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

Betz, R.; Gerber, T.; Hosten, E.; Dayananda, A.S.; Yathirajan, H.S.; Thomas, S.

doi:10.1107/S160053681104164X

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 67| Part 11| November 2011| Pages o2945-o2946

doi:10.1107/S160053681104164X

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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 and Saji Thomas ^c

^aNelson Mandela Metropolitan University, Summerstrand Campus, Department of Chemistry, University Way, Summerstrand, PO Box 77000, Port Elizabeth 6031, South Africa, ^bUniversity of Mysore, Department of Studies in Chemistry, Manasagangotri, Mysore 570 006, India, and ^cJubilant Life Sciences Ltd, C-26, Sector 59, Noida 201 301, India
^*Correspondence e-mail: richard.betz@webmail.co.za

(Received 21 September 2011; accepted 10 October 2011; online 12 October 2011)

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, P 2₁ /c
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[F² > 2σ(F²)] = 0.045
wR(F²) = 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

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
Symmetry codes: (i) x+1, y, z; (ii) $[x-1, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ .

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 ).

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053681104164X/zl2406sup1.cif

Supporting information file. DOI: 10.1107/S160053681104164X/zl2406Isup2.cdx

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

Supporting information file. DOI: 10.1107/S160053681104164X/zl2406Isup4.cml

checkCIF report

Comment top

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.

Related literature top

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 top

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.

Computing details top

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); 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 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top

	Fig. 1. The molecular structure of the title compound, with atom labels and anisotropic displacement ellipsoids (drawn at 50% probability level).
	Fig. 2. Selected intermolecular contacts, viewed along [0 0 - 1]. For clarity, only the main components of the disordered parts of the molecule are depicted. Blue dashed lines indicate classical hydrogen bonds of the O–H···O type, green dashed lines indicate C–H···N contacts. Symmetry operators: ⁱ x - 1, y, z; ⁱⁱ x - 1, -y + 1/2, z - 1/2; ⁱⁱⁱ x + 1, -y + 1/2, z + 1/2; ^iv x + 1, y, z.
	Fig. 3. Molecular packing of the title compound, viewed along [-1 0 0] (anisotropic displacement ellipsoids drawn at 50% probability level). For clarity, only the main components of the disordered part of the molecule are depicted.

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 top

Crystal data top

C₂₃H₂₇FN₄O₃	F(000) = 904
M_r = 426.49	D_x = 1.366 Mg m⁻³
Monoclinic, P2₁/c	Melting point = 431–433 K
Hall symbol: -P 2ybc	Mo Kα radiation, λ = 0.71073 Å
a = 6.8537 (1) Å	Cell parameters from 8433 reflections
b = 21.5613 (5) Å	θ = 2.4–28.3°
c = 15.3472 (3) Å	µ = 0.10 mm⁻¹
β = 113.857 (1)°	T = 200 K
V = 2074.15 (7) Å³	Platelet, colourless
Z = 4	0.52 × 0.37 × 0.23 mm

Data collection top

Bruker APEXII CCD diffractometer	5138 independent reflections
Radiation source: fine-focus sealed tube	4130 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.015
ϕ and ω scans	θ_max = 28.3°, θ_min = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 2008)	h = −9→5
T_min = 0.944, T_max = 1.000	k = −28→28
19267 measured reflections	l = −19→20

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.045	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.130	H-atom parameters constrained
S = 1.07	w = 1/[σ²(F_o²) + (0.0609P)² + 0.7502P] where P = (F_o² + 2F_c²)/3
5138 reflections	(Δ/σ)_max < 0.001
291 parameters	Δρ_max = 0.39 e Å⁻³
3 restraints	Δρ_min = −0.30 e Å⁻³

Crystal data top

C₂₃H₂₇FN₄O₃	V = 2074.15 (7) Å³
M_r = 426.49	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 6.8537 (1) Å	µ = 0.10 mm⁻¹
b = 21.5613 (5) Å	T = 200 K
c = 15.3472 (3) Å	0.52 × 0.37 × 0.23 mm
β = 113.857 (1)°

Data collection top

Bruker APEXII CCD diffractometer	5138 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2008)	4130 reflections with I > 2σ(I)
T_min = 0.944, T_max = 1.000	R_int = 0.015
19267 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.045	3 restraints
wR(F²) = 0.130	H-atom parameters constrained
S = 1.07	Δρ_max = 0.39 e Å⁻³
5138 reflections	Δρ_min = −0.30 e Å⁻³
291 parameters

