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 (440 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. Thiophen-2-yl-acetyl chloride (92 μL, 0.75 mmol) dissolved in anhydrous THF (8 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 2 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 material was flushed through a pad of silica gel equilibrated with 10% MeOH/CH2Cl2 and concentrated. The crude keto-ester (0.75 mmol) was dissolved in concentrated AcOH (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 0-10% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40-70% CH3CN/H2O over 20 minutes, monitoring at 254 nm. Product eluted at 13.3 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 to give the title compound (13 mg, 5%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.85 (d, J=9.17 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=9.17 Hz, 1H), 7.26-7.18 (m, 5H), 6.98-6.94 (m, 2H), 4.26 (s, 2H), 4.06 (s, 2H), 2.32 (s, 6H). Mass spectrum (m/e) 361 (M+1)+.

1. stirringThe resulting yellow solution was stirred for 2 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. customThe crude material was flushed through a pad of silica gel
9. concentrationconcentrated
10. customA reflux condenser was attached
11. temperaturethe yellow solution was heated at 120° C. for 16 h
12. temperatureThe solution was cooled to room temperature
13. washwashed with EtOAc (3×50 mL)
14. dry with materialThe combined organic washes were dried (Na2SO4)
15. filtrationfiltered
16. concentrationconcentrated
17. customPurification
18. waitConditions: 20 mL/min flow rate, gradient of 40-70% CH3CN/H2O over 20 minutes
19. washProduct eluted at 13.3 minutes
20. customProduct fractions were collected
21. concentrationconcentrated
22. customto remove CH3CN
23. washwashed with EtOAc (3×30 mL)
24. dry with materialThe combined organic washes were dried (Na2SO4)
25. filtrationfiltered
26. concentrationconcentrated