CN110156789B - Synthetic method of azacyclo-quinazoline compound - Google Patents
Synthetic method of azacyclo-quinazoline compound Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- 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
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Abstract
The invention discloses a synthetic method of an azacyclo-quinazoline compound, which comprises the following steps: placing benzaldehyde with a structure shown in a formula A and aromatic amine with a structure shown in a formula B in a methanol water solution or a methanol solution, wherein the molar ratio of the benzaldehyde to the aromatic amine is more than or equal to 2: 1, stirring at a constant temperature of 55-65 ℃ under the catalytic action of porcine gastric mucosal protease, and reacting to obtain an azacyclo-quinazoline compound with a structure shown in a formula C; wherein R1 and R2 form an azacyclic ring. The method has the advantages of mild reaction conditions, biodegradable catalyst, simple steps, low cost, easy implementation of the whole synthesis path, economy, environmental protection, good yield which reaches 41-95 percent, and popularization and use values.
Description
Technical Field
The invention belongs to the field of organic matter synthesis, and particularly relates to a synthetic method of a nitrogen heterocyclic quinazoline compound.
Background
Quinazoline derivatives are nitrogen-containing heterocyclic compounds with good biological activity, and quinazoline skeletons can also be found in active substances in a plurality of natural products. The quinazoline compound is widely applied to the pharmaceutical and pesticide industries and can be applied to the fields of cancer resistance, malaria resistance, hypertension resistance, mite killing, sterilization and the like. Some quinazoline derivatives have been put on the market or subjected to medical clinical tests, such as the anticancer drug gefitinib and the bactericide propoxymidine. Therefore, the synthesis of quinazoline compounds is receiving continuous attention from scientists.
The traditional method for synthesizing quinazoline compounds usually uses o-aminobenzaldehyde, o-aminobenzoic acid, o-amino-formamide or o-aminobenzonitrile and the like as starting materials to synthesize quinazoline compounds
Acids, Lewis acids, transition metals, ionic liquids and the like are synthesized as catalysts, although some green catalysts are reported here, the synthesis methods have some defects compared with green organic synthesis, such as complicated operation process, unrecoverable or degradable catalysts, overhigh cost, small applicable range of substrates and the like. Therefore, the development of an economic and environment-friendly green preparation method with wider application range has positive significance.
Based on the characteristics of high efficiency, low toxicity, mildness, selectivity and the like of biocatalysis, the method has profound influence on the aspects of industry, agriculture, medical treatment, new drug research and development and the like, and is one of the important trends of green chemistry and green chemical engineering development. The enzyme is a commonly used bioactive catalyst, plays an important role in the field of organic synthesis, and has the advantages of high efficiency, specificity, degradability, no pollution, environmental friendliness, economy and the like.
The technical process for synthesizing the [1,2-a ] quinazoline compound by the existing process is complex, has high energy consumption and causes great pollution to the environment, so that the development of the method for synthesizing the [1,2-a ] quinazoline compound by enzyme catalysis has important significance.
Disclosure of Invention
The invention aims to provide a synthetic method of a nitrogen heterocyclic quinazoline compound, which solves the problem of great environmental pollution in the prior art, has mild reaction conditions, biodegradable catalyst, simple steps, low cost, easy implementation of the whole synthetic route, economy, environmental protection and popularization and use values.
In order to achieve the above object, the present invention provides a method for synthesizing an azacyclo-quinazoline compound, the method comprising:
placing benzaldehyde with a structure shown as a formula A and aromatic amine with a structure shown as a formula B in a methanol water solution or a methanol solution, wherein the molar ratio of the benzaldehyde to the aromatic amine is larger than or equal toEqual to 2: 1, oscillating at 55-65 ℃ under the catalytic action of porcine gastric mucosal protease to react to obtain an azacyclo-quinazoline compound with a structure shown as a formula C; wherein R is1And R2Are connected to form a nitrogen heterocycle.
According to the method, the yield of the azacyclo-quinazoline compound can reach 38% at the temperature of 40 ℃; the yield of the azacyclo-quinazoline compound reaches 51 percent at the temperature of 45 ℃; the yield of the azacyclo-quinazoline compound reaches 61 percent at the temperature of 50 ℃; the yield of the azacyclo-quinazoline compound reaches 71 percent at the temperature of 55 ℃; the yield of the azacyclo-quinazoline compound reaches 75 percent at the temperature of 60 ℃; the yield of the azacyclo-quinazoline compound reaches 74 percent at the temperature of 65 ℃. Therefore, the temperature range is preferably 55-60 ℃ to improve the yield of the azacyclo-quinazoline compound.
According to the method, when the porcine gastric mucosa protease is used as the catalyst, the yield of the azacyclo-quinazoline compound is good, and no product is generated when the catalyst is not added. Therefore, the reaction of the present invention must be catalyzed by porcine gastric mucosal protease to greatly improve the yield.
Preferably, the volume ratio of methanol to water in the methanol aqueous solution is 1: 2-2: 1.
preferably, the rotating speed of the oscillation is 150-250 rpm.
Preferably, the reaction time is not less than 36 h. More preferably, the reaction time is 36-48 h. The yield increased with longer reaction time, but after 48h the yield decreased.
Preferably, the mass molar ratio of the porcine gastric mucosa protease to the aromatic amine is 75mg:1 mmol-150 mg:1 mmol; the volume mol ratio of the methanol water solution to the aromatic amine is 5mL:1 mmol-10 mL:1 mmol.
Preferably, after the reaction is finished, the reaction product is separated and purified by column chromatography.
Preferably, the eluent used for the column chromatography is ethyl acetate-petroleum ether or dichloromethane-n-hexane. More preferably, the eluent is ethyl acetate and petroleum ether in a volume ratio of 1:15, or dichloromethane and n-hexane in a volume ratio of 1: 1.
Preferably, R1And R2Comprises the following steps: -CH2-(CH2)m-CH2-, m is 1 to 6; or
n is 0 to 4, and D is a carbocyclic ring or a heterocyclic ring. More specifically, R1And R2The N heterocyclic ring comprises:
more specifically, the carbocyclic or heterocyclic ring includes carbocyclic or heterocyclic rings of five or more members, such as carbocyclic or heterocyclic rings of five members, six-membered carbocyclic or heterocyclic rings, seven-membered carbocyclic or heterocyclic rings, and eight-membered carbocyclic or heterocyclic rings.
