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

Richard Betz; Thomas Gerber; Eric Hosten; Alaloor S Dayananda; Hemmige S Yathirajan; Saji Thomas

doi:10.1107/S160053681104164X

. 2011 Oct 12;67(Pt 11):o2945–o2946. doi: 10.1107/S160053681104164X

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

Richard Betz ^a,^*, Thomas Gerber ^a, Eric Hosten ^a, Alaloor S Dayananda ^b, Hemmige S Yathirajan ^b, Saji Thomas ^c

PMCID: PMC3247356 PMID: 22219974

Abstract

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.

Related literature

For pharmacological background, see: de Leon et al. (2010 ▶); Spina & Crupi (2011 ▶). For related structures, see: Peeters et al. (1993 ▶); Ravikumar et al. (2005 ▶); Sun & Zhang (2009 ▶); 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 ▶).

Experimental

Crystal data

C₂₃H₂₇FN₄O₃
M _r = 426.49
Monoclinic,
a = 6.8537 (1) Å
b = 21.5613 (5) Å
c = 15.3472 (3) Å
β = 113.857 (1)°
V = 2074.15 (7) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 200 K
0.52 × 0.37 × 0.23 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.944, T _max = 1.000
19267 measured reflections
5138 independent reflections
4130 reflections with I > 2σ(I)
R _int = 0.015

Refinement

R[F ² > 2σ(F ²)] = 0.045
wR(F ²) = 0.130
S = 1.07
5138 reflections
291 parameters
3 restraints
H-atom parameters constrained
Δρ_max = 0.39 e Å⁻³
Δρ_min = −0.30 e Å⁻³

Data collection: APEX2 (Bruker, 2010 ▶); cell refinement: SAINT (Bruker, 2010 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S160053681104164X/zl2406sup1.cif

e-67-o2945-sup1.cif^{(33.7KB, cif)}

Supplementary material file. DOI: 10.1107/S160053681104164X/zl2406Isup2.cdx

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681104164X/zl2406Isup3.hkl

e-67-o2945-Isup3.hkl^{(251.7KB, hkl)}

Supplementary material file. DOI: 10.1107/S160053681104164X/zl2406Isup4.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O2ⁱ	0.84	1.86	2.6945 (16)	174
O1B—H1B⋯O2ⁱ	0.84	2.39	3.153 (8)	152
C4—H4A⋯N4ⁱⁱ	0.99	2.55	3.4830 (19)	157

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

ASD thanks the University of Mysore for research facilities. HSY thanks Jubilant Life Sciences Ltd, Noida, for the gift sample of the title compound.

supplementary crystallographic information

Comment

Paliperidone, or 9-hydroxyrisperidone, is one of the most recently available atypical antipsychotics (Spina & Crupi, 2011). It is a benzisoxazole derivative and the major active metabolite of risperidone, a widely used atypical antipsychotic approved for the treatment of schizophrenia and other psychiatric disorders. The pharmacokinetics of paliperidone versus risperidone have been published (de Leon et al., 2010). Related crystal structures, viz. 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl}-6,7,8,9-tetrahydro-\ 2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one [risperidone] (Peeters et al., 1993), risperidone N-oxide hydrogen peroxide methanol solvate (Ravikumar et al., 2005), risperidone chloride 2.5 hydrate (Wang & Pan, 2006), 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2-methyl-4-oxo- 6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-3-yl)ethyl]piperidinium nitrate (Sun & Zhang, 2009) have been reported. In view of the importance of the title compound we herein report its molecular and crystal structure.

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 ¹C₄ conformation (^N3C_C23) and the hydroxy-tetrahydropyrido ring annulated on the pyrimidin-4-one ring adopts a ⁵H₄ conformation (^C4H_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 C¹₁(7) whereas the C–H···N contacts necessitate a C¹₁(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.

Experimental

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.