N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid → 1-[2-(4-aminophenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea

Participants

Reaction Steps

A solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenyl]-2,2-dimethyl-succinamic acid (190 mg, 0.33 mmol) in 3 mL THF was treated with borane-methylsulfide complex (2M, 1.0 mL, 2.0 mmol, 6 eq). The reaction mixture was heated at reflux under nitrogen for 4 h. The reaction mixture was then cooled to room temperature, slowly quenched by the addition of 0.6 mL EtOH and 2 mL 2N HCl. The reaction mixture was heated again at reflux for 1 hr, then cooled to room temperature, basified by the addition of 1N NaOH, extracted with DCM, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 2% to 6% MeOH in DCM) to afford 80 mg of semi-pure 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea. Preparative HPLC purification using 5-80% H2O in acetonitrile (containing 0.5% TFA) afforded 33 mg (18%) of the desired product. 1H-NMR (DMSO-d6) δ 9.14 (s, 1H), 8.40 (dd, J=1.6 & 4.8 Hz, 2H), 8.17 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 7.07 (d, J=9 Hz, 2H), 6.85 (dd, J=1.5 & 4.9 Hz, 2H), 6.62 (d, J=8.9 Hz, 2H), 6.28 (s, 1H), 5.83 (t, J=5.2 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.14 (d, J=5.4 Hz, 2H), 3.06-3.01 (m, 2H), 1.52-1.48 (m, 2H), 1.25 (s, 9H), 0.87 (s, 6H); MS LC-MS [M+H]+=543.2, RT=2.31 min.

Provenance & Evidence