Water → Crenolanib

Participants

Reaction Steps

The compound, (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester (2 g, 3.68 mmol, 1 equivalent), sodium t-butoxide (1.77 g, 18.4 mmol, 5 equivalents), 2-methyltetrahydrofuran (30 mL, 15 volumes), and water (66 mL, 1 equivalent) were added to a 100 mL round bottom flask. The mixture was heated to reflux and held at reflux for 24–30 hours. At reaction completion, the mixture was cooled to 20–30° C. The reaction was quenched into a 20% citric acid solution (10 volumes) and stirred at 20–30° C. for 30–60 minutes. The citrate salt precipitated out of solution during this time. A 50% sodium hydroxide solution (˜1 weight equivalent) was charged to basify the reaction mixture (pH 10–12). The layers were separated at 30–40° C. The aqueous layer was washed with ethyl acetate (10 volumes) and then the combined organics were concentrated to low volume. Ethyl acetate (14 mL, 7 volumes) was charged and the slurry was allowed to granulate for 10–20 hours. The solids were filtered and 1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine (1.4 g, 86% yield) was isolated.

Provenance & Evidence