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

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%.

Key words

solid-phase synthesis - Gefitinib - quinazoline - FMP resin - colorimetric assays

• References and Notes

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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: ν_max (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.