Preferably, D is an aromatic ring, more particularly, it includes a benzene ring, R1And R2The N heterocyclic ring comprises:
preferably, the aromatic amine has a structure as shown in formula E or F:
wherein R is3And R4Each independently is H, or an electron donating substituent, or an electron withdrawing substituent; g is a carbocyclic or heterocyclic ring, and can be a saturated carbocyclic or heterocyclic ring, and can also be an unsaturated carbocyclic or heterocyclic ring. Wherein the electron donating substituent is an electron donating substituent that does not affect the reaction of the amino group in the aromatic amine with benzaldehyde, and does not comprise: amino and hydroxyl. More specifically, the unsaturated carbocyclic or heterocyclic ring, or the saturated carbocyclic or heterocyclic ring, may be a five-membered ring, a six-membered ring, and the unsaturated carbocyclic ring comprises a benzene ring.
Preferably, the electron-donating substituent is selected from any one of methyl, ethyl, methoxy and ethoxy; the electron-withdrawing substituent is selected from any one of halogen, trifluoromethyl, nitro and cyano.
The synthetic method of the azacyclo-quinazoline compound solves the problem that the existing process has great environmental pollution, and has the following advantages:
the method has the advantages of mild reaction conditions, biodegradable catalyst, simple steps, low cost, easy implementation of the whole synthesis path, economy, environmental protection, good yield which reaches 41-95 percent, and popularization and use values.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A synthetic method of an azacyclo-quinazoline compound comprises the following synthetic route:
the method specifically comprises the following steps:
1) in a 10mL stoppered tube, 0.4mmol of 2- (1-pyrrolidinyl) benzaldehyde, 0.2mmol of aniline, 30mg of porcine gastric mucosal protease and 2mL of 50% aqueous methanol solution were added;
2) putting the test tube in the step 1) into a constant-temperature oil bath at 60 ℃, and reacting for 36 hours under magnetic stirring to obtain a crude product;
3) and (3) carrying out column chromatography separation on the crude product obtained in the step 2), wherein ethyl acetate and petroleum ether are adopted as eluent in a volume ratio of 1:10, and drying at 40 ℃ for 3-4 h to prepare the azacyclo-quinazoline compound.
The prepared azacyclo-quinazoline compound is 4-phenyl-1, 2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 75%, and the azacyclo-quinazoline compound is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.32(dd,J＝10.6,5.1Hz,2H),7.20-7.11(m,4H),6.97(d,J＝7.4Hz,1H),6.65(t,J＝7.4Hz,1H),6.54(d,J＝8.1Hz,1H),4.64(dd,J＝8.3,5.3Hz,1H),4.39(d,J＝14.9Hz,1H),4.13-4.11(m,1H),3.46(td,J＝8.7,3.0Hz,1H),3.38(dd,J＝16.5,8.2Hz,1H),2.08(dd,J＝8.6,3.6Hz,1H),1.98(ddd,J＝9.9,5.3,2.3Hz,1H),1.95-1.87(m,1H),1.73(ddd,J＝16.5,10.1,5.5Hz,1H)。13C NMR(126MHz,CDCl3)150.28,143.47,128.99,127.82,125.97,125.22,124.81,120.84,116.18,111.36,76.72,57.37,47.10,32.00,22.29。
example 2
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-methylaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (p-tolyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 66%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.17-7.05(m,5H),6.95(d,J＝7.3Hz,1H),6.63(t,J＝7.3Hz,1H),6.52(d,J＝8.0Hz,1H),4.60(dd,J＝8.3,5.2Hz,1H),4.35(d,J＝14.9Hz,1H),4.06(d,J＝14.9Hz,1H),3.52-3.29(m,2H),2.32(s,3H),2.04-1.87(m,3H),1.71(ddd,J＝11.5,9.9,5.7Hz,1H)。13C NMR(126MHz,CDCl3)147.70,143.42,134.62,129.65,127.81,126.03,125.26,120.84,116.08,111.29,76.93,57.62,47.14,32.09,22.34,20.96。
example 3
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that the aromatic amine is 3-methylaniline, and the prepared azacyclo-quinazoline compound is 4- (m-tolyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 68%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.20(t,J＝7.7Hz,1H),7.13(t,J＝7.6Hz,1H),7.10-6.88(m,4H),6.64(t,J＝7.4Hz,1H),6.53(d,J＝8.0Hz,1H),4.61(dd,J＝8.3,5.2Hz,1H),4.34(d,J＝14.8Hz,1H),4.10(d,J＝14.8Hz,1H),3.53-3.33(m,2H),2.34(s,3H),2.11-1.84(m,3H),1.73(tt,J＝11.5,8.2Hz,1H)。13C NMR(126MHz,CDCl3)150.26,143.33,138.72,128.75,127.76,125.94,125.85,125.61,121.87,120.83,116.07,111.30,76.69,57.47,47.12,32.10,22.28,21.50。
example 4
