Acetic Acid → Tert-butyl 4-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]-pyridin-2-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Participants

Reaction Steps

A suspension of 1-cyclopropyl-3-(3-fluoro-4-(2-(5-formylpyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea (47, 3 g, 5.90 mmol, acetate salt), 1-boc-piperazine (1.65 g, 8.85 mmol) and acetic acid (675 μL, 11.80 mmol) in NMP (50 mL) at RT under nitrogen was sonicated for 3 h in order to obtain a solution, then NaBH(OAc)3 (3.95 g, 17.70 mmol) was added. The reaction mixture was stirred at RT for 3 days then quenched by addition of water. The pH was adjusted to 12-13 with 4N NaOH and the suspension was stirred and sonicated for 1 h. The solid was collected by filtration, rinsed with water and air-dried. The residue was purified twice by Biotage (SNAP 50 g KP-Sil cartridge; MeOH/DCM: 1/99 to 10/90 over 20 CV). The desired fractions were collected, concentrated, and co-precipitated with AcOEt with traces of methanol/hexanes to afford the compound 48 (1.511 g, 2.44 mmol, 41% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.56 (bd, J=2.0 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.87 (dd, J=8.1, 2.1 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bdd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.3 Hz, 1H), 6.57 (bd, J=2.5 Hz, 1H), 3.57 (s, 2H), 4H are hidden by water's peak, 2.59-2.51 (m, 1H), 2.42-2.27 (m, 4H), 1.39 (s, 9H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 619.4 (M+H).

Provenance & Evidence