反应详情

A 100 mL round bottom flask was charged with 1-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanone (2.74 g, 7.20 mmol). THF (36.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and a solution of methylmagnesium chloride (3 M in THF, 6.00 mL, 18.0 mmol) was added slowly while keeping the internal temperature between about −30° C. and −40° C. After about 15 min, the mixture was cooled to about −55° C. followed by the slow addition of a saturated ammonium chloride solution (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL), DCM (75 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL) then the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give a foam. The material was dissolved in 95:5 DCM/MeOH (about 20 mL) with warming and sonication and then loaded onto a 120 g silica column and eluted with 94:6 DCM/MeOH (about 1 L) followed by 92:8 DCM/MeOH (about 500 mL). Evaporation of the fractions gave the title compound as a yellow foam (2.88 g, 91%) that contained about 9 wt % DCM by 1H NMR. This material was combined with a second batch of the title compound (3.4 g that also contained about 9 wt % DCM). The combined material (5.7 g) was dissolved into ACN (150 mL), followed by a rapid precipitation of the title compound as an off-white powder (4.69 g, 82% recovery): LC/MS (Table 1, Method g) Rt=1.58 min; MS m/z: 397.2 (M+H)+; 1H NMR (DMSO-d6) δ 8.18 (d, 1H), 7.65 (m, 1H), 7.29 (m, 1H), 7.19 (m, 1H), 6.93 (m, 1H), 5.46 (s, 1H), 4.36 (t, 2H), 2.90 (t, 2H), 2.68-2.54 (m, 2H), 1.70 (s, 6H); mp 221.6-222.7° C.; Anal. calcd. for C20H18F2N6O: C, 60.60; H, 4.58; N, 21.20; F, 9.59. found C, 60.43; H, 4.46; N, 21.38; F, 9.56.

1. temperatureThe slurry was cooled to about −40° C.
2. customthe internal temperature between about −30° C. and −40° C
3. waitAfter about 15 min
4. temperaturethe mixture was cooled to about −55° C.
5. temperatureThe mixture was then warmed to ambient temperature
6. customthe layers were separated
7. extractionThe aqueous layer was extracted with DCM (2×50 mL)
8. dry with materialthe combined organic extracts were dried over MgSO4
9. filtrationfiltered
10. concentrationconcentrated under reduced pressure
11. customto give a foam
12. temperaturewith warming
13. customsonication
14. washeluted with 94:6 DCM/MeOH (about 1 L)
15. customEvaporation of the fractions