Synthetic process of antitumor drug dacomitinib

CHENG Haibo; XU Bin; ZHANG Huibin; ZHOU Jinpei

doi:10.11665/j.issn.1000-5048.20140206

Journal of China Pharmaceutical University > 2014 > 45(2): 165-169. > DOI: 10.11665/j.issn.1000-5048.20140206

CHENG Haibo, XU Bin, ZHANG Huibin, ZHOU Jinpei. Synthetic process of antitumor drug dacomitinib[J]. Journal of China Pharmaceutical University, 2014, 45(2): 165-169. DOI: 10.11665/j.issn.1000-5048.20140206

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Synthetic process of antitumor drug dacomitinib

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Abstract

This paper describes a practical process for the preparation of antitumor drug dacomitinib. It was synthesized by eleven steps from 2-amino-4-fluorobenzoic acid by cyclization, nitration, halogenation, coupling and reduction reactions with the total yield of 36. 1% and one-step yield of 75%-90 %. The intermediates and target compound were characterized by NMR and MS. This practical synthetic process of dacomitinib highlights comparable yield, low-cost, optimized condition and easier purification.
- dacomitinib,
- tyrosine kinase inhibitor,
- synthetic process,
- antitumor

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[1]	Fry DW,Kraker AJ,McMichael A,et al.A specific inhibitor of the epidermal growth factor receptor tyrosine kinase[J].Science,1994,265(5 175):1 093-1 095.
[2]	Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804,an irreversible pan-ERBB inhibitor,is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib[J].Cancer Res,2007,67(24):11 924-11 932.
[3]	Ercan D,Zejnullahu K,Yonesaka K,et al.Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor[J].Oncogene,2010,29(16):2 346-2 356.
[4]	Rewcastle GW,Denny W A,Bridges AJ,et al.Tyrosine kinase inhibitors.5.Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]-and 4-(phenylamino)quinazolines as potent adenosine 5′-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor[J].J Med Chem,1995,38(18):3 482-3 487.
[5]	Kalous O,Conklin D,Desai AJ,et al.Dacomitinib(PF-00299804),an irreversible Pan-HER inhibitor,inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib[J].Mol Cancer Ther,2012,11(9):1 978-1 987.
[6]	Wu J,Chen W,Xia G,et al.Design,Synthesis,and biological evaluation of novel conformationally constrained inhibitors targeting EGFR[J].ACS Med Chem Lett,2013,4(10):974-978.
[7]	Heuckmann,Johannes M,Rauh D,et al.Epidermal growth factor receptor(EGFR)signaling and covalent EGFR inhibition in lung cancer[J].J Clin Oncol,2012,30(27):3 417-3 420.
[8]	Brugger,Wolfram,Michael T.EGFR-TKI resistant non-small cell lung cancer(NSCLC):new developments and implications for future treatment[J].Lung Cancer,2012,77(1):2-8.
[9]	Barf, Tjeerd, Kaptein A. Irreversible protein kinase inhibitors: balancing the benefits and risks[J].J Med Chem,2012,55(14):6 243-6 262.
[10]	Bain J,Plater L,Elliott M,et al.The selectivity of protein kinase inhibitors:a further update[J].Biochem J,2007,408:297-315.
[11]	Minisci F,Recupero F,Cecchetto A,et al.Polar effects in free-radical reactions.A novel homolytic acylation of heteroaromatic bases by aerobic oxidation of aldehydes,catalysed by N-hydroxyphthalimide and Co salts[J].J Heterocyclic Chem,2003,40(2):325-328.
[12]	Kundu SK, Mahindaratne MPD,Quintero MV,et al.One-pot reductive cyclization to antitumor quinazoline precursors[J].Arkivoc,2008,2:33-42.
[13]	Lin GY,Yan WW,Chen XM,et al.Synthesis of(3-chloro-4-fluoro-phenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine:CN,200910103605.2[P].2011-01-05[2013-12-24] .
[14]	Fakhoury, Lee, Reed, et al. 4-phenylamino-quinazolin-6-yl-amides:US,7772243 B2[P].2010-08-10.
[15]	Lin KC,Mo GN.Synthesis of EGFR inhibitor dacomitinib:CN,201310245229.7[P].2013-09-18[2013-12-24] .
[16]	Roth HF,Li M,Jiang J,et al.Heck reaction and Stille coupling as the key steps in the synthesis of carbon-14-labeled gsk-3 inhibitor alsterpaullone[J].J Labelled Comp Radiopharm,2011,54(5):272-277.
[17]	Pospíil J,Potáek M.Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromenopyrroles:scope and limitations[J].Tetrahedron,2007,63(2):337-346.
[18]	Khazaei A, Vaghei RG, Karkhanei E. Bromination of organic allylic compounds by using N,N′-dibromo-N,N′-1,2-ethane diyl bis(2,5-dimethyl benzene sulphonyl)amine[J].Synthetic Commun,2002,32(14):2 107-2 113.

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[10]	TOTAL SYNTHESIS OF QUASSINOIDS B,C,D,E MODEL SYSTEM[J]. Journal of China Pharmaceutical University, 1985, (4): 1-7.

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