A method for synthesizing 1,4-benzodiazepine heterocyclic derivatives

Abstract

The invention discloses a method for synthesizing 1,4-benzodiazepine heterocyclic derivatives. Using catalytic amount of non-toxic reagent acetic acid as a promoter, cheap and easily available air as an oxidant, o-aminobenzylamine and o-hydroxyketone compounds are subjected to an oxidative cyclization tandem reaction under visible light at room temperature to obtain 1,4-benzodiazepine heterocyclic derivatives in one step. The method does not require the use of expensive transition metal catalysts and ligands, uses ethanol and water as reaction solvents, air as an oxidant, and does not require the addition of other large amounts of chemical oxidants, so that the product has no transition metal residues, few byproduct wastes, and is suitable as a precursor for drug preparation. The method has mild reaction conditions, high atom economy, and water is the only byproduct, and has certain research value and industrial production application potential.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a high-efficiency green synthesis method of 1,4-benzodiazepine heterocyclic derivatives. Background Art

[0002] Nitrogen-containing seven-membered heterocyclic compounds such as 1,4-benzodiazepine heterocyclic derivatives have many pharmacological and physiological activities, and their derivatives are often used as therapeutic drugs for antianxiety, antidepressants, anticonvulsants, sedation, analgesia, etc. Although there have been many reports on the synthesis methods of 1,5-benzodiazepine heterocyclic derivatives, there are still few methods for 1,4-benzodiazepine heterocyclic derivatives. Known methods include the cyclocondensation reaction of o-aminobenzylamine with o-dicarbonyl compounds, the cyclooxidation reaction of o-aminobenzylamine with 1,2-disubstituted alkynyl compounds, etc., but these methods still have many disadvantages, or require harsh conditions such as high temperature and excess oxidant, or require a long reaction time, or require a multi-step reaction process. Therefore, using stable and readily available raw materials, developing a green and efficient synthesis method for 1,4-benzodiazepine heterocyclic derivatives that is environmentally friendly, free of transition metal residues, short steps, simple and efficient is a difficult problem faced by the current fields of organic and drug synthesis, and is a very meaningful research for organic and drug synthesis chemists.

[0003] Chinese Patent 202010725330.2 discloses a method for synthesizing 5H-1,4-benzodiazepine compounds. Compared with previously reported methods, this method does not require heating and can efficiently react under room temperature, light conditions, and under the action of a catalytic amount of acid, using clean and readily available mixed ethanol and water as reaction solvents. However, compared with the original thermal catalytic reaction, this method requires high temperature reaction conditions and excess acid as a reaction solvent, which will produce a large amount of solid waste. At the same time, when synthesized in large quantities, the safety factor of the reaction is poor. Summary of the invention

[0004] The present invention provides a green and efficient synthesis method of 1,4-benzodiazepine heterocyclic derivatives. The method can use cheap, easily available, stable and low-toxic o-aminobenzylamine compounds and o-hydroxyketone compounds as raw materials, and can achieve intermolecular oxidation cyclization tandem reaction in one step to construct 1,4-benzodiazepine heterocyclic derivatives under the simple conditions of no transition metal catalyst, air as an oxidant, catalytic amount of acetic acid as a promoter, and a mixture of ethanol and water as a reaction solvent at room temperature and under the action of visible light.

[0005] To achieve the above object, the technical solution of the present invention is: a method for synthesizing a 1,4-benzodiazepine heterocyclic derivative, comprising:

[0006] At room temperature, using acetic acid as a promoter and air as an oxidant, under the action of visible light, an o-aminobenzylamine compound and an o-hydroxyketone compound undergo an oxidative cyclization tandem reaction to synthesize a 1,4-benzodiazepine heterocyclic derivative in one step.

[0007]

[0008] R is a series of substituent groups such as methyl, trifluoromethyl, halogen (-Cl, -Br), etc.;

[0009] R 1 ,R 2 It is a series of heteroaryl substituents such as methylphenyl, methoxyphenyl, chlorophenyl, iodophenyl, trifluoromethylphenyl, nitrilephenyl, naphthyl, thienyl and the like.

[0010] Preferably, the solvent of the reaction system can be any one of conventional solvents such as acetonitrile, ethyl acetate, toluene, dimethyl sulfoxide, ethanol, dioxane, ethanol, a mixture of ethanol and water, and preferably a mixture of ethanol and water.

