CN104804002A - Synthesis method for 9H-pyrimido(4,5-b) indole compounds - Google Patents

Synthesis method for 9H-pyrimido(4,5-b) indole compounds Download PDF

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CN104804002A
CN104804002A CN201510161043.2A CN201510161043A CN104804002A CN 104804002 A CN104804002 A CN 104804002A CN 201510161043 A CN201510161043 A CN 201510161043A CN 104804002 A CN104804002 A CN 104804002A
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mmol
kui linpyrimido
linpyrimido quinoline
dmso
phenyl
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CN104804002B (en
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范学森
李彬
张新迎
郭胜海
张举
沈娜娜
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Henan Normal University
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention discloses a synthesis method for 9H-pyrimido(4,5-b) indole compounds, and belongs to the technical field of organic synthesis. The synthesis method is characterized by comprising the following steps: dissolving 1-bromine-2-(2,2-dibromoethylene)benzene or derivatives of 1-bromine-2-(2,2-dibromoethylene)benzene, ammonia water and aldehyde compounds in an organic solvent; adding catalyst transitional metal salt and an additive; under the presence of air, carrying out a reaction at 60-100 DEG C to obtain the 9H-pyrimido(4,5-b) indole compounds. According to the synthesis method, a synthesis process is a one-pot multi-component series reaction; the operation is simple and convenient; the resource waste and environmental pollution caused by the problems such as the utilization of various reagents in multi-step reactions, and the purification treatment on reaction intermediates in all the steps, are avoided. Therefore, the synthesis method is economical, practical, environmental-friendly and novel for synthesis of the 9H-pyrimido(4,5-b) indole compounds.

Description

A kind of synthetic method of 9H-Kui Linpyrimido quinoline [4,5-b] Benzazole compounds
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of 9 h-Kui Linpyrimido quinoline [4,5- b] synthetic method of Benzazole compounds.
Background technology
Indoles and derivative thereof are a kind of alkaloids extensively existed at nature.Because this compounds has various biological activity, so be subject to the extensive concern of chemist and medicine scholar for many years always.In numerous indole derivativeses, 9 h-Kui Linpyrimido quinoline [4,5- b] indoles is the important feature unit of many function micromolecular compounds.In addition, with 9 h-Kui Linpyrimido quinoline [4,5- b] indoles be base synthesize obtain base expansion nucleosides, be also successfully introduced in oligonucleotide, and be used as bioprobe with the space structure of researching DNA and performance.About 9 h-Kui Linpyrimido quinoline [4,5- b] synthesis of Benzazole compounds, existing method mainly by carrying out functional group and obtaining on existing indoles skeleton, and this not only makes the scope of reaction substrate be restricted, and improves raw materials cost, is unfavorable for that it is applied in actual production.In view of 9 h-Kui Linpyrimido quinoline [4,5- b] importance of Benzazole compounds, further develop efficient, the economic novel method of this compounds of synthesis and have great importance.
Summary of the invention
The technical problem that the present invention solves there is provided a kind of 9 h-Kui Linpyrimido quinoline [4,5- b] synthetic method of Benzazole compounds, this synthetic method, from the raw material being simple and easy to prepare, by one pot of polycomponent cascade reaction, directly obtains 9 h-Kui Linpyrimido quinoline [4,5- b] Benzazole compounds, namely in one pot reaction, construct out indole ring and pyrimidine ring, combined coefficient is high simultaneously, and mild condition is easy to operate, wide application range of substrates, is suitable for suitability for industrialized production.
