CN101891690A - Synthesis method of N-substituted-4-amino-quinazoline compound - Google Patents
Synthesis method of N-substituted-4-amino-quinazoline compound Download PDFInfo
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Abstract
The invention discloses a synthesis method of N-substituted-4-amino-quinazoline compound, which comprises the steps of: mixing quinazoline-4 (3H)-ketone compound shown in formula (II), amine compound shown in formula (III) and hexamethyl disilazane according to the molar ratio of 1 to 1-2.5 to 1-2.5; adding catalyst ammonium sulfate, stirring under the protection of nitrogen, and heating to 105-125 DEG C for reaction; carrying out TLC monitoring until complete reaction; and after the reaction, treating reactant by separation and obtaining the N-substituted-4-amino-quinazoline compound. The synthesis method has simple and short synthetic route, simple and safe operation, no need for solvent in the reaction, high product yield, low synthesis cost and higher implementation valve as well as social and economical benefits.
Description
(1) technical field
The present invention relates to a kind of synthetic method of N-substituted-4-amino-quinazoline compound, the method for the synthetic N-substituted-4-amino-quinazoline compound of particularly a kind of one kettle way.
(2) background technology
The N-substituted-4-amino-quinazoline compound has physiologically active widely, has now become one of research focus of new drug development initiative.For example, 6,7,8-trimethoxy-N-aryl-4-amido quinazoline derivatives to tumour cells such as PC3, A431, Bcap-37 and GC823 have inhibiting (Bioorg.Med.Chem.2007,15:6608-6617); 5-replacement-4-aniline quinazoline derivative be the erbB2 receptor tyrosine kinase effective inhibitor (Bioorg.Med.Chem.Lett.2008,18:674-678); The cyclosubstituted 4-amido quinazoline derivatives of the last pyrazoles of N, as Aurora B kinase inhibitor have activity (J.Med.Chem.2007,50,2213-2224).In recent years, the medicine of some tool N-substituted-4-amino quinazoline structures, for example: Gefitinib (Gefitinib), erlotinib (Erlotinib), xylene monosulfonic acid lapatinibditosylate (Lapatinib ditosylate), the card knob is for all listings successively such as Buddhist nun's dihydrochlorides (Canertinibdihydrochloride).
The synthetic method of traditional N-substituted-4-amino-quinazoline compound is to be raw material with quinazoline-4 (3H)-ketone compounds, obtain 4-chloro-quinazoline compounds through chlorination reaction, under alkalescence or acidic conditions, S takes place in 4-chloro-quinazoline compounds and aminated compounds
NThe Ar substitution reaction obtains the N-substituted-4-amino-quinazoline compound.Mainly there is following shortcoming in this route: 1) chlorination reagent generally is SOCl
2, POCl
3Or PCl
5, environment friendly is poor; 2) the chlorination reagent consumption that uses in the chlorination reaction is too much, causes wastage of material, the aftertreatment difficulty; 3) intermediate product 4-chloro-quinazoline compounds activity is higher, the conditional request height of prolonged preservation; 4) two-step reaction, yield are not high.
(3) summary of the invention
The objective of the invention is to overcome the various shortcomings of prior art, the route method of the synthetic N-substituted-4-amino-quinazoline compound of an one kettle way that route is simple, easy and simple to handle, reaction yield is high is provided.
The technical solution used in the present invention is as follows:
A kind of synthetic method suc as formula the N-substituted-4-amino-quinazoline compound shown in (I), described method is: suc as formula quinazoline-4 (the 3H)-ketone compounds shown in (II), is 1: 1～2.5: 1～2.5 to mix suc as formula the aminated compounds shown in (III) and hexamethyldisilazane with the ratio of amount of substance, add the catalyst sulfuric acid ammonium, being heated with stirring to 105 ℃～125 ℃ under the nitrogen protection reacts, the TLC monitoring is to reacting completely, usually the reaction times is 0.5～20 hour, after reaction finished, reactant obtained described N-substituted-4-amino-quinazoline compound through separating treatment;
In formula (I) or the formula (II), the benzene ring hydrogen is substituted basic R
1Replace or be not substituted described substituent R
1Be alkyl or the C1～C3 alkoxyl group of halogen, nitro, C1～C4, described halogen is F, Cl, Br or I; R
2Be H, methyl or ethyl; In formula (I) or the formula (III), R
3For on the benzyl, α-Jia Bianji, 4 or 5 the 1H-pyrazole-3-yl of the alkyl substituent of C1～C4, the alkyl of C4～C10 or the cycloalkyl of C5～C8 are arranged.