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that the aromatic amine is 2-methylaniline, and the prepared azacyclo-quinazoline compound is 4- (o-tolyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 55%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.27-7.19(m,1H),7.15(t,J＝7.9Hz,2H),7.08(t,J＝7.1Hz,2H),6.94(d,J＝7.3Hz,1H),6.64(t,J＝7.3Hz,1H),6.58(d,J＝8.0Hz,1H),4.74(t,J＝14.4Hz,1H),4.14(s,1H),3.89(d,J＝15.0Hz,1H),3.52(t,J＝7.2Hz,1H),3.37(dd,J＝16.2,8.6Hz,1H),2.34(d,J＝12.1Hz,3H),2.05-1.81(m,3H),1.51(tt,J＝11.6,8.1Hz,1H)。13C NMR(126MHz,CDCl3)146.08,143.76,136.74,130.55,127.56,126.66,125.95,125.06,115.87,111.76,109.69,99.93,76.35,56.67,47.65,32.69,22.54,17.97。
example 5
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-methoxyaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-methoxyphenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 50%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.16-7.08(m,3H),6.95(d,J＝7.3Hz,1H),6.88-6.82(m,2H),6.63(t,J＝7.2Hz,1H),6.52(d,J＝8.0Hz,1H),4.57(dd,J＝8.3,5.0Hz,1H),4.36(d,J＝14.9Hz,1H),4.01(d,J＝14.9Hz,1H),3.79(s,3H),3.46(td,J＝8.6,2.6Hz,1H),3.36(dd,J＝15.9,8.6Hz,1H),2.01–1.82(m,3H),1.69(ddd,J＝11.2,8.3,3.6Hz,1H)。13C NMR(126MHz,CDCl3)157.13,143.39,143.09,127.80,126.80,126.07,120.82,116.02,114.18,111.23,77.27,57.63,55.44,47.13,32.01,22.33。
example 6
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-fluoroaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-fluorophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 60%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.53(d,J＝8.5Hz,2H),7.16(d,J＝8.4Hz,3H),6.99(d,J＝7.3Hz,1H),6.70(t,J＝7.4Hz,1H),6.57(d,J＝8.0Hz,1H),4.65(dd,J＝8.3,5.4Hz,1H),4.42(d,J＝15.0Hz,1H),4.21(d,J＝15.0Hz,1H),3.48-3.32(m,2H),2.22(tdd,J＝7.7,5.5,2.7Hz,1H),2.08-1.87(m,2H),1.74(ddd,J＝18.9,12.0,8.6Hz,1H)。13C NMR(126MHz,CDCl3)153.01,143.78,128.07,126.14,126.05,125.86,123.24,120.93,116.99,111.73,75.88,55.69,46.75,31.62,22.01。
example 7
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-chloroaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-chlorophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 61%, and the product is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.25(dd,J＝9.5,2.7Hz,2H),7.14(t,J＝7.7Hz,1H),7.11-7.03(m,2H),6.96(d,J＝7.3Hz,1H),6.65(t,J＝7.3Hz,1H),6.53(d,J＝8.0Hz,1H),4.60(dd,J＝8.3,5.3Hz,1H),4.37(d,J＝15.0Hz,1H),4.07(d,J＝15.0Hz,1H),3.49-3.28(m,2H),2.13-1.81(m,3H),1.68(tt,J＝11.2,8.3Hz,1H).13C NMR(126MHz,CDCl3)148.69,143.44,130.07,129.06,127.96,126.59,125.98,120.46,116.36,111.41,76.62,57.19,47.02,31.78,22.24。
example 8
The synthesis route of the azacyclo-quinazoline compound is as above, the preparation method is basically the same as that in example 1, except that 4-bromoaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-bromophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 52%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.41(d,J＝8.6Hz,2H),7.14(t,J＝7.6Hz,1H),7.03(d,J＝8.6Hz,2H),6.96(d,J＝7.3Hz,1H),6.66(t,J＝7.3Hz,1H),6.53(d,J＝8.0Hz,1H),4.61(dd,J＝8.2,5.4Hz,1H),4.37(d,J＝15.0Hz,1H),4.08(d,J＝15.0Hz,1H),3.54-3.38(m,1H),3.38-3.29(m,1H),2.11-1.88(m,3H),1.69(ddd,J＝20.0,11.3,8.4Hz,1H)。13C NMR(126MHz,CDCl3)148.98,143.38,132.03,127.98,126.89,125.98,120.34,117.91,116.44,111.46,76.56,57.05,47.01,31.70,22.21。
example 9
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-iodoaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-iodophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 43%, and the product is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.60(d,J＝8.6Hz,2H),7.14(t,J＝7.6Hz,1H),6.93(dd,J＝28.0,8.0Hz,3H),6.66(t,J＝7.3Hz,1H),6.53(d,J＝8.0Hz,1H),4.61(dd,J＝8.3,5.3Hz,1H),4.37(d,J＝15.0Hz,1H),4.09(d,J＝15.0Hz,1H),3.49-3.28(m,2H),2.14-2.03(m,1H),2.02-1.84(m,2H),1.70(tt,J＝11.1,8.4Hz,1H)。13C NMR(126MHz,CDCl3)149.89,143.47,137.98,127.96,127.13,125.94,120.47,116.43,111.44,88.56,76.38,56.95,46.97,31.74,22.21。
example 10
A synthetic method of an azacyclo-quinazoline compound, which has the same synthetic route as that of the azacyclo-quinazoline compound in example 1, except that 4-aminobenzonitrile is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-cyanophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 49%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.53(d,J＝8.8Hz,2H),7.20(t,J＝7.4Hz,1H),7.02(dd,J＝17.1,8.1Hz,3H),6.77(t,J＝7.4Hz,1H),6.64(d,J＝8.0Hz,1H),4.58(dd,J＝8.3,5.5Hz,1H),4.46(d,J＝14.7Hz,1H),4.29(d,J＝14.7Hz,1H),3.44(td,J＝8.3,6.4Hz,1H),3.33(td,J＝8.8,5.3Hz,1H),2.37(tdd,J＝8.4,5.5,3.3Hz,1H),2.14-1.92(m,2H),1.77(ddd,J＝18.0,12.2,9.1Hz,1H)。13C NMR(126MHz,CDCl3)152.86,144.28,133.13,128.25,125.69,122.16,120.08,119.73,118.09,112.23,103.30,75.02,52.64,46.16,31.29,21.52。