[0011] Specifically, the volume ratio of ethanol to water is 1:1.

[0012] Preferably, the amount of acetic acid used is 10 mol% to 50 mol% of the o-aminobenzylamine compound; preferably 10 mol%.

[0013] Preferably, the reaction is carried out under 30W, 420nm LED light.

[0014] Preferably, the reaction time is 24 to 48 hours; preferably 24 hours.

[0015] Compared with the prior art, the method is under room temperature and visible light, without the use of expensive transition metal catalysts and ligands, using catalytic amounts of acetic acid as a promoter, air as an oxidant, without the need for other large amounts of oxidants, and using a mixture of ethanol and water as a reaction solvent. Therefore, the product has no transition metal residue, less byproduct waste, and is suitable as a precursor for drug preparation. The method has simple conditions, is easy to operate, has low requirements for equipment, and can use air as an economical, safe and green oxidant, and recyclable non-toxic solvent ethanol as a solvent. It has low cost, the only byproduct is water, and the atom economy is high. It has certain research value and industrial production application potential.

[0016] The present invention is further described below in conjunction with specific implementation modes. DETAILED DESCRIPTION

[0017] The present invention is specifically described below through embodiments, which are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Technical engineers in this field can make some non-essential improvements and adjustments to the present invention based on the contents of the above invention.

[0018] The invention provides a green and efficient construction method for preparing 1,4-benzodiazepine heterocyclic derivatives in one step by carrying out an oxidative cyclization tandem reaction of o-aminobenzylamine and o-hydroxyketone compounds under the action of visible light at room temperature, using a catalytic amount of acetic acid as a promoter, air as an effective oxidant, and a mixture of ethanol and water as a reaction solvent.

[0019] Example 1

[0020] Preparation of 5H-1,4-benzodiazepine Compounds from 2-aminobenzylamine and 2-hydroxy-2-phenylacetophenone

[0021]

[0022] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), benzoin (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED lamp (30 W, 420 nm) at room temperature. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 97%. 1 H NMR (400MHz, CDCl3): δ7.85-7.84(m,2H),7.55(t,J=7.8Hz,3H),7.42(dd,J=7.4,2.9Hz,2H ),7.37(d,J=5.0Hz,3H),7.27-7.21(m,4H),4.89(d,J=10.6Hz,1H),3.99(d,J=10.6Hz,1H). 13 C NMR (100MHz, CDCl3): δ164.5,160.5,147.4,137.7,137.2,130.7,130.6,129.9 ,128.6,128.5,128.4,128.3,128.3,127.9,126.9,125.6,54.7.HRMS(ESI):m / z calcd for C 21 H 16 N2(M+H):297.1347; found:297.1391.

[0023] Example 2

[0024] Preparation of 2,3-Di-p-tolyl-5H-1,Benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-tolyl-1-one

[0025]

[0026] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-tolyl-1-one (120.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 96%. 1 H NMR (400MHz, CDCl3): δ7.76(d,J=8.2Hz,2H),7.54(d,J=7.8Hz,1H),7.47-7.38(m,4H),7.23(d,J=7.4Hz,1H),7.17 (d,J=8.0Hz,2H),7.04(d,J=8.1Hz,2H),4.85(d,J=10.6Hz,1H),3.98(d,J=10.6Hz,1H),2.35(s,3H),2.26(s,4H). 13 CNMR (100MHz, CDCl3): δ164.6,160.4,147.7,140.9,139.9,135.1,134.8,130.8,129.2,129. 0,128.4,128.4,128.4,128.25,127.86,126.44,125.52,54.62,21.51,21.34.HRMS(ESI):m / z calcd for C 23 H 20 N2(M+H):325.1699; found:325.1714.

[0027] Example 3

[0028] Preparation of 2,3-Di-p-methoxyphenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-methoxyphenyl-1-one

[0029]

[0030] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-methoxyphenyl-1-one (136.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 90%. 1 H NMR (400MHz, CDCl3): δ7.81-7.75(m,2H),7.51-7.47(m,3H),7.41-7.34(m,2H),7.21-7.16(m,1H),6.88- 6.84(m,2H),6.75-6.72(m,2H),4.79(d,J=10.7Hz,1H),3.96(d,J=10.7Hz,1H),3.80(s,3H),3.74(s,3H). 13 C NMR (100MHz, CDCl3): δ163.7,161.5,160.9,159.8,147.7,130.8,130.4,130.1,1 30.0,128.5,127.8,126.3,125.4,113.9,113.6,55.4,55.2,54.4.HRMS(ESI):m / z calcd for C 23 H 20 N2O2(M+H):357.1598; found:357.1593.