Comparatively preferred, described R
1Be methyl, F, Cl, Br, nitro, methoxy or ethoxy.
Described R
2Be preferably H or methyl.
Described R
3Be preferably benzyl, α-Jia Bianji, 5-methyl isophthalic acid H-pyrazole-3-yl, 4-methyl isophthalic acid H-pyrazole-3-yl, normal-butyl, isobutyl-, n-hexyl, n-octyl, cyclopentyl or cyclohexyl.
Described is 1: 1～2.5: 1～2.5 suc as formula quinazoline-4 (the 3H)-ketone compounds shown in (II), suc as formula the aminated compounds shown in (III) and hexamethyldisilazane with the ratio of amount of substance, preferred 1: 1.4～2: 1.4～2.
The amount of substance ratio of the amount of substance of described catalyst sulfuric acid ammonium and quinazoline-4 (3H)-ketone compounds is 5～20: 100, preferred 8～12: 100.
Described temperature of reaction is 105 ℃～125 ℃, is preferably 120～125 ℃.
The described reaction times is generally 0.5～20h, is preferably 1.5～14 hours.
Described reactants separate treatment process is: after reaction finishes, reactant is cooled to room temperature, add methylene dichloride solubilizing reaction thing, carry out column chromatography for separation, do eluent with sherwood oil and 5: 1 blended mixed solutions of ethyl acetate volume ratio, TLC detects, and collects the elutriant that contains the N-substituted-4-amino-quinazoline compound, and the elutriant distillation is removed eluent and obtained described N-substituted-4-amino-quinazoline compound.
Comparatively concrete; recommend method of the present invention to carry out: suc as formula quinazoline-4 (the 3H)-ketone compounds shown in (II) according to following steps; is 1: 1.4～2: 1.4～2 to mix suc as formula the aminated compounds shown in (III) and hexamethyldisilazane with the ratio of amount of substance; add ammonium sulfate; the ratio of described ammonium sulfate and quinazoline-4 (3H)-ketone compounds amount of substances is 8～12: 100; being heated with stirring to 120～125 ℃ under the nitrogen protection reacts; the TLC monitoring is to reacting completely; usually react 1.5～14h; after reaction finishes; reactant is cooled to room temperature; add methylene dichloride solubilizing reaction thing; carry out column chromatography for separation; 5: 1 blended mixed solutions of volume ratio with sherwood oil and ethyl acetate are cooked eluent; TLC detects; collection contains the elutriant of N-substituted-4-amino-quinazoline compound, and the elutriant distillation is removed eluent and obtained described N-substituted-4-amino-quinazoline compound.
The present invention compared with prior art, its beneficial effect is embodied in: need not solvent, product yield height in brief, simple to operate safe, the reaction of this synthetic route, synthetic cost is low, has bigger implementary value and economic results in society.
(4) embodiment
The invention will be further described below by embodiment, but protection scope of the present invention is not limited to this.
The structural formula of the prepared N-substituted-4-amino-quinazoline compound of following embodiment is respectively suc as formula shown in (1)～(16):
The preparation of embodiment 1:N-benzyl-4-amido quinazoline (formula (1))
In being arranged, the reactor of magneton adds 0.4mmol quinazoline-4 (3H)-ketone; 0.56mmol benzylamine; 0.56mmol hexamethyldisilazane and the ammonium sulfate of 0.04mmol; the following 125 ℃ of stirring reactions of nitrogen protection; the TLC monitoring; reaction 2h reacts completely, and reaction finishes, and reaction mixture is cooled to room temperature; add 5mL methylene dichloride solubilizing reaction thing; directly upper prop is done eluent with the mixed solution (v/v, 5: 1) of sherwood oil and ethyl acetate; TLC detects; collection contains the elutriant of product, and the elutriant distillation is removed eluent and obtained target product, and yield is 97%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.71(s，1H)，7.86(d，1H)，7.71-7.76(m，2H)，7.31-7.47(m，6H)，6.07(br，s，1H)，4.88(d，2H)；
13C?NMR(CDCl
3)δppm：159.45，155.5，149.5，138.1，132.8，1298.0，128.79，128.1，127.9，126.2，120.6，114.9，45.4；
MS(ESI)m/z：235.6[M+H
+]；
IR?v
max(KBr)/cm
-1?3228，3060，2966，2935，1619，1575，1541，1495，1415，1340。
The preparation of embodiment 2:N-benzyl-4-amido quinazoline (formula (1))
Reactions steps is with embodiment 1, and different is that temperature of reaction is 105 ℃, and the reaction times is 5h, and product yield is 56%.