example 11
The synthesis route of the azacyclo-quinazoline compound is as above, the preparation method is basically the same as that in example 1, except that 4-nitroaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-nitrophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 43%, and the yellow oily liquid is obtained.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)8.18-8.11(m,2H),7.24(t,J＝7.5Hz,1H),7.10(d,J＝7.3Hz,1H),6.93-6.87(m,2H),6.83(t,J＝7.3Hz,1H),6.71(d,J＝7.9Hz,1H),4.59-4.49(m,2H),4.36(d,J＝14.3Hz,1H),3.51(td,J＝8.7,4.8Hz,1H),3.29(td,J＝8.9,6.6Hz,1H),2.59-2.46(m,1H),2.17-1.95(m,2H),1.82(ddt,J＝12.3,10.0,8.2Hz,1H)。13C NMR(126MHz,CDCl3)153.74,144.60,139.39,128.39,125.59,125.47,123.36,118.98,116.16,112.57,74.53,50.45,45.61,31.16,21.10。
example 12
A synthetic method of an azacyclo-quinazoline compound, which has the synthetic route as above and is prepared basically as in example 1, except that the aromatic amine used is 3, 4-dimethoxyaniline, and the prepared azacyclo-quinazoline compound is 4- (3, 4-dimethoxyphenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 41%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.13(t,J＝7.5Hz,1H),6.96(d,J＝7.2Hz,1H),6.87-6.69(m,3H),6.64(t,J＝7.3Hz,1H),6.52(d,J＝8.0Hz,1H),4.59(dd,J＝7.9,5.1Hz,1H),4.37(d,J＝14.8Hz,1H),4.04(d,J＝14.8Hz,1H),3.85(d,J＝22.8Hz,6H),3.57-3.29(m,2H),2.12-1.81(m,3H),1.71(dt,J＝19.4,8.4Hz,1H)。13C NMR(126MHz,CDCl3)148.93,146.70,143.22,127.83,126.05,120.59,116.67,116.02,111.20,111.05,110.22,57.71,55.96,55.82,47.16,31.98,22.32。
example 13
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 3-chloroaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (3-chlorophenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 74%, and the product is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.22(dd,J＝14.3,6.3Hz,1H),7.18-7.11(m,2H),7.09(d,J＝7.9Hz,1H),7.04(d,J＝8.0Hz,1H),6.96(d,J＝7.3Hz,1H),6.67(t,J＝7.4Hz,1H),6.54(d,J＝8.0Hz,1H),4.60(dd,J＝8.3,5.3Hz,1H),4.35(d,J＝14.9Hz,1H),4.12(d,J＝14.9Hz,1H),3.52–3.30(m,2H),2.11(ddd,J＝12.2,7.3,2.3Hz,1H),2.05-1.86(m,2H),1.72(tt,J＝11.2,8.3Hz,1H)。13C NMR(126MHz,CDCl3)151.51,143.36,134.33,129.87,127.92,125.89,124.73,124.49,123.05,120.50,116.44,111.48,76.34,56.85,46.99,31.79,22.16。
example 14
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 1, except that 4-trifluoromethylaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 4- (4-trifluoromethylphenyl) -1,2,3,3a,4, 5-hexahydropyrrolo [1,2-a ] quinazoline, the yield is 76%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.53(d,J＝8.5Hz,2H),7.16(d,J＝8.4Hz,3H),6.99(d,J＝7.3Hz,1H),6.70(t,J＝7.4Hz,1H),6.57(d,J＝8.0Hz,1H),4.65(dd,J＝8.3,5.4Hz,1H),4.42(d,J＝15.0Hz,1H),4.21(d,J＝15.0Hz,1H),3.48-3.32(m,2H),2.22(tdd,J＝7.7,5.5,2.7Hz,1H),2.08-1.87(m,2H),1.74(ddd,J＝18.9,12.0,8.6Hz,1H)。13C NMR(126MHz,CDCl3)153.01,143.78,128.07,126.14,126.05,125.86,123.24,120.93,116.99,111.73,75.88,55.69,46.75,31.62,22.01。
example 15
A synthetic method of an azacyclo-quinazoline compound comprises the following synthetic route:
the method specifically comprises the following steps:
1) taking a 10mL test tube with a plug, adding 0.4mmol of 2- (1-azepanyl) benzaldehyde, 0.2mmol of aniline, 15mg of porcine gastric mucosa protease and 2mL of 50% methanol aqueous solution;
2) putting the reaction bottle in the step 1) into a constant-temperature oil bath at 55 ℃, and reacting for 36 hours under magnetic stirring to obtain a crude product;
3) and (3) carrying out column chromatography separation on the crude product obtained in the step 2), wherein dichloromethane and n-hexane are adopted as eluent in a volume ratio of 1:1, and drying for 4h at 40 ℃ to prepare the azacyclo-quinazoline compound.
The prepared azacyclo-quinazoline compound is 6-phenyl-5, 6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 84%, and the compound is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.24-7.20(m,2H),7.09(t,J＝7.4Hz,1H),7.00(d,J＝7.3Hz,1H),6.95(d,J＝7.9Hz,2H),6.83(t,J＝7.3Hz,1H),6.64-6.55(m,2H),4.88(dd,J＝9.9,4.2Hz,1H),4.58(d,J＝16.1Hz,1H),4.38(d,J＝16.1Hz,1H),3.88(ddd,J＝15.0,6.3,3.2Hz,1H),3.28-3.18(m,1H),2.18-2.09(m,1H),1.97-1.84(m,2H),1.68-1.58(m,3H),1.48(ddd,J＝17.2,9.6,4.0Hz,1H),1.35(ddd,J＝13.6,8.8,4.5Hz,1H)。13C NMR(126MHz,CDCl3)149.75,142.61,129.26,129.17,127.75,126.53,117.82,117.38,115.56,110.05,75.08,47.12,46.31,32.95,26.42,26.03,24.77.
