反应详情

温度

-78 °C

(6-Methyl-2-p-tolyl-imidazo[1,2,a]pyridin-3-yl)-acetic acid methyl ester 35a (447 mg, 1.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to −78° C. Potassium hexamethyldisilazide (0.5M in toluene, 3.0 mL, 1.5 mmol) was added slowly and the resulting bright orange solution was stirred at −78° C. for 10 minutes. 2,3-Dihydro-benzo[1,4]dioxine-2-carbonyl chloride (150 mg, 0.76 mmol) dissolved in anhydrous THF (10 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 1 h at −78° C. and quenched with H2O (30 mL). After the solution warmed to room temperature, it was washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. The crude keto-ester (0.76 mmol) was dissolved in concentrated acetic acid (4.5 mL) and concentrated HCl (4.5 mL). A reflux condenser was attached and the yellow solution was heated at 120° C. for 16 h. The solution was cooled to room temperature and saturated aqueous K2CO3 was added slowly until pH=6. The suspension was poured into saturated aqueous K2CO3 and washed with EtOAc (3×50 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Purification was affected via silica gel column chromatography with 0-5% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40-80% CH3CN/H2O over 20 minutes, monitoring at 254 nm. The product eluted at 14.3 minutes. Product fractions were collected and concentrated to remove CH3CN, then washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Final purification by silica gel column chromatography with 0-5% MeOH/CH2Cl2 yielded 1-(2,3-Dihydro-benzo [1,4]dioxin-2-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (6.0 mg, 2%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.56-7.50 (m, 3H), 7.42 (s, 1H), 7.23 (d, J=8.07, 2H), 7.04 (dd, J=1.1, 9.2 Hz, 1H), 6.95-6.89 (m, 4H), 4.82-4.80 (m, 1H), 4.51-4.42 (m, 2H), 4.33-4.26 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H). Mass spectrum (m/e) 399 (M+1)+.

1. stirringThe resulting yellow solution was stirred for 1 h at −78° C.
2. customquenched with H2O (30 mL)
3. temperatureAfter the solution warmed to room temperature
4. washit was washed with EtOAc (3×30 mL)
5. dry with materialThe combined organic washes were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. customA reflux condenser was attached
9. temperaturethe yellow solution was heated at 120° C. for 16 h
10. temperatureThe solution was cooled to room temperature
11. washwashed with EtOAc (3×50 mL)
12. dry with materialThe combined organic washes were dried (Na2SO4)
13. filtrationfiltered
14. concentrationconcentrated
15. customPurification
16. waitConditions: 20 mL/min flow rate, gradient of 40-80% CH3CN/H2O over 20 minutes
17. washThe product eluted at 14.3 minutes
18. customProduct fractions were collected
19. concentrationconcentrated
20. customto remove CH3CN
21. washwashed with EtOAc (3×30 mL)
22. dry with materialThe combined organic washes were dried (Na2SO4)
23. filtrationfiltered
24. concentrationconcentrated
25. customFinal purification by silica gel column chromatography with 0-5% MeOH/CH2Cl2