The present invention adopts following technical scheme for solving the problems of the technologies described above, and a kind of 9 h-Kui Linpyrimido quinoline [4,5- b] synthetic method of Benzazole compounds, it is characterized in that: by bromo-for 1-2-(2,2-dibromo vinyl) benzene or derivatives thereof, ammoniacal liquor and aldehyde compound be dissolved in organic solvent, then adds catalyzer transition metal salt and additive, in the presence of the air in 60-100 DEG C of reaction obtained 9 h-pyrimidine [4,5- b] Benzazole compounds, the reaction equation in this synthetic method is:
Wherein R 1for hydrogen, fluorine, chlorine, trifluoromethyl, methyl or methoxy, R 2for 1-naphthyl, 2-thienyl, phenyl or substituted-phenyl, substituting group on this substituted-phenyl phenyl ring is fluorine, chlorine, bromine, methyl, one or more in trifluoromethyl or methoxyl group, substituent position is the ortho position on phenyl ring, between position or contraposition, organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, methyl-2-pyrrolidone, Virahol or dioxane, catalyzer transition metal salt is cuprous chloride, cuprous bromide, cuprous iodide, venus crystals or cupric chloride, additive is 1, 10-phenanthroline, L-PROLINE, one or more in triethylene diamine or trimethylacetic acid.
Further restriction, bromo-2-(2, the 2-dibromo vinyl of described 1-) ratio of the amount of substance that feeds intake of benzene or derivatives thereof, ammoniacal liquor and aldehyde compound is 1:7-42:2-3.
The present invention compared with prior art has the following advantages: (1) building-up process is one pot of polycomponent cascade reaction, easy and simple to handle, avoid due to the use of plurality of reagents in polystep reaction and the wasting of resources caused the purification process etc. of each step reaction intermediate and environmental pollution; (2) building-up process is one pot of polycomponent cascade reaction, and in one pot reaction, construct out indole ring and pyrimidine ring, combined coefficient is high simultaneously; (3) raw materials used cheap and easy to get or raw material is easy to preparation; (4) reaction is carried out below 100 DEG C, and mild condition is easy and simple to handle; (5) substrate is applied widely.Therefore, the present invention is 9 h-Kui Linpyrimido quinoline [4,5- b] synthesis of Benzazole compounds provides a kind of economical and practical and novel method of environmental protection.
Embodiment
Be described in further details foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, add 5 mL saturated ammonium chloride solution cancellation reactions, be extracted with ethyl acetate (10 mL × 2), organic phase washed with water and saturated aqueous common salt wash successively afterwards, anhydrous sodium sulfate drying.Filter, be spin-dried for, cross silicagel column separation (petrol ether/ethyl acetate=10/1) and obtain white solid product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(88 mg, 55%).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.18 (t, j=7.2 Hz, 1H), 7.47-7.58 (m, 5H), 7.66 (d, j=7.2 Hz, 3H), 7.81 (d, j=7.6 Hz, 1H), 8.01 (d, j=6.4 Hz, 2H), 8.55 (d, j=6.0 Hz, 2H), 12.56 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 109.4,112.4,119.3,121.2,122.3,128.0,128.3,129.0,129.3,129.4,130.5,130.7,138.6,139.1,139.6,157.7,159.6,159.9. MS:m/z 322 [MH] +.
Embodiment 2
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 100 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(45 mg, 42%).
Embodiment 3
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and dimethyl sulfoxide (DMSO) (3 mL), then add strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(54 mg, 50%).
Embodiment 4
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and Virahol (3 mL), then add strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(40 mg, 37%).
Embodiment 5
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous chloride (0.05 mmol, 4.9 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(46 mg, 43%).
Embodiment 6
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous bromide (0.05 mmol, 7.2 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(51 mg, 48%).
Embodiment 7
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), venus crystals (0.05 mmol, 9.1 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 60 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(31 mg, 29%).
Embodiment 8
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cupric chloride (0.05 mmol, 6.8 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(34 mg, 32%).
Embodiment 9
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (6 mL), then adds strong aqua (14 mmol, 1 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(51 mg, 47%).
Embodiment 10
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and DMF (1.5 mL), then strong aqua (3.5 mmol, 0.25 mL) is added.Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(38 mg, 35%).
Embodiment 11
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1 mmol, 106 mg), cuprous iodide (0.05 mmol, 9.5 mg), 1,10-phenanthroline (0.1 mmol, 18.0 mg) and DMF (3 mL), then add strong aqua (21 mmol, 1.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(26 mg, 24%).