The preparation of embodiment 3:N-benzyl-4-amido quinazoline (formula (1))
Reactions steps is with embodiment 1, and the consumption of different is benzylamine and hexamethyldisilazane is 0.40mmol, and product yield is 81%.
The preparation of embodiment 4:N-benzyl-4-amido quinazoline (formula (1))
Reactions steps is with embodiment 1, and the consumption of different is ammonium sulfate is 0.02mmol, and product yield is 81%.
The preparation of embodiment 5:N-benzyl-4-amino-5-methyl quinazoline (formula (2))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 5-methyl quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 14h, and product is a yield 88%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.61(s，1H)，7.71(d，1H)，7.55-7.58(m，1H)，7.31-7.43(m，5H)，7.20(d，1H)，6.35(br，s，1H)，4.85(d，2H)，2.84(s，1H)；
13C?NMR(CDCl
3)δppm：160.7，154.6，151.5，138.2，132.8，131.9，129.2，128.9，127.8，127.7，127.0，115.5，46.0，24.3；
HRMS(ESI)m/z：250.1332(M+H
+)，calcd.for?C
16H
15N
3+H
+＝250.1339；
IR?v
max(KBr))/cm
-1?3498，3060，3029，2924，2872，1578，1524，1349。
The preparation of embodiment 6:N-benzyl-4-amino-6-methyl quinazoline (formula (3))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 6-methyl quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 2h, and product is a yield 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.67(s，1H)，7.77(d，1H)，7.56-7.58(m，1H)，7.46(s，1H)，7.33-7.43(m，5H)，5.93(br，s，1H)，4.87(d，2H)，2.49(s，3H)；
13C?NMR(CDCl
3)δppm：159.0，154.7，147.8，138.3，136.2，134.6，128.9，128.4，128.1，127.8，119.8，114.7，45.4，21.7；
MS(ESI)m/z：250.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3275，1584，1538，1420，1352，1314。
The preparation of embodiment 7:N-benzyl-4-amino-8-methyl quinazoline (formula (4))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 8-methyl quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 4.5h, and product is a yield 92%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.78(s，1H)，7.60(d，1H)，7.54(d，1H)，7.32-7.42(m，6H)，5.96(br，s，1H)，4.87(d，2H)，2.71(s，3H)；
13C?NMR(CDCl
3)δppm：159.7，154.4，148.5，138.2，136.9，132.9，128.9，128.0，127.8，125.6，118.1，114.6，45.5，18.0；
HRMS(ESI)m/z：250.1353(M+H
+)，calcd.for?C
16H
15N
3+H
+＝250.1339；
IR?v
max(KBr)/cm
-1?3250，3126，2935，1585，1531，1492，1417，1357，1329。
The preparation of embodiment 8:N-benzyl-4-amino-5-chloro-quinazoline (formula (5))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 5-chloro-quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 2h, and product yield is 93%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.61(s，1H)，8.04(br，s，1H)，7.75-7.76(m，1H)，7.57(t，1H)，7.30-7.43(m，6H)，4.86(d，2H)；
13C?NMR(CDCl
3)δppm：158.9，155.4，152.2，137.8，131.9，128.8，128.5，128.2，128.1，127.7，127.6，113.1，45.8；
HRMS(ESI)m/z：270.0793(M+H
+)，calcd.for?C
15H
12ClN
3+H
+＝270.0793；
IR?v
max(KBr)/cm
-1?3430，3059，3026，2925，1606，1577，1533，1484，1401，1341。
The preparation of embodiment 9:N-benzyl-4-amino-6-chloro-quinazoline (formula (6))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 6-chloro-quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 3h, and product yield is 93%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.69(s，1H)，7.81(d，1H)，7.66-7.68(m，2H)，7.32-7.42(m，5H)，5.91(br，s，1H)，4.86(d，2H)；
13C?NMR(CDCl
3)δppm：158.5，155.6，148.1，137.8，133.4，131.5，130.3，128.9，128.1，127.9，120.1，115.6，45.5；
HRMS(ESI)m/z：270.0793(M+H
+)，calcd.for?C
15H
12ClN
3+H
+＝270.0792；
IR?v
max(KBr)/cm
-1?3232，3101，3072，2964，1572，1542，1493，1418，1340，1324。
