Reaction Steps
A mixture of methyl 2-(2-ethynylphenyl)acetate (I4) (0.472 g, 2.71 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I27) (1.10 g, 2.26 mmol), triphenylphosphine (59 mg, 10 mol %), copper(I) iodide (43 mg, 10 mol %), bis(triphenylphosphine)palladium(II) chloride (79 mg, 5 mol %), DMF (12 mL) and triethylamine (1.26 mL, 9.04 mmol) was degassed with nitrogen in a microwave tube then heated under microwave irradiation at 120° C. for 15 minutes. Three additional tubes were prepared and heated as described above (i.e. a total of 4.40 g of I27). The cooled mixtures were combined, and poured into water (600 mL). The resulting mixture was extracted with dichloromethane (3×250 mL) then the combined organic phases were washed with water (2×300 mL), brine (300 mL), dried over sodium sulfate and evaporated to dryness. The residue was chromatographed (120 g silica cartridge, 0-50% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I28) (5.52 g, 98% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.00 (s, 1H), 7.69 (dd, J=7.7, 0.9 Hz, 1H), 7.43 (td, J=7.6, 1.4 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.32 (dd, J=7.5, 1.4 Hz, 1H), 6.87 (dd, J=8.4, 1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 3.97 (s, 2H), 3.91 (s, 3H), 3.71 (s, 3H), 2.81 (t, J=12.6 Hz, 2H), 2.64 (tt, J=12.2, 3.6 Hz, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.69-1.55 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.05 min; m/z (625.1 [M+H]+, 569.1 [M-tBu+2H]+; m/z 623.2 [M−H]−.
