CN108276419A - The synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative - Google Patents

The synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative Download PDF

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CN108276419A
CN108276419A CN201810122942.5A CN201810122942A CN108276419A CN 108276419 A CN108276419 A CN 108276419A CN 201810122942 A CN201810122942 A CN 201810122942A CN 108276419 A CN108276419 A CN 108276419A
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quinazoline
synthetic method
azoles
pyrimidine
reaction
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CN108276419B (en
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陈定奔
黄凌
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Taizhou University
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Taizhou 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • 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
    • C07D487/22—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 four or more hetero rings

Abstract

The present invention relates to the synthetic methods of a kind of azoles and quinazoline ternary fused heterocyclic derivative, more particularly to benzimidazole azoles [1,2 a] pyrimidine [1,2 c] quinazoline, pyrimidine [1,2 c] [1,2,4] triazole [1,5 a] quinazoline, pyrazoles [1,5 a] pyrimidine [1,2 c] quinazoline and purine [7,8 a] pyrimidine [1,2 c] quinazoline.This method is raw material to replace 2 (2 bromophenyl) Isosorbide-5-Nitraes, 5,6 tetrahydropyrimidines and azoles heterocycle, and under cheap metal catalysis, intermolecular C N cross-couplings/intramolecular C H bond activation ring closure reactions synthesis target ternary condensed hetero ring product occurs.This hair product is new condensed hetero ring, and the operating method is easy, until efficient yield obtains diversified product in.

