反应详情

温度

170 °C

As shown in step 1-iv, a mixture of 2-(4-amino-2,6-difluorophenyl)propanoic acid (19 g, 94.45 mmol), glycerol (35.83 g, 28.41 mL, 389.1 mmol), nitrobenzene (7.209 g, 6.028 mL, 58.56 mmol) and concentrated sulfuric acid (30.57 g, 16.61 mL, 311.7 mmol) was heated gently. After cessation of the initial vigorous reaction, the mixture was heated to 170° C. for 16 hours. After cooling, the volatiles were removed under reduced pressure, the residue dissolved in MeOH (150 mL), 150 mL of 6N NaOH were added, and the mixture was heated at 110° C. for 3 hours. After cooling to RT, the mixture was acidified with concentrated HCl to a pH of 3. The resulting dark precipitate was collected by filtration and washed with water. The precipitate was taken up in ethanol and thionyl chloride (11.24 g, 6.891 mL, 94.45 mmol) was carefully added dropwise. After addition was complete, the mixture was heated at 50° C. for 20 hours. After cooling to RT, the volatiles were removed under reduced pressure and the residue was dissolved in a mixture of sat'd NaHCO3 and DCM. The layers were separated and the aqueous layer extracted with DCM. The combined organics were dried over MgSO4, reduced in volume under reduced pressure, and subjected to medium-pressure silica gel chromatography (0% EtOAc/Hexanes to 30% in 36 minutes) to provide methyl 2-(5,7-difluoroquinolin-6-yl)propanoate (14 g, 56% yield for two steps). The methyl ester (5.0 g) was saponified by taking it up in methanol (30 mL), treating the resulting solution with NaOH (16.58 mL of 6 M, 99.50 mmol), and stirring at RT for 20 hours. After careful acidification with conc. HCl to a pH of 2, the resulting precipitate was collected by filtration and dried under high vacuum to provide 2-(5,7-difluoroquinolin-6-yl)propanoic acid, which was used as is in subsequent reactions.

1. temperaturewas heated gently
2. customAfter cessation of the initial vigorous reaction
3. temperatureAfter cooling
4. customthe volatiles were removed under reduced pressure
5. dissolutionthe residue dissolved in MeOH (150 mL)
6. addition150 mL of 6N NaOH were added
7. temperaturethe mixture was heated at 110° C. for 3 hours
8. temperatureAfter cooling to RT
9. filtrationThe resulting dark precipitate was collected by filtration
10. washwashed with water
11. additionAfter addition
12. temperaturethe mixture was heated at 50° C. for 20 hours
13. temperatureAfter cooling to RT
14. customthe volatiles were removed under reduced pressure
15. dissolutionthe residue was dissolved in a mixture of sat'd NaHCO3 and DCM
16. customThe layers were separated
17. extractionthe aqueous layer extracted with DCM
18. dry with materialThe combined organics were dried over MgSO4
19. customsubjected to medium-pressure silica gel chromatography (0% EtOAc/Hexanes to 30% in 36 minutes)