Crystal structure of vilazodone hydrochloride methanol monosolvate

In the title compound, the protonated piperazine ring adopts a chair conformation while the indole ring plane is nearly perpendicular to the benzofuran ring system.


Chemical context
Major depression disorder (MDD) currently ranks as the world's fourth greatest cause of illness and is expected to rank second by the year 2020 according to WHO studies (Murray & Lopez, 1996). The title compound, viladozone hydrochloride (marketed as Viibryd by Forest Pharmaceuticals), is a new treatment option for MDD. It was approved on January 21, 2011 by the FDA, licensed by Merck KGaA.
Vilazodone hydrochloride is a selective serotonin re-uptake inhibitor (SSRI) with properties that are most similar to those of citalopram, escitalopram (levapro), fluoveline, proxetin, and sertraline. The new drug differs from its predecessors by also acting as a partial agonist at serotonergic 5-HT 1A receptors. The mechanism of the antidepressant effect of vilazodone is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin re-uptake. Vilazodone binds with high affinity to the serotonin re-uptake site but not to the norepinephrine or dopamine reuptake site. As a result, vilazodone potently and selectively inhibits the re-uptake of serotonin (Choi et al., 2012;Reed et al., 2012;Schwartz & Singh, 2012). Many patents and papers have been reported on the synthesis, polymorphism and bioavailability of this drug (Bathe et al., 2011;Heinrich & Bö ttcher, 2004;Leksic et al., 2013;Lu et al., 2012) but up till now, its three-dimensional structure has not been reported. This work concerns the crystal structure of vilazodone hydrochloride methanol solvate, (I), studied at 275 K.

Structural commentary
The title compound combines indole-butyl-amine and chromenonyl piperazine structural elements in a single molecular entity. The asymmetric unit of (I) contains one protonated vilazodone cation, one Cl À anion and one methanol molecule (Fig. 1).
The expected proton transfer from hydrochloric acid to atom N3 of piperazine occurs; the H atom on the piperazine N3 atom was located unequivocally in the electron-density map. The six-membered piperazine ring adopts a chair conformation. The electron-withdrawing cyano group at position 5 on the indole is twisted out of the mean plane of the indole unit, as indicated by the relevant torsion angles N1-C1-C2-C7 and N1-C1-C2-C3 [144.3 (2) and 34.0 (2) , respectively]. The conformation of the cyano group is similar to that of other drugs containing nitrile groups, such as bicalutamide and Febuxostat (Hu & Gu, 2005;Jiang et al., 2011). The indole moiety is connected by an n-butyl linker to the piperazine ring. The conformation of the butyl chain is of some interest. Three C atoms of the butyl group (C10, C11 and C12) are coplanar with atom C9 of the indole, as confirmed by the C9-C10-C11-C12 torsion angle of 179.2 (2) , meanwhile atoms C11, C12 and C13 are coplanar with piperazine atom N3. A dihedral angle of 80.9 (2) is formed between the mean planes of N3/C11-C13 and C9-C12. The dihedral angle between the C9-C12 mean plane and the indole plane is 10.0 (2) . The second piperazine N atom, N4, is bonded to the benzofuran ring. The formamide group is almost coplanar with the connected benzofuran ring, making a dihedral angle of 2.53 (2) . The indole ring is almost perpendicular to the benzofuran ring, as indicated by the dihedral angle of 85.77 (2) between them. The molecular structure of the title compound, showing the atomlabelling scheme and displacement ellipsoids at 40% probability level. H atoms are shown as small circles of arbitrary radii.

Figure 2
Part of the crystal packing of the title compound. Hydrogen bonds are shown as dashed lines. H atoms not involved in hydrogen bonding have been omitted for clarity. Table 1 Hydrogen-bond geometry (Å , ).
Cg5 is the centroid of the C18-C22 ring.

Synthesis and crystallization
Vilazodone hydrochloride was supplied by Hangzhou HEZE pharmaceutical Technology Co., Ltd. It was recrystallized from methanol solution, giving single crystals suitable for X-ray diffraction.

Refinement
Experimental details including the crystal data, data collection and refinement are summarized in Table 2   Data collection: PROCESS-AUTO (Rigaku, 2006); cell refinement: PROCESS-AUTO (Rigaku, 2006); data reduction: CrystalStructure (Rigaku, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.31 e Å −3 Δρ min = −0.43 e Å −3 Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.096 (6) 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.