Triphenylphosphine Oxide → 6-{2-Amino-6-[(3r)-3-ethyl-4-morpholinyl]-4-pyrimidinyl}-1h-indazol-3-amine

Participants

Reaction Conditions

Reaction Steps

Into a 25 mL sealable tube under nitrogen were combined 4-chloro-6-[(3R)-3-ethyl-4-morpholinyl]-2-pyrimidinamine (140 mg, 0.58 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.114 g, 0.69 mmol) in 1,4-dioxane (9 mL). Saturated aqueous NaHCO3 (3 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.76 g, 0.066 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 100° C. for 3 hours. The reaction was cooled to room temperature, the solids and other insoluble impurities formed during the reaction were filtered and the filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90/10/1 CHCl3/CH3OH/NH4OH) afforded a mixture of the desired Suzuki product with triphenylphosphine oxide. LC-MS (ES) m/z=328 [M+H]+. In a 25 mL sealable tube under nitrogen were combined the crude containing the Suzuki product 4-{2-amino-6-[(3R)-3-ethyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile and hydrazine monohydrate (0.42 mL) in EtOH (6 mL). The vial was sealed, and the reaction mixture was stirred at 100° C. for 2 days. The reaction was filtered to remove some impurities and the filtrate was concentrated. The resulting solid was dissolved in a mixture of CH3CN/H2O/DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). The CH3CN was evaporated, and saturated aqueous NaHCO3 was added to the remaining water where a precipitate crashed out. The precipitate was filtered, triturated in Et2O and dried in vacuo to afford the title compound (47 mg) as a tan solid. LC-MS (ES) m/z=340 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (t, J=7.5 Hz, 3H), 1.63-1.80 (m, 2H), 3.09 (td, J=12.8, 3.2 Hz, 1H), 3.37-3.46 (m, 2H), 3.51 (dd, J=11.4, 2.8 Hz, 1H), 3.80-3.91 (m, 2H), 4.30 (bs, 1H), 5.38 (s, 2H), 6.09 (bs, 2H), 6.56 (s, 1H), 7.56 (dd, J=8.6, 1.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 11.52 (s, 1H).

Provenance & Evidence