Embodiment 12
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2a(1 mmol, 106 mg), cuprous iodide (0.05 mmol, 9.5 mg), L-PROLINE (0.1 mmol, 11.5 mg) and DMF (3 mL), then add strong aqua (21 mmol, 1.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain product 2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3a(26 mg, 24%).
Embodiment 13
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1b(0.5 mmol, 179 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain fluoro-2, the 4-phenylbenzene-9 of white solid product 6- h-Kui Linpyrimido quinoline [4,5- b] indoles 3b(94 mg, 56%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.35-7.45 (m, 2H), 7.52-7.60 (m, 4H), 7.66-7.71 (m, 3H), 7.99 (d, j=5.6 Hz, 2H), 8.53-8.55 (m, 2H), 12.61 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 107.7,108.0,109.3,113.6,113.7,115.6,115.9,119.8,119.9,128.4,129.1,129.27,129.34,130.8,130.9,136.1,138.4,138.7,156.3,158.3,160.3,160.4. HRMS calcd for C 22h 15fN 3: 340.1250 [M+H], found:340.1242.
Embodiment 14
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1c(0.5 mmol, 188 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain chloro-2, the 4-phenylbenzene-9 of white solid product 6- h-Kui Linpyrimido quinoline [4,5- b] indoles 3c(103 mg, 58%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.48-7.67 (m, 9H), 7.98 (d, j=5.6 Hz, 2H), 8.53 (d, j=5.6 Hz, 2H), 12.69 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 108.8,114.0,120.7,121.4,125.3,127.8,128.4,129.1,129.27,129.30,130.8,130.9,138.1,138.3,138.7,158.0,160.3,160.5. HRMS calcd for C 22h 15clN 3: 356.0954 [M+H], found:356.0958.
Embodiment 15
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1d(0.5 mmol, 204 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 6-trifluoromethyl-2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3d(110 mg, 57%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.53-7.54 (m, 3H), 7.56-7.71 (m, 3H), 7.76 (d, j=8.8 Hz, 1H), 7.81-7.83 (m, 1H), 8.02-8.05 (m, 3H), 8.54-8.57 (m, 2H), 12.98 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 109.2,113.3,119.10,119.14,119.2,121.5,121.8,123.9,124.5,126.6,128.4,128.5,129.1,129.30,129.33,131.0,131.1,132.0,138.2,138.6,141.7,158.6,160.6,160.9. HRMS calcd for C 23h 15f 3n 3: 390.1218 [M+H], found:390.1200.
Embodiment 16
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1e(0.5 mmol, 185 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 6-methoxyl group-2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3e(88 mg, 50%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 3.68 (s, 3H), 7.14-7.17 (m, 1H), 7.27 (s, 1H), 7.49-7.55 (m, 4H), 7.65-7.71 (m, 3H), 8.02 (d, j=7.2 Hz, 2H), 8.54 (d, j=6.0 Hz, 2H), 12.38 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 55.8,105.8,109.4,113.2,116.5,119.8,128.3,129.0,129.1,129.4,130.6,130.7,134.2,138.6,138.8,154.4,157.8,159.6,159.7. HRMS calcd for C 23h 18n 3o:352.1450 [M+H], found:352.1458.
Embodiment 17
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1f(0.5 mmol, 177 mg), 2a(1.5 mmol, 159 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 under air oc, stirs after 30 hours, obtains white solid product 7-methyl-2,4-phenylbenzene-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3f(90 mg, 54%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 2.46 (s, 3H), 7.01 (d, j=8.0 Hz, 1H), 7.37 (s, 1H), 7.53 (d, j=7.6 Hz, 3H), 7.65-7.70 (m, 4H), 8.01 (d, j=6.4 Hz, 2H), 8.54 (d, j=6.4 Hz, 2H), 12.42 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 22.0,109.5,112.4,116.9,122.1,122.7,128.2,129.0,129.2,129.3,130.5,130.6,138.0,138.6,139.1,140.1,157.8,158.9,159.5. HRMS calcd for C 23h 18n 3: 336.1500 [M+H], found:336.1471.
