methyl 2-(2,6-difluoro-4-hydroxyphenyl)acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl (2,6-difluoro-4-hydroxyphenyl)acetate (1.46 g, 7.22 mmol) in 10 ml anhydrous dichloromethane at RT was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.79 g, 11.4 mmol), and di-tert-butyl azodicarboxylate (1.83 g, 7.94 mmol). The reaction mixture was stirred at RT for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 50 g) using a gradient eluent of 0-40% ethyl acetate in hexanes (900 ml) to afford the title compound. LC/MS (m/z) 476.4 (M+H)+. The mixture was filtered through Celite concentrated under reduced pressure The residue was purified by column chromatography on silica gel (Biotage column, 50 g)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of (2,6-difluoro-4-methoxyphenyl)acetic acid (1.50 g, 7.42 mmol) in 20 ml anhydrous dichloromethane at 0° C. was added a solution of boron tribromide (4.29 ml, 44.5 mmol) in 10 ml anhydrous dichloromethane. The cooling bath was removed and the mixture allowed to warm to RT for 2 hours. The reaction was diluted with 20 ml anhydrous methanol, and stirred for 30 minutes. The mixture was concentrated under reduced pressure, and the residue purified by column chromatography on silica gel, (Biotage column, 50 g) using a gradient eluent of 0-30% ethyl acetate in hexanes (700 ml) to afford the title compound. 1H NMR (CDCl3): δ 6.30 (d, J=8.3 Hz, 2H), 6.12 (br, 1H), 3.76 (s, 3H), 3.63 (s, 2H). The cooling bath was removed The reaction was diluted with 20 ml anhydrous methanol The mixture was concentrated under reduced pressure the residue purified by column chromatography on silica gel, (Biotage column, 50 g)