Phosphorus oxychloride → 2-Chloro-8-iodo-3-methyl-quinazolin-4-one

Participants

Reaction Conditions

Reaction Steps

At RT, to the off-white solid of 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol) was added POCl3 (46.5 mL, 508 mmol). The resulting white suspension was treated with DIPEA (14.73 mL, 85 mmol) dropwise. The heterogeneous mixture was heated in an oil bath at 105° C. for 26 h. LCMS indicated the reaction was about 60% conversion. It was cooled to RT, and treated with additional POCl3 (12 mL) and DIPEA (14.73 mL, 85 mmol). The resulting dark homogeneous solution was heated at 110° C. in an oil bath for 24 h. LCMS indicated the reaction was about >95% conversion. It was concentrated under reduced pressure. The brown sticky solution was treated with 50 mL of toluene and concentrated under reduced pressure again. The brown residue was cooled with an ice bath, ice was added to the flask, followed by 5 N NaOH solution till pH >9. It was extracted with 3×250 mL of EtOAc. The combined organic solution was washed with 2×25 mL of brine, dried over Na2SO4, filtered and concentrated. The brown residue was purified via silica gel chromatography (25-50% EtOAc in hexanes) to afford 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700; 10.51 g, 32.8 mmol, 77% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.21-8.32 (m, 2H), 7.22 (t, J=7.82 Hz, 1H), 3.77 (s, 3H). m/z (ES, +ve) 328.8 (M+H)+.

Provenance & Evidence