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
F1	0.9472 (2)	−0.23734 (5)	0.06766 (8)	0.0637 (3)
C1	0.3065 (2)	0.34124 (6)	0.10562 (9)	0.0263 (3)
C2	0.4057 (3)	0.38777 (13)	0.0575 (3)	0.0303 (5)	0.856 (2)
H2	0.5363	0.4076	0.1061	0.036*	0.856 (2)
O1	0.4566 (2)	0.35414 (7)	−0.00902 (10)	0.0441 (4)	0.856 (2)
H1	0.5676	0.3332	0.0197	0.066*	0.856 (2)
C2B	0.371 (2)	0.3800 (9)	0.0602 (19)	0.0303 (5)	0.144 (2)
H2B	0.3836	0.3531	0.0096	0.036*	0.144 (2)
O1B	0.5863 (13)	0.4016 (4)	0.1090 (6)	0.0441 (4)	0.144 (2)
H1B	0.6707	0.3714	0.1204	0.066*	0.144 (2)
O2	−0.19649 (16)	0.28148 (5)	0.07163 (8)	0.0385 (3)
O3	0.98743 (17)	−0.07016 (5)	0.27657 (8)	0.0355 (2)
N1	0.09124 (17)	0.33395 (5)	0.07005 (8)	0.0243 (2)
N2	0.43993 (18)	0.30815 (6)	0.17546 (9)	0.0304 (3)
N3	0.19463 (19)	0.10440 (5)	0.16460 (8)	0.0297 (3)
N4	0.8250 (2)	−0.02973 (6)	0.27986 (10)	0.0358 (3)
C3	0.2461 (2)	0.43659 (7)	0.00112 (11)	0.0352 (3)
H3A	0.2185	0.4652	0.0453	0.042*
H3B	0.3052	0.4611	−0.0371	0.042*
C4	0.0400 (2)	0.40636 (7)	−0.06404 (10)	0.0343 (3)
H4A	−0.0587	0.4382	−0.1050	0.041*
H4B	0.0687	0.3760	−0.1058	0.041*
C5	−0.0608 (2)	0.37407 (7)	−0.00587 (10)	0.0310 (3)
H5A	−0.1195	0.4056	0.0238	0.037*
H5B	−0.1811	0.3484	−0.0486	0.037*
C6	−0.0004 (2)	0.28750 (6)	0.10498 (10)	0.0257 (3)
C7	0.1457 (2)	0.24916 (6)	0.17907 (10)	0.0256 (3)
C8	0.3594 (2)	0.26122 (6)	0.21256 (10)	0.0283 (3)
C9	0.5251 (2)	0.22464 (8)	0.29070 (12)	0.0410 (4)
H9A	0.6444	0.2519	0.3278	0.061*	0.68 (2)
H9B	0.5769	0.1909	0.2629	0.061*	0.68 (2)
H9C	0.4623	0.2073	0.3325	0.061*	0.68 (2)
H9D	0.4780	0.1815	0.2877	0.061*	0.32 (2)
H9E	0.5455	0.2425	0.3525	0.061*	0.32 (2)
H9F	0.6601	0.2261	0.2830	0.061*	0.32 (2)
C10	0.0456 (2)	0.19768 (6)	0.21276 (11)	0.0321 (3)
H10A	−0.0903	0.2126	0.2135	0.038*
H10B	0.1416	0.1864	0.2788	0.038*
C11	0.0019 (2)	0.13990 (7)	0.14944 (12)	0.0365 (3)
H11A	−0.1000	0.1128	0.1624	0.044*
H11B	−0.0659	0.1528	0.0818	0.044*
C21	0.1578 (3)	0.06087 (7)	0.08649 (12)	0.0398 (4)
H21A	0.1067	0.0839	0.0255	0.048*
H21B	0.0453	0.0310	0.0833	0.048*
C22	0.3598 (3)	0.02553 (7)	0.09942 (11)	0.0370 (3)
H22A	0.4695	0.0550	0.0983	0.044*
H22B	0.3286	−0.0040	0.0461	0.044*
C23	0.4457 (2)	−0.01007 (7)	0.19418 (11)	0.0325 (3)
H23	0.3353	−0.0411	0.1920	0.039*
C24	0.4728 (3)	0.03595 (7)	0.27396 (11)	0.0370 (3)
H24A	0.5180	0.0134	0.3352	0.044*
H24B	0.5860	0.0662	0.2794	0.044*
C25	0.2667 (3)	0.07031 (7)	0.25493 (11)	0.0371 (3)
H25A	0.1553	0.0403	0.2526	0.044*
H25B	0.2889	0.0997	0.3076	0.044*
C31	0.6466 (2)	−0.04472 (6)	0.20962 (10)	0.0299 (3)
C32	0.6772 (2)	−0.09575 (6)	0.15598 (10)	0.0300 (3)
C33	0.8930 (2)	−0.10890 (6)	0.20159 (10)	0.0296 (3)
C34	0.9956 (3)	−0.15634 (7)	0.17502 (11)	0.0346 (3)