The preparation of embodiment 10:N-benzyl-4-amino-7-chloro-quinazoline (formula (7))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 7-chloro-quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 2h, and product yield is 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.68(s，1H)，7.84(d，1H)，7.65(d，1H)，7.31-7.40(m，6H)，6.07(br，s，1H)，4.86(d，2H)；
13C?NMR(CDCl
3)δppm：159.2，156.4，150.4，138.8，137.8，128.9，128.1，127.9，127.7，126.9，122.2，113.2，45.45；
MS(ESI)m/z：270.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3444，3217，3101，3028，2964，1609，1570，1540，1446，1338。
The preparation of embodiment 11:N-benzyl-4-amino-7-fluquinconazole quinoline (formula (8))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 7-chloro-quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 2h, and product yield is 92%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.68(s，1H)，7.72-7.75(m，1H)，7.48-7.50(m，1H)，7.31-7.42(m，5H)，7.18-7.22(m，1H)，6.02(br，s，1H)，4.87(d，2H)；
13C?NMR(CDCl
3)δppm：165.4，163.4，159.2，156.2，151.3，151.2，139.2，128.3，127.2，126.8，126.0，125.9，115.1，114.4，112.0，111.5，111.3，43.6；
HRMS(ESI)m/z：254.1096(M+H
+)，calcd.for?C
15H
12FN
3+H
+＝254.1088；
IR?v
max(KBr)/cm
-1?3240，3074，3030，2935，1627，1579，1544，1458，1340。
The preparation of embodiment 12:N-benzyl-4-amino-6-nitro-quinazoline (formula (9))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 6-nitro-quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 1.5h, and product yield is 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.81(s，1H)，8.71(d，1H)，8.50-8.53(m，1H)，7.96(d，1H)，7.37-7.45(m，5H)，6.28(br，s，1H)，4.92(d，2H)；
13C?NMR(DMSO-d
6)δppm：160.2，158.2，152.8，144.1，138.6，129.1，128.4，127.5，127.0，126.3，120.6，114.0，43.9；
MS(ESI)m/z：281.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3234，3084，3028，2929，1625，1585，1495，1446，1328。
The preparation of embodiment 13:N-benzyl-4-amino-6-nitro-quinazoline (formula (9))
Reactions steps is with embodiment 12, and different is is 0.5h in the reaction times, and product yield is 75%.
The preparation of embodiment 14:N-normal-butyl-4-amido quinazoline (formula (10))
Reactions steps is with embodiment 1, and different is that benzylamine changes n-Butyl Amine 99 into, and the consumption of reactant is constant, and the reaction times is 1.5h, and product yield is 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.67(s，1H)，7.84(d，1H)，7.68-7.76(m，2H)，7.46-7.49(m，1H)，5.67(br，s，1H)，3.65-3.69(m，2H)，1.72-1.75(m，2H)，1.47-1.51(m，2H)，1.00(t，3H)；
13C?NMR(CDCl
3)δppm：159.5，155.5，149.4，132.5，128.6，125.9，120.5，115.0，41.2，31.5，20.3，13.9；
MS(ESI)m/z：202.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3258，3129，2959，2922，2855，1619，1578，1543，1470，1422，1348，1325。
The preparation of embodiment 15:N-n-octyl-4-amido quinazoline (formula (11))
Reactions steps is with embodiment 1, and different is that benzylamine changes n-octyl amine into, and the consumption of reactant is constant, and the reaction times is 2h, and product yield is 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.67(s，1H)，7.84(d，1H)，7.71-7.74(m，2H)，7.44-7.47(m，1H)，5.90(br，s，1H)，3.64-3.68(m，2H)，1.72-1.75(m，2H)，1.26-1.45(m，10H)，0.88(t，3H)；
13C?NMR(CDCl
3)δppm：159.5，155.4，149.2，132.5，128.4，126.0，120.5，114.9，41.5，31.8，29.4，29.3，29.2，27.1，22.6，14.1；
MS(ESI)m/z：258.2(M+H
+)；
IR?v
max(KBr)/cm
-1?3221，2956，2927，2854，1581，1542，1498，1356，1326。
The preparation of embodiment 16:N-n-octyl-4-amido quinazoline (formula (11))
Reactions steps is with embodiment 15, and different is that temperature of reaction is 120 ℃, and the reaction times is 5h, and product yield is 94%.
