Abstract
Background Tinibs were a kind of important epidermal growth factor receptor (EGFR) inhibitors used as potential therapeutic agents in treating non-small cell lung cancer (NSCLC) in clinic. The drug resistance of clinical used tinibs made the development of more active tinib analogues an attractive field in research. Quinazoline ring was regarded as the key fragment in tinibs and quinazolinone was indispensible intermediate in the synthesis of quinazoline. Thus, synthesis of quinazolinone intermediates was a key step which would further limit the overall yield of final product of tinib analogues. However, the commonly used synthetic scheme was somewhat complicated and time consuming with relatively low yield in heterocylization of quinazolinone and its derivatives.
Aim In this work, we intended to explore an effective way to improve synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5), the key fragment of erlotinib analogues, in both reaction procedure and yield, thus to provide reference to synthesis of other quinazolinone derivatives.
Methods A simple microwave-assisted one-pot reaction was employed to improve the synthesis of heterocyclization of quinazolinone ring. The reaction conditions, including microwave power, temperature and time of reaction, were screened to achieve high yield under simple operation.
Results 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5) was successfully synthesized from starting material of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile by microwave reaction, which was finished in 1 hour just by one step. The yield of heterocyclization was increased from 29.8% of commonly used three-step scheme to 50% herein.
Conclusion Microwave reaction efficiently improved synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one into "quinazolinone in both synthetic procedure and yield. The results may provide valuable reference to synthesis of other quinazolinone derivatives.
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References
Zhao C, Han S Y, Li P P. Pharmacokinetics of Gefitinib: Roles of Drug Metabolizing Enzymes and Transporters. Curr Drug Deliv. 2017; 14(2): 282-8. doi:10.2174/1567201813666160709021605
Tagliamento M, Genova C, Rijavec E, et al. Afatinib and Erlotinib in the treatment of squamous-cell lung cancer. Expert Opin Pharmacother. 2018; 19(18): 2055-62. doi:10.1080/14656566.2018.1540591.
Tan F, Yang G, Wang Y, et al. Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models. Biomed Pharmacother. 2018; 98: 399-405. doi:10.1016/j.biopha.2017.12.073
Midha A, Dearden S, Mccormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5(9): 2892-911.
Chen L, Fu W, Zheng L, et al. Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer. J Med Chem. 2018; 61(10): 4290-300. doi:10.1021/acs.jmedchem.7b01310.
Song Z, Ge Y, Wang C, et al. Challenges and Perspectives on the Development of Small-Molecule EGFR Inhibitors against T790M-Mediated Resistance in Non-Small-Cell Lung Cancer. J Med Chem. 2016; 59(14): 6580-94. doi:10.1021/acs.jmedchem.5b00840.
Stamos J, Sliwkowski M X, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002; 277(48): 46265-72. doi:10.1074/jbc.M207135200.
Park J H, Liu Y, Lemmon M A, et al. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J. 2012; 448(3): 417-23. doi:10.1042/BJ20121513.
Ju Y, Wu J, Yuan X, et al. Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold. J Med Chem. 2018; 61(24): 11372-83. doi:10.1021/acs.jmedchem.8b01612.
Nara H, Sato K, Naito T, et al. Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach. J Med Chem. 2014;57(21):8886?8902. doi:10.1021/jm500981k.
Betebenner D A, Maring C J, Rockway T W, et al. Antiviral compounds, their preparation, pharmaceutical compositions, and use in therapy: USA, WO 2008133753. 2007-12-19[2008-12-06].
Kundu S K, Mahindaratne M P D, Quintero M V, et al. One-pot reductive cyclization to antitumor quinazoline precursors. Arkivoc. 2008: 33-42. doi:10.3906/kim-1906-50
Saari R, Torma J C, Nevalainen T. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg Med Chem. 2011; 19(2): 939-50. doi:10.1016/j.bmc.2010.11.059.
Saemian N, Arjomandi O K, Shirvani G. Synthesis of a series of carbon-14 labelled 4-aminoquinazolines and quinazolin-4(3H)-ones. Journal of Labelled Compounds and Radiopharmaceuticals. 2009; 52(11): 453-6. doi:10.1016/j.bmcl.2006.04.080.
Wang J Q, Gao M, Miller K D, et al. Synthesis of [11C] Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase. Bioorg Med Chem Lett. 2006; 16(15): 4102-6. doi:10.1016/j.bmcl.2006.04.080.
Xiong Y, Li F, Babault N, et al. Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase. J Med Chem. 2017; 60(5): 1876-91. doi:10.1021/acs.jmedchem.6b01645.
Li Feng, Liu Pengcheng, Lu Lei. (2016) Method for synthesizing erlotinib: CN, CN 107337648. State Intellectual Property Office of the People's Republic of China.
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