Description

The synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative
Technical field
The present invention relates to the synthetic methods of a kind of azoles and quinazoline ternary fused heterocyclic derivative, more particularly to benzimidazole azoles [1,2-a] pyrimidine [1,2-c] quinazoline, pyrimidine [1,2-c] [1,2,4] triazole [1,5-a] quinazoline, pyrazoles [1,5-a] are phonetic The synthetic method of pyridine [1,2-c] quinazoline and purine [7,8-a] pyrimidine [1,2-c] quinazoline.
Background technology
Nitrogen heterocyclic ring is widely present in natural products, synthesis medicine, pesticide, functional material.Therefore in organic chemistry, Develop new method structure nitrogen heterocyclic ring to be very important.Quinazoline derivant have extensive bioactivity, such as it is antitumor, Anti-inflammatory, anti-spasm, treating tuberculosis, anti-oxidant, anti-malarial, anti-hypertension, anti-fat, antipsychotic and anti-diabetic etc. [Chandregowda,V.et al,EurJMed Chem 2009,44,3046；Alagarsamy,V.et al,Bioorg Med Chem 2007,15,235；Lakhan,R.et al,JIndian Chem Soc 1987,64,316；Hess,H.J.et al, JMed Chem 1968,11,130.].Condensed hetero ring containing quinazoline, such as pyrimidine [1,2-c] quinazoline and imidazoles [1,2-c] quinoline azoles Quinoline is equally a kind of potential drug and functional material [Ohmori, J.et al, J.Med.Chem.1997,40,2053； Rohini,R.et al,Eur.J.Med.Chem.2009,44,3330；Knowles,D.B.et al,World wide patent 2008156879,2008；Park,T.Y.et al,Korean patent,2010097797,2010.].Azoles and miaow The synthesis of azoles [1,2-c] quinazoline and pyrimidine [1,2-c] quinazoline seldom reports that existing method is defective, such as needs multistep Reaction, unstable substrate, very expensive catalyst, harsh conditions, substrate spreading range finite sum react inefficient [Yuan, G.et al,J.Org.Chem.2014,79,1749；Reddy,V.R.K.Indian J.Chem.Sect.B,1992,499.].Azoles simultaneously- 2,3- dilzydro-pyrimidines [1,2-c] quinazoline is a kind of new ternary condensed hetero ring, and the synthesis document about it is not reported.It has Hoping becomes a kind of potential bioactive substance.
Invention content
The problem to be solved in the present invention is to provide the synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative, the party For method to replace 2- (2- bromophenyls)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle are raw material, are that operating method easy " one pot " is anti- It answers.
Here, applicant is intended to explanation, the technical scheme is that in Zhejiang Province basis public good project item It is accomplished under the subsidy of mesh (LY18B020003), expresses thanks herein.
To achieve the purpose that invention, the technical solution adopted by the present invention are as follows：
The synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative, the structural formula of this kind of compound are as follows. It is characterized in that the structure of this kind of condensed hetero ring, wherein R1=hydrogen, halogen, methoxyl group, nitro, C1-C6 alkyl, R2= Hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R3=hydrogen, C1-C6Alkyl.
The synthetic method of the present invention is raw material to replace 2- (2- bromophenyls)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle, In solvent, using cheap metal as catalyst, is reacted in the case of appropriate alkali and ligand, under certain temperature, intermolecular C-N occurs Cross-coupling/intramolecular c h bond activation ring closure reaction synthesizes target ternary condensed hetero ring product.Specific reaction equation is as follows：
Preferably, the above-mentioned reaction equation replaces 2- (2- bromophenyls)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines, wherein R1=hydrogen, halogen Element, methoxyl group, nitro, C1-C6Alkyl, R2=hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R3=hydrogen, C1-C6Alkyl.
Preferably, the above-mentioned reaction equation azoles heterocycle, such as benzimidazole, triazole, pyrazoles, theophylline.
Preferably, the catalyst is cheap catalyst, such as NiCl2、FeCl3、CuCl2、CoCl2。
Preferably, the alkali is inorganic base, such as potassium carbonate, potassium phosphate, sodium hydroxide, sodium ethoxide, potassium tert-butoxide.
Preferably, the ligand, such as L-PROLINE, N, N '-dimethyl ethylenediamine, 1,10- ferrosins, N, N- dimethyl Glycine.
