Trifluoroacetic acid → Tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A 5 L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <32° C. 1-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12 L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of <32° C. The reaction was stirred at 20-32° C. for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3 L of 5N NaOH maintaining a temperature of <45° C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3 L of 2N NaOH at 40° C. (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 40° C. (with external heating), and concentrated to ˜2 L by distillation. The resulting solution was cooled to ˜20° C. The resulting slurry was filtered, washed (3×200 mL of MTBE), and dried in a vacuum oven at ˜60° C. Approximately 536 g of tert-Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was isolated as a solid (82% yield).

Provenance & Evidence