Proton sponge → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide

Participants

Reaction Steps

To a 100 ml round bottom flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (530 mg, 0.88 mmol) and proton sponge (132 mg, 0.62 mmol) was added 1,2 dichloroethane (20 ml). The clear solution was stirred under nitrogen and cooled in an ice bath for 10 min. To this was added 1-chloroethyl chloroformate (0.19 ml, 1.77 mmol). The reaction was stirred in the ice bath for 5 min, the bath removed and the reaction warmed to room temperature for 20 min. The reaction was placed in an oil bath and heated at 85° C. for 4 h then allowed to cool to room temperature overnight and concentrated. The residue was suspended in methanol (20 ml) and heated at reflux for 3 h then removed from the heat and allowed to cool to room temperature. Some product precipitated during cooling and was filtered off and washed with methanol. The remaining product was recovered from the mother liquor. The liquid was concentrated, suspended in ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous solution with solids was extracted four times with dichloromethane. The organic layers were combined and washed with brine (100 ml), dried over magnesium sulfate, filtered, concentrated, and dried from a mixture of ethyl acetate and hexanes. The crude was suspended in boiling ethyl acetate (20 ml), cooled, filtered and washed with ethyl acetate and hexanes to afford 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide as a white solid. This material was combined with the product that precipitated from the reaction and was used without further purification. LC-MS: (M+H)+=510.

Provenance & Evidence