[0031] Example 4

[0032] Preparation of 2,3-di-p-oxyphenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-m-methoxyphenyl-1-one

[0033]

[0034] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-dimethoxyphenyl-1-one (136.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 88%. 1H NMR (400MHz, CDCl3): δ7.56(d,J=7.6Hz,1H),7.51(s,1H),7.45-7.39(m,2H),7.31(d,J=7.2Hz,1H),7.23(d,J=7.9Hz,2H),7.09(d, J=7.8Hz,1H),7.02(d,J=7.0Hz,1H),6.93(d,J=7.8Hz,1H),6.82(d,J=8.0Hz,1H),4.89(d,J=10.5Hz,1H),3.98(s,1H),3.78(s,1H). 13 C NMR(100MHz,CD Cl3): δ164.3,160.4,159.8,159.5,147.4,139.0,138.6,130.5,129.6,129.3,128.6,12 7.9,126.9,125.6,121.6,121.3,117.1,116.3,112.3,55.3,55.2,54.6.HRMS(ESI):m / z calcd for C 23 H 20 N2O2(M+H):357.1598; found:357.1592.

[0035] Example 5

[0036] Preparation of 2,3-Di-p-chlorophenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-chlorophenyl-1-one

[0037]

[0038] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-dichlorophenyl-1-one (140.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 92%. 1H NMR (400MHz, CDCl3): δ7.75(d,J=8.1Hz,2H),7.52(d,J=7.3Hz,1H),7.44(t,J=7.4Hz,4H),7.34(d,J=7 .9Hz,2H),7.27(d,J=7.3Hz,1H),7.21(d,J=7.9Hz,2H),4.88(d,J=10.6Hz,1H),3.95(d,J=10.5Hz,1H). 13 C NMR (100MHz, CDCl3): δ162.8,158.9,147.2,136.9,136.3,135.8,135.5,130.3,12 9.7,129.5,129.6,128.9,128.7,128.1,127.9,127.3,125.7,54.8.HRMS(ESI):m / z calcd for C 21 H 14 Cl2N2(M+H):365.0607; found:365.0637.

[0039] Example 6

[0040] Preparation of 2,3-Dichlorophenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-dichlorophenyl-1-one

[0041]

[0042] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-dichlorophenyl-1-one (140.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 85%. 1 H NMR (400MHz, CDCl3): δ7.98(s,1H),7.64(s,1H),7.57(d,J=6.9Hz,1H),7.49(d,J=6.9Hz,1H),7.43(d,J=6.8Hz,2 H),7.37(d,J=7.7Hz,1H),7.31-7.25(m,4H),7.15(t,J=6.8Hz,1H),4.91(d,J=10.0Hz,1H),3.95(d,J=9.7Hz,1H). 13CNMR (100MHz, CDCl3): δ162.3,158.9,146.9,139.2,138.4,134.9,134.7,130.9,130.3,130.0 ,129.8,129.7,128.9,128.1,127.9,127.7,127.5,127.2,126.9,125.9,54.7.HRMS(ESI):m / z calcd for C 21 H 14 Cl2N2(M+H):365.0607; found:365.0637.

[0043] Example 7

[0044] Preparation of 2,3-di-o-chlorophenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-o-chlorophenyl-1-one

[0045]

[0046] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-dichlorophenyl-1-one (140.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 63%. 1 H NMR (400MHz, CDCl3): δ7.97(d,J=7.3Hz,1H),7.67(d,J=7.3Hz,1H),7.61(d,J=7.8Hz,1H),7.45(dd,J=14.8,7.3Hz,2H),7.35(d,J=7.2Hz,1H) ,7.31(t,J=8.6Hz,1H),7.18(dd,J=10.4,4.2Hz,2H),7.17-7.12(m,1H),7.04(d,J=7.8Hz,1H),4.99(d,J=10.4Hz,1H),4.32(d,J=10.2Hz,1H). 13C NMR (100MHz, CDCl3): δ163.1,161.5,146.9,137.4,136.2,132.5,132.3,131.4,131.2,130.8 ,130.7,130.4,129.1,129.0,128.8,128.1,128.0,127.0,126.8,125.8,54.7.HRMS(ESI):m / z calcd forC 21 H 14 Cl2N2(M+H):365.0607; found:365.0637.