The preparation of embodiment 17:N-cyclohexyl-4-amido quinazoline (formula (12))
Reactions steps is with embodiment 1, and different is that benzylamine changes hexahydroaniline into, and the consumption of hexahydroaniline and hexamethyldisilazane is 0.8mmol, and the reaction times is 14h, and product yield is 92%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.65(s，1H)，7.83(d，J＝8.5Hz，1H)，7.68-7.74(m，2H)，7.44-7.47(m，1H)，5.61(d，J＝7Hz，1H)，4.24-4.30(m，1H)，2.14-2.17(m，2H)，1.79-1.83(m，2H)，1.69-1.73(m，1H)，1.46-1.55(m，2H)，1.25-1.35(m，3H)；
13C?NMR(CDCl
3)δppm：158.67，155.47，149.38，132.43，128.48，125.79，120.42，114.92，49.65，33.06，25.66，24.94；
MS(ESI)m/z：227.6(M+H
+)；
IR?v
max(KBr)/cm
-1?3450，3235，3058，2932，2854，1617，1579，1535，1497，1426，1362，1323。
The preparation of embodiment 18:N-cyclohexyl-4-amido quinazoline (formula (12))
Reactions steps is with embodiment 17, and different is is 20h in the reaction times, and product yield is 94%.
The preparation of embodiment 19:N-cyclohexyl-4-amido quinazoline (formula (12))
Reactions steps is with embodiment 17, and the consumption of different is ammonium sulfate is 0.08mmol, and product yield is 94%.
The preparation of embodiment 20:N-(1-styroyl)-4-amido quinazoline (formula (13))
Reactions steps is with embodiment 1, and different is that benzylamine changes the 1-phenyl-ethyl amine into, and the consumption of reactant is constant, and the reaction times is 13h, and product yield is 95%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：8.66(s，1H)，7.84(d，1H)，7.71-7.75(m，2H)，744-746(m，3H)，730-738(m，2H)，727-729(m，1H)，6.01(d，1H)，5.62-5.68(m，1H)，1.69(d，3H)；
13C?NMR(CDCl
3)δppm：158.6，155.4，149.4，143.2，132.6，128.8，128.6，127.6，126.4，126.0，120.5，114.9，50.2，21.8；
MS(ESI)m/z：250.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3250，3059，2980，1619，1575，1531，1419，1358，1318。
The preparation of embodiment 21:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-4-amido quinazoline (formula (14))
Reactions steps is with embodiment 1, and different is that benzylamine changes 5-methyl isophthalic acid H-pyrazoles-3-amine into, and the consumption of 5-methyl isophthalic acid H-pyrazoles-3-amine and hexamethyldisilazane is 0.8mmol, and the reaction times is 14h, and product yield is 83%.
This compound
1H NMR,
13The data of C NMR, HRMS and IR are as described below:
1H?NMR(DMSO-d
6)δppm：12.18(br，s，1H)，10.31(br，s，1H)，8.58-8.61(m，2H)，7.74-7.83(m，2H)，7.56(t，1H)，6.58(br，s，1H)，2.27(m，3H)；
13C?NMR(DMSO-d
6)δppm：157.5，155.0，149.8，147.7，139.2，133.3，128.0，126.6，123.7，115.5，98.5，11.5；
HRMS(ESI)m/z：226.1083(M+H
+)，calcd.for?C
12H
12N
5+H
+＝226.1087；
IR?v
max(KBr)/cm
-1?3271，3177，3072，2928，2868，1625，1599，1550，1483，1403，1320。
The preparation of embodiment 22:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-4-amido quinazoline (formula (14))
Reactions steps is with embodiment 21, and the consumption of different is 5-methyl isophthalic acid H-pyrazoles-3-amine is 0.8mmol, and the consumption of hexamethyldisilazane is 0.6mmol, and the reaction times is 14h, and product yield is 81%.
