反应详情

In an oven-dried round bottom flask, 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 487) (0.75 g, 1.62 mmol), DCM (2.00 mL), and oxalyl chloride (0.97 mL, 1.94 mmol) were combined under argon. DMF (3-5 drops) was added to aid in dissolution. Stirred at RT overnight. Solvent was removed and the crude acid chloride was coevaporated with DCM (3-5 mL×3) and dried in vacuo to give an orange solid. In a separate oven-dried flask, in an argon atmosphere, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in THF (3.00 mL) was cooled to −78° C. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stirred for 30 min at −78° C. The acid chloride prepared as described above was added dropwise as a solution in THF. The reaction was warmed to RT. After 30 min, the reaction was cooled (0° C.) and 10% citric acid (5.0 mL) added. The crude product was extracted in EtOAc, washed with 5% NaHCO3, dried over Na2SO4, filtered, and concentrated to a crude brown oil. Recrystallization from DCM and hexane. Filtered a beige solid, dried in vacuo (0.41 g, 47%). 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J=9.2 Hz), 6.66 (s, 1H), 5.36 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H), 1.99 (s, 3H), 1.23 (t, 3H, J=7.2 Hz). ES HRMS m/z 534.0744 and 536.0746 (M+H calculated for C25H23BrF2NO5 requires 534.0722 and 536.0706).

1. customSolvent was removed
2. customdried in vacuo
3. customto give an orange solid
4. customIn a separate oven-dried flask
5. stirringThe solution was stirred for 30 min at −78° C
6. temperatureThe reaction was warmed to RT
7. waitAfter 30 min
8. additionadded
9. extractionThe crude product was extracted in EtOAc
10. washwashed with 5% NaHCO3
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated to a crude brown oil
14. customRecrystallization from DCM and hexane
15. filtrationFiltered a beige solid
16. customdried in vacuo (0.41 g, 47%)