Embodiment 18
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2b(1.5 mmol, 210 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(4-chloro-phenyl-)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3g(118 mg, 61%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.21 (t, j=7.6 Hz, 1H), 7.52 (t, j=7.6 Hz, 1H), 7.58-7.61 (m, 3H), 7.74 (d, j=8.4 Hz, 2H), 7.81 (d, j=8.4 Hz, 1H), 8.04 (d, j=8.0 Hz, 2H), 8.53 (d, j=8.4 Hz, 2H), 12.59 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 109.6,112.5,119.1,121.5,122.5,128.2,129.1,129.4,130.0,131.2,135.4,135.6,137.3,137.7,139.7,157.7,158.3,158.8. MS:m/z 390 [MH] +.
Embodiment 19
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2c(1.5 mmol, 277 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(4-bromophenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3h(150 mg, 63%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.22 (t, j=7.6 Hz, 1H), 7.52 (t, j=8.0 Hz, 1H), 7.59 (d, j=7.6 Hz, 1H), 7.74 (d, j=8.0 Hz, 2H), 7.81 (d, j=8.4 Hz, 1H), 7.88 (d, j=8.4 Hz, 2H), 7.97 (d, j=8.0 Hz, 2H), 8.46 (d, j=8.8 Hz, 2H), 12.60 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 109.6,112.6,119.1,121.5,122.5,124.1,124.6,128.3,130.3,131.5,132.1,132.3,137.7,138.0,139.8,157.7,158.4,158.9. MS:m/z 478 [MH] +.
Embodiment 20
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2d(1.5 mmol, 261 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(4-trifluoromethyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3i(107 mg, 47%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.22 (t, j=7.6 Hz, 1H), 7.54 (t, j=7.6 Hz, 1H), 7.61 (d, j=8.4 Hz, 1H), 7.77 (d, j=8.4 Hz, 1H), 7.90 (d, j=8.0 Hz, 2H), 8.05 (d, j=8.0 Hz, 2H), 8.23 (d, j=8.0 Hz, 2H), 8.71 (d, j=7.6 Hz, 2H), 12.72 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 110.3,112.6,118.8,121.6,122.6,125.9,126.0,126.20,126.23,127.8,128.0,128.6,128.8,128.9,130.2,134.1,140.0,142.1,142.7,148.6,157.6,157.9,158.4,162.3. HRMS calcd for C 24h 14f 6n 3: 458.1092 [M+H], found:458.1077.
Embodiment 21
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2e(1.5 mmol, 180 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(4-aminomethyl phenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3j(89 mg, 51%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 2.38 (s, 3H), 2.47 (s, 3H), 7.17 (t, j=7.6 Hz, 1H), 7.34 (d, j=8.0 Hz, 2H), 7.47-7.50 (m, 3H), 7.56 (d, j=8.8 Hz, 1H), 7.83 (d, j=8.0 Hz, 1H), 7.91 (d, j=7.6 Hz, 2H), 8.43 (d, j=8.0 Hz, 2H), 12.44 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 21.5,21.6,109.1,112.3,119.5,121.1,122.3,127.8,128.3,129.3,129.6,129.7,136.0,136.3,139.5,140.2,140.4,157.8,159.7,160.0. MS:m/z 350 [MH] +.
Embodiment 22
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2f(1.5 mmol, 204 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(4-p-methoxy-phenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3k(99 mg, 52%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 3.83 (s, 3H), 3.89 (s, 3H), 7.08 (d, j=8.8 Hz, 2H), 7.17 (t, j=7.2 Hz, 1H), 7.22 (d, j=8.8 Hz, 2H), 7.44-7.48 (m, 1H), 7.54 (d, j=8.0 Hz, 1H), 7.87 (d, j=8.4 Hz, 1H), 7.99 (d, j=8.8 Hz, 2H), 8.48 (d, j=8.4 Hz, 2H), 12.40 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 55.7,55.8,108.4,112.2,114.3,114.5,119.6,121.0,122.2,127.5,129.9,130.9,131.1,131.4,139.3,157.8,159.3,159.7,161.2,161.6. MS:m/z 382 [MH] +.
