Reaction Steps
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (93.9 mg, 0.200 mmol), 1,2,3,4-tetrahydroisoquinoline (53.3 mg, 0.400 mmol), cupric acetate (36.3 mg, 0.200 mmol), pyridine (32 μL, 0.40 mmol) and DCM (5 mL, 80 mmol) was stirred at rt under an atmosphere of air (Reaction A). Another reaction was set up with the same amount of above reagents, and 4 Å molecular sieves (53 mg, 264 mg/mmol SM) was added (Reaction B). After stirring overnight at rt, the same amount of molecular sieve as in reaction B was added to reaction A. After stirring at rt for 7 h, both reaction mixtures were combined, washed with EDTA solution (2%, 3×30 ml), water (30 ml) and brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark-blue solid. Purification by prep. TLC eluting with 5% MeOH/DCM gave 4-{4-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as brown oil; MS(ES+): m/z=475.12 [MH+]. This brown oil was dissolved in MeOH (10 mL), 1.0 M of HCl in Et2O (10 mL) was added, and the solution was stirred at rt for 3 d. The solvent was removed; the residue was dissolved in DMSO and purified by Gilson HPLC to give the title compound as light-brown oil. 1H NMR (400 MHz, DMSO-d6): δ=1.99-2.11 (m, 2H), 2.12-2.19 (m, 2H), 2.89-2.99 (m, 2H), 3.00-3.05 (m, 2H), 3.12-3.18 (m, 2H), 3.26-3.33 (m, 2H), 4.10 (s, 2H), 4.33-4.43 (m, 1H), 5.51 (brs, 2H), 7.13-7.19 (m, 4H), 7.47 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 8.30 (brs, 2H). MS(ES+): m/z=375.17 (42) [MH+]. HPLC: tR=1.73 min (ZQ2, polar—5 min).
