A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases

Abstract

Afatinib (systematic name: N-{4-(3-chloro-4-fluoroanilino)-7-[(tetrahydrofuran-3-yl)oxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide), is a specific inhibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from acetonitrile as a mixed water–acetonitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent molecules (A and B) in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two molecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetrahydrofuranyl substituents of the two independent molecules. This can, in turn, be traced back to C—H...N and C—H...O interactions of the acetonitrile solvent molecules with the tetrahydrofuran oxygen and CH2 units. In the crystal, neighboring molecules are connected via N—H...O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent molecules, which are engaged in O—H...O and O—H...N hydrogen bonds connecting to the dimethylamino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring molecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by acetonitrile solvent molecules situated on that axis, and parallel channels which are not occupied by any solvent.

Keywords

• crystal structure
• pseudo-symmetry
• pseudo-inversion center
• ErbB tyrosine kinase inhibitor
• hydrogen bonding