CN108276419B - 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 PDFInfo
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- CN108276419B CN108276419B CN201810122942.5A CN201810122942A CN108276419B CN 108276419 B CN108276419 B CN 108276419B CN 201810122942 A CN201810122942 A CN 201810122942A CN 108276419 B CN108276419 B CN 108276419B
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- quinazoline
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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
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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
- C07D487/22—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, in particular 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.For this method to replace 2- (2- bromophenyl)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle are raw material, and under cheap metal catalysis, intermolecular C-N cross-coupling/intramolecular c h bond activation ring closure reaction 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
Technical field
The present invention relates to the synthetic methods of a kind of azoles and quinazoline ternary fused heterocyclic derivative, in particular 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 technique
Nitrogen-containing heterocycle be widely present in natural products, synthesis medicine, pesticide, in functional material.Therefore in organic chemistry,
Develop new method building nitrogen-containing heterocycle 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 is limited and reacts 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.
Summary of the invention
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- bromophenyl)-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 illustrate, 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 invention is 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.
Synthetic method of the invention, to replace 2- (2- bromophenyl)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle are raw material, In
In solvent, using cheap metal as catalyst, is reacted in the case where 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- bromophenyl)-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- ferrosin, 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 embodiment
Below with reference to embodiment, the present invention will be further described, but the scope of protection of the present invention is not limited thereto.
In embodiment 1:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyl) -1,4,5,6- tetrahydropyrimidine (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, it is extracted with dichloromethane three times, 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.
In embodiment 2:Schlenk reaction tube, be added stirring magneton, nickel chloride (6.5mg, 0.05mmol, 10mol%),
Potassium phosphate (1mmol), 1,10- ferrosin (0.1mmol, 20mol%), 2- (the bromo- 4,5- Dimethoxyphenyl 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, methylene chloride 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 purification, 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.
In embodiment 3:Schlenk reaction tube, be added stirring magneton, nickel chloride (6.5mg, 0.05mmol, 10mol%),
Potassium carbonate (1mmol), 1,10- ferrosin (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, methylene chloride 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 purification, 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.
In embodiment 4:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 4- fluorophenyl 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 methylene chloride
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.
In embodiment 5:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyl) -1,4,5,6- tetrahydropyrimidine (0.5mmol)
With 1,2,4- triazole heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).Syringe is infused under oxygen atmosphere
Enter 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
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
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.
In embodiment 6:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), 1,10- ferrosin (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyl of 2-) -1,4,5,6- tetrahydropyrimidine
(0.5mmol) and 1,2,4- triazole heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).In oxygen atmosphere
Lower syringe injects 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.It is chromatographed using column
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.
In embodiment 7:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 4,5- Dimethoxyphenyl of 2-) -1,4,5,6- tetrahydro
Pyrimidine (0.5mmol) and 1,2,4- triazole 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, methylene chloride 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 purification, 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.
In embodiment 8:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (2- bromophenyl) -5,5- dimethyl -1,4,5,6- tetrahydro are phonetic
Pyridine (0.5mmol) and 1,2,4- triazole 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 methylene chloride
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.
In embodiment 9:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), 1,10- ferrosin (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyl of 2-) dimethyl-1,4,5-5,5-,
6- tetrahydropyrimidine (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 methylene chloride
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.
In embodiment 10:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 10- nitrobenzophenone of 2-) dimethyl-1,4,5-5,5-,
6- tetrahydropyrimidine (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 methylene chloride
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.
In embodiment 11:Schlenk reaction tube, stirring magneton, copper chloride (7mg, 0.05mmol, 10mol%), carbon is added
Sour potassium (1mmol), L-PROLINE (0.1mmol, 20mol%), 2- (the bromo- 5- chlorphenyl of 2-) -1,4,5,6- tetrahydropyrimidine
(0.5mmol) and theophylline heterocycle (0.5mmol).Reaction tube, which vacuumizes, to be oxygenated (repeatedly for three times).The syringe under oxygen atmosphere
It injects DMF (2.0mL).The seal of tube is reacted, 150 DEG C, is reacted 24 hours.After reaction, it is extracted with dichloromethane three times, it is 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 (3)
1. the synthetic method of a kind of azoles and quinazoline ternary fused heterocyclic derivative, which is characterized in that the structural formula of the compound
It is as follows,
Wherein R1=hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R2=hydrogen, halogen, methoxyl group, nitro, C1-C6Alkyl, R3=
Hydrogen, C1-C6Alkyl；
With substituted 2- (2- bromophenyl)-Isosorbide-5-Nitrae, 5,6- tetrahydropyrimidines and azoles heterocycle are raw material, in a solvent, with NiCl2、
CuCl2、FeCl3For catalyst, in the case of alkali and ligand presence, 100-150 DEG C, " one pot " reaction occurs and synthesizes above-mentioned target three
First condensed hetero ring product, reaction equation is as follows,
Ligand is selected from: L-PROLINE, N, N '-dimethyl ethylenediamine, 1,10- ferrosin.
2. synthetic method according to claim 1, which is characterized in that the alkali is selected from potassium carbonate, potassium phosphate, hydroxide
Sodium, sodium ethoxide, potassium tert-butoxide.
3. synthetic method according to claim 1, which is characterized in that the solvent is selected from HMPA, DMF, DMSO, NMP, 1,
4-dioxane。
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| "Copper-catalyzed N-arylation and aerobic oxidative C–H/C–H coupling: one-pot synthesis of indoloimidazoquinoline derivatives";Meng Wang et al.;《RSC Advances》;20130410;第3卷;第8211-8214页 * |
| "Synthesis of novel azole-fused quinazolines via one-pot, sequential Ullmann-type coupling and intramolecular dehydrogenative C–N bonding";Nitesh Kumar Nandwana et al.;《Organic & Biomolecular Chemistry》;20141223;第13卷;第2947-2950页 * |
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