example 16
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-methylaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (p-tolyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 92%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.11-6.95(m,4H),6.86(d,J＝8.5Hz,2H),6.64-6.53(m,2H),4.80(dd,J＝10.1,4.0Hz,1H),4.56(d,J＝16.2Hz,1H),4.31(d,J＝16.2Hz,1H),3.85(ddd,J＝15.0,6.3,3.3Hz,1H),3.27-3.13(m,1H),2.24(s,3H),2.13(dtd,J＝16.2,10.8,5.4Hz,1H),1.96-1.78(m,2H),1.72-1.56(m,3H),1.54-1.41(m,1H),1.40-1.28(m,1H)。13C NMR(126MHz,CDCl3)147.70,142.67,129.71,129.53,127.73,126.55,117.93,117.85,115.48,109.97,75.74,47.11,46.54,33.14,26.37,26.13,24.80,20.56。
example 17
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that the aromatic amine is 3-methylaniline, and the prepared azacyclo-quinazoline compound is 6- (m-tolyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 89%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.14-7.04(m,2H),7.00(d,J＝7.2Hz,1H),6.75(d,J＝8.5Hz,2H),6.68-6.54(m,3H),4.87(dd,J＝9.9,4.2Hz,1H),4.56(d,J＝16.1Hz,1H),4.37(d,J＝16.1Hz,1H),3.88(ddd,J＝15.0,6.3,3.1Hz,1H),3.29-3.19(m,1H),2.30(s,3H),2.19-2.10(m,1H),1.94-1.81(m,2H),1.70-1.58(m,3H),1.53-1.44(m,1H),1.35(ddd,J＝18.6,9.2,4.2Hz,1H)。13C NMR(126MHz,CDCl3)149.68,142.60,138.81,128.99,127.71,126.54,120.79,118.08,117.92,115.55,114.31,110.07,75.07,47.12,46.27,32.73,26.43,26.03,24.76,21.90。
example 18
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-methoxyaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-methoxyphenyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 95%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.08(t,J＝7.4Hz,1H),6.94(dd,J＝24.2,8.1Hz,3H),6.82-6.71(m,2H),6.65-6.52(m,2H),4.72-4.53(m,2H),4.23(d,J＝16.3Hz,1H),3.88-3.76(m,1H),3.72(s,3H),3.16(ddd,J＝15.4,10.2,5.6Hz,1H),2.16-2.05(m,1H),1.95(d,J＝6.1Hz,1H),1.86(dtd,J＝13.5,10.1,3.6Hz,1H),1.74-1.54(m,3H),1.53-1.41(m,1H),1.34(dtd,J＝14.1,9.8,4.4Hz,1H)。13C NMR(126MHz,CDCl3)154.07,144.36,142.81,127.73,126.49,120.30,117.83,115.44,114.35,109.87,76.79,55.51,47.25,47.02,33.87,26.35,26.21,24.79。
example 19
A synthetic method of an azacycloquinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-trifluoromethylaniline is used as aromatic amine, and the prepared azacycloquinazoline compound is 6- (4-trifluoromethylphenyl) -5,6,6a,7,8,9,10, 11-octahydroazepino [1,2-a ] quinazoline, the yield is 82%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.47(d,J＝8.7Hz,2H),7.11(t,J＝7.8Hz,1H),7.03(d,J＝7.5Hz,1H),6.94(d,J＝8.7Hz,2H),6.69-6.60(m,2H),4.96(dd,J＝9.3,5.0Hz,1H),4.51(dd,J＝45.7,16.0Hz,2H),3.91(ddd,J＝15.1,6.6,3.0Hz,1H),3.31-3.19(m,1H),2.17(ddt,J＝20.3,10.4,6.2Hz,1H),1.91-1.83(m,2H),1.71-1.62(m,3H),1.54-1.47(m,1H),1.39-1.33(m,1H)。13C NMR(126MHz,CDCl3)151.50,142.35,128.03,126.70,126.59,126.50,125.82,117.45,116.13,115.34,110.50,73.78,47.31,45.90,32.35,26.59,25.82,24.67。
example 20
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-aminobenzonitrile is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-cyanophenyl) -5,6,6a,7,8,9,10, 11-octahydro azacyclo [1,2-a ] quinazoline, the yield is 83%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.50(d,J＝8.9Hz,2H),7.13(t,J＝7.5Hz,1H),7.03(d,J＝7.3Hz,1H),6.87(d,J＝8.9Hz,2H),6.73-6.61(m,2H),5.07-4.93(m,1H),4.57-4.42(m,2H),3.92(ddd,J＝15.1,6.6,2.7Hz,1H),3.35–3.21(m,1H),2.25-2.12(m,1H),1.86(dd,J＝12.7,6.9Hz,2H),1.76-1.56(m,3H),1.56-1.45(m,1H),1.45-1.33(m,1H)。13C NMR(126MHz,CDCl3)151.29,142.23,133.64,128.17,126.58,120.14,117.40,116.56,114.55,110.86,100.23,72.77,47.51,45.52,31.82,26.85,25.63,24.61。
example 21
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-chloroaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-chlorophenyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 85%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.22-7.14(m,2H),7.09(t,J＝7.5Hz,1H),6.99(d,J＝7.3Hz,1H),6.90-6.83(m,2H),6.66-6.56(m,2H),4.79(dd,J＝10.0,4.2Hz,1H),4.56(d,J＝16.2Hz,1H),4.31(d,J＝16.2Hz,1H),3.87(ddd,J＝15.0,6.3,3.3Hz,1H),3.25-3.14(m,1H),2.20-2.09(m,1H),1.96-1.81(m,2H),1.67(dddd,J＝27.8,13.9,8.7,4.8Hz,3H),1.54-1.43(m,1H),1.40-1.30(m,1H)。13C NMR(126MHz,CDCl3)148.45,142.48,129.04,127.91,126.54,124.81,118.77,117.41,115.78,110.16,75.25,47.12,46.50,33.15,26.37,26.01,24.72。
example 22
