D
A. Sequeira et al.
Letter
Synlett
Table 2 Reaction Conditions for the Alkylation Step with 4-(3-Chloropropyl)morpholine (7)a
Entry
Base (equiv)
Solvent
Reaction time (h)
Observations
1
2
3
K2CO3(5)
NaOH (5)
K2CO3(5)
DMF
DMSO
–
144
72
incomplete
complete
72
formation of dialkylated product 10
a Reactions performed with 5 equiv of compound 7 at 80 °C.
The removal of Gefitinib (1) from the resin was per-
formed using TFA 10% in DCM at room temperature.28,24 Ge-
fitinib was obtained as the major product over a five-step
synthesis with a reasonable overall yield of 40% (in an opti-
mized synthetic sequence which started with 400 mg of
FMP resin).32,33 In the steps where side products were ob-
served, optimizations were performed to minimize or elim-
inate these compounds. The yield of each reaction was esti-
mated by weighting the resin after each reaction step,
showing that the removal of Gefitinib from the resin was
the yield-determinant step (44% as a crude, HPLC purity of
99%). Since no significative degradation products were ob-
served, it is proposed that the final cleavage of 1 with TFA is
an incomplete process and possibly requires stronger acidic
conditions.
In conclusion, we have developed an efficient SPS ap-
proach to produce Gefitinib (1) using FMP resin. Compound
1 was obtained in 40% overall yield, a result that overcomes
the first patented synthesis of Gefitinib by Gibson et al.
Tracking of the reaction intermediates was easily per-
formed by stepwise removal and analysis of resin aliquots.
This is a novel approach to obtain Gefitinib via solid-phase
synthesis, with applicability to other quinazoline deriva-
tives and potentially towards a continuous-flow process.
(2) Liu, Y.; Ramirez, J.; House, L.; Ratain, M. J. Drug Metab. Dispos.
2010, 38, 32.
(3) Lynch, T. J.; Bell, D. W.; Sordella, R.; Gurubhagavatula, S.;
Okimoto, R. A.; Brannigan, B. W.; Harris, P. L.; Haserlat, S. M.;
Supko, J. G.; Haluska, F. G.; Louis, D. N.; Christiani, D. C.;
Settleman, J.; Haber, D. A. N. Engl. J. Med. 2004, 350, 2129.
(4) Kris, M. G.; Natale, R. B.; Herbst, R. S.; Lynch, T. J.; Prager, D.;
Belani, C. P.; Schiller, J. H.; Kelly, K.; Spiridonidis, H.; Sandler, A.;
Albain, K. S.; Cella, D.; Wolf, M. K.; Averbuch, S. D.; Ochs, J. J.;
Kay, A. C. JAMA, J. Am. Med. Assoc. 2003, 290, 2149.
(5) Gibson, K. H. WO 1996033980, 1996.
(6) Knesl, P.; Roseling, D.; Jordis, U. Molecules 2006, 11, 286.
(7) Gilday, J. P.; Welham, J. W. WO 2005023783, 2005.
(8) Zhang, X.; Xizhou, L. WO 2015188318, 2015.
(9) Aggarwal, A. K.; Jain, A. K.; Chidambaram, V. S.; Wadhwa, L. A.
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, V. L.; Graebin, C. S.; Uchoa, F. D.; Duarte, P. D.;
Correa, A. G. J. Braz. Chem. Soc. 2010, 21, 1401.
(13) Chen, Z. P.; Hemmasi, B. Biol. Chem. Hoppe-Seyler 1993, 374,
1057.
(14) Deadman, B. J.; Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Org.
Biomol. Chem. 2013, 11, 1766.
(15) Porta, R.; Benaglia, M.; Puglisi, A. Org. Process Res. Dev. 2016, 20,
2.
(16) Antonow, D.; Graebin, C. S.; Eifler-Lima, V. L. J. Braz. Chem. Soc.
2004, 15, 782.
(17) Carvalho, L. R.; Corvo, M. C.; Enugala, R.; Marques, M. M. B.;
Cabrita, E. J. Magn. Reson. Chem. 2010, 48, 323.
Funding Information
(18) Power, W. P. 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, P. R.; 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, T. M.; Baindur, N.; Player, M. R. J. Comb. Chem. 2004,
6, 224.
This work was supported by the Associated Laboratory for Sustain-
able Chemistry - Clean Processes and Technologies LAQV, which is fi-
nanced 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.
M
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1
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(25) Abreu, P. M.; Branco, P. S. J. Braz. Chem. Soc. 2003, 14, 675.
(26) Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.;
Arya, P. Chem. Rev. 2009, 109, 1999.
Supporting Information
Supporting information for this article is available online at
(27) Pendri, A.; Dodd, D. S.; Chen, J.; Cvijic, M. E.; Rang, L. Y.; Baska, R.
A.; Carlson, K. E.; Burford, N. T.; Sun, C. Q.; Ewing, W. R.; Gerritz,
S. W. ACS Comb. Sci. 2012, 14, 197.
(28) Kwak, S. H.; Kim, M. J.; Lee, S. D.; You, H.; Kim, Y. C.; Ko, H. ACS
Comb. Sci. 2015, 17, 60.
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References and Notes
(1) Dhillon, S. Target. Oncol. 2015, 10, 153.
(29) Shannon, S. K.; Barany, G. J. Comb. Chem. 2004, 6, 165.
(30) Boas, U.; Mirsharghi, S. Org. Lett. 2014, 16, 5918.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E