[0047] Example 8

[0048] Preparation of 2,3-di-p-iodophenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-iodophenyl-1-one

[0049]

[0050] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-iodophenyl-1-one (232.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 87%. 1 H NMR (400MHz, CDCl3): δ7.70(d,J=7.4Hz,2H),7.58(d,J=7.6Hz,2H),7.52(d,J=5.7Hz,3 H),7.41(d,J=6.1Hz,2H),7.27-7.22(m,3H),4.88(d,J=10.3Hz,1H),3.94-3.89(m,1H). 13 C NMR (100MHz, CDCl3): δ159.3,147.2,137.9,137.7,136.8,130.1,129.9,129.8,128.8,128.0,127.4,125.8,98.1,54.7.HRMS(ESI):m / z calcdfor C 21 H 14 I2N2(M+H):548.9319; found:548.9319.

[0051] Example 9

[0052] Preparation of 2,3-Di-p-trifluoromethylphenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-trifluoromethylphenyl-1-one

[0053]

[0054] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-trifluoromethylphenyl-1-one (174.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography, with a separation yield of 83%. 1 H NMR (400MHz, CDCl3): δ7.95(d,J=8.1Hz,2H),7.61(t,J=9.7Hz,6H),7.52(d,J=8.1Hz,2H),7 .43(t,J=6.4Hz,2H),7.28(t,J=7.4Hz,1H),4.98(d,J=10.6Hz,1H),3.99(d,J=10.5Hz,1H). 13 C NMR (100MHz, CDCl3): δ162.4,158.9,147.1,140.5,140.1,132.2(q,J C-F =32.0Hz),128.9,128.7,128.6,128.1,127.8,126.1,125.8(q,J C-F =8.0Hz),125.5,125.5,125.5,125.4,125.0(q,J C-F =271.0Hz),54.8.HRMS(ESI):m / z calcd for C 23 H 14 F6N2(M+H):433.1134; found:433.1145.

[0055] Example 10

[0056] Preparation of 2,3-Di-p-nitrophenyl-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di-p-nitrophenyl-1-one

[0057]

[0058] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-nitrophenyl-1-one (174.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 87%. 1 H NMR (400MHz, CDCl3): δ7.87(d,J=7.3Hz,2H),7.66(d,J=7.0Hz,2H),7.54(d,J=9.2Hz,5H), 7.44(d,J=8.1Hz,2H), 7.33(d,J=6.2Hz,1H), 4.96(d,J=9.9Hz,1H), 3.94(d,J=10.0Hz,1H). 13 C NMR (100MHz, CDCl3): δ161.6,158.3,146.9,140.9,132.5,132.3,129.8,129.1,12 8.8,128.7,128.3,126.2,118.2,118.1,114.4,113.8,55.2.HRMS(ESI):m / zcalcd for C 23 H 14 N4(M+H):347.1291; found:347.1275.

[0059] Embodiment 11

[0060] Preparation of 2,3-di(naphthalen-1-yl)-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di(naphthalen-1-yl)ethane-1-one

[0061]

[0062] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di(naphthalen-1-yl)ethane-1-one (156.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 44%. 1H NMR (400MHz, CDCl3): δ8.87(d,J=8.3Hz,1H),8.26(d,J=8.2Hz,1H),7.84(d,J=7.9Hz,1H),7.75(d,J=8.1Hz,1H),7.67(dd,J=15.2,8.0Hz,4H),7 .59-7.54(m,2H),7.52-7.46(m,3H),7.39-7.33(m,3H),7.28(d,J=7.1Hz ,1H),7.14-7.08(m,1H),5.18(d,J=12.3Hz,1H),4.42(d,J=11.1Hz,1H). 13 C NMR (100MHz, CDCl3): δ166.8,163.3,147.3,135.3,134.3,133.9,133.6,130.9,130.7,130.4,130.2,129.7,128.8,128.6,12 8.6,128.2,128.1,127.8,127.7,127.2,126.9,126.0,125.9,124.9,124.8,124.8,124.7,124.5,55.2.HRMS(ESI):m / zcalcd for C 29 H 20 N2(M+H):397.1699; found:397.1716.

