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

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]−).

1. temperatureheating
2. waitAfter 2 h
3. custompartitioned between CH3CN and brine
4. dry with materialThe organic phase was dried over MgSO4
5. filtrationfiltered
6. customevaporated
7. washwas eluted (gradient, 0 to 100% EtOAc in petroleum ether)
8. additionCombining fractions containing the major UV
9. customabsorbing portion of the product mixture
10. customyielded a white solid which
11. customwas used without further purification
12. additionTo a portion of this material (100 mg) was added DMF (3 mL), K2CO3 (100 mg), and iodomethane (100 mg)
13. temperatureThe reaction mixture was cooled to room temperature
14. additionan excess of sodium hydride (NaH; 60% dispersion in mineral oil) was added
15. stirringThe whole mixture was stirred for 30 min
16. temperatureheated to 45° C. for 2.5 h
17. filtrationThe crude mixture was filtered
18. custompurified by reverse phase chromatography

ORD record

ord-389f566a2fae43498bb2b59f758da788

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08916579B2