Yield: 55.2%

Reaction Conditions:

Stage #1:2-chloro-5-fluoro-3-methylpyridine with Benzophenone imine;sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium⁽⁰⁾;rac-BINAP in toluene at 80; for 1 h;
Stage #2: with hydrogenchloride;water in tetrahydrofuran at 20; for 1.5 h;
Stage #3: with sodium hydrogencarbonate in tetrahydrofuran;water

Steps:

39
To a solution of 2-chloro-5-fluoro-3-methylpyridine D38 (0.50 g, 2.82 mmol) in dry toluene (12.5 ml) were added sodium t-butoxyde (0.462 g, 4.81 mmol), Pd₂(dba)₃ (0.315 g, 0.344 mmol), BINAP (0.642 g, 1.031 mmol) and benzophenone imine (0.692 ml, 4.12 mmol). The resulting mixture was degassed (3×pump/N₂) and then heated to 80° C. After 1 h stirring, the mixture was cooled down to room temperature, diluted with Et₂O (400 ml) and filtered through a celite pad. Volatiles were evaporated, the resulting oil was dissolved in THF (34 ml) and HCl (1.408 ml of a 2 M aqueous solution, 2.82 mmol) was added. The mixture was stirred at room temperature for 1.5 h, then neutralized with a saturated NaHCO₃ aqueous solution and diluted with DCM (200 ml). The inorganic layer was back-extracted with DCM (2×50 ml). The collected organic layers were dried (Na₂SO₄), filtered and evaporated. The residue was purified by flash chromatography on silica gel (Biotage SP4 12M, Cy/EtOAc 60/40). Collected fractions gave the title compound D39 (0.20 g, 1.554 mmol, 55.2% yield from D38, two steps), as an orange solid. MS: (ES/+) m/z: 127 (M+1). C₆H₇FN₂ requires 126.¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 7.73 (d, 1H), 7.23 (dd, 1H), 5.60 (bs, 2H), 2.04 (s, 3H).

References:

ALVARO, GIUSEPPE;AMANTINI, DAVID;BELVEDERE, SANDRO US2009/22670, 2009, A1 Location in patent:Page/Page column 20