Triethylamine → (5R)-3-(6-chloro-3-pyridinyl)-5-ethyl-5-methyl-2,4-imidazolidinedione

Temperatur

60 °C

6-Chloropyridin-3-amine (3.0 g, 23.3 mmol) was dissolved in a 3:1 v/v mixture of CH3CN/ethyl acetate (20 mL) and (2R)-2-amino-2-methylbutanoic acid hydrochloride (3.97 g, 25.63 mmol) was added, followed by a 50% w/w solution in ethyl acetate of T3P (15.3 mL, 25.63). The mixture was heated to 60° C. for 2 hrs, then quenched with NaOH 3N while the pH was ˜10 and then diluted with ethyl acetate (100 mL). The organic phase was collected, dried over Na2SO4 and concentrated under vacuum to a final volume of ˜15 mL. The solution was cooled down to 0-5° C. and Et3N (11.4 ml, 81.9 mmol) was added. A solution of triphosgene (2.76 g, 6.96 mmol) in 10 mL of ethyl acetate was added drop wise in 15 min, keeping the internal temperature below 5° C. The mixture was stirred at 5° C. for 30 minutes then quenched with water (100 mL) and finally diluted with additional ethyl acetate (100 mL). Two phases were separated and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was suspended in 15 mL of ethyl acetate followed by the drop wise addition of 65 mL of n-heptane. The resulting suspension was stirred at room temperature for 2 hrs, filtered, and the cake washed with a 2:8 v/v mixture of ethyl acetate/n-heptane (2×10 mL) before being dried at 40° C. for 18 hrs affording the title compound (3.5 g) as white solid.

1. additionwas added
2. customquenched with NaOH 3N while the pH was ˜10
3. additiondiluted with ethyl acetate (100 mL)
4. customThe organic phase was collected
5. dry with materialdried over Na2SO4
6. concentrationconcentrated under vacuum to a final volume of ˜15 mL
7. temperatureThe solution was cooled down to 0-5° C.
8. customthe internal temperature below 5° C
9. customthen quenched with water (100 mL)
10. additionfinally diluted with additional ethyl acetate (100 mL)
11. customTwo phases were separated
12. washthe organic layer was washed with water and brine
13. dry with materialdried over Na2SO4
14. concentrationconcentrated under vacuum
15. additionfollowed by the drop wise addition of 65 mL of n-heptane
16. stirringThe resulting suspension was stirred at room temperature for 2 hrs
17. filtrationfiltered
18. washthe cake washed with a 2:8 v/v mixture of ethyl acetate/n-heptane (2×10 mL)
19. custombefore being dried at 40° C. for 18 hrs

ORD-Eintrag

ord-cdb9620f18354544b92b28dd96d484b0

Quelldatensatz

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09346790B2