[0063] Example 12

[0064] Preparation of 2,3-di(thiophen-2-yl)-5H-1,4-benzodiazepine from 2-aminobenzylamine and 2-hydroxy-1,2-di(thiophen-2-yl)ethane-1-one

[0065]

[0066] In a 10 mL reaction tube, 2-aminobenzylamine (91.6 mg, 0.75 mmol), 2-hydroxy-1,2-di(thiophen-2-yl)ethane-1-one (112.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 52%. 1H NMR (400MHz, CDCl3): δ7.54(d,J=4.3Hz,1H),7.46(s,1H),7.37(d,J=5.7Hz,2H),7.32(d,J=4.0Hz,1H),7.26(s,1H ),7.21(t,J=7.1Hz,1H),7.09-6.99(m,2H),6.88(t,J=4.1Hz,1H),4.74(d,J=10.9Hz,1H),4.05(d,J=11.1Hz,1H). 13 CNMR (100MHz, CDCl3): δ153.9,147.3,143.8,132.3,131.4,130.9,130.4,129.2,128.7,128.1,127.8,127.6,126.8,54.3.HRMS(ESI):m / z calcd for C 17 H 12 N2S2(M+H):309.0515; found:309.0514.

[0067] Embodiment 13

[0068] Preparation of 8-methyl-2,3-diphenyl-5H-1,4-benzodiazepine from 2-amino-4-methylbenzylamine and 2-hydroxy-2-phenylacetophenone

[0069]

[0070] In a 10 mL reaction tube, 2-amino-4-methylbenzylamine (102.1 mg, 0.75 mmol), 2-hydroxy-2-phenylacetophenone (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 88%. 1 H NMR (400MHz, CDCl3): δ7.86-7.76(m,2H),7.56-7.48(m,2H),7.41-7.32(m,4H),7.28(d,J=7.7Hz,1H), 7.27-7.18(m,3H),7.05(d,J=7.7Hz,1H),4.85(d,J=10.7Hz,1H),3.94(d,J=10.7Hz,1H),2.39(s,3H). 13C NMR (100MHz, CDCl3): δ160.5,147.3,138.5,137.8,130.6,129.9,128.5,128.4,128.4,127.8,127.7,127.6,126.1,54.1,21.2.HRMS(ESI):m / z calcd for C 22 H 18 N2(M+H):311.1543; found:311.1537.

[0071] Embodiment 14

[0072] Preparation of 7-chloro-2,3-diphenyl-5H-1,4-benzodiazepine from 2-amino-5-chlorobenzylamine and 2-hydroxy-2-phenylacetophenone

[0073]

[0074] In a 10 mL reaction tube, 2-amino-5-chlorobenzylamine (117.5 mg, 0.75 mmol), 2-hydroxy-2-phenylacetophenone (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 89%. 1 H NMR (400MHz, CDCl3): δ7.84-7.78(m,2H),7.53(d,J=6.8Hz,2H),7.48(d,J=8.5Hz,1H),7.41(d,J=2 .0Hz,1H),7.36(d,J=6.7Hz,4H),7.28-7.22(m,3H),4.82(d,J=10.7Hz,1H),3.96(d,J=10.7Hz,1H). 13 C NMR (100MHz, CDCl3): δ165.1,160.9,145.9,137.4,137.1,132.8,132.4,131.9 ,130.9,130.1,129.9,129.1,128.7,128.5,127.9,126.9,54.2.HRMS(ESI):m / z calcd for C 21 H 15 ClN2(M+H):331.0997; found:331.1001.

[0075] Embodiment 15

[0076] Preparation of 6-chloro-2,3-diphenyl-5H-1,4-benzodiazepine from 2-amino-6-chlorobenzylamine and 2-hydroxy-2-phenylacetophenone

[0077]

[0078] In a 10 mL reaction tube, 2-amino-6-chlorobenzylamine (117.5 mg, 0.75 mmol), 2-hydroxy-2-phenylacetophenone (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography, with a separation yield of 71%. 1 H NMR (400MHz, CDCl3): δ7.86-7.79(m,2H),7.57-7.52(m,2H),7.45-7.41(m,1H),7.38(t,J=7.6 Hz,3H),7.32-7.26(m,4H),7.26-7.23(m,2H),5.51(d,J=10.8Hz,1H),3.73(d,J=10.8Hz,1H). 13 C NMR (100MHz, CDCl3): δ165.3,161.2,148.7,137.3,136.8,132.5,130.8,130.1 ,129.5,128.5,128.5,128.5,128.3,128.3,127.1,124.1,50.2.HRMS(ESI):m / z calcd for C 21 H 15 ClN2(M+H):331.0997; found:331.1006.