H34	1.1440	−0.1646	0.2068	0.041*
C35	0.8610 (3)	−0.19004 (7)	0.09821 (12)	0.0415 (4)
C36	0.6432 (3)	−0.17991 (8)	0.04974 (12)	0.0480 (4)
H36	0.5604	−0.2055	−0.0026	0.058*
C37	0.5487 (3)	−0.13217 (7)	0.07852 (12)	0.0414 (4)
H37	0.4001	−0.1242	0.0465	0.050*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
F1	0.0769 (8)	0.0536 (7)	0.0580 (7)	0.0184 (6)	0.0246 (6)	−0.0218 (5)
C1	0.0285 (7)	0.0250 (6)	0.0276 (6)	0.0007 (5)	0.0135 (5)	−0.0010 (5)
C2	0.0238 (10)	0.0304 (11)	0.0399 (8)	−0.0053 (8)	0.0161 (9)	0.0069 (7)
O1	0.0381 (7)	0.0552 (8)	0.0450 (8)	0.0164 (6)	0.0231 (6)	0.0159 (6)
C2B	0.0238 (10)	0.0304 (11)	0.0399 (8)	−0.0053 (8)	0.0161 (9)	0.0069 (7)
O1B	0.0381 (7)	0.0552 (8)	0.0450 (8)	0.0164 (6)	0.0231 (6)	0.0159 (6)
O2	0.0243 (5)	0.0380 (6)	0.0518 (7)	0.0046 (4)	0.0138 (5)	0.0109 (5)
O3	0.0336 (5)	0.0306 (5)	0.0390 (6)	0.0009 (4)	0.0111 (4)	−0.0088 (4)
N1	0.0258 (5)	0.0229 (5)	0.0244 (5)	0.0036 (4)	0.0105 (4)	0.0017 (4)
N2	0.0257 (6)	0.0310 (6)	0.0342 (6)	0.0010 (5)	0.0118 (5)	0.0038 (5)
N3	0.0293 (6)	0.0254 (5)	0.0320 (6)	0.0026 (4)	0.0099 (5)	0.0025 (5)
N4	0.0368 (7)	0.0295 (6)	0.0396 (7)	0.0040 (5)	0.0137 (6)	−0.0069 (5)
C3	0.0407 (8)	0.0291 (7)	0.0355 (8)	−0.0008 (6)	0.0153 (6)	0.0053 (6)
C4	0.0366 (8)	0.0336 (7)	0.0306 (7)	0.0041 (6)	0.0114 (6)	0.0057 (6)
C5	0.0289 (7)	0.0325 (7)	0.0286 (7)	0.0055 (5)	0.0085 (5)	0.0061 (5)
C6	0.0260 (6)	0.0237 (6)	0.0305 (6)	0.0032 (5)	0.0146 (5)	0.0000 (5)
C7	0.0275 (6)	0.0229 (6)	0.0297 (6)	0.0043 (5)	0.0151 (5)	0.0021 (5)
C8	0.0280 (7)	0.0271 (6)	0.0300 (7)	0.0037 (5)	0.0118 (5)	0.0020 (5)
C9	0.0302 (8)	0.0421 (9)	0.0441 (9)	0.0054 (6)	0.0082 (7)	0.0151 (7)
C10	0.0314 (7)	0.0280 (7)	0.0419 (8)	0.0047 (5)	0.0201 (6)	0.0080 (6)
C11	0.0264 (7)	0.0284 (7)	0.0512 (9)	−0.0004 (5)	0.0120 (6)	0.0038 (6)
C21	0.0369 (8)	0.0350 (8)	0.0362 (8)	0.0028 (6)	0.0031 (6)	−0.0050 (6)
C22	0.0392 (8)	0.0373 (8)	0.0293 (7)	0.0052 (6)	0.0086 (6)	−0.0032 (6)
C23	0.0336 (7)	0.0256 (6)	0.0385 (8)	0.0021 (5)	0.0148 (6)	0.0002 (5)
C24	0.0460 (9)	0.0348 (8)	0.0297 (7)	0.0147 (6)	0.0149 (6)	0.0054 (6)
C25	0.0453 (9)	0.0310 (7)	0.0407 (8)	0.0096 (6)	0.0233 (7)	0.0089 (6)
C31	0.0349 (7)	0.0238 (6)	0.0316 (7)	−0.0001 (5)	0.0141 (6)	0.0001 (5)
C32	0.0352 (7)	0.0249 (6)	0.0294 (7)	−0.0002 (5)	0.0125 (6)	−0.0011 (5)
C33	0.0367 (7)	0.0237 (6)	0.0292 (7)	−0.0020 (5)	0.0144 (6)	−0.0012 (5)
C34	0.0396 (8)	0.0301 (7)	0.0367 (8)	0.0040 (6)	0.0182 (6)	0.0000 (6)
C35	0.0566 (10)	0.0321 (8)	0.0377 (8)	0.0082 (7)	0.0211 (7)	−0.0054 (6)
C36	0.0575 (11)	0.0385 (9)	0.0383 (9)	0.0000 (8)	0.0093 (8)	−0.0139 (7)
C37	0.0396 (8)	0.0360 (8)	0.0385 (8)	−0.0001 (6)	0.0055 (7)	−0.0071 (6)

