Cesium fluoride → (S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1099, 642 mg, 1.70 mmol), 5-bromo-3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1100, 543 mg, 1.418 mmol), and CsF (1.5 M, 2.84 mL, 4.26 mmol) in 7 mL DMF was degassed with nitrogen for 30 minutes, at which point 1,1′-Bis(diphenylphosphino)ferrocene]palladium dichloride (174 mg, 0.212 mmol) was added and the mixture was degassed an additional 15 minutes before heating to 120° C. under an atmosphere of nitrogen. After 1 hour, LCMS analysis indicated that the reaction was complete. Methylene chloride (10 mL) and satd' aqueous sodium bicarbonate (10 mL) were added, and the reaction mixture extracted with methylene chloride (2×10 mL), the combined organics concentrated under reduced pressure, and the residue purified via silica gel chromatography (50-100% ethyl acetate in hexanes) to give (S)-tert-Butyl 3-(4-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Compound 1101) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.25-7.16 (m, 2H), 6.94-6.88 (m, 2H), 6.31 (s, 2H), 4.15-4.01 (m, 1H), 3.96 (s, 3H), 3.28 (d, J=11.5 Hz, 1H), 2.98-2.81 (m, 2H), 2.62 (dd, J=2.7, 22.8 Hz, 1H), 2.62 (s, 1H), 2.14-2.10 (m, 1H), 1.97-1.73 (m, 1H), 1.62 (s, 9H) and 1.57-1.47 (m, 1H) ppm.

Provenance & Evidence