Paliperidone: 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-1,6,7,8,9,9a-hexahydropyrido[1,2-a]pyrimidin-4-one

The title compound (also known as 9-hydroxyrisperidone), C23H27FN4O3, is a heterocyclic compound with manifold pharmacological properties. The hydroxy group shows disorder over two positions, with site-occupancy factors of 0.856 (2) and 0.144 (2). The piperidine ring adopts a chair conformation, while the annulated ring bearing the hydroxy group is present in a half-chair conformation. Classical O—H⋯O hydrogen bonds as well as C—H⋯N contacts connect the molecules into undulating sheets lying perpendicular to the crystallographic b axis. The shortest centroid–centroid distance between two centers of gravity is 3.5867 (8) Å and is apparent between the benzoxazole moiety and the six-membered ring bearing the keto substituent.

The title compound (also known as 9-hydroxyrisperidone), C 23 H 27 FN 4 O 3 , is a heterocyclic compound with manifold pharmacological properties. The hydroxy group shows disorder over two positions, with site-occupancy factors of 0.856 (2) and 0.144 (2). The piperidine ring adopts a chair conformation, while the annulated ring bearing the hydroxy group is present in a half-chair conformation. Classical O-HÁ Á ÁO hydrogen bonds as well as C-HÁ Á ÁN contacts connect the molecules into undulating sheets lying perpendicular to the crystallographic b axis. The shortest centroid-centroid distance between two centers of gravity is 3.5867 (8) Å and is apparent between the benzoxazole moiety and the sixmembered ring bearing the keto substituent.  Wang & Pan (2006). For graph-set analysis of hydrogen bonds, see: Etter et al. (1990); Bernstein et al. (1995). For puckering analysis, see: Cremer & Pople (1975 Table 1 Hydrogen-bond geometry (Å , ).
It is a benzisoxazole derivative and the major active metabolite of risperidone, a widely used atypical antipsychotic ap- The hydroxy group as well as the hydrogen atoms of the methyl group show disorder. While the hydroxy group is disordered over two defined positions with site occupancy factors of of 0.856 (2) and 0.144 (2), rotational disorder is observed for the hydrogen atoms of the methyl group (occupancy ratio 0.68 (2) to 0.32 (2)). The low puckering amplitude of the six-membered ring bearing the keto group preculdes a conformational analysis (Cremer & Pople, 1975). The piperidine ring is present in a 1 C 4 conformation ( N3 C C23 ) and the hydroxy-tetrahydropyrido ring annulated on the pyrimidin-4-one ring adopts a 5 H 4 conformation ( C4 H C3 ) (Fig. 1). Proton NMR spectra of dissolved crystals of the title compound do not indicate the presence of the two stereoisomers as became apparent upon modelling the disorder for the hydroxy group in an axial-equatorial configuration.
In the crystal, classical hydrogen bonds of the O-H···O type as well as C-H···N contacts whose range falls by 0.2 Å below the sum of van-der-Waals radii can be observed. While the classical hydrogen bonds are apparent between the hydroxy group as donor and the keto group as acceptor, the C-H···N contacts appear between one of the methylene groups of the central aza-cyclohexane moiety and the nitrogen atom of the oxazol subunit. In terms of graph-set analysis (Etter et al., 1990;Bernstein et al., 1995), the descriptor for the classical hydrogen bonds is C 1 1 (7) whereas the C-H···N contacts necessitate a C 1 1 (14) descriptor on the same level. In total, the molecules are connected to undulated sheets perpendicular to the crystallographic b axis. The shortest intercentroid distance between two centers of gravity was found at 3.5871 (8) Å and is observed between the oxazol subunit and the six-membered heterocycle bearing the keto-group (Fig. 2). Furthermore, a F···C g contact (d F···Cg : 3.2038 (12) Å) is observed between the fluorine atom and the six-membered ring bearing the keto group.
The packing of the title compound is shown in Figure 3.
The title compound was obtained as a gift sample from Jubilant Life Sciences Ltd., Noida, India. Paliperidone was recrystallized from N,N-dimethylformamide by slow evaporation at room temperature.

Refinement
Four reflections, 1 0 4, -1 3 1, 0 4 4 and 0 1 1 were found to be obstructed by the beam stop and were omitted from the refinement. Carbon-bound H atoms were placed in calculated positions (C-H = 0.95 Å for aromatic carbon atoms and C-H = 0.99 Å for methylene groups) and were included in the refinement in the riding model approximation, with U(H) set to 1.2U eq (C). The H atoms of the methyl groups were refined as rotationally disordered over two positions (orientations separated by 60° rotation of the H atoms) and allowed to rotate with a fixed angle around the C-C bond to best fit the experimental electron density and to account for rotational disorder (HFIX 127 in the SHELX program suite (Sheldrick, 2008)), with U(H) set to 1.5U eq (C). Occupancies refined to 0.68 (2) and 0.32 (2). The H atom of the hydroxy group was allowed to rotate with a fixed angle around the C-O bond to best fit the experimental electron density (HFIX 147 in the SHELX program suite (Sheldrick, 2008)), with U(H) set to 1.5U eq (O). The disorder of the hydroxy group was handled with a disorder model over two positions and site occupancy factors of 0.856 (2) and 0.144 (2). The anisotropic displacement parameters of the two oxygen atoms and of the two carbon atoms of the disordered group were each constrained to be identical.