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that the aromatic amine is 2-methylaniline, and the prepared azacyclo-quinazoline compound is 6- (m-tolyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 90%, and the product is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.08(d,J＝7.2Hz,1H),7.03(t,J＝7.7Hz,1H),6.93(dd,J＝10.8,4.3Hz,1H),6.85(dd,J＝13.6,6.9Hz,3H),6.52(t,J＝7.1Hz,2H),4.65(d,J＝16.9Hz,1H),4.16(dd,J＝10.1,4.3Hz,1H),3.88(d,J＝16.9Hz,1H),3.09-2.86(m,1H),2.26(s,3H),2.11-1.85(m,3H),1.64-1.24(m,6H)。13C NMR(126MHz,CDCl3)151.34,143.27,132.78,130.86,127.68,126.71,126.17,123.41,121.79,118.35,115.25,109.57,76.95,47.77,46.93,35.43,26.49,26.17,24.87,18.47。
example 23
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that the aromatic amine is 3-chloroaniline, and the prepared azacyclo-quinazoline compound is 6- (3-chlorophenyl) -5,6,6a,7,8,9,10, 11-octahydro-azacyclo [1,2-a ] quinazoline, the yield is 82%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.16-7.07(m,2H),7.00(d,J＝7.4Hz,1H),6.89(t,J＝2.1Hz,1H),6.82-6.77(m,2H),6.67-6.59(m,2H),4.88-4.80(m,1H),4.54(d,J＝16.0Hz,1H),4.37(d,J＝16.1Hz,1H),3.90(ddd,J＝15.1,6.5,3.0Hz,1H),3.25(ddd,J＝15.8,10.3,5.9Hz,1H),2.15(ddt,J＝12.2,10.5,6.1Hz,1H),1.91-1.82(m,2H),1.71-1.60(m,3H),1.53-1.45(m,1H),1.40-1.31(m,1H)。13C NMR(126MHz,CDCl3)150.70,142.45,134.97,130.22,128.00,126.64,119.50,117.51,116.78,115.97,114.94,110.38,74.51,47.19,46.28,32.66,26.51,25.95,24.72。
example 24
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-nitroaniline is used as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-nitrophenyl) -5,6,6a,7,8,9,10, 11-octahydroazepino [1,2-a ] quinazoline, the yield is 71%, and the yellow oily liquid is obtained.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)8.14(d,J＝9.3Hz,2H),7.16(t,J＝7.6Hz,1H),7.06(d,J＝7.4Hz,1H),6.82(d,J＝9.3Hz,2H),6.78–6.64(m,2H),5.09(t,J＝7.3Hz,1H),4.54(q,J＝15.9Hz,2H),3.94(ddd,J＝15.3,6.5,2.4Hz,1H),3.38-3.23(m,1H),2.25-2.13(m,1H),1.87(dd,J＝12.9,6.9Hz,2H),1.78-1.66(m,2H),1.66-1.48(m,2H),1.47-.35(m,1H)。13C NMR(126MHz,CDCl3)152.47,142.18,138.32,128.30,126.60,126.14,117.47,116.93,112.62,111.16,72.44,47.71,45.58,31.44,27.13,25.49,24.60。
example 25
A process for the synthesis of an azacyclo-quinazoline compound according to the above scheme, substantially as described in example 15, except that the aromatic amine used is 3, 4-dimethoxyaniline, and the azacyclo-quinazoline compound prepared is 6- (3, 4-dimethoxyphenyl) -5,6,6a,7,8,9,10, 11-octahydroazepino [1,2-a ] quinazoline, in 89% yield as a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.09(t,J＝7.5Hz,1H),6.98(d,J＝7.3Hz,1H),6.72(d,J＝8.7Hz,1H),6.60(dd,J＝17.2,8.6Hz,3H),6.49(dd,J＝8.6,2.3Hz,1H),4.74-4.55(m,2H),4.24(d,J＝16.0Hz,1H),3.83(t,J＝13.5Hz,7H),3.19(ddd,J＝15.4,10.1,5.6Hz,1H),2.12(qd,J＝10.7,5.5Hz,1H),2.03-1.82(m,2H),1.77-1.56(m,3H),1.54-1.44(m,1H),1.41-1.31(m,1H)。13C NMR(126MHz,CDCl3)149.27,144.88,143.77,142.67,127.78,126.43,117.75,115.50,111.75,110.43,109.88,104.59,76.88,56.16,55.85,47.49,46.99,33.89,26.31,26.20,24.76。
example 26
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-bromoaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-bromophenyl) -5,6,6a,7,8,9,10, 11-octahydro azacyclo [1,2-a ] quinazoline, the yield is 88%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.34-7.28(m,2H),7.10(t,J＝7.4Hz,1H),6.99(d,J＝7.7Hz,1H),6.85-6.78(m,2H),6.67-6.55(m,2H),4.80(dd,J＝10.0,4.2Hz,1H),4.55(d,J＝16.2Hz,1H),4.32(d,J＝16.2Hz,1H),3.87(ddd,J＝15.0,6.4,3.2Hz,1H),3.22(ddd,J＝15.6,10.2,5.8Hz,1H),2.24-2.08(m,1H),1.96-1.80(m,2H),1.74-1.60(m,3H),1.54-1.44(m,1H),1.41-1.30(m,1H)。13C NMR(126MHz,CDCl3)148.86,142.49,132.00,127.98,126.60,119.07,117.44,115.85,112.08,110.24,75.04,47.16,46.41,33.08,26.42,26.04,24.75。
example 27
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that 4-iodoaniline is adopted as aromatic amine, and the prepared azacyclo-quinazoline compound is 6- (4-iodophenyl) -5,6,6a,7,8,9,10, 11-octahydro azacyclo [1,2-a ] quinazoline, the yield is 93%, and the compound is white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.48(d,J＝8.6Hz,2H),7.09(t,J＝7.7Hz,1H),6.99(d,J＝7.3Hz,1H),6.77-6.53(m,4H),4.81(dd,J＝9.9,4.1Hz,1H),4.53(d,J＝16.1Hz,1H),4.32(d,J＝16.1Hz,1H),3.87(ddd,J＝14.8,6.2,3.0Hz,1H),3.34-3.05(m,1H),2.23-2.08(m,1H),1.96-1.78(m,2H),1.77-1.58(m,3H),1.48(ddd,J＝18.4,11.9,3.8Hz,1H),1.41-1.29(m,1H)。13C NMR(126MHz,CDCl3)149.35,142.41,137.88,127.94,126.56,119.37,117.40,115.83,110.22,81.76,74.76,47.16,46.18,32.92,26.40,25.97,24.71。
example 28
A synthetic method of an azacyclo-quinazoline compound, the synthetic route is as above, the preparation method is basically the same as that in example 15, except that the aromatic amine is 1-naphthylamine, and the prepared azacyclo-quinazoline compound is 6- (1-naphthyl) -5,6,6a,7,8,9,10, 11-octahydroazepino [1,2-a ] quinazoline, the yield is 78%, and the product is a white solid.
