A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.
Afatinib (systematic name:N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol-ecules (AandB) in the asymmetric unit of the chiral space groupP4212, but exhibits close to perfect pseudo-inversion symmetry, emulatingP4/nccthat relates the two mol-ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2moieties of the outer tetra-hydro-furanyl substituents of the two independent mol-ecules. This can, in turn, be traced back to C-H⋯N and C-H⋯O inter-actions of the aceto-nitrile solvent mol-ecules with the tetra-hydro-furan oxygen and CH2units. In the crystal, neighboring mol-ecules are connectedviaN-H⋯O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol-ecules, which are engaged in O-H⋯O and O-H⋯N hydrogen bonds connecting to the di-methyl-amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol-ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of thecaxis; one along the fourfold rotational axis, occupied by aceto-nitrile solvent mol-ecules situated on that axis, and parallel channels which are not occupied by any solvent.
Department of Chemistry, Purdue University, 560 Oval Dr., W. Lafayette, IN 47907-2084, USA.
Matthias
M
Zeller
Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of Sao Paulo, Sao Paulo, SP, Brazil.
Gabriel Lima Barros
GL
de Araujo
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Trev
T
Parker
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Amrinder
A
Singh Rai
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Stephen R
SR
Byrn
ErbB tyrosine kinase inhibitor; crystal structure; hydrogen bonding; pseudo-inversion center; pseudo-symmetry