Febuxostat ethanol monosolvate

Febuxostat and ethanol molecules are linked into an O—H⋯O and O—H⋯N bonded chain structure.


Chemical context
Febuxostat is a novel, small-molecule, non-purine-selective inhibitor of xanthine oxidase developed for the treatment of chronic gout and hyperuricemia, via oral administration (Pascual et al., 2009;Gray & Walters-Smith, 2011;Kataoka et al., 2015). This drug is currently marketed by Takeda Pharmaceuticals Inc. under the trade name Uloric. Matsumoto et al. (1999) disclosed the existence of five solid forms of febuxostat, i.e. of the anhydrous forms A, B and C, a methanol solvate D and a hemihydrate G. The crystal structures of two polymorphs were reported by Maddileti et al. (2013) and Yadav et al. (2017). Additionally, solvate structures containing the febuxostat molecule and methanol (Jiang et al., 2011), acetic acid (Wu et al., 2015 or pyrdine (Zhu et al., 2009) have been described.
The current study was carried out as part of an investigation with the aim of establishing a modified synthetic route for febuxostat (Lutra et al., 2012), avoiding harsh conditions, toxic reagents to form the thioamide and the highly toxic cyanides. One of the key aspects of the novel route of synthesis was the introduction of a modified version of the Duff reaction (Duff & Bills, 1932, 1934 in the first step, which finally resulted in improved overall yields compared to the original synthesis by Hasegawa (1998). ISSN 2056-9890

Structural commentary
The febuxostat molecule ( Fig. 1) is essentially planar. This is illustrated by the fact that the mean plane defined by all its non-H atoms, except for C22 of the isobutyl group, results in a root-mean-square deviation for the 21 fitted atoms of only 0.0890 Å . Atom C22 is located at a distance of 1.498 (3) Å from this mean plane. All bond lengths and angles are in good agreement with the geometrical characteristics of previously determined febuxostat structures (see below). The relative mutual orientation of the CN substituent at the phenyl ring and the Me group at the thiazole ring is characterized by the torsion angle S1-C2-C6-C7 of À6.5 (3) . This torsion is also defined as in the Scheme. The isobutoxy group adopts the expected extended chain geometry with C9-O18-C19-C20 = 175.3 (2) and O18-C19-C20-C21 = 170.7 (2) .

Supramolecular features
The carboxyl group of the febuxostat molecule is linked to the OH group of an EtOH molecule via an O23-H23Á Á ÁN3(Àx + 1, y + 1 2 , Àz + 1) interaction. The hydroxy group of the solvent additionally serves as a hydrogen-bond donor group for an O14-H14Á Á ÁO23(x À 1, y, z) bond to a second febuxostat molecule (see Table 1). Together, these two interactions result in a hydrogen-bonded chain composed of alternating febuxostat and ethanol molecules that displays a 2 1 symmetry and propagates parallel to the b axis (Fig. 2). The same hydrogen-bonded structure is also present in the analogous MeOH solvate of febuxostat, first reported (at 296 K) by Jiang et al. (2011) and redetermined by us at 173 K as part of this study (Gelbrich et al., 2020a). Indeed, a comparison with the program XPac (Gelbrich & Hursthouse, 2005) reveals that the EtOH and MeOH solvates are isostructural. The comparison of corresponding geometrical parameters generated from the complete set of 22 non-H atomic positions in the febuxostat molecule resulted in a dissimilarity index (Gelbrich et al., 2012) of x = 3.3, which indicates a high agreement of the febuxostat packing in the EtOH and MeOH solvates.  Groom et al., 2016) that relate to crystal structures containing the febuxostat molecule. The febuxostat geometries in most of these structures are in good agreement with the parameters of (I), i.e. the torsion (see Scheme) typically adopts a value close to 0 . However, an opposite geometry with values close to 180 has been reported for the polymorphs Q and H1, a co-crystal with 4-aminobenzoic acid and a 2-(pyridin-2-ylamino)pyridinium salt.

Synthesis
The preparation of febuxostat was carried out according to the scheme in Fig. 3 in a modified procedure based on the original synthesis by Hasegawa (1998).

Figure 2
Hydrogen-bonded layer structure of (I), viewed along the a axis.

Figure 3
Synthetic scheme for the preparation of febuxostat (1).

Figure 1
Asymmetric unit of (I) with displacement ellipsoids drawn at the 50% probability level and hydrogen atoms drawn as spheres of arbitrary size. and trifluoroacetic acid was distilled out. The obtained residue was cooled to 298 K, water (200 ml) was added slowly, and the slurry was stirred for 4 h. After filtration, the product was washed and dried under vacuum to give 9.60 g of 3.
After stirring, EtOAc (2.5 l) was added. The solution was stirred, and the layers were separated. The pH of the aqueous solution was adjusted to 2.5AE0.2 by adding diluted hydrochloric acid solution at 313 K. After stirring for 1 h, the slurry was filtered, and the product was washed with water and dried under vacuum to give 215 g of 1.

Crystallization
Febuxostat (1 g) was dissolved in ethanol (10 ml), which yielded a clear solution upon heating to 338 K. After filtration, the solution was allowed to cool to room temperature, and the subsequent crystallization resulted in febuxostat ethanol solvate.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All H atoms were identified in difference maps. Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip (C-H = 0.98 Å ), and their U iso parameters were set to 1.5U eq (C) of the parent carbon atom. H atoms bonded to secondary CH 2 (C-H = 0.99 Å ) or tertiary CH (C-H = 0.99 Å ) carbon atoms and H atoms bonded to C atoms in aromatic rings (C-H = 0.95 Å ) were positioned geometrically and refined with U iso set to 1.2U eq (C) of the parent carbon atom. H atoms in OH groups were identified in difference maps, refined with a distance restraint [O-H = 0.84 (2) Å ] and a free U iso parameter. Two outliers (474) and (2,16,2) were omitted in the final cycles of refinement.

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.