[0079] Example 16

[0080] Preparation of 7-bromo-2,3-diphenyl-5H-1,4-benzodiazepine from 2-amino-5-bromobenzylamine and 2-hydroxy-2-phenylacetophenone

[0081]

[0082] In a 10 mL reaction tube, 2-amino-5-bromobenzylamine (150.8 mg, 0.75 mmol), 2-hydroxy-2-phenylacetophenone (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography, with a separation yield of 82%. 1 H NMR (400MHz, CDCl3): δ7.85-7.78(m,2H),7.58-7.47(m,5H),7.43-7.34(m,4H),7.26-7.22(m,2H),4.81(d,J=10.7Hz,1H),3.95(d,J=10.7Hz,1H). 13 C NMR (100MHz, CDCl3): δ165.2,160.8,146.4,137.4,132.3,131.7,130.9,130.8 ,130.1,129.9,128.7,128.4,128.4,128.2,127.2,120.3,54.2.HRMS(ESI):m / z calcd forC 21 H 14 BrN2(M+H):375.0491; found:375.0503.

[0083] Embodiment 17

[0084] Preparation of 8-Trifluoromethyl-2,3-diphenyl-5H-1,4-benzodiazepine from 2-amino-4-trifluoromethylbenzylamine and 2-hydroxy-2-phenylacetophenone

[0085]

[0086] In a 10 mL reaction tube, 2-amino-4-trifluoromethylbenzylamine (142.5 mg, 0.75 mmol), 2-hydroxy-2-phenylacetophenone (106.1 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 79%. 1H NMR (400MHz, CDCl3): δ7.87-7.81(m,3H),7.53(d,J=7.5Hz,3H),7.47(d,J=7.8Hz,1H),7 .39(t,J=7.2Hz,3H),7.29-7.22(m,3H),4.93(d,J=10.7Hz,1H),4.02(d,J=10.6Hz,1H). 13 C NMR (100MHz, CDCl3): δ166.1,160.9,147.5,137.2,136.9,134.2,134.1,131.2,130 .2,128.7,128.6,128.7,128.3,123.1,123.05,122.6,122.5,54.2.HRMS(ESI):m / z calcd for C 22 H 15 F3N2(M+H):365.1260; found:365.1277.

[0087] Embodiment 18

[0088] Preparation of 7-chloro-2,3-di-p-tolyl-5H-1,4-benzodiazepine from 2-amino-5-chlorobenzylamine and 2-hydroxy-1,2-di-p-tolyl-1-one

[0089]

[0090] In a 10 mL reaction tube, 2-amino-5-chlorobenzylamine (117.0 mg, 0.75 mmol), 2-hydroxy-1,2-di-p-tolyl-1-one (120.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred for 24 h under LED light at room temperature, and after the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 90%. 1H NMR (400MHz, CDCl3): δ7.89(d,J=7.6Hz,1H),7.74(d,J=7.3Hz,2H),7.45(d,J=7.9Hz,3H),7.39(s,1H),7.33(d,J=8.4Hz,1H),7.29(d,J=7.8 Hz,1H),7.16(d,J=7.7Hz,2H),7.04(d,J=7.7Hz,2H),4.77(d,J=10.7Hz,1H),3.94(d,J=10.6Hz,1H),2.41(s,2H),2.33(s,2H),2.25(s,2H). 13 C NMR (100MHz, CDCl3): δ165.2,160.7,146.2,141.4,140.3,134.9,132.2,130.8,130.1 ,129.7,129.4,129.2,128.48,128.29,127.7,126.8,54.2,21.8,21.4.HRMS(ESI):m / z calcd for C 23 H 19 ClN2(M+H):359.1310; found:359.1325.

[0091] Embodiment 19

[0092] Preparation of 7-chloro-p-bromophenyl-5H-1,4-benzodiazepine from 2-amino-5-chlorobenzylamine and 2-hydroxy-p-bromophenyl-1-one

[0093]

[0094] In a 10 mL reaction tube, 2-amino-5-chlorobenzylamine (117.0 mg, 0.75 mmol), 2-hydroxy-p-bromophenyl-1-one (185.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 88%. 1 H NMR (400MHz, CDCl3): δ7.64(d,J=8.4Hz,2H),7.48(d,J=8.5Hz,2H),7.44(d,J= 8.4Hz,1H),7.38-7.34(m,6H),4.81(d,J=10.7Hz,1H),3.89(d,J=10.7Hz,1H). 13C NMR (100MHz, CDCl3): δ163.4,159.4,145.7,135.8,135.7,132.9,131.9,13 1.8,131.5,129.8,128.9,127.8,126.8,125.7,124.9,54.2.HRMS(ESI):m / z calcd forC 21 H 13 Br2ClN2(M+H):486.9207; found:486.9230.

