Synlett 2018; 29(10): 1346-1350
DOI: 10.1055/s-0037-1610127
letter
© Georg Thieme Verlag Stuttgart · New York

A Different Approach to the EGFR Inhibitor Gefitinib Involving Solid-Phase Synthesis

André Sequeira
a   LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal   Email: luisa_carvalho@campus.fct.unl.pt
,
Ana Lourenço
a   LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal   Email: luisa_carvalho@campus.fct.unl.pt
,
Luísa Maria Ferreira
a   LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal   Email: luisa_carvalho@campus.fct.unl.pt
,
Paula Sério Branco
a   LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal   Email: luisa_carvalho@campus.fct.unl.pt
,
Zita Mendes
b   Hovione FarmaCiencia SA, R&D, Campus do Lumiar, Building S, 1649-038 Lisboa, Portugal
,
Nuno M. T. Lourenço
b   Hovione FarmaCiencia SA, R&D, Campus do Lumiar, Building S, 1649-038 Lisboa, Portugal
,
Margarida Figueiredo
b   Hovione FarmaCiencia SA, R&D, Campus do Lumiar, Building S, 1649-038 Lisboa, Portugal
,
a   LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal   Email: luisa_carvalho@campus.fct.unl.pt
› Author Affiliations
This work was supported by the Associated Laboratory for Sustainable Chemistry - Clean Processes and Technologies LAQV, which is financed by national funds from FCT/MEC(UID/QUI/50006/2013) and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007265). The NMR spectrometers are part of The National NMR Facility, supported by Fundação para a Ciência e Tecnologia (RECI/BBB-BQB/0230/2012). Moreover, the authors would like to thank Hovione FarmaCiencia SA for financial support.

Further Information

Publication History

Received: 20 February 2018

Accepted after revision: 30 March 2018

Publication Date:
09 May 2018 (online)


Abstract

An efficient solid-phase synthesis approach is here reported for the first time to prepare the EGFR inhibitor Gefitinib. The five-step synthetic strategy used FMP resin as the solid support, and FTIR and colorimetric assays were used to track the reaction’s progress. Gefitinib was obtained with an overall yield of 40%.

