Hydrochloric Acid → HCID 86632022, Verbindung

To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (1.0 g, 4.1 mmol) in methanol (15 mL) were added cyclohexanecarbaldehyde (0.82 mL, 6.14 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.665 g, 4.1 mmol, 1.0 equiv.) and isocyanomethyl-benzene (0.48 mL, 10.24 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (10 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) and cooled to 0° C. Sodium nitrite (7.4 g, 107 mmol) were added in portions. After the addition the reaction was warmed to rt and stirred for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) and a pre-prepared solution of LiOH (2.1 g, 48.7 mmol) in hydrogen peroxide (10 mL, 30% solution in water) was added drop wise. The mixture was stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with ethyl acetate. The intermediate was not further purified but used as crude material for further modification. MS (ES−): 404 (M−H).

1. stirringthe reaction mixture stirred at rt for 3 h
2. concentrationThe solution was concentrated by evaporation under reduced pressure
3. additionthe pH adjusted to 9 by addition of a solution of 1 M NaHCO3
4. extractionthe aqueous layer extracted with ethyl acetate
5. dry with materialThe combined organic phases were dried over MgSO4
6. concentrationconcentrated by evaporation under reduced pressure
7. dissolutionThe crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml)
8. temperaturecooled to 0° C
9. additionAfter the addition the reaction
10. temperaturewas warmed to rt
11. stirringstirred for 3 h
12. concentrationThe solution was concentrated by evaporation under reduced pressure
13. additionthe pH adjusted to 9 by addition of a solution of 1 M NaHCO3
14. extractionthe aqueous layer extracted with ethyl acetate
15. additionThe resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL)
16. stirringThe mixture was stirred at rt for 30 min
17. concentrationThe solution was concentrated by evaporation under reduced pressure
18. additionthe pH adjusted to 4 by addition of acetic acid
19. extractionthe aqueous layer extracted with ethyl acetate
20. customThe intermediate was not further purified

ORD-Eintrag

ord-025cde6716ce4ad5b728964de5f9f20c

Quelldatensatz

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07816540B2