Embodiment 23
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2g(1.5 mmol, 186 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(3-fluorophenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3l(103 mg, 58%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.19-7.23 (m, 1H), 7.32-7.37 (m, 1H), 7.47-7.56 (m, 2H), 7.58-7.61 (m, 2H), 7.70-7.82 (m, 3H), 7.86 (d j=7.6 Hz, 1H), 8.21-8.24 (m, 1H), 8.38 (d, j=7.6 Hz, 1H). 12.65 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 109.8,112.6,114.5,114.7,116.0,116.2,117.3,117.46,117.54,117.7,118.9,121.5,122.4,124.3,125.5,128.4,131.1,131.2,131.3,131.4,139.8,140.9,141.0,141.1,141.2,157.6,158.0,158.5,161.6,161.8,164.0,164.2. HRMS calcd for C 22h 14f 2n 3: 358.1156 [M+H], found:358.1142.
Embodiment 24
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2h(1.5 mmol, 180 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(3-aminomethyl phenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3m(92 mg, 53%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 2.42 (s, 3H), 2.47 (s, 3H), 7.16-7.20 (m, 1H), 7.32 (d, j=8.0 Hz, 1H), 7.40-7.51 (m, 3H), 7.56 (t, j=7.6 Hz, 2H), 7.77-7.79 (m, 3H), 8.33-8.35 (m, 2H), 12.50 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 21.53,21.66,109.4,112.4,119.4,121.2,122.3,125.6,126.4,127.9,128.87,128.93,129.1,129.8,131.0,131.4,138.1,138.5,138.6,139.1,139.6,157.7,159.9,160.0. HRMS calcd for C 24h 20n 3: 350.1657 [M+H], found:350.1669.
Embodiment 25
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2i(1.5 mmol, 180 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-bis-(2-aminomethyl phenyl)-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3n(84 mg, 48%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, CDCl 3) δ: 2.31 (s, 3H), 2.62 (s, 3H), 6.14 (d, j=7.6 Hz, 1H), 7.06 (t, j=7.6 Hz, 1H), 7.21 (t, j=8.0 Hz, 1H), 7.25-7.26 (m, 1H), 7.37-7.51 (m, 6H), 7.55 (d, j=7.2 Hz, 1H), 7.92 (d, j=7.2 Hz, 1H), 12.86 (s, 1H). 13c NMR (100 MHz, CDCl 3) δ: 19.6,20.6,111.1,111.8,119.3,121.1,122.1,126.1,126.3,127.4,128.9,129.0,129.2,130.5,130.7,131.2,135.9,137.0,137.9,138.8,139.6,156.8,160.7,162.9. MS:m/z 350 [MH] +.
Embodiment 26
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2j(1.5 mmol, 234 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-dinaphthyl-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3o(97 mg, 46%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 6.81 (d, j=8.0 Hz, 1H), 6.97 (t, j=7.6 Hz, 1H), 7.44 (t, j=8.0 Hz, 2H), 7.52-7.55 (m, 2H), 7.58 (t, j=7.6 Hz, 2H), 7.65 (t, j=7.6 Hz, 1H), 7.75-7.78 (m, 2H), 7.88 (d, j=7.2 Hz, 1H), 7.99-8.02 (m, 1H), 8.05 (d, j=8.4 Hz, 1H), 8.11 (d, j=8.4 Hz, 1H), 8.17-8.21 (m, 2H), 8.88-8.90 (m, 1H), 12.68 (s, 1H). 13c NMR (100 MHz, CDCl 3) δ: 111.5,112.1,119.1,121.0,122.6,123.6,125.4,125.57,125.62,125.9,126.1,126.2,126.8,127.0,127.3,128.4,128.50,128.52,129.2,129.9,130.7,131.5,133.8,134.2,135.9,137.2,138.7,157.0,159.8,162.4. HRMS calcd for C 30h 20n 3: 422.1657 [M+H], found:422.1642.
