Hydrochloric Acid → 3-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-[2-(4-methylpiperazin-1-yl)-thiazol-5-yl]-pyridin-2-ylamine trihydrochloride

Participants

Reaction Conditions

Reaction Steps

A solution of 1-(5-bromothiazol-2-yl)-4-methylpiperazine (45 mg, 0.17 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB5) (89.2 mg, 0.223 mmol), potassium carbonate (71.2 mg, 0.515 mmol), and Pd(PPh3)4 (11.9 mg, 0.0103 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×), and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in a pure yellow solid. This sample was then dissolved in a minimum of DCM then charged with 3 equiv of 1M HCl in ether and the reaction mixture was concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.83 (d, J=4.0 Hz, 3H), 3.13-3.28 (m, 2H), 3.45-3.60 (m, 4H), 4.07 (d, J=14.3 Hz, 2H), 7.67 (t, J=8.0 Hz, 1H), 7.84 (s, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.27 (d, J=2.2 Hz, 1H), 8.54 (s, 1H), 8.61 (s, 1H), 9.67 (s, 1H), 11.05 (br. s., 1H). MS (ES+): m/z=455.07/457.08 (76/24) [MH+]. HPLC: tR=1.99 min (ZQ2, polar—5 min).

Provenance & Evidence