1,4-Dioxane → benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate

Participants

Reaction Conditions

Reaction Steps

A pressure vial was charged with benzyl {7-bromo-2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (0.032 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.013 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The reaction mixture was sealed with a screw cap and heated at 80° C. for 1 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on a 20 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give benzyl [2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.16 g, 50%, LCMS calc. for C39H42F3N6O6[M+H]+: m/z=747.3. found: 747.4) and the corresponding benzyl carbamate deprotected product, tert-butyl [(3S,5R)-1-[3-({[3-amino-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.13 g, 50%, LCMS calc. for C31H36F3N6O4 [M+H]+: m/z=613.3. found: 613.4).

Provenance & Evidence