Synthesis method of dibenzodiazepine compound

Abstract

The invention relates to the field of catalytic synthesis, in particular to a synthesis method of a dibenzodiazepine compound. The copper salt catalyst, the alkali, the benzamidine, the cyclic iodonium salt and the organic solvent react and then are filtered, the filtrate is separated and purified, the dibenzodiazepine compound is obtained, the copper salt is adopted as the catalyst, the catalytic activity and selectivity are high, the dosage of the catalyst is low, harm to equipment is obviously reduced, corrosivity is controlled, industrial production is facilitated, and the method is suitable for industrial production. The synthesis method of the dibenzodiazepine compound is simple to operate, high in product yield and low in production cost, and is atom-economical and environment-friendly.

Description

Technical Field

[0001] The present invention relates to the field of catalytic synthesis, in particular to a method for synthesizing dibenzodiazepine compounds. Background Art

[0002] Benzodiazepines, an important class of fused bicyclic nitrogen heterocycles, are crucial skeletal motifs in many natural products and pharmaceuticals, and have long been a focus of interest in organic synthesis and medicine. In recent years, research into their design, synthesis, and activity analysis has advanced rapidly. Dibenzodiazepines are a particularly important class of compounds, and their derivative, clozapine, is considered an atypical antipsychotic. However, to date, research on dibenzo[d,f][1,3]diazepines is limited, and these compounds have been shown to have effects on the central nervous system. As compounds with distinctive structures, they hold great promise for diverse synthesis and the development of broader applications.

[0003] Currently, there are two main methods for synthesizing dibenzodiazepines: single-step and multi-step. The multi-step synthesis primarily involves an Ullmann coupling reaction between an o-halogenated benzoic acid / ester and o-nitroaniline, or an o-aminobenzoic acid / ester and o-nitrohalobenzene, followed by reduction of the nitro group to an amino group. Finally, an intramolecular amidation reaction forms the dibenzodiazepine structure. This method is mature and widely used, with excellent yields in each step. However, the numerous reaction steps result in only moderate overall yields. With improvements to the reaction steps and the introduction of more active palladium (Pd) catalysts, the overall yield of the target compound has been significantly improved. Some researchers have directly used the intermediate 2-[(2-aminophenyl)amino]-benzoic acid obtained in this method as a starting material to obtain dibenzodiazepines via a single intramolecular amidation reaction. Other approaches take the opposite approach, first linking the reactants through an intermolecular amidation reaction, then reducing the ortho-nitro group, and finally undergoing an intramolecular Ullmann coupling reaction to obtain the diazepine structure. Compared to the former method, this method not only fails to overcome the drawbacks of multiple reaction steps and low overall yield, but also requires the use of an acyl chloride to increase the yield of the amidation reaction. Furthermore, the influence of the amide bond complicates the subsequent intramolecular Ullmann coupling reaction, making this method less widely used. Currently, the only known one-step synthesis of dibenzodiazepines involves using o-chlorobenzoic acid and o-phenylenediamine as raw materials, using copper as a catalyst, to directly react in chlorobenzene to obtain the diazepine structure. This method offers advantages such as simple reaction steps and easy post-processing. However, due to the low yield of the target compound, despite its early publication, it has not been widely used. Given these difficulties, the development of a new, efficient route for the synthesis of dibenzodiazepines is imperative. Summary of the Invention

[0004] In view of the above-mentioned shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing dibenzodiazepine compounds with high activity, high selectivity, mild reaction conditions, greenness, environmental protection, and industrial production potential.

[0005] To achieve the above-mentioned and other related objectives, the present invention provides a method for synthesizing a dibenzodiazepine compound. A copper salt catalyst, a base, benzamidine, a cyclic iodonium salt, and an organic solvent are reacted, filtered, and the filtrate is separated and purified to obtain a dibenzodiazepine compound. The reaction formula is as follows:

[0006]

[0007] Wherein, R1 is selected from any one of phenyl, diphenylbenzyl, substituted phenyl, and piperidinyl;

[0008] R2 is selected from any one of hydrogen, phenyl, and substituted phenyl;

[0009] R3 is selected from any one of hydrogen and fluorine;

[0010] R4 is selected from any one of hydrogen, methyl, trifluoromethyl, tert-butyl, methoxy and halogen groups.

