Reaction Steps
To a mixture of N,N-diethyl-1-(3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)methanesulfonamide (0.730 g, 1.27 mmol) and TEA (0.529 mL, 3.80 mmol) in 1,4-dioxane (12.7 mL) was added SOCl2 (0.185 mL, 2.53 mmol). The reaction mixture was heated at about 80° C. for about 2 h. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 (30 mL) and DCM (30 mL). The aqueous layer was washed with DCM (2×30 mL). The organic layers were combined, concd under reduced pressure, and purified by silica gel (80 g) chromatography eluting with a gradient of 0-60% MeOH in DCM to give a brown solid. The resulting solid was suspended in Na2CO3 (2 M aqueous, 2 mL), EtOH (2 mL) and 1,4-dioxane (2 mL). The reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature and purified by RP-HPLC (Table 1, Method d) to afford N,N-diethyl-1-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (0.300 g, 58%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z: 405 (M+H)+. The solid was further purified by using General Procedure AA to give N,N-diethyl-1-((1S,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=11.8 min, or =negative) (0.021 g, 7%) [Example #1.1]; N,N-diethyl-1-((1R,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methane-sulfonamide (Table 2, Method 27, Rt=11.1 min, or =positive) (0.018 g, 6%) [Example #1.2]; N,N-diethyl-1-((1S,3S,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentyl)methanesulfonamide (Table 2, Method 27, Rt=10.7 min, or =positive) (0.018 g, 6%) [Example #1.3]; N,N-diethyl-1-((1R,3R,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 28, Rt=20.1 min, or =negative) (0.031 g, 11%) [Example #1.4]; N,N-diethyl-1-((1S,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.002 g, 1%) [Example #1.5]; and N,N-diethyl-1-((1R,3S,4R)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methanesulfonamide (Table 2, Method 27, Rt=12.8 min, or =positive) (0.001 g, 1%) [Example #1.6].