The preparation of embodiment 23:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-4-amino-6-methoxyl group quinazoline (formula (15))
Reactions steps is with embodiment 21, and different is that quinazoline-4 (3H)-ketone changes 6-methoxyl group quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 18h, and product yield is 81%.
This compound
1H NMR,
13The data of C NMR and MS are as described below:
1H?NMR(DMSO-d
6)δppm：12.17(br，s，1H)，10.27(br，s，1H)，8.49(s，1H)，8.05(s，1H)，7.68-7.69(d，1H)，7.43-7.45(d，1H)，6.67(s，1H)，3.92(s，3H)，2.28(s，3H)；
13C?NMR(DMSO-d
6)δppm：157.7，156.8，153.1，148.4，145.4，138.6，129.6，124.7，115.9，102.7，98.3，56.8，11.25；
MS(ESI)m/z：256.1(M+H
+)。
The preparation of embodiment 24:N-(5-methyl isophthalic acid H-pyrazole-3-yl)-4-amino-6-methoxyl group quinazoline (formula (15))
Reactions steps is with embodiment 23, and the consumption of different is 5-methyl isophthalic acid H-pyrazoles-3-amine and hexamethyldisilazane is 1.0mmol, and the reaction times is 18h, and product yield is 89%.
The preparation of embodiment 25:N-benzyl-4-amino-2-methyl quinazoline (formula (16))
Reactions steps is with embodiment 1, and different is that quinazoline-4 (3H)-ketone changes 2-methyl quinazoline-4 (3H)-ketone into, and the consumption of reactant is constant, and the reaction times is 2.5h, and product yield is 93%.
This compound
1H NMR,
13The data of C NMR, MS and IR are as described below:
1H?NMR(CDCl
3)δppm：7.79(d，1H)，7.65-7.70(m，2H)，7.30-7.42(m，6H)，5.94(br，s，1H)，4.88(d，2H)，2.67(s，3H)；
13C?NMR(CDCl
3)δppm：164.5，159.3，150.0，138.5，132.6，128.8，128.2，127.8，127.7，125.1，120.4，112.9，45.2，26.6；
MS(ESI)m/z：250.1(M+H
+)；
IR?v
max(KBr)/cm
-1?3427，3219，3115，1575，1539，1386，1353。
Claims (10)
1. synthetic method suc as formula the N-substituted-4-amino-quinazoline compound shown in (I), it is characterized in that described method is: suc as formula quinazoline-4 (the 3H)-ketone compounds shown in (II), is 1: 1～2.5: 1～2.5 to mix suc as formula the aminated compounds shown in (III) and hexamethyldisilazane with the ratio of amount of substance, add the catalyst sulfuric acid ammonium, being heated with stirring to 105 ℃～125 ℃ under the nitrogen protection reacts, the TLC monitoring is to reacting completely, after reaction finished, reactant obtained described N-substituted-4-amino-quinazoline compound through separating treatment;
In formula (I) or the formula (II), the benzene ring hydrogen is substituted basic R
1Replace or be not substituted described substituent R
1Be the alkyl of halogen, nitro, C1～C4 or the alkoxyl group of C1～C3, described halogen is F, Cl, Br or I; R
2Be H, methyl or ethyl; In formula (I) or the formula (III), R
3For on the benzyl, α-Jia Bianji, 4 or 5 the 1H-pyrazole-3-yl of the alkyl substituent of C1～C4, the alkyl of C4～C10 or the cycloalkyl of C5～C8 are arranged.
2. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that described R
1Be methyl, F, Cl, Br, nitro, methoxy or ethoxy.
3. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that described R
2Be H or methyl.
4. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that described R
3Be benzyl, α-Jia Bianji, 5-methyl isophthalic acid H-pyrazole-3-yl, 4-methyl isophthalic acid H-pyrazole-3-yl, normal-butyl, isobutyl-, n-hexyl, n-octyl, cyclopentyl or cyclohexyl.
5. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that described quinazoline-4 (3H)-ketone compounds, aminated compounds are 1: 1.4～2: 1.4～2 with the ratio of the amount of substance of hexamethyldisilazane.
6. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that the ratio of the amount of substance of the amount of substance of described catalyst sulfuric acid ammonium and quinazoline-4 (3H)-ketone compounds is 5～20: 100.
7. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that the ratio of the amount of substance of the amount of substance of described catalyst sulfuric acid ammonium and quinazoline-4 (3H)-ketone compounds is 8～12: 100.
8. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1 is characterized in that described temperature of reaction is 120～125 ℃.
9. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1, it is characterized in that described reactants separate treatment process is: after reaction finishes, reactant is cooled to room temperature, add methylene dichloride solubilizing reaction thing, carry out column chromatography for separation, do eluent with sherwood oil and 5: 1 blended mixed solutions of ethyl acetate volume ratio, TLC detects, collection contains the elutriant of N-substituted-4-amino-quinazoline compound, and the elutriant distillation is removed eluent and obtained described N-substituted-4-amino-quinazoline compound.
10. the synthetic method of N-substituted-4-amino-quinazoline compound according to claim 1; it is characterized in that described method is: suc as formula quinazoline-4 (the 3H)-ketone compounds shown in (II); is 1: 1.4～2: 1.4～2 to mix suc as formula the aminated compounds shown in (III) and hexamethyldisilazane with the ratio of amount of substance; add ammonium sulfate; the ratio of described ammonium sulfate and quinazoline-4 (3H)-ketone compounds amount of substances is 8～12: 100; being heated with stirring to 120～125 ℃ under the nitrogen protection reacts; the TLC monitoring is to reacting completely; after reaction finishes; reactant is cooled to room temperature; add methylene dichloride solubilizing reaction thing; carry out column chromatography for separation; with sherwood oil and 5: 1 blended mixed solutions of ethyl acetate volume ratio is eluent; TLC detects; collection contains the elutriant of N-substituted-4-amino-quinazoline compound, and the elutriant distillation is removed eluent and obtained described N-substituted-4-amino-quinazoline compound.
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| CN101547696A (en) * | 2006-08-08 | 2009-09-30 | 奥斯拜客斯制药有限公司 | Preparation and utility of substituted quinazoline compounds with alpha-adrenergic blocking effects |
| WO2010025451A2 (en) * | 2008-08-29 | 2010-03-04 | Dow Agrosciences Llc | 5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals |
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| WO2010025451A2 (en) * | 2008-08-29 | 2010-03-04 | Dow Agrosciences Llc | 5,8-difluoro-4-(2-(4-(heteroaryloxy)-phenyl)ethylamino)quinazolines and their use as agrochemicals |
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|---|
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| CN103980209A (en) * | 2014-05-21 | 2014-08-13 | 贵州大学 | 4-N-substituted-5-chloroquinazoline compound and preparation method and application thereof |
| CN103980209B (en) * | 2014-05-21 | 2016-03-09 | 贵州大学 | A kind of 4-N-replaces-5-chloro-quinazoline compounds and preparation method and application |
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Application publication date: 20101124 Assignee: Hangzhou Zhiguo Enterprise Service Co.,Ltd. Assignor: JIANG University OF TECHNOLOGY Contract record no.: X2023980033596 Denomination of invention: Synthesis of N-substituted 4-aminoquinazoline derivatives Granted publication date: 20121114 License type: Common License Record date: 20230316 Application publication date: 20101124 Assignee: Hangzhou Guangyoujiu Enterprise Management Partnership (L.P.) Assignor: JIANG University OF TECHNOLOGY Contract record no.: X2023980033595 Denomination of invention: Synthesis of N-substituted 4-aminoquinazoline derivatives Granted publication date: 20121114 License type: Common License Record date: 20230316 Application publication date: 20101124 Assignee: Hangzhou baibeiyou Biotechnology Co.,Ltd. Assignor: JIANG University OF TECHNOLOGY Contract record no.: X2023980033594 Denomination of invention: Synthesis of N-substituted 4-aminoquinazoline derivatives Granted publication date: 20121114 License type: Common License Record date: 20230315 |