[0011] In some embodiments of the present invention, the copper salt is selected from cuprous iodide.

[0012] In some embodiments of the present invention, the base is selected from potassium carbonate or potassium acetate.

[0013] In some embodiments of the present invention, the organic solvent is selected from acetonitrile.

[0014] In some embodiments of the present invention, the copper salt catalyst is used in an amount of 8% to 12% of the molar equivalent of benzamidine.

[0015] In some embodiments of the present invention, the ratio of the organic solvent to the benzamidine is (10-15) mL:1 mmol.

[0016] In some embodiments of the present invention, the molar ratio of the cyclic iodonium salt to the benzamidine is 1.0-1.5:1.

[0017] In some embodiments of the present invention, the amount of the base used is 1.5 to 2 times the molar equivalent of benzamidine.

[0018] In some embodiments of the present invention, the reaction temperature is 75-85° C., and the reaction time is 5-8 hours.

[0019] In some embodiments of the present invention, stirring is included during the reaction.

[0020] In some embodiments of the present invention, the copper salt catalyst, base, benzamidine, cyclic iodonium salt and organic solvent are placed in a pressure reactor for reaction.

[0021] In some embodiments of the present invention, the separation and purification is performed by column chromatography to collect the target product and remove the solvent to obtain a dibenzodiazepine compound.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The synthesis method of dibenzodiazepine compounds provided by the present invention uses cuprous iodide as a catalyst, has high catalytic activity and selectivity, low catalyst dosage, significantly reduced harm to equipment, and controlled corrosion, which is beneficial to industrial production and has good application prospects.

[0024] 2. The method for synthesizing dibenzodiazepine compounds provided by the present invention has simple operation, high product yield, and low production cost. It is an atom-economical and environmentally friendly method for synthesizing dibenzodiazepine compounds and has the value of promotion and utilization. DETAILED DESCRIPTION

[0025] In order to make the purpose of the invention, technical solutions and beneficial technical effects of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0026] The inventors of the present invention have discovered that dibenzodiazepine compounds can be effectively synthesized using benzamidine and cyclic iodide as raw materials, cuprous iodide as a catalyst, and potassium carbonate or potassium acetate as an additive. The synthesis has high activity and high selectivity, and the reaction conditions are mild, green and environmentally friendly. The present invention was completed on this basis.

[0027] The present invention provides a method for synthesizing a dibenzodiazepine compound. The method comprises reacting a copper salt catalyst, a base, benzamidine (I), a cyclic iodonium salt (II) and an organic solvent, filtering the reaction mixture, and separating and purifying the filtrate to obtain a dibenzodiazepine compound (III). The reaction formula is as follows:

[0028]

[0029] Wherein, R1 is selected from any one of phenyl, diphenylbenzyl, substituted phenyl, and piperidinyl;

[0030] R2 is selected from any one of hydrogen, phenyl, and substituted phenyl;

[0031] R3 is selected from any one of hydrogen and fluorine;

[0032] R4 is selected from any one of hydrogen, methyl, trifluoromethyl, tert-butyl, methoxy and halogen groups.

[0033] In the present invention, the term "phenyl" generally refers to an unsubstituted phenyl group.

[0034] In the present invention, the term "substituted phenyl" generally refers to a phenyl group substituted by an alkoxy group, a halogen group or a nitro group.

[0035] As used herein, the term "methoxy" refers generically to a methyl-O- group wherein the bond to the parent moiety is through the ether oxygen.

[0036] In the present invention, the term "halogen" generally refers to F, Cl, Br or I.

[0037] Cuprous iodide is commonly used to synthesize biologically important compounds. This catalyst can effectively catalyze the formation and reduction of carbon-carbon double bonds to produce a variety of organic molecules. The reactions typically require relatively low reaction conditions and are relatively fast, making it widely used in organic synthesis. This catalyst is also immobilized and recyclable, effectively reducing the generation of chemical waste, making it a green catalyst with broad application prospects. In some embodiments of the present invention, the copper salt is selected from cuprous iodide.

[0038] In some embodiments of the present invention, the base is selected from potassium carbonate or potassium acetate.

