反应详情

Potassium hydroxide (237 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (450 mg) and iodomethane (0.76 mL) in DMSO (5 mL) at RT. The reaction mixture was stirred at RT for 4 hours. Then the reaction was quenched with saturated ammonium chloride, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the crude product as a brown oil. This oil was dissolved in THF (4 mL) and water (4 mL). Sodium hydroxide (100 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 hour, and then at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E106) (249 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.31 (6H, d), 2.53 (2H, t), 2.88 (2H, t), 3.33 (3H, s), 4.89-4.95 (1H, m), 7.02 (1H, t), 7.11 (1H, s), 7.50 (1H, d), 7.75 (1H, dd), 8.36 (1H, dd), 8.49 (1H, d), 12.06 (1H, br s); δF (DMSO-d6, 376 MHz): −123.0; MS (ES): C24H21FN4O4 requires 448; found 449.1 (M+H+).

1. customThen the reaction was quenched with saturated ammonium chloride
2. extractionextracted with EtOAc for 3 times
3. washThe combined organic solution was washed with brine
4. dry with materialdried over anhydrous sodium sulfate
5. concentrationThe dried solution was concentrated
6. customto afford the crude product as a brown oil
7. stirringThe reaction mixture was stirred at 90° C. for 1 hour
8. waitat RT for another 24 hours
9. concentrationThe solvent was concentrated
10. dissolutionthe residue was dissolved in water
11. customThe precipitated solid was purified by MDAP