Water → 4-[4-(6-Amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 2-naphthylboronic acid (43 mg, 0.25 mmol), Pd(PPh3)4 (23 mg, 0.020 mmol), and a mixture of 4-[4-(6-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester and 4-[4-(2-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (together 92.2 mg, 0.138 mmol) in 1,4-dioxane (3.5 mL, 45 mmol) in a sealable microwave tube was charged with a solution of Cs2CO3 (140 mg, 0.44 mmol) in H2O (0.90 mL, 50 mmol), flushed with nitrogen, sealed and irradiated in the microwave reactor at 105° C. for 60 min. More 2-naphthylboronic acid (11 mg, 0.064 mmol) and Pd(PPh3)4 (5.6 mg, 0.0048 mmol) were added, and the solution was heated in the microwave reactor at 105° C. for 30 min. Further 2-naphthylboronic acid (12 mg, 0.070 mmol) and Pd(PPh3)4 (4.5 mg, 0.0039 mmol) were added to the solution, which was then heated in the microwave reactor to 105° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 solution, water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. One obtained a mixture of the title compound and its regioisomer, 4-[4-(2-amino-5-naphthalen-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester, as yellow-brown solid. This mixture of regioisomers was separated using the MDPS. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.4 Hz, 1H), 7.99-7.45 (m, 10H), 4.60 (s, 2H), 4.39-4.21 (m, 3H), 2.98-2.85 (brm, 2H), 2.19 (brt, J=13.0 Hz, 2H), 2.05-1.89 (mc, 2H), 1.48 (s, 9H). MS(ES+): m/z=470.19 (100) [MH+]. HPLC: tR=2.85 min (polar—5 min, ZQ3).

Provenance & Evidence