[0039] In the present invention, the organic solvent is usually a good solvent for the reaction system, so that the reactants are fully dispersed and a certain concentration is guaranteed to allow the reaction to proceed smoothly. In some embodiments of the present invention, the organic solvent is selected from acetonitrile.

[0040] In some embodiments of the present invention, the amount of the copper salt catalyst is 8% to 12% of the molar equivalent of benzamidine, which can be 8% to 9%, 9% to 10%, 10% to 11% or 11% to 12%; preferably 10%.

[0041] In some embodiments of the present invention, the ratio of the organic solvent to the benzamidine is (10-15) mL:1 mmol, which may be (10-11) mL:1 mmol, (11-12) mL:1 mmol, (12-13) mL:1 mmol, (13-14) mL:1 mmol, or (14-15) mL:1 mmol.

[0042] In some embodiments of the present invention, the molar ratio of the cyclic iodonium salt to the benzamidine is 1.0-1.5:1, and may be 1.0-1.1:1, 1.1-1.2:1, 1.2-1.3:1, 1.3-1.4:1 or 1.4-1.5:1, and is preferably 1.1:1.

[0043] In some embodiments of the present invention, the amount of the base used is 1.5 to 2 times the molar equivalent of benzamidine.

[0044] In the present invention, the reaction temperature is a temperature condition that allows the reaction to proceed fully in the forward direction. In some embodiments of the present invention, the reaction temperature is 75-85°C, which can be 75-76°C, 76-77°C, 77-78°C, 78-79°C, 79-80°C, 80-81°C, 81-82°C, 82-83°C, 83-84°C, or 84-85°C; the reaction time is 5-8h, which can be 5-5.5h, 5.5-6h, 6-6.5h, 6.5-7h, 7-7.5h, or 7.5-8h.

[0045] In some embodiments of the present invention, the reaction process includes stirring, and the stirring is not particularly limited and can be mechanical stirring or magnetic stirring, preferably magnetic stirring.

[0046] In some embodiments of the present invention, the copper salt catalyst, base, benzamidine, cyclic iodonium salt and organic solvent are placed in a pressure reactor for reaction. The pressure reactor is not particularly limited as long as it can meet the reaction requirements, for example, it can be a pressure reaction tube.

[0047] In some embodiments of the present invention, the separation and purification is performed by column chromatography to collect the target product and remove the solvent to obtain the dibenzodiazepine compound. Preferably, the solvent removal method is vacuum distillation, more preferably rotary evaporation.

[0048] In some embodiments of the present invention, the eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 80 to 120:1, which can be 80 to 90:1, 90 to 100:1, 100 to 110:1, or 110 to 120:1.

[0049] The dibenzodiazepine compound synthesized by the present invention is an important heterocyclic compound, has a special seven-membered heterocyclic structure and electronic state, and has good physiological activity and multiple pharmaceutical values.

[0050] The present invention is further described below by way of examples, but the scope of the invention is not limited thereto.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition to the specific methods, devices, and materials used in the examples, any prior art methods, devices, and materials similar or equivalent to those in the examples may be used to implement the present invention, based on the knowledge of the prior art by those skilled in the art and the disclosure of this invention.

[0052] Example 1

[0053] Synthesis of 5,6-diphenyl-5H-dibenzo[d,f][1,3]diazepine

[0054] N-phenylbenzamidine (0.2 mmol, 1.0 equiv) and a cyclic iodonium salt (0.22 mmol, 1.1 equiv) were placed in a clean, dry pressure reaction tube. Potassium acetate (55.3 mg, 0.4 mmol, 2.0 equiv), cuprous iodide (3.809 mg, 0.02 mmol, 0.1 equiv), and acetonitrile (2.0 mL) were added sequentially. The reaction was stirred at 80°C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The desired product was collected by column chromatography using petroleum ether / ethyl acetate (100:1) as the eluent. The solvent was then evaporated to give 62.31 mg of the product, with a yield of 90%.