Geometric parameters (Å, º) top

F1—C35	1.3537 (18)	C9—H9A	0.9800
C1—C2B	1.277 (18)	C9—H9B	0.9800
C1—N2	1.3042 (18)	C9—H9C	0.9800
C1—N1	1.3596 (17)	C9—H9D	0.9800
C1—C2	1.556 (2)	C9—H9E	0.9800
C2—O1	1.406 (4)	C9—H9F	0.9800
C2—C3	1.512 (3)	C10—C11	1.533 (2)
C2—H2	1.0000	C10—H10A	0.9900
O1—H1	0.8400	C10—H10B	0.9900
C2B—O1B	1.434 (16)	C11—H11A	0.9900
C2B—C3	1.555 (15)	C11—H11B	0.9900
C2B—H2B	1.0000	C21—C22	1.521 (2)
O1B—H1B	0.8400	C21—H21A	0.9900
O2—C6	1.2363 (16)	C21—H21B	0.9900
O3—C33	1.3559 (16)	C22—C23	1.536 (2)
O3—N4	1.4309 (16)	C22—H22A	0.9900
N1—C6	1.3990 (17)	C22—H22B	0.9900
N1—C5	1.4865 (16)	C23—C31	1.499 (2)
N2—C8	1.3811 (18)	C23—C24	1.528 (2)
N3—C11	1.4615 (18)	C23—H23	1.0000
N3—C21	1.4619 (19)	C24—C25	1.515 (2)
N3—C25	1.4671 (18)	C24—H24A	0.9900
N4—C31	1.3019 (19)	C24—H24B	0.9900
C3—C4	1.509 (2)	C25—H25A	0.9900
C3—H3A	0.9900	C25—H25B	0.9900
C3—H3B	0.9900	C31—C32	1.4392 (19)
C4—C5	1.503 (2)	C32—C33	1.386 (2)
C4—H4A	0.9900	C32—C37	1.399 (2)
C4—H4B	0.9900	C33—C34	1.392 (2)
C5—H5A	0.9900	C34—C35	1.374 (2)
C5—H5B	0.9900	C34—H34	0.9500
C6—C7	1.4344 (18)	C35—C36	1.390 (3)
C7—C8	1.3667 (19)	C36—C37	1.381 (2)
C7—C10	1.5023 (19)	C36—H36	0.9500
C8—C9	1.4994 (19)	C37—H37	0.9500