Preferably, the solvent, such as HMPA, DMF, DMSO, NMP, Isosorbide-5-Nitrae-dioxane, PhMe.
Preferably, reaction temperature is 50-150 DEG C.
The present invention provides " one kettle ways " of a kind of simplicity to react synthesizing new diversification azoles [1,2-a] pyrimidine [1,2-c] Quinazoline.Starting material is easy to get, and reaction condition is mild, and reaction yield reaches 40-96%.Product is expected to become a kind of potential biology Active material.
Specific implementation mode
With reference to embodiment, the present invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyls) -1,4,5,6- tetrahydropyrimidines (0.5mmol) With benzimidazoles heterocyclic (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).Syringe injects under oxygen atmosphere DMF(2.0mL).The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, three times with dichloromethane extraction, organic layer is again Three times with saturated common salt water washing, organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.It is purified, is obtained using column chromatography for separation Product 1, yield 96%.Its structure and characterize data are as follows：
13,14-dihydro-10H-benzimidazo[1,2-a]pyrimido[1,2-c]quinazoline(1)
Yellow solid；mp 180-181℃；1H NMR(500MHz,CDCl3) δ 8.37 (dd, J=8.0,1.4Hz, 1H), 8.03 (d, J=8.2Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.70-7.60 (m, 2H), 7.37-7.29 (m, 2H), 7.27 (d, J=1.3Hz, 1H), 4.25 (t, J=6.0Hz, 2H), 3.75 (t, J=5.6Hz, 2H), 2.10 (dt, J=11.6, 5.9Hz,2H)ppm；13C NMR(125MHz,CDCl3)δ147.5,143.8,142.8,134.8,132.1,131.0,127.3, 124.7,123.5,121.6,119.1,118.4,114.1,112.0,44.3,43.3,20.0ppm；HRMS(ESI):m/z calcd.ForC17H15N4(M+H)+275.1297,found 275.1292.
Embodiment 2：In Schlenk reaction tubes, be added stirring magneton, nickel chloride (6.5mg, 0.05mmol, 10mol%), Potassium phosphate (1mmol), 1,10- ferrosins (0.1mmol, 20mol%), 2- (the bromo- 4,5- Dimethoxyphenyls of 2-) -1,4,5,6- Tetrahydropyrimidine (0.5mmol) and benzimidazoles heterocyclic (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen Syringe injection DMF (2.0mL) under atmosphere.The seal of tube is reacted, 130 DEG C, is reacted 24 hours.After reaction, dichloromethane is used Three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate for extraction, is concentrated under reduced pressure.Utilize column Chromatography purifies, and obtains product 2, yield 65%.Its structure and characterize data are as follows：
8,9-dimethoxy-13,14-dihydro-10H-benzimidazo[1,2-a]pyrimido[1,2-c] quinazoline(2)
Yellow solid；mp 236-237℃；1H NMR(500MHz,CDCl3) δ 7.82 (s, 1H), 7.80 (d, J= 8.1Hz, 1H), 7.68 (d, J=7.9Hz, 1H), 7.52 (s, 1H), 7.32 (t, J=7.3Hz, 1H), 7.29-7.23 (m, 1H), 4.26 (t, J=6.0Hz, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 3.74 (t, J=5.6Hz, 2H), 2.14-2.07 (m, 2H)；13C NMR(125MHz,CDCl3)δ152.5,147.5,146.5,143.7,142.7,130.8,129.5,123.4, 121.3,118.5,111.8,111.2,108.5,97.7,56.4,56.3,44.2,43.4,20.1.HRMS(ESI):m/z calcd.For C19H19N4O2(M+H)+335.1508,found 335.1501.
Embodiment 3：In Schlenk reaction tubes, be added stirring magneton, nickel chloride (6.5mg, 0.05mmol, 10mol%), Potassium carbonate (1mmol), 1,10- ferrosins (0.1mmol, 20mol%), 2- (the bromo- phenyl of 2-) -5,5- dimethyl -1,4,5,6- Tetrahydropyrimidine (0.5mmol) and benzimidazoles heterocyclic (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen Syringe injection DMF (2.0mL) under atmosphere.The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, dichloromethane is used Three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate for extraction, is concentrated under reduced pressure.Utilize column Chromatography purifies, and obtains product 3, yield 89%.Its structure and characterize data are as follows：
13,13-dimethy-13,14-dihydro-10H-benzimidazo[1,2-a]pyrimido[1,2-c]qui nazoline(3)
Yellow solid；mp 178-179℃；1H NMR(500MHz,CDCl3) δ 8.40 (d, J=7.0Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.66 (s, 2H), 7.33-7.26 (m, 3H), 3.92 (s, 2H),3.44(s,2H),1.12(s,6H)ppm；13C NMR(125MHz,CDCl3)δ147.6,142.7,142.6,134.9, 132.1,131.1,127.4,124.7,123.6,121.6,118.7,118.4,114.1,112.0,56.7,53.926.8, 24.7ppm.HRMS(ESI):m/zcalcd.For C19H19N4(M+H)+303.1610,found 303.1604.
Embodiment 4：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 4- fluorophenyls of 2-) -5,5- dimethyl -1,4,5,6- four Hydrogen pyrimidine (0.5mmol) and benzimidazoles heterocyclic (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere Enclose lower syringe injection DMF (2.0mL).The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, extracted with dichloromethane It takes three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.Utilize column layer Separating-purifying is analysed, product 4, yield 78% are obtained.Its structure and characterize data are as follows：
