Crystal structure of canagliflozin hemihydrate

In canagliflozin hemihydrate, the hydropyran ring exhibits a chair conformation in both canagliflozin molecules. In the crystal, the canagliflozin molecules and lattice water molecules are connected via O—H⋯O hydrogen bonds into a three-dimensional supramolecular architecture.


Chemical context
Canagliflozin is a member of a new class of anti-diabetic drugs which are used to improve glycemic control of diabetics (Cefalu et al., 2013). The crystalline forms of canagliflozin have been reported (Mitsubishi et al., 2013;Ahmed et al., 2013;Chen et al., 2013), we report here the single-crystal structure of the title compound.

Structural commentary
The title compound crystallizes with two independent canagliflozin molecules and one water molecule in the asymmetric unit (Fig. 1). The water molecule links the two canagliflozin molecules (A and B) via two O-HÁ Á ÁO hydrogen bonds ( Table 1).
The conformations of the two canagliflozin molecules are somewhat different with regard to the orientation of the central benzene ring (C12-C17) with respect to the thiophene ring, as indicated by torsion angles C9A-C10A-C11A- C12A = 113.3 (6) in molecule A and C9B-C10B-C11B-C12B = 108.0 (6) in molecule B. The conformational difference is also shown by the angle C10-C11-C12, which is 115.7 (4) in molecule A and 111.7 (4) in molecule B. The terminal aromatic rings (C1-C6) are inclined to the thiophene rings, forming dihedral angles of 24.2 (6) and 20.5 (9) in molecules A and B, respectively. The tetrahydropyran rings ISSN 2056-9890 exhibit a distorted chair conformation in both molecules A and B.

Figure 1
The molecular structure of the title compound, (I), showing the atom-labeling scheme and displacement ellipsoids at the 40% probability level. H atoms are shown as small circles of arbitrary radii.

Synthesis and crystallization
The crude product was supplied by Zhejiang Huadong Pharmaceutical Co., Ltd. It was recrystallized from methanol solution, giving colorless crystals suitable for X-ray diffraction.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.