C2B—C1—N2	121.6 (7)	H9D—C9—H9E	109.5
C2B—C1—N1	114.6 (7)	C8—C9—H9F	109.5
N2—C1—N1	123.57 (12)	H9A—C9—H9F	56.3
N2—C1—C2	116.57 (14)	H9B—C9—H9F	56.3
N1—C1—C2	119.70 (13)	H9C—C9—H9F	141.1
O1—C2—C3	106.2 (2)	H9D—C9—H9F	109.5
O1—C2—C1	107.2 (2)	H9E—C9—H9F	109.5
C3—C2—C1	111.50 (15)	C7—C10—C11	112.43 (12)
O1—C2—H2	110.6	C7—C10—H10A	109.1
C3—C2—H2	110.6	C11—C10—H10A	109.1
C1—C2—H2	110.6	C7—C10—H10B	109.1
C1—C2B—O1B	116.0 (15)	C11—C10—H10B	109.1
C1—C2B—C3	126.9 (14)	H10A—C10—H10B	107.9
O1B—C2B—C3	104.9 (11)	N3—C11—C10	113.10 (12)
C1—C2B—H2B	101.6	N3—C11—H11A	109.0
O1B—C2B—H2B	101.6	C10—C11—H11A	109.0
C3—C2B—H2B	101.6	N3—C11—H11B	109.0
C2B—O1B—H1B	109.5	C10—C11—H11B	109.0
C33—O3—N4	107.11 (10)	H11A—C11—H11B	107.8
C1—N1—C6	120.76 (11)	N3—C21—C22	111.62 (12)
C1—N1—C5	123.39 (11)	N3—C21—H21A	109.3
C6—N1—C5	115.84 (11)	C22—C21—H21A	109.3
C1—N2—C8	118.38 (12)	N3—C21—H21B	109.3
C11—N3—C21	111.13 (12)	C22—C21—H21B	109.3
C11—N3—C25	110.49 (12)	H21A—C21—H21B	108.0
C21—N3—C25	109.50 (12)	C21—C22—C23	110.76 (13)
C31—N4—O3	107.63 (11)	C21—C22—H22A	109.5
C4—C3—C2	110.17 (15)	C23—C22—H22A	109.5
C4—C3—C2B	101.3 (7)	C21—C22—H22B	109.5
C4—C3—H3A	109.6	C23—C22—H22B	109.5
C2—C3—H3A	109.6	H22A—C22—H22B	108.1
C2B—C3—H3A	107.6	C31—C23—C24	113.02 (12)
C4—C3—H3B	109.6	C31—C23—C22	112.03 (12)
C2—C3—H3B	109.6	C24—C23—C22	108.06 (12)
C2B—C3—H3B	120.2	C31—C23—H23	107.8
H3A—C3—H3B	108.1	C24—C23—H23	107.8
C5—C4—C3	109.78 (12)	C22—C23—H23	107.8
C5—C4—H4A	109.7	C25—C24—C23	111.19 (13)
C3—C4—H4A	109.7	C25—C24—H24A	109.4
C5—C4—H4B	109.7	C23—C24—H24A	109.4
C3—C4—H4B	109.7	C25—C24—H24B	109.4
H4A—C4—H4B	108.2	C23—C24—H24B	109.4
N1—C5—C4	112.96 (12)	H24A—C24—H24B	108.0
N1—C5—H5A	109.0	N3—C25—C24	111.00 (12)
C4—C5—H5A	109.0	N3—C25—H25A	109.4
N1—C5—H5B	109.0	C24—C25—H25A	109.4
C4—C5—H5B	109.0	N3—C25—H25B	109.4
H5A—C5—H5B	107.8	C24—C25—H25B	109.4
O2—C6—N1	119.85 (12)	H25A—C25—H25B	108.0
O2—C6—C7	124.13 (12)	N4—C31—C32	111.00 (13)
N1—C6—C7	116.02 (11)	N4—C31—C23	120.13 (13)
C8—C7—C6	119.12 (12)	C32—C31—C23	128.87 (13)
C8—C7—C10	125.46 (12)	C33—C32—C37	119.37 (13)
C6—C7—C10	115.42 (12)	C33—C32—C31	103.89 (12)
C7—C8—N2	122.05 (12)	C37—C32—C31	136.70 (14)
C7—C8—C9	123.40 (13)	O3—C33—C32	110.37 (12)
N2—C8—C9	114.54 (12)	O3—C33—C34	125.22 (13)
C8—C9—H9A	109.5	C32—C33—C34	124.39 (13)
C8—C9—H9B	109.5	C35—C34—C33	113.34 (14)
H9A—C9—H9B	109.5	C35—C34—H34	123.3
C8—C9—H9C	109.5	C33—C34—H34	123.3
H9A—C9—H9C	109.5	F1—C35—C34	117.38 (15)
H9B—C9—H9C	109.5	F1—C35—C36	117.24 (15)
C8—C9—H9D	109.5	C34—C35—C36	125.38 (14)
H9A—C9—H9D	141.1	C37—C36—C35	119.17 (15)
H9B—C9—H9D	56.3	C37—C36—H36	120.4
H9C—C9—H9D	56.3	C35—C36—H36	120.4
C8—C9—H9E	109.5	C36—C37—C32	118.34 (15)
H9A—C9—H9E	56.3	C36—C37—H37	120.8
H9B—C9—H9E	141.1	C32—C37—H37	120.8
H9C—C9—H9E	56.3

