반응 #1592533

반응 방정식

6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine

Intermediate 50

6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine

(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid

Et3N

T3P

→

title compound

수율 119.3%

(2R)-2-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)butanamide

수율 119.3%

용매

ethyl acetate

Ethyl acetate

반응 조건

후처리

1. 1
   온도maintaining the temperature at ˜0° C
2. 2
   세척for washing the line
3. 3
   workup.ADDITION10% w/w sodium carbonate aqueous solution (2.5 L) was added
4. 4
   workup.STIRRINGthe mixture was stirred for 20 minutes
5. 5
   workup.ADDITIONThen water (1.5 L) and ethyl acetate (1 L) were added
6. 6
   기타the two phases separated
7. 7
   세척The organic layer was washed with 10% w/w sodium carbonate aqueous solution (2.5 L)
8. 8
   workup.STIRRINGstirring the mixture for 10 minutes
9. 9
   기타before separation of phases
10. 10
    농축The organic solution was concentrated to the lowest volume (<2 L), acetonitrile (5 L)
11. 11
    workup.ADDITIONwas added
12. 12
    농축the solution was concentrated to the lowest volume (<2 L) and acetonitrile
13. 13
    workup.ADDITIONwas added up to 12.5 L (it
14. 14
    workup.ADDITIONTo this solution, 5-6N HCl solution in Isopropanol (2.5 L) was added at 20° C.
15. 15
    기타the resulting reaction mixture
16. 16
    workup.STIRRINGwas stirred at 45° C. for 1.5 hours
17. 17
    온도The obtained suspension was cooled to 20° C.
18. 18
    workup.STIRRINGstirred for 1 hour
19. 19
    여과filtered
20. 20
    세척The collected solid was washed with 5/1 acetonitrile/Isopropanol (3×1.5 L)
21. 21
    기타dried under vacuum at 40° C., until constant weight

실험 절차

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).

출처