Potassium Phosphate, Tribasic → (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)-phenyl)-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)acetate

Participants

Reaction Conditions

Reaction Steps

Palladium (II) acetate (6.61 mg, 0.029 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.294 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (120 mg, 0.324 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (24.18 mg, 0.059 mmol) and potassium phosphate tribasic (469 mg, 2.208 mmol) in dioxane (2 ml) and water (0.4 ml) stirred for 16 h at 80° C. and stirred in a screw-capped pressure vessel. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-100% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)-phenyl)-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)acetate 155 mg (82%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.38 (m, 2H), 7.22-7.21 (m, 1H), 7.15 (t, J=8.4 Hz, 2H), 7.02-6.98 (m, 3H), 5.92 (br. s, 1H), 4.96 (br. s, 1H), 4.23 (t, J=6.6 Hz, 2H), 3.42 (br. s, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.60 (br. s, 2H), 2.46 (s, 3H), 2.06 (br. s, 1H), 2.04 (s, 3H), 1.88-1.70 (m, 2H), 1.62-1.52 (m, 2H), 1.19 (d, J=6.2 Hz, 3H), 1.13 (br. s, 12H). UPLC (M+H)=647.4.

Provenance & Evidence