[0055] 1 HNMR(400MHz,Chloroform-d)δ8.03(ddd,J=15.6,7.1,1.8Hz,2H),7.70(d,J=7.5Hz,1H),7.54–7.47(m,1H),7.38(t,J=7.5Hz,2 H),7.35–7.17(m,8H),7.02–6.93(m,3H),6.88–6.80(m,1H),6.78–6.72(m,1H).13CNMR(101MHz,Chloroform-d)δ154.28,150.01 ,148.36,147.80,139.98,139.18,135.28,132.47,131.97,130.50,130.27,129.25,128.86,128.83,128.79,128.69,126.22,12 6.04,125.25,125.11,123.57,123.21,121.82,121.68,120.82,120.69,120.21,119.85,114.29,111.81.HRMS(APCI)m / z:[M+H] + :exactmass:347.1548;obtainedmass:347.1550.

[0056] The product structure is as follows:

[0057]

[0058] Example 2

[0059] Synthesis of 5-(2,2-diphenylethyl)-6-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0060] The synthesis method described in Example 1 was followed, except that the substrate used was N-(2,2-diphenylethyl)phenylbenzamidine (60.03 mg, 0.2 mmol), to obtain 74.74 mg of the product with a yield of 83%.

[0061] 1 HNMR(400MHz,Chloroform-d)δ8.19–8.14(m,2H),7.37–7.32(m,4H),7.32–7.26(m,4H), 7.25–7.17(m,8H),7.16–7.11(m,5H),6.83(dd,J=6.6,1.7Hz,2H),4.10(d,J=7.3Hz,2H). 13 CNMR(101MHz,Chloroform-d)δ151.14,142.84,139.38,134.98,131.12,128.62,128.56,128.49,128.41,128.36,128.34 ,126.59,126.34,126.32,125.87,123.31,120.59,120.46,119.50,113.77,111.31,57.23,52.25.HRMS(APCI)m / z:[M+H] + :exactmass:451.2174; obtainedmass:451.2178.

[0062] The product structure is as follows:

[0063]

[0064] Example 3

[0065] Synthesis of 6-phenyl-5-(4-tritylphenyl)-5H-dibenzo[d,f][1,3]diazepine

[0066] The synthesis method described in Example 1 was followed, except that the substrate used was N-(4-tritylphenyl)phenylbenzamidine (87.64 mg, 0.2 mmol), to obtain 70.59 mg of the product with a yield of 67%.

[0067] 1HNMR(400MHz,Chloroform-d)δ8.11–8.06(m,2H),7.87–7.83(m,1H),7.60–7.55(m,1H),7.4 9–7.43(m,2H),7.34–7.16(m,17H),6.99–6.92(m,6H),6.81–6.76(m,2H),6.61–6.57(m,2H). 13 CNMR(101MHz,Chloroform-d)δ154.70,150.24,146.92,146.61,146.45,145.76,143.78 ,141.77,139.95,139.02,135.59,131.98,131.63,131.42,131.23,131.10,130.34,129 .30,128.92,128.59,127.42,127.34,126.22,125.94,125.90,125.82,123.76,121.83, 120.74,120.71,120.12,120.01,119.86,114.36,112.28,64.37.HRMS(APCI)m / z:[M+H] + :exactmass:589.2644;obtainedmass:589.2649.

[0068] The product structure is as follows:

[0069]

[0070] Example 4

[0071] Synthesis of 6-phenyl-5-(piperidin-1-yl)-5H-dibenzo[d,f][1,3]diazepine

[0072] The synthesis method described in Example 1 was followed, except that the substrate used was N-(piperidin-1-yl)phenylbenzamidine (40.63 mg, 0.2 mmol), to obtain 56.51 mg of the product with a yield of 80%.

[0073] 1HNMR(400MHz,Chloroform-d)δ8.15–8.12(m,2H),7.43–7.37(m,3H),7.35(dd,J=8.3,1.9Hz ,1H),7.33–7.29(m,3H),7.29–7.25(m,2H),7.12(d,J=8.1Hz,2H),2.77(t,J=5.0Hz,4H),1.3 5–1.26(m,7H).13CNMR(101MHz,Chloroform-d)δ138.26,135.53,135.42,129.20,128.44,1 26.92,125.80,123.65,120.48,120.03,112.92,54.66,25.21,24.24.HRMS(APCI)m / z:[M+H] + :exactmass:354.1970;obtainedmass:354.1967.

