Methanol → (4R,5R)-4-(2-fluoro-5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one

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Reaction Conditions

Reaction Steps

To a 15 ml sealable vial was added a mixture of (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (30 mg, 0.084 mmol) and its regioisomer in triethylamine (2 mL). To this suspension was added 3-ethynyl-5-fluoropyridine (12.28 mg, 0.101 mmol), triphenylphosphine (6.65 mg, 0.025 mmol) and copper(I) iodide (0.322 mg, 1.690 μmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (1.186 mg, 1.690 μmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy 1% MeOH/99% CH2Cl2 affording a single peak. This single peak was a 60:40 mixture of regioisomers and was subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase: 35% MeOH in CO2 (w/0.1% diethylamine) column temp: 35 C flow rate: 2 mL/min., affording (4R,5R)-4-(2-fluoro-5-((5-fluoropyridin-3-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (25 mg, 0.062 mmol, 73.4% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.51 (d, J=4.0, 1H), 8.45 (s, 1H), 8.14 (dd, J=8.0, 4.0, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.21-7.13 (m, 2H), 6.05 (brs, 1H), 5.39 (d, J=4.0, 1H), 5.04 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.01 min. Mass=396.20 (MH)+.

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