Crystal structure of (S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl}methyl)thiophene-2-carboxamide

The asymmetric unit of the crystal of the title compound contains two rivaroxaban molecules with different conformations.

The asymmetric unit of the crystal of the title compound (common name rivaroxaban), C 19 H 18 ClN 3 O 5 , contains two rivaroxaban molecules with different conformations; the C-C-N-C torsion angles between the oxazolidine and thiophene rings are À171.1 (7) and À106.8 (9) in the two independent molecules. In the crystal, classical N-HÁ Á ÁO hydrogen bonds and weak C-HÁ Á ÁO hydrogen bonds link the molecules into a three-dimensional supramolecular architecture.

Chemical context
At present, the incidence of thromboic disease is extremely high; this is mainly caused by vascular endothelial injury, increased blood coagulation, increased platelet number and decreased anticoagulant activity (Lassila, 2012). In anticoagulants, warfarin and heparin have dominated the market, but they have some defects such as making making patients bleed easily and be prone to thrombocytopenia and osteoporosis (Mega & Carreras, 2012). In recent years, factor Xa inhibitors, the new type of anticoagulant drugs, have received more and more attention, and rivaroxaban is a representative drug of factor Xa inhibitors (Goel & Srivathsan, 2012).
Rivaroxaban is a novel oral direct factor Xa inhibitor that inhibits factor Xa selectively, thereby prolongs prothrombin time and reduces thrombin generation (Ansell, 2007). It does ISSN 2056-9890 not have a direct effect on thrombin but it inhibits the formation of thrombin by inhibiting factor Xa activity, which impedes the formation of fibrin in turn and ultimately inhibits thrombus formation and enlargement (Perzborn et al., 2005). In 2011, rivaroxaban was approved by the US Food and Drug Administration (FDA) for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. The patent WO2007039132 (Ludescher et al., 2012) concerned crystalline form I, form II, form III, the amorphous form, the hydrate, the NMP solvate and the THF clathrate of rivaroxaban. However, there are few reports on the singlecrystal structure of rivaroxaban. As part of our ongoing structural studies of pharmaceutical compounds, the crystal structure of rivaroxaban is presented here.

Structural commentary
The molecular structure of the title compound is shown in Fig. 1. The asymmetric unit contains two molecules with different conformations. In the N-methylformamide moieties of molecules A and B, the C7-C6-N1-C5 torsion angles are À171.1 (7) and À106.8 (9) , respectively ( Table 1). The oxazolidine ring of molecule A is almost planar [the maximum deviation is 0.048 (6) Å for the O2A atom], whereas the oxazolidine ring of molecule B displays an envelope conformation with atom C8B as the flap. The morpholine rings of the two molecules display similar twisted boat conformations. Atoms O4 and C17 deviate from the C16/N3/C19/C18 mean plane by 0.230 (2) and 0.517 (2) Å , respectively, in molecule A and by 0.290 (2) and 0.489 (2) Å in molecule B.

Supramolecular features
In the crystal, N-HÁ Á ÁO hydrogen bonds (Table 2, Fig. 2) link the independent molecules A and B into dimers, and weak C-HÁ Á ÁO hydrogen bonds link the dimers to form a threedimensional supramolecular architecture (Table 2).

Hirshfeld surface analysis
The Hirshfeld surface of a molecule in a crystal is constructed by calculating the spherical atom electron densities.  Table 1 Selected torsion angles ( ).

Figure 2
The supermolecular structure showing the intermolecular interactions (Table 2) as dashed lines.

Figure 3
Plots of d norm mapped on the Hirshfeld surfaces of the title compound showing the N-HÁ Á ÁO hydrogen bonds.

Figure 1
The molecular structure of the title compound,showing the atomlabelling scheme and displacement ellipsoids at the 50% probability level. H atoms are shown as small circles of arbitrary radii.

Figure 4
The two-dimensional fingerprint of title compound showing contributions from different contacts. d norm surface, when intermolecular contacts are shorter than the sum of van der Waals radii, they are highlighted in red, longer contacts in blue and contacts around the sum of van der Waals radii in white. The Hirshfeld surface analyses and twodimensional fingerprint plots for the title compound were generated by CrystalExplorer (Wolff et al., 2013), and are illustrated in Figs. 3 and 4, respectively. The light-red spots on the Hirshfeld surface are the results of N-HÁ Á ÁO, C-HÁ Á ÁO and C-ClÁ Á ÁO interactions (Fig. 3). The HÁ Á ÁH contacts, which comprise 27% of the total Hirshfeld surface area, appear in the central region of the fingerprint plot (Fig. 3b). The OÁ Á ÁH/HÁ Á ÁO interactions (22.4%), which are the most significant intermolecular interactions and link the molecular dimers into infinite chains along the b axis, appear as two obvious spikes (Fig. 3c)

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

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. N-bound atoms H1A and H1B were found in difference-Fourier maps, but placed in calculated positions with N-H = 0.86 Å and refined as riding with U iso (H) = 1.2U eq (N). All other H atoms were placed in calculated positions with C-H = 0.93-0.98 Å and included in the refinement in a riding model, with U iso (H) = 1.2 or 1.5U eq (carrier atom).

(S)-5-Chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl}methyl)thiophene-2-carboxamide
where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.33 e Å −3 Δρ min = −0.47 e Å −3 Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0153 (18) Absolute structure: Flack (1983), 2519 Friedel pairs Absolute structure parameter: −0.07 (13) 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.