[0074] The product structure is as follows:

[0075]

[0076] Example 5

[0077] Synthesis of 5-(2,6-dimethylphenyl)-6-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0078] The synthesis method described in Example 1 was followed, except that the substrate used was N-(2,6-dimethylphenyl)benzimidamidine (44.83 mg, 0.2 mmol), to obtain 56.12 mg of the product with a yield of 75%.

[0079] 1 HNMR(400MHz,Chloroform-d)δ8.13–8.09(m,2H),7.46–7.38(m,3H),7.35–7.25 (m,7H),7.20(d,J=7.7Hz,2H),7.00(d,J=7.5Hz,2H),2.18(s,4H),1.29(s,2H). 13 CNMR(101MHz,Chloroform-d)δ152.55,146.28,140.15,133.78,130.61,128.94,128.63,128 .06,126.86,126.13,125.10,122.88,121.57,119.83,114.67,18.93.HRMS(APCI)m / z:[M+H] +:exactmass:375.1861; obtainedmass:375.1866.

[0080] The product structure is as follows:

[0081]

[0082] Example 6

[0083] Synthesis of 6-(3,5-dichlorophenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0084] The synthesis method described in Example 1 was followed, except that 3,5-dichloro-N-phenylbenzamidine (52.80 mg, 0.2 mmol) was used as the substrate to obtain 52.17 mg of the product with a yield of 63%.

[0085] 1 HNMR(400MHz,Chloroform-d)δ8.11(s,1H),7.76–7.09(m,14H),6.98–6.35(m,3H). 13 CNMR(101MHz,Chloroform-d)δ145.68,144.04,139.72,139.39,134.92,134.64,131.75,130.99,130.78,130.42,130.35,129.74, 128.96,128.76,128.69,127.63,127.03,124.36,124.09,123.87,123.66,123.19,122.27,120.79,120.42.HRMS(APCI)m / z:[M+H] + :exactmass:415.0769;obtainedmass:415.0777.

[0086] The product structure is as follows:

[0087]

[0088] Example 7

[0089] Synthesis of 6-(3,5-difluorophenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0090] The synthesis method described in Example 1 was followed, except that 3,5-difluoro-N-phenylbenzamidine (46.42 mg, 0.2 mmol) was used as the substrate to obtain 45.86 mg of the product with a yield of 60%.

[0091] 1 HNMR(400MHz,Chloroform-d)δ8.16–8.05(m,2H),7.42–7.25(m,7H),7.13–6.98(m,4H),6.95–6.83(m,2H),6.80–6.75(m,1H). 13 CNMR(101MHz,Chloroform-d)δ152.10,145.72,144.06,139.35,135.32,131.73,130.98,130.73,130.25,129.85,129.71,129.62,128 .88,128.72,127.69,124.27,123.81,123.64,123.08,122.21,120.74,112.37,112.12,105.21,104.96,100.48.HRMS(APCI)m / z:[M+H] + :exactmass:383.1360; obtainedmass:383.1361.

[0092] The product structure is as follows:

[0093]

[0094] Example 8

[0095] Synthesis of 6-(4-bromophenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0096] The synthesis method described in Example 1 was followed, except that 4-bromo-N-phenylbenzamidine (54.80 mg, 0.2 mmol) was used as the substrate to obtain 55.98 mg of the product with a yield of 66%.

[0097] 1 HNMR(400MHz,Chloroform-d)δ8.08–8.01(m,2H),7.55(q,J=8.7Hz,3H),7.46–7.42(m,1H),7 .35–7.20(m,6H),7.15–7.11(m,1H),7.07–6.95(m,3H),6.88–6.83(m,1H),6.76–6.73(m,1H). 13CNMR(101MHz,Chloroform-d)δ152.99,148.98,147.76(d,J=48.4Hz),139.79,138.94,132.17,132.13,131.80,130.71,129.03,128.73,126. 79,126.34,126.14,125.35,125.26,123.61,123.48,121.99,121.49,1 20.86,120.81,120.29,119.96,114.12,111.68.HRMS(APCI)m / z:[M+H] + :exactmass:425.0653;obtainedmass:425.0655.

[0098] The product structure is as follows:

[0099]

[0100] Example 9

[0101] Synthesis of 6-(4-chlorophenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0102] The synthesis method described in Example 1 was followed, except that 4-chloro-N-phenylbenzamidine (46.01 mg, 0.2 mmol) was used as the substrate to obtain 53.22 mg of the product with a yield of 70%.

