Comparison of the crystal structures of the potent anticancer and anti-angiogenic agent regorafenib and its monohydrate.

Regorafenib {systematic name: 4-[4-({[4-chloro-3-(tri­fluoro­methy)phen­yl]car­bam­o­yl}amino)-3-fluoro­phen­oxy]-1-methyl­pyridine-2-carboxamide}, C21H15ClF4N4O3, is a potent anti­cancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling mol­ecules. The compound has been crystallized as polymorphic form I and as the mono­hydrate, C21H15ClF4N4O3·H2O. The regorafenib mol­ecule consists of bi­aryl­urea and pyridine-2-carboxamide units linked by an ether group. A comparison of both forms shows that they differ in the relative orientation of the bi­aryl­urea and pyridine-2-carboxamide units, due to different rotations around the ether group, as measured by the C—O—C bond angles [119.5 (3)° in regorafenib and 116.10 (15)° in the monohydrate]. Meanwhile, the conformational differences are reflected in different hydrogen-bond networks. Polymorphic form I contains two inter­molecular N—H⋯O hydrogen bonds, which link the regorafenib mol­ecules into an infinite mol­ecular chain along the b axis. In the monohydrate, the presence of the solvent water mol­ecule results in more abundant hydrogen bonds. The water mol­ecules act as donors and acceptors, forming N—H⋯O and O—H⋯O hydrogen-bond inter­actions. Thus, R42(28) ring motifs are formed, which are fused to form continuous spiral ring motifs along the a axis. The (tri­fluoro­meth­yl)phenyl rings protrude on the outside of these motifs and inter­digitate with those of adjacent ring motifs, thereby forming columns populated by halogen atoms.