Fig. 2: Synthesis of the N-linked bivalent inhibitor (1) inspired by the parent allosteric inhibitors 8 and 9. | Communications Chemistry

Fig. 2: Synthesis of the N-linked bivalent inhibitor (1) inspired by the parent allosteric inhibitors 8 and 9.

From: Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors

Fig. 2

Reagents and conditions are as follows: i) (COCl)2, DMF cat., DCM, rt; then 5-Fluoro-2-iodoaniline, Et3N, DCM, rt, 38% over two steps; ii) 3-Bromobenzyl bromide, NaH (60% dispersion in mineral oil), THF, rt, 91%; iii) Fe, NH4Cl, THF/MeOH/H2O, 50 °C, quant.; iv) CuI, K2CO3, DMSO, 135 °C, 76%; v) Bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, 1,4-dioxane, 90 °C, quant.; vi) 4-Bromo-2-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole, K3PO4 trihydrate, P(t-Bu)3 Pd G3, 1,4-dioxane/H2O, 50 °C, 70%; vii) NBS, ACN, -30 °C, 70%; viii) N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide, K3PO4 trihydrate, P(t-Bu)3 Pd G3, 1,4-dioxane/H2O, 50 °C, 64%; ix) 33% TFA in DCM, rt, 62%. With adaptions from44,50.

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