Dichloromethane → Tert-butyl (4-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]-2-pyridyl]-4-cyano-piperidine-1-carboxylate)

Participants

Reaction Conditions

Reaction Steps

tert-butyl 4-cyano-4-(4-iodo-2-pyridyl)piperidine-1-carboxylate (1.01 g, 2.444 mmol) was dissolved in dioxane (15 mL) and bis(pinacolato)diboron (934.0 mg, 3.678 mmol) followed by potassium acetate (721.9 mg, 7.356 mmol) were added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles. [PdCl2(dppf)].dichloromethane (199.6 mg, 0.2444 mmol) was then added and the reaction heated to 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature and tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.150 g, 2.444 mmol) and a 2 M aqueous solution of sodium carbonate (3.666 mL of 2 M, 7.332 mmol) were added. The reaction mixture was degassed with 3× vacuum/nitrogen cycles then Pd(PPh3)4 (283.2 mg, 0.2451 mmol) was added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles and then heated to 90° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate/water. The aqueous layer was extracted with ethyl acetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column), loaded in dichloromethane eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as a beige solid (749 mg, 51% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.33 (s, 18H), 1.38 (s, 9H), 2.07 (dt, 2H), 2.21 (d, 2H), 3.01 (br s, 2H), 4.10 (br d, 2H), 4.99 (s, 1H), 8.11 (dd, 1H), 8.25 (s, 1H), 8.78 (d, 1H) and 9.40 (s, 1H) ppm; LC/MS m/z 605.3 [M+H]+.

Provenance & Evidence