Phosphorus oxide (P4O10) → 3-(Trifluoromethyl)imidazo[1,5-a]pyrazine

2,2,2-Trifluoro-N-pyrazin-2-ylmethyl-acetamide 1i (21.0 g, 100 mmol) was added into a reaction flask, followed by addition of 100 mL of phosphorus oxychloride. After stirring for 30 minutes, phosphorous pentoxide (17.8 g, 125 mmol) was added to the solution. The reaction mixture was heated to reflux for 5 hours. The mixture was concentrated under reduced pressure, and the reaction system was quenched with deionized water. The mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath and then extracted with ethyl acetate (250 mL×4). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system A as eluant to obtain the title compound 3-trifluoromethyl-imidazo[1,5-a]pyrazine 1j (12.0 g, yield 65%) as a yellow solid. MS m/z (ESI): 188.0 [M+1]. 1H NMR (400 MHz, CDCl3, ppm): δ 9.15 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H).

1. temperatureThe reaction mixture was heated
2. temperatureto reflux for 5 hours
3. concentrationThe mixture was concentrated under reduced pressure
4. customthe reaction system was quenched with deionized water
5. customThe mixture was adjusted to pH 5-6 with 20% sodium hydroxide solution in an ice-water bath
6. extractionextracted with ethyl acetate (250 mL×4)
7. dry with materialThe combined organic phase was dried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customThe resulting residues were purified by silica gel column chromatography with system A as eluant

ORD record

ord-3c4c193d0d674e12a8f6dd64025c14d5

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08518946B2