Crystal structure of idelalisib tert-butanol monosolvate dihydrate

Molecules of the three components, idelalisib, tert-butanol and water, are linked into a hydrogen-bonded chain structure with the topology of a 2,3,4,5-connected 4-nodal net.


Chemical context
Idelalisib is a novel, orally available small-molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta). This compound was developed for the oral treatment of chronic lymphocytic leukemia and is currently marketed under the trade name Zydelig by Gilead Sciences, Inc. Carra et al. (2013) reported the existence of seven solid forms of idelalisib and unit-cell parameters for five of these, namely for two polymorphs, an i-PrOH solvate hydrate, a DMF and a DMSO solvate. The current study is part of an investigation of a modified synthetic route for idelalisib, which ultimately resulted in improved yields compared to the original synthesis by Kesicki & Zhichkin (2005).

Structural commentary
The asymmetric unit of the title compound, (I), contains one formula unit, i.e. a molecule each of idelalisib and of t-BuOH as well as two water molecules, denoted as w1 (O37) and w2 (O38) (Fig. 1). The conformation of the idelalisib molecule can be described in terms of the relative orientations adopted by the three planar fragments of the quinazoline group N1>C10, the phenyl ring C11>C16, and the purine group C20 >C28. The mean planes of the phenyl and purine units both lie approximately perpendicular to the quinazoline mean plane and form dihedral angles of 88.10 (8) and 86.97 (6) , respectively, with the latter. The dihedral angle between the phenyl and purine mean planes is 73.75 (7) . The torsion angles around the C30-C18 bond are C31-C30-C18-C6 = 165.5 (2) (propyl group) and C31-C30-C18-N19 = À71.6 (3) .

Supramolecular features
The endocyclic NH group of the purine unit donates a hydrogen bond to the t-BuOH molecule, via N25-H25Á Á ÁO36(Àx + 1, y + 1, Àz + 2). Additionally, the secondary amino function attached to the pyrimidine ring of the purine fragment donates a hydrogen bond to a w2 water molecule, via N19-H19Á Á ÁO38. In turn, the idelalisib molecule accepts three hydrogen bonds. Its quinazoline group is linked to the w1 water molecule via an O37-H37AÁ Á ÁN5 bond, and additionally each of N23 and N27 of the purine group is hydrogenbonded to a water molecule of type w2 [O38-H38AÁ Á ÁN23(x, y À 1, z)] or w1 [O37-H37BÁ Á ÁN27(Àx + 1, y, Àz + 2)]. Moreover, the water molecule w1 is an acceptor for two Hbonds, O36-H36Á Á ÁO37 from a t-BuOH molecule and O38-H38BÁ Á ÁO37 from a w2-type water molecule. There are no hydrogen bonds between neighbouring idelalisib molecules. Overall, the seven classical hydrogen-bonding interactions listed in Table 1 result in a chain that possesses a central twofold rotational axis and propagates parallel to the b axis ( Fig. 2). Each idelalisib molecule represents a five-connected node within this hydrogen-bonded chain structure and is linked to one t-BuOH, two w1 and two w2 molecules. The t-BuOH molecule is a two-connected node and serves as a bridge between an idelalisib and a w1 molecule. The water molecule w1 is four-connected (2 Â idelalisib, 1 Â t-BuOH, 1 Â w2), whilst w2 serves as a three-connected node (2 Â idelalisib, 1 Â w1). The hydrogen-bonded chain of (I) has the topology of the 2,3,4,5-connected 4-nodal 1D net depicted in Fig. 3, which has the point symbol (3.4.5 2 .6 2 )(3.4.5 2 .6 4 .7 2 )(3.5.6)(5). The topology of the hydrogen-bonded structure was determined and classified with the programs ADS and IsoTest of the TOPOS package (Blatov, 2006) in the manner described by Baburin & Blatov (2007).

Figure 2
Hydrogen-bonded chain structure of (I), viewed along the a axis. H, N and O atoms directly engaged in hydrogen bonding are drawn as spheres.
All other H atoms are omitted for clarity.

Figure 1
Asymmetric unit of (I) with displacement ellipsoids drawn at the 50% probability level and hydrogen atoms as spheres of arbitrary size.

Synthesis and crystallization
The preparation of idelalisib was carried out according to the scheme displayed in Fig. 4, which represents a modification of the original synthesis by Kesicki & Zhichkin (2005), and yielded the polymorphic form I described by Carra et al. (2013). To amorphous idelalisib (180 mg), which was obtained by lyophilization of form I in dioxane, were added 500 mL of t-BuOH/water 95:5 (v/v) at 296 K. The amorphous material was dissolved. Precipitation of solid material was observed after 5 min of stirring of the solution. The suspension was then stirred at 296 K for five days, which was followed by centrifugation and separation of the precipitate. Subsequent drying of the solid material yielded the title compound (I) as a crystalline, free-flowing white powder (120 mg, 55%).

Figure 3
2,3,4,5-Connected 4-nodal topological net representing the hydrogenbonded chain structure of (I) which is based on the seven intermolecular interactions listed in Table 1. rotate but not to tip and were refined with U iso (H) = 1.5U eq (C) of the parent carbon atom. All other hydrogen atoms bonded to carbon atoms were positioned geometrically (C-H = 0.95 Å ) and refined with U iso (H) = 1.5U eq (C) of the parent carbon atom. Hydrogen atoms of OH and NH groups were refined with restrained distances [O-H = 0.84 (1) Å ; N-H = 0.88 (1) Å ] and their U iso parameters were refined freely. The absolute structure was established by anomalous-dispersion effects ( Table 2). The largest residual peak of 0.73 e Å À3 is located 1.00 Å from C30. An alternative refinement of a disorder model with a split C30 position was attempted but resulted in a few unreasonably short intramolecular HÁ Á ÁH distances for the minor disorder fragment. This feature could not be eliminated even with the application of an anti-bumping restraint.

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.