C2B—C1—C2—O1	−86 (16)	C6—C7—C8—C9	179.06 (14)
N2—C1—C2—O1	82.2 (2)	C10—C7—C8—C9	−1.5 (2)
N1—C1—C2—O1	−93.42 (18)	C1—N2—C8—C7	−0.7 (2)
C2B—C1—C2—C3	30 (16)	C1—N2—C8—C9	178.41 (13)
N2—C1—C2—C3	−161.95 (19)	C8—C7—C10—C11	−95.84 (17)
N1—C1—C2—C3	22.4 (3)	C6—C7—C10—C11	83.63 (15)
N2—C1—C2B—O1B	−22 (3)	C21—N3—C11—C10	−164.00 (13)
N1—C1—C2B—O1B	163.6 (13)	C25—N3—C11—C10	74.24 (15)
C2—C1—C2B—O1B	−9 (14)	C7—C10—C11—N3	75.21 (16)
N2—C1—C2B—C3	−158.1 (15)	C11—N3—C21—C22	177.66 (13)
N1—C1—C2B—C3	27 (3)	C25—N3—C21—C22	−60.00 (17)
C2—C1—C2B—C3	−146 (18)	N3—C21—C22—C23	58.12 (17)
C2B—C1—N1—C6	171.9 (15)	C21—C22—C23—C31	−179.23 (12)
N2—C1—N1—C6	−2.7 (2)	C21—C22—C23—C24	−54.09 (17)
C2—C1—N1—C6	172.62 (19)	C31—C23—C24—C25	179.45 (12)
C2B—C1—N1—C5	−9.0 (15)	C22—C23—C24—C25	54.90 (17)
N2—C1—N1—C5	176.46 (13)	C11—N3—C25—C24	−177.07 (12)
C2—C1—N1—C5	−8.2 (2)	C21—N3—C25—C24	60.21 (17)
C2B—C1—N2—C8	−171.1 (16)	C23—C24—C25—N3	−59.11 (17)
N1—C1—N2—C8	3.1 (2)	O3—N4—C31—C32	0.47 (16)
C2—C1—N2—C8	−172.37 (19)	O3—N4—C31—C23	−179.79 (12)
C33—O3—N4—C31	−0.26 (15)	C24—C23—C31—N4	−7.0 (2)
O1—C2—C3—C4	66.51 (17)	C22—C23—C31—N4	115.40 (16)
C1—C2—C3—C4	−50.0 (3)	C24—C23—C31—C32	172.73 (14)
O1—C2—C3—C2B	106 (7)	C22—C23—C31—C32	−64.91 (19)
C1—C2—C3—C2B	−11 (6)	N4—C31—C32—C33	−0.51 (16)
C1—C2B—C3—C4	−53 (3)	C23—C31—C32—C33	179.79 (14)
O1B—C2B—C3—C4	167.3 (14)	N4—C31—C32—C37	176.94 (18)
C1—C2B—C3—C2	165 (9)	C23—C31—C32—C37	−2.8 (3)
O1B—C2B—C3—C2	25 (5)	N4—O3—C33—C32	−0.07 (15)
C2—C3—C4—C5	64.6 (2)	N4—O3—C33—C34	−178.55 (13)
C2B—C3—C4—C5	57.3 (11)	C37—C32—C33—O3	−177.66 (13)
C1—N1—C5—C4	21.57 (18)	C31—C32—C33—O3	0.33 (16)
C6—N1—C5—C4	−159.23 (12)	C37—C32—C33—C34	0.8 (2)
C3—C4—C5—N1	−48.73 (16)	C31—C32—C33—C34	178.83 (13)
C1—N1—C6—O2	−179.85 (12)	O3—C33—C34—C35	177.88 (14)
C5—N1—C6—O2	0.92 (18)	C32—C33—C34—C35	−0.4 (2)
C1—N1—C6—C7	−0.04 (17)	C33—C34—C35—F1	−179.75 (14)
C5—N1—C6—C7	−179.26 (11)	C33—C34—C35—C36	−0.3 (2)
O2—C6—C7—C8	−178.03 (13)	F1—C35—C36—C37	179.98 (16)
N1—C6—C7—C8	2.17 (18)	C34—C35—C36—C37	0.5 (3)
O2—C6—C7—C10	2.5 (2)	C35—C36—C37—C32	−0.1 (3)
N1—C6—C7—C10	−177.33 (11)	C33—C32—C37—C36	−0.6 (2)
C6—C7—C8—N2	−1.9 (2)	C31—C32—C37—C36	−177.72 (17)
C10—C7—C8—N2	177.58 (13)