The nuclear magnetic characterization data are:13C NMR(126MHz,CDCl3)149.11,142.97,134.81,129.56,128.60,127.81,126.34,126.18,125.79,125.65,123.85,123.76,118.26,117.55,115.40,109.71,77.90,60.58,48.70,46.90,26.42,26.15,24.86,17.88。
example 29
A synthetic method of [1,2-a ] quinazoline compounds comprises the following synthetic route:
the method specifically comprises the following steps:
1) taking a 10mL test tube with a stopper, and adding 0.4mmol of 2- (3, 4-dihydro-2 (1H) isoquinolyl) benzaldehyde, 0.2mmol of aniline, 25mg of porcine gastric mucosa protease and 2mL of methanol aqueous solution;
2) putting the reaction bottle in the step 1) into a constant-temperature oil bath at 60 ℃, and reacting for 48 hours under magnetic stirring to obtain a crude product;
3) and (3) carrying out column chromatography separation on the crude product obtained in the step 2), wherein dichloromethane and n-hexane are adopted as eluent in a volume ratio of 1:1, and drying for 3h at 50 ℃ to prepare the azacyclo-quinazoline compound.
The prepared azacyclo-quinazoline compound is 5-phenyl-4 b,5,12,13 tetrahydro-6H-isoquinolino [2,1-a ]]Quinazoline, yield 88%, white solid, nuclear magnetic characterization data:1H NMR(500MHz,CDCl3)7.60(d,J＝7.4Hz,1H),7.32-7.11(m,6H),7.09(t,J＝7.6Hz,1H),7.02(d,J＝7.2Hz,1H),6.95(d,J＝8.2Hz,1H),6.88(t,J＝6.6Hz,2H),6.66(t,J＝7.3Hz,1H),6.03(s,1H),4.40(d,J＝16.6Hz,1H),4.32(d,J＝16.6Hz,1H),4.22(dd,J＝14.4,5.2Hz,1H),3.45(td,J＝14.2,3.8Hz,1H),3.22-3.02(m,1H),2.62-2.42(m,1H)。13C NMR(126MHz,CDCl3)150.86,143.84,137.40,136.66,129.32,129.03,127.70,127.59,126.96,126.43,125.99,122.15,120.81,118.54,118.14,113.72,73.90,46.52,45.33,24.96。
example 30
A process for the synthesis of an azacycloquinazoline compound, which comprises the steps of providing the compound in the above-mentioned order, and reacting the compound with an aromatic amine, wherein the aromatic amine is 4-methylaniline, and the azacycloquinazoline compound is 5- (4-methylphenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline, and the yield is 93%, and the compound is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.72(d,J＝7.3Hz,1H),7.34-7.23(m,2H),7.20-7.06(m,6H),7.02(d,J＝8.1Hz,1H),6.96(d,J＝7.0Hz,1H),6.73(t,J＝7.1Hz,1H),6.05(s,1H),4.47(d,J＝16.7Hz,1H),4.31(dd,J＝26.7,11.2Hz,2H),3.51(t,J＝11.9Hz,1H),3.19(t,J＝11.8Hz,1H),2.59(d,J＝16.3Hz,1H),2.32(s,3H)。13C NMR(126MHz,CDCl3)148.61,143.89,137.51,136.66,130.37,129.79,128.94,127.60,127.51,126.92,126.37,126.03,122.20,118.99,118.03,113.62,74.45,46.69,45.27,25.02,20.66。
example 31
A process for the synthesis of an azacycloquinazoline compound, which comprises the following steps, wherein the process is substantially the same as in example 29, except that the aromatic amine used is 3-methylaniline, and the azacycloquinazoline compound is prepared as 5- (3-methylphenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline, in a yield of 86% as a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.58(d,J＝7.4Hz,1H),7.23-7.05(m,4H),7.02(d,J＝7.3Hz,1H),6.99-6.91(m,3H),6.88(d,J＝7.3Hz,1H),6.77-6.58(m,2H),6.04(s,1H),4.39(d,J＝16.6Hz,1H),4.30(d,J＝16.7Hz,1H),4.23(dd,J＝14.5,5.3Hz,1H),3.54-3.38(m,1H),3.20-3.03(m,1H),2.51(dd,J＝16.6,3.4Hz,1H),2.29(s,3H)。13CNMR(126MHz,CDCl3)150.87,143.81,139.03,137.51,136.67,129.18,129.03,127.65,127.57,126.94,126.41,125.97,122.23,121.63,119.13,118.14,115.27,113.74,73.86,46.28,45.39,24.88,21.92。
example 32
A process for the synthesis of an azacycloquinazoline compound according to the general formula given in example 29, which comprises the steps of providing the aromatic amine 4-fluoroaniline, and providing an azacycloquinazoline compound which is 5- (4-fluorophenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline in a yield of 81% as a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.65(d,J＝7.6Hz,1H),7.27-7.14(m,2H),7.14-7.05(m,3H),7.03(d,J＝7.4Hz,1H),6.99-6.82(m,4H),6.67(t,J＝7.3Hz,1H),5.87(s,1H),4.40(d,J＝16.8Hz,1H),4.27-4.15(m,2H),3.52-3.31(m,1H),3.19-2.97(m,1H),2.52(dd,J＝16.5,3.2Hz,1H)。13C NMR(126MHz,CDCl3)158.84,156.93,147.29,143.94,137.11,136.63,128.97,127.79,126.99,126.41,126.08,121.88,121.18,121.12,118.23,115.73,115.56,113.65,74.78,47.67,45.13,25.19。
example 33
A process for the synthesis of an azacycloquinazoline compound, which comprises the steps of providing the compound in the above-mentioned order, and reacting the compound with an aromatic amine, wherein the aromatic amine is 4-chloroaniline, and the azacycloquinazoline compound is 5- (4-chlorophenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline, and the yield is 67% as a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.56(d,J＝7.4Hz,1H),7.26-7.14(m,4H),7.14-7.00(m,4H),6.96(d,J＝8.3Hz,1H),6.88(d,J＝7.3Hz,1H),6.68(t,J＝7.3Hz,1H),5.96(s,1H),4.40(d,J＝16.6Hz,1H),4.25(dt,J＝20.5,7.4Hz,2H),3.51-3.35(m,1H),3.17-3.02(m,1H),2.54(dd,J＝16.6,3.5Hz,1H)。13C NMR(126MHz,CDCl3)149.39,143.70,136.87,136.57,129.12,129.04,127.84,127.68,126.97,126.42,125.88,125.71,121.72,120.06,118.31,113.79,73.95,46.98,45.28,24.99。
example 34
A process for the synthesis of an azacycloquinazoline compound, which comprises the steps of providing the compound in the above-mentioned order, and reacting the compound with an aromatic amine, wherein the aromatic amine is 4-trifluoromethylaniline, and the azacycloquinazoline compound is 5- (4-trifluoromethylphenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline, and the yield is 71%, and the compound is a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.54-7.39(m,3H),7.25-7.08(m,5H),7.07-7.01(m,1H),6.98(d,J＝8.2Hz,1H),6.90(d,J＝7.3Hz,1H),6.69(t,J＝7.3Hz,1H),6.12(s,1H),4.50-4.33(m,2H),4.26(dd,J＝14.5,5.3Hz,1H),3.50(td,J＝14.3,4.0Hz,1H),3.22-3.03(m,1H),2.56(dd,J＝16.7,3.3Hz,1H)。13C NMR(126MHz,CDCl3)153.04,143.46,136.52,136.48,129.21,127.99,127.83,127.00,126.66,126.63,126.50,125.65,121.56,118.56,116.87,114.01,72.82,46.25,45.48,24.75。
example 35
A process for the synthesis of an azacycloquinazoline compound, which comprises the steps of providing the compound in the above-mentioned manner, and substantially the same preparation as in example 29, except that 4-aminobenzonitrile is used as the aromatic amine, and 5- (4-aminophenyl) -4b,5,12, 13-tetrahydro-6H-isoquinolino [2,1-a ] quinazoline is prepared in a yield of 43% as a white solid.