[0103] 1 HNMR(400MHz,Chloroform-d)δ8.12–8.00(m,2H),7.67–7.62(m,1H),7.40–7.18 (m,8H),7.07–6.96(m,3H),6.85(td,J=7.0,6.4,2.9Hz,1H),6.77–6.72(m,1H). 13 CNMR(101MHz,Chloroform-d)δ152.96,148.88,147.51,139.80,138.95,138.23,133.77,131.63,130.55,129.51,129.21,129.15,129 .02,128.72,126.33,126.13,125.34,123.62,121.98,121.50,120.85,120.83,120.29,119.96,114.13,111.69.HRMS(APCI)m / z:[M+H] +:exactmass:381.1159; obtainedmass:381.1156.

[0104] The product structure is as follows:

[0105]

[0106] Example 10

[0107] Synthesis of 6-(4-methoxyphenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0108] The synthesis method described in Example 1 was followed, except that 4-methoxy-N-phenylbenzamidine (45.22 mg, 0.2 mmol) was used as the substrate to obtain 69.21 mg of the product with a yield of 92%.

[0109] 1 HNMR(400MHz,Chloroform-d)δ8.13(ddd,J=18.1,5.9,2.1Hz,2H),7.74(d,J=8.3Hz,1H),7.46–7.25(m,7H),7.15–6.80(m,8H),3.91(d,J=15.5Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ161.12,153.95,139.29,132.15,131.13,128.92,128.62,127.64,126.15,125.98,124.76 ,123.49,123.07,121.63,120.81,120.57,120.16,119.84,114.21,114.15,114.13,111.83,55.46.HRMS(APCI)m / z:[M+H] + :exactmass:377.1654; obtainedmass:377.1655.

[0110] The product structure is as follows:

[0111]

[0112] Example 11

[0113] Synthesis of 6-(3-fluorophenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0114] The synthesis method described in Example 1 was followed, except that 3-fluoro-N-phenylbenzimidamide (42.82 mg, 0.2 mmol) was used as the substrate to obtain 52.44 mg of the product with a yield of 72%.

[0115] 1 HNMR(400MHz,Chloroform-d)δ8.15–8.06(m,2H),7.59(dt,J=9.8,2.1Hz,1H),7.4 7–7.24(m,8H),7.20–7.01(m,4H),6.95–6.88(m,1H),6.81(dd,J=7.6,1.7Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ161.85,152.68,148.77(d,J=3.4Hz),147.92,147.42,139.78,138.97 ,137.77,137.69,130.59,130.51,130.41,130.33,128.96,128.73,126.35,126.14,126.07,126.04,1 25.45,125.31,124.94,124.91,123.63,123.54,122.04,121.45,120.87,120.83,120.31,119.94,119 .06,118.85,117.81,117.60,117.34,117.11,116.09,115.86,114.16,111.65.HRMS(APCI)m / z:[M+H] + :exactmass:365.1454; obtainedmass:365.1451.

[0116] The product structure is as follows:

[0117]

[0118] Example 12

[0119] Synthesis of 5-(4-bromophenyl)-6-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0120] The synthesis method described in Example 1 was followed, except that 4-bromo-N-phenylbenzamidine (54.83 mg, 0.2 mmol) was used as the substrate to obtain 58.52 mg of the product with a yield of 69%.

[0121] 1HNMR(400MHz,Chloroform-d)δ8.11–8.05(m,2H),7.74–7.69(m,1H),7.66–7.53(m,1H),7.49–7.40(m ,2H),7.38–7.27(m,8H),7.15–7.11(m,1H),7.03–6.99(m,1H),6.78–6.74(m,1H),6.70–6.64(m,1H). 13 CNMR(101MHz,Chloroform-d)δ154.82,150.61,146.82,139.87,139.02,134.96,132.22,131.86,131.80,130.77,130.19,129.30,129.01,128 .91,128.68,126.31,126.22,125.37,123.62,123.47,122.61,122.05, 120.94,120.38,119.89,118.34,114.39,111.66.HRMS(APCI)m / z:[M+H] + :exactmass:425.0653;obtainedmass:425.0651.

