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Synlett 2018; 29(10): 1346-1350
DOI: 10.1055/s-0037-1610127
DOI: 10.1055/s-0037-1610127
letter
A Different Approach to the EGFR Inhibitor Gefitinib Involving Solid-Phase Synthesis
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.
Weitere Informationen
Publikationsverlauf
Received: 20. Februar 2018
Accepted after revision: 30. März 2018
Publikationsdatum:
09. Mai 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
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610127.
- Supporting Information
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- 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.