13,13-dimethy-8-fluoro-13,14-dihydro-10H-benzimidazo[1,2-a]pyrimido [1,2-c]quinazoline(4)
Yellow solid；mp 213-214℃；1H NMR(500MHz,CDCl3) δ 8.40 (dd, J=8.9,6.4Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.72 (dt, J=9.8,2.4Hz, 1H), 7.66 (d, J=7.8Hz, 1H), 7.33 (t, J =7.6Hz, 1H), 7.29 (d, J=7.9Hz, 1H), 7.10-6.99 (m, 1H), 3.90 (s, 2H), 3.41 (s, 2H), 1.11 (s, 6H)；13C NMR(125MHz,CDCl3) δ 164.9 (d, J=250.0Hz, 1C), 147.7,142.7,142.1,135.5 (d, J= 11.25Hz, 1C), 130.8,129.9 (d, J=10.0Hz, 1C), 124.0,121.9,118.6,115.1,112.2 (d, J= 21.25Hz, 1C), 111.7,101.7 (d, J=27.5Hz, 1C), 56.6,53.8,26.9,24.7ppm.HRMS (ESI):m/z calcd.For C19H18FN4(M+H)+321.1515,found 303.1509.
Embodiment 5：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyls) -1,4,5,6- tetrahydropyrimidines (0.5mmol) With 1,2,4- triazoles heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).Syringe is noted under oxygen atmosphere Enter DMF (2.0mL).The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, three times with dichloromethane extraction, organic layer Use saturated common salt water washing three times again, organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.It is purified, is obtained using column chromatography for separation To product 5, yield 80%.Its structure and characterize data are as follows：
6,7-dihydro-5H-pyrimido[1,2-c][1,2,4]triazolo[1,5-a]quinazoline(5)
Yellow solid；Mp 182-183℃；1H NMR(500MHz,CDCl3) δ 8.25 (dd, J=8.1,1.1Hz, 1H), 7.88 (dd, J=8.1,0.6Hz, 1H), 7.82 (s, 1H), 7.67-7.56 (m, 1H), 7.42-7.32 (m, 1H), 4.13 (t, J=6.0Hz, 2H), 3.75-3.72 (m, 2H), 2.07 (dt, J=11.7,5.9Hz, 2H)；13C NMR(125MHz, CDCl3)δ150.8,149.3,143.6,133.5,132.4,126.6,126.2,118.9,114.5,44.2,43.2, 19.6ppm.HRMS(ESI):m/z calcd.For C12H12N5(M+H)+226.1093,found 226.1083.
Embodiment 6：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), 1,10- ferrosins (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyls of 2-) -1,4,5,6- tetrahydropyrimidines (0.5mmol) and 1,2,4- triazoles heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere Lower syringe injection DMF (2.0mL).The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, it is extracted with dichloromethane Three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.Utilize column chromatography Separating-purifying obtains product 6, yield 80%.Its structure and characterize data are as follows：
10-chloro-6,7-dihydro-5H-pyrimido[1,2-c][1,2,4]triazolo[1,5-a] quinazoline(6)
Yellow solid；Mp 196-197℃；1H NMR(500MHz,CDCl3) δ 8.25 (d, J=2.3Hz, 1H), 7.82-7.80 (m, 2H), 7.56 (dd, J=8.7,2.3Hz, 1H), 4.12 (t, J=6.0Hz, 2H), 3.73 (t, J=5.5Hz, 2H), 2.06 (dt, J=11.6,5.9Hz, 2H) ppm；13C NMR(125MHz,CDCl3)δ151.0,149.2,142.6, 132.5,132.2,132.0,126.5,120.3,116.1,44.2,43.4,19.5ppm.HRMS(ESI):m/z calcd.For C12H11ClN5(M+H)+260.0703,found 260.0696.
Embodiment 7：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 4,5- Dimethoxyphenyls of 2-) -1,4,5,6- tetrahydrochysenes Pyrimidine (0.5mmol) and 1,2,4- triazoles heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen Syringe injection DMF (2.0mL) under atmosphere.The seal of tube is reacted, 130 DEG C, is reacted 24 hours.After reaction, dichloromethane is used Three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate for extraction, is concentrated under reduced pressure.Utilize column Chromatography purifies, and obtains product 7, yield 68%.Its structure and characterize data are as follows：
10,11-dimethoxy-6,7-dihydro-5H-pyrimido[1,2-c][1,2,4]triazolo[1,5-a] quinazoline(7)
Yellow solid；Mp 217-218℃；1H NMR(500MHz,CDCl3)δ7.81(s,1H),7.65(s,1H), 7.34 (s, 1H), 4.14 (t, J=6.0Hz, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.72 (t, J=5.5Hz, 2H), 2.06 (dt, J=11.6,5.9Hz, 2H) ppm；13C NMR(125MHz,CDCl3)δ153.1,150.3,148.9,147.9,143.7, 128.3,111.2,107.2,97.1,56.5,56.3,44.1,43.4,19.7ppm.HRMS(ESI):m/z calcd.For C14H16N5O2(M+H)+286.1304,found 286.1300.
Embodiment 8：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyls) -5,5- dimethyl -1,4,5,6- tetrahydrochysenes are phonetic Pyridine (0.5mmol) and 1,2,4- triazoles heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere Enclose lower syringe injection DMF (2.0mL).The seal of tube is reacted, 100 DEG C, is reacted 24 hours.After reaction, extracted with dichloromethane It takes three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.Utilize column layer Separating-purifying is analysed, product 8, yield 59% are obtained.Its structure and characterize data are as follows：
