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

Participants

Reaction Conditions

Reaction Steps

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)+

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