Abstract：OBJECTIVE To establish a new synthesis method of N-arylquinazolin-4-amines, the key intermediates of tinib drugs, optimize the reaction conditions, determine the applicability of reaction substrates, and speculate the possible reaction mechanism. METHODSN-Arylquinazolin-4-amines(3a-3g) were synthesized via Cu(OTf)2-catalyzed one-pot multicomponent tandem reactions of substituted 2-aminobenzonitriles(1a-1e), arylamines(2a-2e) and formic acid. The effects of catalyst and its dosage, the solvent, the amount of reactants, the reaction temperature, and the reaction time on the multicomponent tandem reaction were investigated. RESULTS The tandem addition/condensation/cyclization reactions of substituted 2-aminobenzonitriles, arylamines and formic acid catalyzed by Cu(OTf)2 were achieved successfully to give seven N-arylquinazolin-4-amines with yields of 80%-95% under the conditions of substituted 2-aminobenzonitrile 5 mmol, arylamines 6 mmol, formic acid 20 mL, Cu(OTf)2 0.5 mmol,reaction temperature 110 ℃, reaction time 12 h. The structures of the target compounds were confirmed by 1H-NMR and 13C-NMR. CONCLUSION The method is a green process for the efficient and facile synthesis of N-arylquinazolin-4-amines, the key intermediates of tinib drugs, which is mild in reaction condition, high in yield, simple and safe in operation, and friendly to environment.
ZHENG Y G, ZHANG W Q, MENG L, et al. Design, synthesis and biological evaluation of 4-aniline quinazoline derivatives conjugated with hydrogen sulfide(H2S) donors as potent EGFR inhibitors against L858R resistance mutation[J]. Eur J Med Chem, 2020, 202, 112522.Doi:10.1016/j.ejmech.2020.112522
[2]
LIU W Q, GAO J L, FENG Z Y, et al. Research progress in population pharmacokinetics of multiple target tyrosine kinase inhibitors in the treatment of malignant tumors[J]. Chin Pharm J(中国药学杂志), 2020, 55(13): 1060-1067.
[3]
AL-ASHMAWY A A K, ELOKELY K M, PEREZ-LEAL O, et al. Discovery and SAR of novel disubstituted quinazolines as dual PI3Kalpha/mTOR inhibitors targeting breast cancer[J]. ACS Med Chem Lett, 2020, 11(11): 2156-2164.
[4]
CHANG J, REN H, ZHAO M, et al. Development of a series of novel 4-anlinoquinazoline derivatives possessing quinazoline skeleton: Design, synthesis, EGFR kinase inhibitory efficacy, and evaluation of anticancer activities in vitro[J]. Eur J Med Chem, 2017, 13:669-688. Doi:10.1016/j.ejmech.2017.07.005
[5]
ALAFEEFY A M, AHMAD R, ABDULLA M, et al. Development of certain new 2-substituted-quinazolin-4-yl-aminobenzenesulfonamide as potential antitumor agents[J]. Eur J Med Chem, 2016, 109:247-253.Doi:10.1016/j.ejmech.2016.01.001
[6]
HENNEQUIN L F, ALLEN J, BREED J, et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor[J]. J Med Chem, 2006, 49(22): 6465-6488.
[7]
CHEN J N, LI T, CHENG L, et al. Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives[J]. Eur J Med Chem, 2020, 205:112661. Doi:10.1016/j.ejmech.2020.112661
[8]
ZHANG G, WANG M, ZHAO J, et al. Design, synthesis and in vitro anti-influenza A virus evaluation of novel quinazoline derivatives containing S-acetamide and NH-acetamide moieties at C-4[J]. Eur J Med Chem, 2020, 206:112706. Doi:10.1016/j.ejmech.2020.112706
[9]
MALASALA S, AHMAD M N, AKUNURI R, et al. Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis[J]. Eur J Med Chem, 2020, 206:112996. Doi:10.1016/j.ejmech.2020.112996
[10]
HAILE P A, CASILLAS L N, VOTTA B J, et al. Discovery of a first-in-class receptor interacting protein 2(RIP2) kinase specific clinical candidate, 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate, for the treatment of inflammatory diseases[J]. J Med Chem, 2019, 62(14): 6482-6494.
[11]
MALASALA S, AHMAD M N, GOUR J, et al. Synthesis, biological evaluation and molecular modelling insights of 2-arylquinazoline benzamide derivatives as anti-tubercular agents[J]. J Mol Struct, 2020, 1218:128493. Doi:10.1016/j.molstruc.2020.128493
[12]
GILSON P R, TAN C, JARMAN K E, et al. Optimization of 2-anilino 4-amino substituted quinazolines into potent antimalarial agents with oral in vivo activity[J]. J Med Chem, 2017, 60(3): 1171-1188.
[13]
HUMPHREY J M, MOVSESIAN M, ENDE C W, et al. Discovery of potent and selective periphery-restricted quinazoline inhibitors of the cyclic nucleotide phosphodiesterase PDE1[J]. J Med Chem, 2018, 61(10): 4635-4640.
[14]
ZHENG J, JEON S, JIANG W, et al. Conversion of quinazoline modulators from inhibitors to activators of β-glucocerebrosidase[J]. J Med Chem, 2019, 62(3): 1218-1230.
[15]
TU Y, OU YANG Y, XU Shan, et al. Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors[J]. Bioorgan Med Chem, 2016,24(7): 1495-1503.
[16]
WAIKER D K, KARTHIKEYAN C, POONGAVANAM V, et al. Synthesis, biological evaluation and molecular modelling studies of 4-anilinoquinazoline derivatives as protein kinase inhibitors[J]. Bioorgan Med Chem, 2014, 22(6): 1909-1915.
[17]
GAROFALO A, GOOSSENS L, BALDEYROU B, et al. Design, synthesis, and DNA-binding of N-alkyl(anilino)quinazoline derivatives[J]. J Med Chem, 2010, 53(22): 8089-8103.
[18]
ASQUITH C R M, NAEGELI K, EAST M, et al. Design of a cyclin G associated kinase(GAK)/epidermal growth factor receptor(EGFR) inhibitor set to interrogate the relationship of EGFR and GAK in chordoma[J]. J Med Chem, 2019, 62(9): 4772-4778.
[19]
PATEL G, KARVER C E, BEHERA R, et al. Kinase scaffold repurposing for neglected disease drug discovery: Discovery of an efficacious, lapatanib-derived lead compound for trypanosomiasis [J]. J Med Chem, 2013, 56(10): 3820-3832.
[20]
SCHMITT J, HUANG S, GOODFELLOW E, et al. Design and synthesis of a trifunctional molecular system “programmed” to block epidermal growth factor receptor tyrosine kinase, induce high levels of DNA damage, and inhibit the DNA repair enzyme(poly(ADP-ribose) polymerase) in prostate cancer cells[J]. J Med Chem, 2020, 63(11): 5752-5762.
[21]
YIN L F, MAO Y J, ZHAO Z W, et al. Preparation of irbinitinib and its intermediates: China, 109942576 B[P]. 2020-09-11.
[22]
YIN L, MAO Y, LIU Y, et al. New synthetic route to tucatinib[J]. Synthesis, 2019, 51(13): 2660-2664.
[23]
LIU C C, GU Y Y, LIANG E. Synthesis of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine under microwave irradiation[J]. Fine Chem(精细化工), 2019, 36(4): 776-780.
2022, Vol. 57 
