反应详情

温度

0 °C

6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine (Intermediate 50, 500 g), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (530 g) and Et3N (905 mL) are mixed together in ethyl acetate (2 L) and stirred at 0° C. until complete dissolution. ®T3P (2.15 L) was added dropwise in 30 minutes maintaining the temperature at ˜0° C. Ethyl acetate (500 mL) was added for washing the line. Work-up: 10% w/w sodium carbonate aqueous solution (2.5 L) was added and the mixture was stirred for 20 minutes. Then water (1.5 L) and ethyl acetate (1 L) were added and the two phases separated. The organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L), stirring the mixture for 10 minutes before separation of phases, then with 28% malic acid aqueous solution (2.5 L) and finally with 20% NaCl aqueous solution (2.5 L). The organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L) was added, the solution was concentrated to the lowest volume (<2 L) and acetonitrile was added up to 12.5 L (it is a solution of Intermediate 64 in acetonitrile). To this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C. and the resulting reaction mixture was stirred at 45° C. for 1.5 hours. The obtained suspension was cooled to 20° C., stirred for 1 hour and then filtered. The collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L), then dried under vacuum at 40° C., until constant weight, obtaining the title compound (817 g).

1. temperaturemaintaining the temperature at ˜0° C
2. washfor washing the line
3. addition10% w/w sodium carbonate aqueous solution (2.5 L) was added
4. stirringthe mixture was stirred for 20 minutes
5. additionThen water (1.5 L) and ethyl acetate (1 L) were added
6. customthe two phases separated
7. washThe organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L)
8. stirringstirring the mixture for 10 minutes
9. custombefore separation of phases
10. concentrationThe organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L)
11. additionwas added
12. concentrationthe solution was concentrated to the lowest volume (<2 L) and acetonitrile
13. additionwas added up to 12.5 L (it
14. additionTo this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C.
15. customthe resulting reaction mixture
16. stirringwas stirred at 45° C. for 1.5 hours
17. temperatureThe obtained suspension was cooled to 20° C.
18. stirringstirred for 1 hour
19. filtrationfiltered
20. washThe collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L)
21. customdried under vacuum at 40° C., until constant weight