Example 4
To a 2 L 3-neck round bottom flask was added 7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidin-4-ol (12a) (120 g, 435 mmol), Benzyltriethylammonium chloride (198 g, 869 mmol), and N,N-Diethylaniline (104 ml, 652 mmol) in Acetonitrile (500 ml). Phosphorus oxychloride (122 ml, 1304 mmol) was added dropwise to the mixture via addition funnel over 20 min. During addition the solution temperature increased from 15° C. to 29° C. After complete addition, the solution was heated to 75° C. for about 1 h and deemed complete by LCMS and HPLC. The reaction was then transferred via cannula to 1 L of cold water, maintaining internal temperature below 15° C. Yellow solids formed upon addition and the suspension was allowed to stir for 1 h. The precipitate was filtered, washed with heptane (400 mL) and dried on a filter funnel under vacuum/nitrogen for 3 h. The solids were then transferred to dry in a vacuum oven at 35° C. for 72 h (112 g, 88% isolated, 98.5% LCAP). 1H NMR (500 MHz, DMSO) δ 8.93-8.87 (d, J=2.1 Hz, 1H), 8.48-8.43 (d, J=2.1 Hz, 1H), 6.91-6.67 (t, J=52.9 Hz, 1H); LC-MS calculated for C26H29BrN3O3(M+H)+: m/z=510.1 and 512.1; found: 510.0 and 512.0.