6,6-dimethyl-6,7-dihydro-5H-pyrimido[1,2-c][1,2,4]triazolo[1,5-a] quinazoline(8)
Yellow solid；Mp 117-118℃；1H NMR(500MHz,CDCl3) δ 8.28 (dd, J=8.1,1.0Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.82 (s, 1H), 7.69-7.55 (m, 1H), 7.41-7.32 (m, 1H), 3.78 (s, 2H),3.42(s,2H),1.09(s,6H).13C NMR(125MHz,CDCl3)δ150.7,149.4,142.7,133.5,132.5, 126.8,126.2,118.4,114.5,56.6,53.9,26.4,24.6ppm.HRMS(ESI):m/z calcd.For C14H16N5 (M+H)+254.1406,found 254.1398.
Embodiment 9：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), 1,10- ferrosins (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyls of 2-) dimethyl-1,4,5-5,5-, 6- tetrahydropyrimidines (0.5mmol) and pyrazole heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere Enclose lower syringe injection DMF (2.0mL).The seal of tube is reacted, 130 DEG C, is reacted 24 hours.After reaction, extracted with dichloromethane It takes three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.Utilize column layer Separating-purifying is analysed, product 9, yield 42% are obtained.Its structure and characterize data are as follows：
10-chloro-6,6-dimethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimido[1,2-c] quinazoline(9)
Yellow solid；Mp 127-128℃；1H NMR(500MHz,CDCl3) δ 8.25 (d, J=2.3Hz, 1H), 7.94 (d, J=8.7Hz, 1H), 7.62 (d, J=1.9Hz, 1H), 7.52 (dd, J=8.7,2.3Hz, 1H), 5.66 (d, J= 2.0Hz,1H),3.40(s,2H),3.37(s,2H),1.09(s,6H)ppm.13C NMR(125MHz,CDCl3)δ141.8, 141.7,141.3,133.7,132.2,131.0,126.2,119.4,115.9,86.8,56.2,55.7,26.7, 24.8ppm.HRMS(ESI):m/z calcd.For C15H16ClN4(M+H)+287.1063,found 287.1059.
Embodiment 10：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 10- nitrobenzophenones of 2-) dimethyl-1,4,5-5,5-, 6- tetrahydropyrimidines (0.5mmol) and pyrazole heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere Enclose lower syringe injection DMF (2.0mL).The seal of tube is reacted, 130 DEG C, is reacted 24 hours.After reaction, extracted with dichloromethane It takes three times, organic layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.Utilize column layer Separating-purifying is analysed, product 10, yield 45% are obtained.Its structure and characterize data are as follows：
6,6-dimethyl-10-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimido[1,2-c] quin azoline(10)
Yellow solid；Mp 152-153℃；1H NMR(500MHz,CDCl3) δ 9.14 (d, J=2.5Hz, 1H), 8.41 (dd, J=9.0,2.5Hz, 1H), 8.11 (d, J=9.0Hz, 1H), 7.68 (d, J=1.9Hz, 1H), 5.69 (d, J= 1.9Hz,1H),3.41(s,4H),1.10(s,6H)ppm.13C NMR(125MHz,CDCl3)δ144.9,143.5,142.2, 141.1,138.9,127.0,123.2,118.8,115.5,87.3,56.3,55.7,26.7,24.8ppm.HRMS(ESI):m/z calcd.For C15H16N5O2(M+H)+298.1304,found 298.1299.
Embodiment 11：In Schlenk reaction tubes, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyls of 2-) -1,4,5,6- tetrahydropyrimidines (0.5mmol) and theophylline heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).The syringe under oxygen atmosphere Inject DMF (2.0mL).The seal of tube is reacted, 150 DEG C, is reacted 24 hours.After reaction, three times with dichloromethane extraction, organic Layer uses saturated common salt water washing three times again, and organic layer is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure.It is purified using column chromatography for separation, Obtain product 11, yield 40%.Its structure and characterize data are as follows：6-chloro-2,2,11,13-tetramethyl-2,3- dihydro-1H-purino[7,8-a]pyrimido[1,2-c]quinazoline-10,12(11H,13H)-dione(11)
Yellow solid；Mp 228-229℃；1H NMR(500MHz,CDCl3) δ 9.50 (d, J=9.0Hz, 1H), 8.28 (d, J=2.4Hz, 1H), 7.54 (dd, J=9.0,2.5Hz, 1H), 3.82 (s, 2H), 3.61 (s, 3H), 3.47 (s, 3H),3.42(s,2H),1.10(s,6H).13C NMR(125MHz,CDCl3)δ153.7,151.1,150.7,146.9,140.9, 132.4,132.0,131.9,126.0,121.4,119.8,103.6,56.6,53.9,30.1,28.9,26.7, 24.6ppm.HRMS(ESI):m/z calcd.ForC19H20ClN6O2(M+H)+399.1336,found 399.1330.
It will be recognized by those skilled in the art, can be to above-mentioned under the premise of without departing from protection scope of the present invention Embodiment is carry out various modifications, changes and is combined, and thinks that this modification, variation and combination are the models in originality thought Within enclosing.

