzoic acid through Friedel-Crafts acylation, which is then nitrated to obtain 2-(2-nitro-4, 5-dichlorobenzoyl)-benzoic acid.

9. The synthesis method according to claim 8, characterized in that The solvent for the Friedel-Crafts acylation reaction is any one or more of dichloromethane, chloroform, benzene, toluene, chlorobenzene, and o-dichlorobenzene; The Friedel-Crafts acylation catalyst is any one or more of AlCl3, FeCl3, SnCl4, BF3, TiCl4, ZnCl2, HF, H2SO4, and H3PO4; The nitrating agent for the nitration reaction is any one or more of concentrated nitric acid, fuming nitric acid and concentrated sulfuric acid.

10. The synthesis method according to claim 9, characterized in that The molar ratio of phthalic anhydride to catalyst is 1:0.5-4, the reaction temperature of Friedel-Crafts acylation is 25-125°C, and the reaction time is 2-10h; The molar ratio of 2-(3, 4-dichlorobenzoyl)-benzoic acid to the nitrating agent is 1:1~3, the reaction temperature is -10~80°C, and the reaction time is 5~30h.

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