Embodiment 27
By the method described in embodiment 1, add in the reaction tubes of 25 mL 1a(0.5 mmol, 170 mg), 2k(1.5 mmol, 168 mg), cuprous iodide (0.05 mmol, 9.5 mg), triethylene diamine (0.1 mmol, 11.2 mg), trimethylacetic acid (0.5 mmol, 51 mg) and N, dinethylformamide (3 mL), then adds strong aqua (7 mmol, 0.5 mL).Be heated to 80 DEG C under air, stir after 30 hours, obtain white solid product 2,4-dithienyl-9 h-Kui Linpyrimido quinoline [4,5- b] indoles 3p(67 mg, 40%) (petrol ether/ethyl acetate=10/1).The characterization data of this compound is as follows: 1h NMR (400 MHz, DMSO- d 6) δ: 7.21-7.24 (m, 1H), 7.28 (t, j=7.6 Hz, 1H), 7.38-7.40 (m, 1H), 7.50-7.57 (m, 2H), 7.74 (d, j=5.6 Hz, 1H), 7.95 (d, j=4.8 Hz, 1H), 7.99-8.00 (m, 1H), 8.13 (d, j=4.0 Hz, 1H), 8.28 (d, j=8.0 Hz, 1H), 12.59 (s, 1H). 13c NMR (100 MHz, DMSO- d 6) δ: 107.6,112.4,119.3,121.5,122.4,128.0,128.7,128.8,128.9,129.8,130.6,131.2,139.5,142.3,144.1,152.9,156.5,157.8. HRMS calcd for C 18h 12n 3s 2: 334.0472 [M+H], found:334.0460.
Embodiment above describes ultimate principle of the present invention, principal character and advantage.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; under the scope not departing from the principle of the invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the scope of protection of the invention.

Claims (2)

1. one kind 9 h-Kui Linpyrimido quinoline [4,5- b] synthetic method of Benzazole compounds, it is characterized in that: by bromo-for 1-2-(2,2-dibromo vinyl) benzene or derivatives thereof, ammoniacal liquor and aldehyde compound be dissolved in organic solvent, then adds catalyzer transition metal salt and additive, in the presence of the air in 60-100 DEG C of reaction obtained 9 h-pyrimidine [4,5- b] Benzazole compounds, the reaction equation in this synthetic method is:
，
Wherein R 1for hydrogen, fluorine, chlorine, trifluoromethyl, methyl or methoxy, R 2for 1-naphthyl, 2-thienyl, phenyl or substituted-phenyl, substituting group on this substituted-phenyl phenyl ring is fluorine, chlorine, bromine, methyl, one or more in trifluoromethyl or methoxyl group, substituent position is the ortho position on phenyl ring, between position or contraposition, organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, methyl-2-pyrrolidone, Virahol or dioxane, catalyzer transition metal salt is cuprous chloride, cuprous bromide, cuprous iodide, venus crystals or cupric chloride, additive is 1, 10-phenanthroline, L-PROLINE, one or more in triethylene diamine or trimethylacetic acid.
2. according to claim 19 h-Kui Linpyrimido quinoline [4,5- b] synthetic method of Benzazole compounds, it is characterized in that: bromo-2-(2, the 2-dibromo vinyl of described 1-) ratio of the amount of substance that feeds intake of benzene or derivatives thereof, ammoniacal liquor and aldehyde compound is 1:7-42:2-3.
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CN105198883A (en) * 2015-10-12 2015-12-30 河南师范大学 Synthesis method of 11H-indolo [3,2-c] quinoline compounds
CN110156792A (en) * 2019-06-28 2019-08-23 广州暨南生物医药研究开发基地有限公司 A kind of pyrimido benzazolyl compounds and its preparation method and application
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