Claims (7)

1. the synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative, the structural formula of this kind of compound is as follows, he Synthetic method to replace 2- (2- bromophenyls)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle are raw material, in a solvent, with cheap Metal is catalyst, is reacted in the case of appropriate alkali and ligand, and under certain temperature, " one pot " reaction synthesis target ternary occurs Condensed hetero ring product.
Wherein R1=hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R2=hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R3= Hydrogen, C1-C6Alkyl.
2. synthetic method according to claim 1, which is characterized in that azoles heterocycle raw material is selected from benzimidazole, triazole, pyrrole Azoles, theophylline it is one or more.
3. synthetic method according to claim 1, which is characterized in that the catalyst is selected from NiCl2、FeCl3、 CuCl2、CoCl2In it is one or more.
4. synthetic method according to claim 1, which is characterized in that the alkali such as inorganic base, such as potassium carbonate, phosphoric acid Potassium, sodium hydroxide, sodium ethoxide, potassium tert-butoxide.
5. synthetic method according to claim 1, which is characterized in that the ligand such as L-PROLINE, N, N '-dimethyl Ethylenediamine, 1,10- ferrosins, N, N- dimethylglycines.
6. synthetic method according to claim 1, which is characterized in that the solvent such as HMPA, DMF, DMSO, NMP, Isosorbide-5-Nitrae- dioxane、PhMe。
7. synthetic method according to claim 1, which is characterized in that reaction temperature is 50-150 DEG C.
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KR20100097797A (en) * 2009-02-27 2010-09-06 주식회사 엘지화학 Nitrogen containing compound and organic electronic device using the same

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KR20100097797A (en) * 2009-02-27 2010-09-06 주식회사 엘지화학 Nitrogen containing compound and organic electronic device using the same

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Title
MENG WANG ET AL.: ""Copper-catalyzed N-arylation and aerobic oxidative C–H/C–H coupling: one-pot synthesis of indoloimidazoquinoline derivatives"", 《RSC ADVANCES》 *
NITESH KUMAR NANDWANA ET AL.: ""Synthesis of novel azole-fused quinazolines via one-pot, sequential Ullmann-type coupling and intramolecular dehydrogenative C–N bonding"", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *

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