[0122] The product structure is as follows:

[0123]

[0124] Example 13

[0125] Synthesis of 6-(4-(tert-butyl)phenyl)-5-phenyl-5H-dibenzo[d,f][1,3]diazepine

[0126] The synthesis method described in Example 1 was followed, except that the substrate used was 4-tert-butyl-N-phenylbenzamidine (50.45 mg, 0.2 mmol), to obtain 69.99 mg of the product with a yield of 87%.

[0127] 1 HNMR(400MHz,Chloroform-d)δ8.12–8.05(m,2H),7.71–7.66(m,1H),7.45(d,J=8.6Hz,1H),7.38–7.21(m ,7H),7.11–6.99(m,3H),6.97–6.92(m,1H),6.90–6.84(m,1H),6.84–6.79(m,1H),1.36(d,J=14.2Hz,9H). 13CNMR(101MHz,Chloroform-d)δ155.64,149.92,147.95,140.10,139.33,132.43,130.15,129.03,128.85,128.67,126.16,126.03,12 5.88,125.69,124.95,123.50,123.13,121.68,120.83,120.58,120.21,119.86,114.24,111.82,35.07,31.20.HRMS(APCI)m / z:[M+H] + :exactmass:403.2174; obtainedmass:403.2176.

[0128] The product structure is as follows:

[0129]

[0130] Example 14

[0131] Synthesis of 10-methoxy-5,6-diphenyl-5H-dibenzo[d,f][1,3]diazepine

[0132] The synthesis method described in Example 1 was followed, with N-phenylbenzamidine remaining unchanged, except that 2-methoxydibenzo[b,d]iodonium-5-ium trifluoromethanesulfonate (91.59 mg, 0.2 mmol) was used as the cyclic iodonium salt to obtain 35.40 mg of the product with a yield of 47%.

[0133] 1 HNMR(400MHz,Chloroform-d)δ8.05–7.98(m,1H),7.74–7.70(m,1H),7.56–7.49(m,2H),7.45–7.39(m,1H),7.35– 7.29(m,2H),7.28–7.17(m,3H),7.05–6.96(m,2H),6.93–6.84(m,3H),6.80–6.75(m,1H),3.92(d,J=11.7Hz,3H). 13CNMR(101MHz,Chloroform-d)δ158.73,158.63,155.89,154.83,148.64,147.78,138.94,138.47,138. 39,137.89,128.98,128.78,128.34,128.15,127.98,127.80,127.04,127.00,126.93,126.68,126.08 ,123.65,123.45,121.39,120.68,119.53,114.87,114.80,114.68,114.16,114.14,113.88,112.29,1 11.09,110.72,102.75,98.40,87.07,86.07,76.19,55.05,54.44,54.40,54.28.HRMS(APCI)m / z:[M+H] + :exactmass:377.1654;obtainedmass:377.1657.

[0134] The product structure is as follows:

[0135]

[0136] Example 15

[0137] Synthesis of 5,6-diphenyl-10-(trifluoromethyl)-5H-dibenzo[d,f][1,3]diazepine

[0138] The synthesis method described in Example 1 was followed, with N-phenylbenzamidine remaining unchanged, except that 2-(trifluoromethyl)dibenzo[b,d]iodonium-5-ium trifluoromethanesulfonate (99.18 mg, 0.2 mmol) was used as the cyclic iodonium salt to obtain 73.94 mg of the product with a yield of 89%.

[0139] 1 HNMR(400MHz,Chloroform-d)δ8.36–8.30(m,1H),8.13–8.05(m,1H),7.72–7.66(m,1H),7.58–7.48(m,2H),7.45–7.39(m,2H), 7.36–7.29(m,3H),7.27(d,J=3.5Hz,1H),7.26–7.22(m,1H),7.12–6.98(m,3H),6.91–6.84(m,1H),6.75(dd,J=8.4,1.3Hz,1H). 13CNMR(101MHz,Chloroform-d)δ153.90,149.16,147.92,147.46,141.52,140.62,140.56,139.96,134.71 ,132.28,131.98,130.85,130.16,129.95,129.10,129.01,128.99,128.96,128.84,127.18,127.09,126 .04,125.43,125.02,124.39,123.63,123.23,122.99,122.94,122.90,122.86,122.80,122.38,121.54, 121.42,120.54,120.17,117.91,117.87,117.35,114.41,114.34,112.03,111.67.HRMS(APCI)m / z:[M+H] + :exactmass:415.4122;obtainedmass:415.4121.

