Water → HCID 86600753, compound

Participants

Reaction Conditions

Reaction Steps

A flask was charged with 4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (20) (1 equiv.) and toluene (15 volumes). Residual water was removed by azeotropic distillation and the supernatant was analyzed for water content (KF: <200 ppm water). The flask was then charged with 3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (1.05 equiv.) at about 77° C. Triethyl amine (1.2 equiv) and diphenylphosphoryl azide (1.2 equiv) were added between 77–85° C. The reaction was heated at ˜87° C. until it was found complete by HPLC. The reaction was cooled to 25° C. diluted with THF (15 volumes) and washed with 10% K2CO3 (10 volumes), saturated NaCl (10 volumes) and water (10 volumes) respectively. The rich organic was polish filtered and distilled at atmospheric pressure until the pot temperature was >100° C. The final volume was adjusted to 15 volumes by adding toluene (if necessary). The mixture was cooled to 80° C., water (1 equiv) was added and the product was crystallized. The slurry was cooled to 25° C. over 1 h and held for 17 h. The solid was collected by filtration and the filter cake was rinsed with toluene (2×2 volumes). The solid was air dried overnight and then dried under vacuum at 50° C. to give the product in 82% yield.

Provenance & Evidence