1,4-Dioxane → 7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-(trifluoromethyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine

Participants

Reaction Conditions

Reaction Steps

To a round bottom flask was added 2,2,2-trifluoro-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)acetamide (0.086 g, 0.213 mmol, prepared using J.1 from Preparation #I.1 with trifluoroacetic anhydride and M with TBAF), 1,4-dioxane (5 mL) and Lawesson's reagent (0.052 g, 0.128 mmol). The mixture was heated at about 85° C. for about 90 min. More Lawesson's reagent (0.052 g, 0.128 mmol) was added and the mixture was stirred at about 85° C. for about 3 h. The mixture was cooled to rt and stirred overnight. To the mixture was added mercury(II) acetate (0.075 g, 0.235 mmol) and the mixture was stirred at rt for about 16 h. The mixture was diluted with EtOAc (50 mL) and filtered through Celite®. The organic layer was washed with water (50 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo to give a residue. The residue was added to a round bottom flask and 1,4-dioxane (5 mL) and mercury(II) trifluoroacetate (0.122 g, 0.286 mmol) were added. The mixture was stirred at rt for about 30 min. The mixture was diluted with EtOAc (50 mL), filtered through Celite® and concentrated in vacuo. The crude material was purified by flash chromatograph (40 g silica gel column, DCM/MeOH 1:0 to 10:1) to give a solid. The material was purified again by flash chromatography (120 g silica gel column, heptane/EtOAc 1:0 to 0:1) to give a solid. The solid was purified by reverse phase preparatory HPLC (Table 2, method e) to give fractions with product. The fractions were combined and extracted with EtOAc (50 mL). The organic was washed with water (50 mL), dried with anhydrous MgSO4, filtered and concentrated in vacuo. The solid was dried in under reduced pressure at about 60° C. for about 16 h to give the title compound (0.007 g, 7%): LC/MS (Table 2, Method a) Rt=2.41 min; MS m/z 386 (M+H)+. Syk IC50=B.

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