Hydrogen-bond geometry (Å, º) top

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

Symmetry codes: (i) x+1, y, z; (ii) x−1, −y+1/2, z−1/2.

Experimental details

Crystal data
Chemical formula	C₂₃H₂₇FN₄O₃
M_r	426.49
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	200
a, b, c (Å)	6.8537 (1), 21.5613 (5), 15.3472 (3)
β (°)	113.857 (1)
V (Å³)	2074.15 (7)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.10
Crystal size (mm)	0.52 × 0.37 × 0.23

Data collection
Diffractometer	Bruker APEXII CCD diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2008)
T_min, T_max	0.944, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	19267, 5138, 4130
R_int	0.015
(sin θ/λ)_max (Å⁻¹)	0.667

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.045, 0.130, 1.07
No. of reflections	5138
No. of parameters	291
No. of restraints	3
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.39, −0.30

Computer programs: APEX2 (Bruker, 2010), SAINT (Bruker, 2010), SHELXS97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 1997) and Mercury (Macrae et al., 2008), SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O2ⁱ	0.84	1.86	2.6945 (16)	173.7
O1B—H1B···O2ⁱ	0.84	2.39	3.153 (8)	151.7
C4—H4A···N4ⁱⁱ	0.99	2.55	3.4830 (19)	156.5

Symmetry codes: (i) x+1, y, z; (ii) x−1, −y+1/2, z−1/2.

Acknowledgements

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

References

Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555–1573. CrossRef CAS Web of Science Google Scholar
Bruker (2008). SADABS. Bruker Inc., Madison, Wisconsin, USA. Google Scholar
Bruker (2010). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358. CrossRef CAS Web of Science Google Scholar
Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256–262. CrossRef CAS Web of Science IUCr Journals Google Scholar
Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565. CrossRef IUCr Journals Google Scholar
Leon, J. de, Wynn, G. & Sandson, N. B. (2010). Psychosomatics, 51, 80–88. CrossRef PubMed Google Scholar
Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466–470. Web of Science CrossRef CAS IUCr Journals Google Scholar
Peeters, O. M., Blaton, N. M. & De Ranter, C. J. (1993). Acta Cryst. C49, 1698–1700. CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
Ravikumar, K., Sridhar, B., Manjunatha, S. G. & Thomas, S. (2005). Acta Cryst. E61, o2515–o2517. Web of Science CSD CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Spina, E. & Crupi, R. (2011). J. Cent. Nerv. Syst. Dis. 3, 27–41. CrossRef CAS PubMed Google Scholar
Sun, Y. & Zhang, H.-H. (2009). Acta Cryst. E65, o1647. Web of Science CSD CrossRef IUCr Journals Google Scholar
Wang, D.-H. & Pan, Y.-J. (2006). Acta Cryst. E62, o768–o770. Web of Science CSD CrossRef IUCr Journals Google Scholar

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Volume 67| Part 11| November 2011| Pages o2945-o2946

doi:10.1107/S160053681104164X

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organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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

Related literature

Experimental

Crystal data

Data collection

Refinement

Supporting information

Acknowledgements

References

organic compounds

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