6-bromo-2H,3H,4H-pyrido(3,2-b)(1,4)oxazine → (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one

Participants

Reaction Conditions

Reaction Steps

In a 10 ml microwave reactor vial were placed (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (150.0 mg, 0.36 mmol), 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (172.5 mg, 0.8 mmol), and Pd(PPh3)4 (21.1 mg, 0.02 mmol) in DME (1 ml) and 2N Na2CO3 (1 ml). The mixture was sonicated and degassed for 1 min, placed in the microwave reactor, and heated at 135° C. for 15 min. Then it was directly loaded onto the pre-packed silica cartridge and purified using flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane). The fractions were collected, concentrated, and further purified by reverse phase flash chromatography. The fractions were collected, neutralized with sat. NaHCO3, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 52.7 mg (34%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.06 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.60 (s, 1H), 7.39 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 4.76 (m, 1H), 4.13 (m, 2H), 3.67 (m, 1H), 3.42 (m, 3H), 3.19 (m, 1H), 2.82 (m, 1H), 2.36 (m, 2H), 1.31 (d, J=5.8 Hz, 3H), 1.05 (m, 4H). MS (ESI+) m/z 420.2 (M+H).

Provenance & Evidence