[0140] The product structure is as follows:

[0141]

[0142] Example 16

[0143] Synthesis of 11-methyl-5,6-diphenyl-5H-dibenzo[d,f][1,3]diazepine

[0144] The synthesis method described in Example 1 was followed, with N-phenylbenzamidine remaining unchanged, except that 2-methyldibenzo[b,d]iodonium-5-ium trifluoromethanesulfonate (88.34 mg, 0.2 mmol) was used as the cyclic iodonium salt to obtain 40.34 mg of the product with a yield of 56%.

[0145] 1 HNMR(400MHz,Chloroform-d)δ8.03–7.95(m,1H),7.82(d,J=11.5Hz,1H),7.71–7.66(m,1H),7.50(t,J=7.4Hz,1H),7.38(t,J=7.8Hz,2H),7.29(d,J =7.9Hz,1H),7.26–7.12(m,4H),7.05(d,J=8.3Hz,1H),6.99(t,J=7.8Hz,2 H),6.87(dd,J=12.5,8.4Hz,2H),6.79–6.75(m,1H),2.47(d,J=8.2Hz,3H). 13CNMR(101MHz,Chloroform-d)δ154.35,150.14,148.47,147.92,140.20,139.30,137.51,135. 40,132.56,131.90,131.34,130.42,130.27,130.14,129.27,128.83,128.80,128.76,128.70 ,127.45,127.37,126.11,125.85,125.06,123.74,123.50,123.10,121.75,120.91,120.51,1 20.23,120.10,119.86,119.75,114.39,114.09,111.84,111.53,21.34.HRMS(APCI)m / z:[M+H] + :exactmass:361.1705; obtainedmass:361.1707.

[0146] The product structure is as follows:

[0147]

[0148] In summary, the present invention effectively overcomes various shortcomings of the prior art and has high industrial utilization value.

[0149] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A method for synthesizing a dibenzodiazepine compound, characterized in that: The copper salt catalyst, base, benzamidine, cyclic iodonium salt and organic solvent are reacted and filtered, and the filtrate is separated and purified to obtain a dibenzodiazepine compound, and the reaction formula is as follows: Wherein, R1 is selected from any one of phenyl, diphenylbenzyl, substituted phenyl, and piperidinyl; R2 is selected from any one of hydrogen, phenyl, and substituted phenyl; R3 is selected from any one of hydrogen and fluorine; R4 is selected from any one of hydrogen, methyl, trifluoromethyl, tert-butyl, methoxy and halogen groups.

2. The synthesis method according to claim 1, wherein Include one or more of the following characteristics: (1) The copper salt is selected from cuprous iodide; (2) the base is selected from potassium carbonate or potassium acetate; (3) The organic solvent is selected from acetonitrile.

3. The synthesis method according to claim 1, wherein The usage of the copper salt catalyst is 8% to 12% of the molar equivalent of benzamidine.

4. The synthesis method according to claim 1, wherein The usage ratio of the organic solvent to the benzamidine is (10-15) mL:1 mmol.

5. The synthesis method according to claim 1, wherein The molar ratio of the cyclic iodonium salt to the benzamidine is 1.0 to 1.5:

1.

6. The synthesis method according to claim 1, wherein The amount of the base used is 1.5 to 2 times the molar equivalent of benzamidine.

7. The synthesis method according to claim 1, wherein Include one or more of the following characteristics: 1) The reaction temperature is 75-85° C. and the reaction time is 5-8 hours; 2) the reaction process includes stirring; 3) The copper salt catalyst, base, benzamidine, cyclic iodonium salt and organic solvent are placed in a pressure reactor for reaction.

8. The synthesis method according to claim 1, wherein The separation and purification is performed by column chromatography to collect the target product and remove the solvent to obtain the dibenzodiazepine compound.

9. The synthesis method according to claim 8, wherein The eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 80 to 120:

1.

10. The synthesis method according to claim 8, wherein The method for removing the solvent is reduced pressure distillation.

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