Acetonitrile → N-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)-N-methyl-C-phenylmethanesulfonamide

Participants

Reaction Steps

4-Amino-5-fluoropyrimidin-2-ol (2 grams (g), 15.5 mmol) was stirred in acetonitrile (CH3CN; 80 mL) at 50° C. To the warm mixture was added N,O-bis(trimethylsilyl)acetamide (BSA; 9.4 g, 46.3 mmol), and stiffing and heating were continued for 1.5 h. Phenylmethanesulfonyl chloride (3.2 g, 16.8 mmol) was added. After 2 h, the reaction mixture was cooled to room temperature and partitioned between CH3CN and brine. The organic phase was dried over MgSO4, filtered, evaporated and placed directly onto a silica gel column which was eluted (gradient, 0 to 100% EtOAc in petroleum ether). Combining fractions containing the major UV absorbing portion of the product mixture yielded a white solid which was used without further purification. To a portion of this material (100 mg) was added DMF (3 mL), K2CO3 (100 mg), and iodomethane (100 mg), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to room temperature and an excess of sodium hydride (NaH; 60% dispersion in mineral oil) was added. The whole mixture was stirred for 30 min and then heated to 45° C. for 2.5 h. The crude mixture was filtered and purified by reverse phase chromatography followed by normal phase chromatography (gradient, 30 to 100% EtOAc in petroleum ether) to yield the title compound as a white solid (28 mg, 27%): mp 159-160° C.; 1H NMR (300 MHz, CDCl3) δ 7.6 (m, 1H), 7.42-7.41 (m, 2H), 7.38-7.36 (m, 3H), 4.8 (s, 2H), 3.5 (s, 3H), 2.82 (s, 3H); ESIMS m/z 312 ([M+H]+), m/z 310 ([M−H]−).

Provenance & Evidence