1,2-Dimethoxyethane → 1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of [4-(methylsulfonyl)phenyl]boronic acid (540 mg, 2.7 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (1 g, 2.7 mmol), Pd(PPh3)2Cl2 (190 mg, 0.27 mmol), DME (10 mL) and 2M Na2CO3 (5 mL) was stirred at 80° C. overnight. The mixture was cooled to ambient temperature, charged with water, and extracted with Et2O. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The aqueous phase was further extracted with CH2Cl2. The CH2Cl2 extracts were combined with the Et2O extracts, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 1.5% MeOH/CH2Cl2, followed by recrystallization from MeOH. The recrystallized material and the mother liquor were combined, then concentrated to give 705 mg (58%) of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as an off-white solid. This material contained a minor impurity which was carried on to the next step. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, 1H, J=2.7 Hz), 8.14 (d, 2H, J=8.4 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.75 (d, 1H, J=8.7 Hz), 7.34 (d, 1H, J=8.2 Hz), 4.26-4.10 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.07 (s, 3H), 2.83-2.66 (m, 2H), 2.10-1.94 (m, 1H), 1.84 (d, 2H, J=12.82 Hz), 1.46 (s, 9H), 1.38-1.21 (m, 2H); LRMS (ESI), m/z 447 (M+H).

Provenance & Evidence