The nuclear magnetic characterization data are:1H NMR(500MHz,CDCl3)7.52(d,J＝8.6Hz,2H),7.31(d,J＝6.4Hz,1H),7.12(ddd,J＝36.9,18.5,9.3Hz,6H),7.01(d,J＝8.2Hz,1H),6.92(d,J＝7.3Hz,1H),6.72(t,J＝7.3Hz,1H),6.17(s,1H),4.52-4.36(m,2H),4.29(dd,J＝14.4,5.3Hz,1H),3.61-3.46(m,1H),3.23-3.07(m,1H),2.67-2.51(m,1H)。13C NMR(126MHz,CDCl3)153.29,143.16,136.36,135.85,133.72,129.32,128.10,127.96,126.96,126.48,125.42,121.20,119.90,118.77,116.32,114.15,101.74,71.96,45.92,45.57,24.55。
the substrate has a great influence on the yield of the azacyclo-quinazoline compound synthesized by the method, and the influence on the yield is shown in table 1.
TABLE 1 influence of the substrates on the yield of the azacyclo-quinazoline compounds synthesized according to the invention
Comparative example
The reaction process is as follows:
the reaction was carried out at 50 ℃ in 2mL of a solvent using 0.2mmol of 2- (1-pyrrolidinyl) benzaldehyde and 0.22mmol of aniline, and the reaction was catalyzed by 15mg of porcine gastric mucosa protease under different conditions as shown in Table 2 below, and it can be seen that the yield was the best when methanol was mixed with water at 1: 1.
TABLE 2 comparison of reaction yields under different solvent conditions
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.
Claims (7)
1. A method for synthesizing an azacyclo-quinazoline compound is characterized by comprising the following steps:
placing benzaldehyde with a structure shown in a formula A and aromatic amine with a structure shown in a formula B in a methanol water solution or a methanol solution, wherein the molar ratio of the benzaldehyde to the aromatic amine is more than or equal to 2: 1, stirring at a constant temperature of 55-65 ℃ under the catalytic action of porcine gastric mucosal protease, and reacting to obtain an azacyclo-quinazoline compound with a structure shown in a formula C;
wherein R is1And R2Are linked to form a nitrogen heterocycle R1And R2is-CH2-(CH2)m-CH2-, m is 1 to 6; or
n is 0-4, and D is a carbocyclic ring or a heterocyclic ring;
the aromatic amine has a structure shown as formula E or F:
wherein R is3And R4Each independently is H, or an electron donating substituent, or an electron withdrawing substituent; g is a carbocyclic or heterocyclic ring;
the electron-donating substituent is selected from any one of methyl, ethyl, methoxy and ethoxy; the electron-withdrawing substituent is selected from any one of halogen, trifluoromethyl, nitro and cyano.
2. The method for synthesizing the azacyclo-quinazoline compound according to claim 1, wherein the volume ratio of methanol to water in the methanol aqueous solution is 1: 2-2: 1.
3. the method for synthesizing the azacyclo-quinazoline compound according to claim 1, wherein the stirring speed is 150-250 rpm.
4. The method for synthesizing the azacyclo-quinazoline compound according to claim 1, wherein the reaction time is not less than 36 h.
5. The method for synthesizing the azacyclo-quinazoline compound as claimed in claim 1, wherein the mass molar ratio of the porcine gastric mucosal protease to the aromatic amine is 75mg:1mmol to 150mg:1 mmol; the volume mol ratio of the methanol water solution to the aromatic amine is 5mL:1 mmol-10 mL:1 mmol.
6. The method for synthesizing the azacyclo-quinazoline compound according to claim 1, wherein after the reaction is completed, the azacyclo-quinazoline compound is separated and purified by column chromatography.
7. The method of claim 1, wherein D is an aromatic ring.
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| CN109651375A (en) * | 2018-12-27 | 2019-04-19 | 上海应用技术大学 | A kind of tetrahydro quinazoline derivative and its synthetic method and application |
Non-Patent Citations (3)
| Title |
|---|
| Chen Zhang，等.Facile Formation of Cyclic Aminals through a Brønsted Acid-Promoted Redox Process.《J. Org. Chem.》.2008,第74卷第419-422页. * |
| Keiji Mori，等.Expeditious Construction of Quinazolines via Brønsted Acid-induced.《Chemistry Letters》.2009,第38卷(第6期),第524-525页. * |
| 胃蛋白酶催化合成2,3-二氢喹唑啉-4(1H)-酮衍生物;谢宗波，等;《有机化学》;20171231;第37卷;第514-519页，尤其参见第515页左栏反应式，第515-516页第1.1-1.3节、表1、表2、表3，第517页第3.2节 * |
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