[0095] Embodiment 20

[0096] Preparation of 7-chloro-2,3-di(thiophen-2-yl)-5H-1,4-benzodiazepine from 2-amino-5-chlorobenzylamine and 2-hydroxy-1,2-di(thiophen-2-yl)ethane-1-one

[0097]

[0098] In a 10 mL reaction tube, 2-amino-5-chlorobenzylamine (117.0 mg, 0.75 mmol), 2-hydroxy-1,2-di(thiophen-2-yl)ethane-1-one (112.0 mg, 0.5 mmol), AcOH (10 mol%), and a mixture of ethanol and water as a reaction solvent (1 mL, V 乙醇 :V 水 =1:1), then stirred at room temperature under LED light for 24 h. After the reaction was completed as monitored by TLC or GC-MS, the product was separated and purified by column chromatography with a separation yield of 58%. 1 H NMR (400MHz, CDCl3): δ8.06(d,J=3.6Hz,1H),7.83(d,J=4.5Hz,1H),7.54(d,J=4.8Hz,1H),7.35(d,J=4.0Hz,1H),7.26(d,J =3.3Hz,1H),7.18(t,1H),7.07(d,J=3.3Hz,1H),7.02(t,1H),6.88(t,1H),4.67(d,J=11.1Hz,1H),4.01(d,J=11.1Hz,1H). 13 C NMR (100MHz, CDCl3): δ158.3,154.2,145.8,143.7,137.6 137.3,132.6,131.6,131.3,129.5,128.8,128.1,127.9,127.6,127.1,53.6.HRMS(ESI):m / z calcd for C 17 H11 ClNN2S2(M+H):343.0125; found:343.0155.

[0099] The present invention develops an efficient and green construction method for preparing 1,4-benzodiazepine heterocyclic derivatives by oxidative cyclization cascade reaction of o-aminobenzylamine and o-hydroxyketone compounds at room temperature, with catalytic amount of acetic acid as a promoter, visible light, air as an oxidant, and a mixture of ethanol and water as a reaction solvent. The method has simple conditions, is easy to operate, uses air as an economical, safe and green oxidant, ethanol and water as solvents, has water as a byproduct, and has high atom economy. The method has low requirements for reaction conditions and has certain industrial production application potential.

Claims

1. A method for synthesizing a 1,4-benzodiazepine heterocyclic derivative, characterized in that: include: At room temperature, using acetic acid as a promoter and air as an oxidant, under the action of visible light, an o-aminobenzylamine compound and an o-hydroxyketone compound undergo an oxidative cyclization tandem reaction to synthesize a 1,4-benzodiazepine heterocyclic derivative in one step. R is any substituent group selected from methyl, trifluoromethyl and halogen; R 1 ,R 2 It is any substituted group selected from methylphenyl, methoxyphenyl, chlorophenyl, iodophenyl, trifluoromethylphenyl, nitrilephenyl, naphthyl and thienyl.

2. The method according to claim 1, characterized in that The solvent of the reaction system is any one of acetonitrile, ethyl acetate, toluene, dimethyl sulfoxide, dioxane and ethanol.

3. The method according to claim 1, characterized in that The solvent of the reaction system is a mixture of ethanol and water.

4. The method according to claim 1, characterized in that The solvent of the reaction system is a mixture of ethanol and water in a volume ratio of 1:

1.

5. The method according to claim 1, characterized in that The amount of acetic acid used is 10 mol% to 50 mol% of the o-aminobenzylamine compound.

6. The method according to claim 1, characterized in that The amount of acetic acid used is 10 mol% of the o-aminobenzylamine compound.

7. The method according to claim 1, characterized in that The reaction was carried out under 30W, 420nm LED light.

8. The method according to claim 1, characterized in that The reaction time is 24 to 48 hours.

9. The method according to claim 1, characterized in that The reaction time is 24 hours.

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