Hydrochloric Acid → 5-(3-Amino-2-methylphenyl)-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one

A 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 14 (2.50 g, 6.16 mmol), 7 (1.79 g, 7.70 mmol), 1,4-dioxane (70 mL) and a solution of sodium carbonate (1.96 g, 18.5 mmol) in water (14 mL). After bubbling nitrogen through the resulting mixture for 30 min, tetrakis(triphenylphosphine)palladium (711 mg, 0.62 mmol) was added and the reaction mixture then heated at reflux for 11 h. After this time the reaction was cooled to room temperature and 2N hydrochloric acid (70 mL) followed by ethyl acetate (70 mL) was added. The mixture was stirred for 0.5 h and then filtered through a pad of Celite 521. The organic layer of the filtrate was separated and extracted with 2N hydrochloric acid (2×30 mL). The acidic extracts were combined and washed with ethyl acetate (4×50 mL). The aqueous solution was then stirred vigorously with ethyl acetate (100 mL) while solid potassium carbonate was added portionwise until a pH of 12 was reached. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (70 mL) and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure and dried in a 49° C. vacuum oven for 24 h to afford 15 in 86% yield (2.32 g) as an amber foam: mp 133-134° C.; 1H NMR (500 MHz, CDCl3) 8.29 (s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.05 (t, 1H, J=8.0 Hz), 6.79 (d, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.68 (s, 1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.20 (m, 1H), 3.01 (m, 1H), 2.99 (s, 3H), 2.66 (m, 1H), 2.24 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z 433.3 (M+H).

1. customA 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer
2. temperaturereflux condenser and nitrogen inlet
3. customAfter bubbling nitrogen through the resulting mixture for 30 min
4. temperaturethe reaction mixture then heated
5. temperatureat reflux for 11 h
6. additionwas added
7. filtrationfiltered through a pad of Celite 521
8. customThe organic layer of the filtrate was separated
9. extractionextracted with 2N hydrochloric acid (2×30 mL)
10. washwashed with ethyl acetate (4×50 mL)
11. stirringThe aqueous solution was then stirred vigorously with ethyl acetate (100 mL) while solid potassium carbonate
12. additionwas added portionwise until a pH of 12
13. customThe aqueous layer was separated
14. extractionextracted with ethyl acetate (2×100 mL)
15. washThe combined organic layers were washed with brine (70 mL)
16. dry with materialdried over magnesium sulfate
17. customThe drying agent was removed by filtration
18. concentrationthe filtrate was concentrated under reduced pressure
19. customdried in a 49° C. vacuum oven for 24 h

ORD 기록

ord-49ff326a4eeb47f488dc641ae1b7242f

출처 데이터셋

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08247550B2