Ammonia → Vatalanib

Participants

Reaction Conditions

Reaction Steps

A mixture of 17.03 g (0.12 mol) phosphorus pentoxide, 11.56 g (0.084 mol) triethylamine hydrochloride and 15.31 g (0.12 mol) 4-chloroaniline is heated and stirred under argon atmosphere at 200° C. (oil bath temperature) until a homogeneous melt has formed (about 45 min). To the melt (internal temperature about 160° C.) 7.12 g (0.03 mol) of 4-(4-pyridylmethyl)-1 (2H)-phthalazinone (for preparation see German Auslegeschriftno. 1 061 788 [published Jul. 23, 1959]) is added and the reaction mixture stirred for 4 h at an internal temperature of 160-170° C. After cooling to about 120° C. (internal temperature) 28 ml tetramethylurea is added dropwise, the temperature rising temporarily to 150° C. For about 10 min at 120° C., 100 ml water is then added to the reaction mixture, which is stirred for 0.5 h at 100-103° C. (internal temperature), then cooled to 60° C., before a mixture of 40 ml water and 37 ml concentrated ammonia solution is added dropwise to the brown solution, whereupon a suspension forms. While cooling to an ultimate temperature of 15° C., the suspension is stirred for 0.5 h, then mixed with 80 ml ether and stirred for a further 10 min. The mixture is filtered, the filter residue is washed with water, then ether, and dried in air. After recrystallization from methanol/ether (under treatment with activated carbon) and drying under HV for 8 h at 120° C., the title compound is obtained with a water content of 0.31%; m.p. 207-209° C.; 1H NMR (DMSO-d6) 9.29 (s, 1H), 8.58-8.63 (m, 1H), 8.44-8.47 (m, 2H), 8.10-8.15 (m, 1H), 7.89-8.05 (m, 4H), 7.37-7.45 (m, 2H), 7.31-7.34 (m, 2H), 4.59 (s, 2H). A further portion of title compound can be obtained from the mother liquor.

Provenance & Evidence