Triethylamine → 1,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate

Participants

Reaction Conditions

Reaction Steps

Methanesulfonyl chloride (1.8 mL, 23.4 mmol) was added to a mixture of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (4.8 g, 22.3 mmol), triethylamine (3.4 mL, 24.5 mmol), and CH2Cl2 (100 mL) at 0° C. The mixture stirred at 0° C. for 1 h. The mixture was washed with water. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The resulting residue was charged with 6-bromo-3-pyridinol (3.88 g, 22.3 mmol), K2CO3 (6.16 g, 44.6 mmol), DMF (50 mL), and was stirred at 90° C. overnight. The mixture was cooled to ambient temperature, and was set at ambient temperature overnight. The mixture was charged with water, and was stirred at ambient temperature for 4 h. The resulting tan precipitate was filtered, washed with water, and air-dried. The precipitate was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 3.6 g (43%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid, and 3.5 g of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate that contained impurities. The impure batch was repurified by chromatography on a silica gel column using 0 to 2.5% MeOH/CH2Cl2 to give 2.8 g (34%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as an off-white solid which still contained a ˜17% impurity. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.0 Hz), 7.34 (d, 1H, J=8.7 Hz), 7.06 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.15 (d, 2H, J=10.3 Hz), 3.80 (d, 2H, J=6.3 Hz), 2.72 (t, 2H, J=12.4 Hz), 2.01-1.85 (m, 1H), 1.79 (d, 2H, J=12.8 Hz), 1.44 (s, 9H), 1.32-1.13 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).

Provenance & Evidence