Supporting Information

 
  • References and Notes

  • 1 Dhillon S. Target. Oncol. 2015; 10: 153
  • 2 Liu Y. Ramirez J. House L. Ratain MJ. Drug Metab. Dispos. 2010; 38: 32
  • 3 Lynch TJ. Bell DW. Sordella R. Gurubhagavatula S. Okimoto RA. Brannigan BW. Harris PL. Haserlat SM. Supko JG. Haluska FG. Louis DN. Christiani DC. Settleman J. Haber DA. N. Engl. J. Med. 2004; 350: 2129
  • 4 Kris MG. Natale RB. Herbst RS. Lynch TJ. Prager D. Belani CP. Schiller JH. Kelly K. Spiridonidis H. Sandler A. Albain KS. Cella D. Wolf MK. Averbuch SD. Ochs JJ. Kay AC. JAMA, J. Am. Med. Assoc. 2003; 290: 2149
  • 5 Gibson KH. WO 1996033980, 1996
  • 6 Knesl P. Roseling D. Jordis U. Molecules 2006; 11: 286
  • 7 Gilday JP. Welham JW. WO 2005023783, 2005
  • 8 Zhang X. Xizhou L. WO 2015188318, 2015
  • 9 Aggarwal AK. Jain AK. Chidambaram VS. Wadhwa LA. WO 2010076810, 2010
  • 10 Chao W. Juanfang X. Yajun K. Yan L. CN 105503748, 2016
  • 11 Gordon K. Balasubramanian S. J. Chem. Technol. Biotechnol. 1999; 74: 835
  • 12 Eifler-Lima VL. Graebin CS. Uchoa FD. Duarte PD. Correa AG. J. Braz. Chem. Soc. 2010; 21: 1401
  • 13 Chen ZP. Hemmasi B. Biol. Chem. Hoppe-Seyler 1993; 374: 1057
  • 14 Deadman BJ. Hopkin MD. Baxendale IR. Ley SV. Org. Biomol. Chem. 2013; 11: 1766
  • 15 Porta R. Benaglia M. Puglisi A. Org. Process Res. Dev. 2016; 20: 2
  • 16 Antonow D. Graebin CS. Eifler-Lima VL. J. Braz. Chem. Soc. 2004; 15: 782
  • 17 Carvalho LR. Corvo MC. Enugala R. Marques MM. B. Cabrita EJ. Magn. Reson. Chem. 2010; 48: 323
  • 18 Power WP. In Annual Reports on NMR Spectroscopy . Academic Press; London: 2003: 261
  • 19 Gaggini F. Porcheddu A. Reginato G. Rodriquez M. Taddei M. J. Comb. Chem. 2004; 6: 805
  • 20 Molchanova N. Hansen PR. Franzyk H. Molecules 2017; 22
  • 21 Verlander M. Int. J. Pept. Res. Ther. 2007; 13: 75
  • 22 Lönnberg H. Bioconjug. Chem. 2009; 20: 1065
  • 23 Gil C. Brase S. J. Comb. Chem. 2009; 11: 175
  • 24 Georgiadis TM. Baindur N. Player MR. J. Comb. Chem. 2004; 6: 224
  • 25 Abreu PM. Branco PS. J. Braz. Chem. Soc. 2003; 14: 675
  • 26 Nandy JP. Prakesch M. Khadem S. Reddy PT. Sharma U. Arya P. Chem. Rev. 2009; 109: 1999
  • 27 Pendri A. Dodd DS. Chen J. Cvijic ME. Rang LY. Baska RA. Carlson KE. Burford NT. Sun CQ. Ewing WR. Gerritz SW. ACS Comb. Sci. 2012; 14: 197
  • 28 Kwak SH. Kim MJ. Lee SD. You H. Kim YC. Ko H. ACS Comb. Sci. 2015; 17: 60
  • 29 Shannon SK. Barany G. J. Comb. Chem. 2004; 6: 165
  • 30 Boas U. Mirsharghi S. Org. Lett. 2014; 16: 5918
  • 31 Blackburn C. In Solid-Phase Synthesis: A Practical Guide . Marcel Dekker; New York: 2000: 198
  • 32 Chandregowda V. Rao GV. Reddy GC. Heterocycles 2007; 71: 39
  • 33 N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine, Gefitinib (1) A solution of TFA 10% in dry DCM was added to the functionalized FMP resin 8 (400 mg, 0.255 mmol). The mixture was stirred for 24 h at room temperature. The resin was filtered and washed with DCM, MeOH/THF (1:1) and H2O/THF (1:1), and the combined phases were collected and evaporated. The crude was resuspended in DCM, and a 2 M NaOH solution was added to neutralize the removed compound. The organic phase was dried over Na2SO4 and evaporated to dryness. Gefitinib (1) was obtained as a yellow solid (50 mg, 0.112 mmol, 44%, crude, HPLC purity: >99%); mp 186–188 oC. 1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1 H, ArH-2), 7.92–7.91 (m, 1 H, ArH-13), 7.59–7.57 (m, 1 H, ArH-16), 7.53 (br s, 1 H, NH), 7.24 (s, 1 H, ArH-7), 7.18–7.13 (m, 2 H, ArH-10 and ArH-17), 4.20 (t, J = 6.5 Hz, 2 H, H-18), 3.99 (s, 3 H, OCH3), 3.77 (m, 4 H, H-22 and H-22′), 2.65–2.55 (m, 6 H, H-21, H-21′ and H-20), 2.15–2.12 (m, 2 H, H-19). 13C NMR (400 MHz, CDCl3): δ = 156.4 (C-4), 155.3 (C-8), 153.6 (C-2), 149.0 (C-9), 147.6 (C-5), 135.6 (C-12), 124.3 (C-16), 122.2 (C-17), 121.8 (C-15), 116.8 (C-13), 109.1 (C-6), 108.1 (C-10), 101.4 (C-7), 67.7 (C-18), 66.6 (C-22 and C-22′), 56.3 (OCH3), 55.5 (C-20), 53.7 (C-21 and C-21′), 25.9 (C-19). FTIR: νmax (KBr): 3400 (m, N–H stretch), 2957, 2809 (m, C–H stretch (aliphatic)), 1625, 1579 (w, C–C stretch (Ar)), 1501 (w, N–H bend), 1219 (m, C–F stretch (Ar)) cm–1.