反应详情

温度

-78 °C

To a magnetically stirred solution of [2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13c (0.075 g, 0.231 mmol) in THF (3.0 mL) at −78° C. under Ar atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (0.508 mL, 0.5M, 0.254 mmol). The reaction mixture was stirred for 15 min at −78° C., then a THF solution of 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.053 g, 0.254 mmol) was added. After an additional 60 min at −78° C., water (20 mL) was added, and the reaction mixture was warmed to room temperature. Water was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude alkylated product. The crude adduct was dissolved in acetic acid (HOAc) (1 mL) and 12 N HCl (1 mL). The reaction mixture refluxed for 2 h. The mixture was cooled to room temperature and treated with aq Na2CO3 solution until basic. The aqueous solution was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.02 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.62 (s, 3H), 2.82 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 8.62 (s, 1H). Mass spectrum m/e 426 (M+).

1. waitAfter an additional 60 min at −78° C.
2. temperaturethe reaction mixture was warmed to room temperature
3. extractionthe aqueous phase was extracted with ethyl acetate (2×100 mL)
4. washThe combined organic layers were washed with water
5. dry with materialdried (MgSO4)
6. concentrationconcentrated in vacuo to the crude alkylated product
7. dissolutionThe crude adduct was dissolved in acetic acid (HOAc) (1 mL)
8. temperatureThe reaction mixture refluxed for 2 h
9. temperatureThe mixture was cooled to room temperature
10. additiontreated with aq Na2CO3 solution until basic
11. extractionThe aqueous solution was extracted with dichloromethane (2×50 mL)
12. washThe combined organic layers were washed with water (20 mL)
13. dry with materialdried (MgSO4)
14. concentrationconcentrated in vacuo to the crude product
15. customThe pure product was obtained by column chromatography over silica gel,(40:60 EtOAc/hexane