Trifluoroacetic acid → 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Temperature

50 °C

To a solution of 3-cyclopropyl-1H-1,2,4-triazole (0.054 g, 0.494 mmol) in DMF (3 mL), sodium hydride (0.019 g, 0.486 mmol, 60% dispersion in mineral oil) was added at about 0° C. and the reaction mixture was stirred for about 10 min. The temperature was raised to about 50° C. and 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.079 g, 0.165 mmol) was added. The reaction mixture was stirred at about 75° C. overnight. The solvent was removed under reduced pressure and the residue partitioned between water and EtOAc (10 mL each). The aqueous phase was further washed with EtOAc (7 mL); the combined extracts were washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to yield a mixture of 1-(4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine and 1-(4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine. This mixture was dissolved in DCM (3 mL) and 2 mL of trifluoroacetic acid was added. The resulting mixture was stirred at ambient temperature for about 2 h. The solvents were removed under reduced pressure. The residue was dissolved in 1,4-dioxane (3 mL); 2 mL of concentrated NH4OH (4 mL) solution in water was added. The mixture was heated at about 60° C. for about 2 hours. The solvents were removed under reduced pressure and the residue was purified by HPLC (Table 2, Method 32) to yield 1-((1S,2R,4S)-4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.028 g, 25% yield) [Example #35] and 1-((1S,2R,4S)-4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-2-ethylcyclopentyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.013 g, 12% yield) [Example #35.1]both as white solids. LC/MS (Table 1, Method a) Rt=1.74 min; MS m/z: 363 (M+H)+ and LC/MS (Table 1, Method a) Rt=1.73 min; MS m/z: 363 (M+H)+

1. stirringThe reaction mixture was stirred at about 75° C. overnight
2. customThe solvent was removed under reduced pressure
3. customthe residue partitioned between water and EtOAc (10 mL each)
4. washThe aqueous phase was further washed with EtOAc (7 mL)
5. washthe combined extracts were washed with brine (10 mL)
6. dry with materialdried over anhydrous MgSO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customto yield
10. stirringThe resulting mixture was stirred at ambient temperature for about 2 h
11. customThe solvents were removed under reduced pressure
12. dissolutionThe residue was dissolved in 1,4-dioxane (3 mL)
13. addition2 mL of concentrated NH4OH (4 mL) solution in water was added
14. temperatureThe mixture was heated at about 60° C. for about 2 hours
15. customThe solvents were removed under reduced pressure
16. customthe residue was purified by HPLC (Table 2, Method 32)

ORD record

ord-9d5157d957824c66831759647ebca9db

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08426411B2