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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 64| Part 10| October 2008| Pages o1865-o1866

8-Chloro-5-(4-phenethylpiperazin-1-­yl)pyrido[2,3-b][1,5]benzoxazepine

aDepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Park Parade, Parkville, Victoria 3052, Australia, and bSchool of Chemistry, Monash University, Clayton, Victoria 3800, Australia
*Correspondence e-mail: craig.forsyth@sci.monash.edu.au

(Received 5 August 2008; accepted 22 August 2008; online 6 September 2008)

As part of an anti­psychotic drug discovery program, we report the crystal structure of the title compound, C24H23ClN4O. The mol­ecule has a tricyclic framework with a characteristic buckled V-shaped pyridobenzoxazepine unit, with the central seven-membered heterocycle in a boat configuration. The piperazine ring displays a chair conformation with the 2-phenyl-ethyl substituent assuming an equatorial orientation. There are two crystallographically independent, but virtually identical, mol­ecules in the asymmetric unit.

Related literature

For related literature see: Andreasen et al. (1994[Andreasen, N. C., Nopoulos, P., Schultz, S., Miller, D., Gupta, S., Swayze, V. & Flaum, M. (1994). Acta Psychiatr. Scand. Suppl. 384, 51-59.], 2000[Andreasen, N. C. (2000). Brain Res. Brain Res. Rev. 31, 106-112.]); Dupont & Liégeois (2003[Dupont, L. & Liégeois, J.-F. (2003). Acta Cryst. E59, o1962-o1963.]); Petcher & Weber (1976[Petcher, T. J. & Weber, H.-P. (1976). J. Chem. Soc. Perkin Trans. 2, pp. 1415-1420.]); Capuano et al. (1999[Capuano, B. (1999). Molecules, 4, 329-332.], 2002[Capuano, B., Crosby, I. T., Lloyd, E. J. & Taylor, D. A. (2002). Aust. J. Chem. 55, 565-576.], 2003[Capuano, B., Crosby, I. T., Lloyd, E. J. & Taylor, D. A. (2003). Aust. J. Chem. 56, 875-886.], 2006[Capuano, B., Crosby, I. T., Forsyth, C. M., Lloyd, E. J., Vom, A. & Yuriev, E. (2006). Acta Cryst. E62, o5434-o5436.]); Gerlach (1991[Gerlach, J. (1991). Schizophr. Bull. 17, 289-309.]); Gerson & Meltzer (1992[Gerson, S. L. & Meltzer, H. (1992). Drug Safety, 7 (Suppl. 1), 17-25.]); Liégeois et al. (1994[Liégeois, J.-F., Rogistert, F. A., Bruhwyler, J., Damas, J., Nguyen, T. P., Inarejos, M.-O., Chleide, E. M. G., Mercier, M. G. A. & Delarget, J. E. (1994). J. Med. Chem. 37, 519-525.], 1997[Liégeois, J.-F., Mouithys-Mickalad, A., Bruhwyler, J., Petit, C., Kauffmann, J. M. & Lamy, M. (1997). Biochem. Biophys. Res. Commun. 238, 252-255.], 2000[Liégeois, J.-F., Zahid, N., Bruhwyler, J. & Uetrecht, J. (2000). Arch. Pharm. Wienheim, Ger. 333, 63-67.]); Mouithys-Mickalad et al. (2001[Mouithys-Mickalad, A., Kauffmann, J. M., Petit, C., Bruhwyler, J., Liao, Y., Wikstrom, H., Damas, J., Delarge, J., Deby-Dupont, G., Geczy, J. & Liegeois, J.-F. (2001). J. Med. Chem. 44, 769-776.]); Vom (2006[Vom, A. (2006). Honours Thesis, Monash University (Parkville), Victoria, Australia.]).

[Scheme 1]

Experimental

Crystal data
  • C24H23ClN4O

  • Mr = 418.91

  • Triclinic, [P \overline 1]

  • a = 9.9253 (2) Å

  • b = 15.0549 (3) Å

  • c = 15.9996 (3) Å

  • α = 107.774 (2)°

  • β = 95.487 (1)°

  • γ = 108.783 (1)°

  • V = 2104.93 (8) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.20 mm−1

  • T = 123 (2) K

  • 0.30 × 0.25 × 0.20 mm

Data collection
  • Nonius KappaCCD diffractometer

  • Absorption correction: none

  • 25726 measured reflections

  • 9532 independent reflections

  • 6353 reflections with I > 2σ(I)

  • Rint = 0.084

Refinement
  • R[F2 > 2σ(F2)] = 0.055

  • wR(F2) = 0.158

  • S = 1.00

  • 9532 reflections

  • 541 parameters

  • H-atom parameters constrained

  • Δρmax = 0.48 e Å−3

  • Δρmin = −0.32 e Å−3

Data collection: COLLECT (Bruker, 2000[Bruker (2000). COLLECT. Bruker AXS BV, Delft, The Netherlands.]); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: X-SEED (Barbour, 2001[Barbour, L. J. (2001). J. Supramol. Chem. 1, 189-191.]); software used to prepare material for publication: CIFTAB (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]).

Supporting information


Comment top

Schizophrenia (Gr., "split mind") is a debilitating mental illness that severely impairs an individual's perception of reality, and damages a variety of emotional, behavioural and cognitive functions that we regard as specifically human (Andreasen et al., 2000). This devastating disease afflicts approximately 1% of the world population thereby making it the most common form of psychosis. The symptoms of schizophrenia are divided into two distinct classifications; positive (delusions and hallucinations) and negative (social and emotional withdrawal) (Andreasen et al., 1994). Antipsychotic drugs are divided into two clinical classes; typical (treat the positive symptoms and have a propensity to induce movement disorders) and atypical (treat both positive and negative symptoms, as well as associated cognitive deficits, and are virtually devoid of movement disorders) (Gerlach, 1991).

Clozapine is an atypical antipsychotic drug far superior in efficacy against treatment-resistant schizophrenia compared to other clinically available therapeutics. However, clozapine has been found to induce the blood disorder agranulocytosis that can, in some cases, be fatal. The synthesis component of this drug discovery programme is a continuation of previous work done in our research group (Capuano et al., 2002, 2003) and is based on the structural hybridisation of two common antipsychotics, namely clozapine and haloperidol. The resulting structural series contains a tricyclic motif attached to piperazine, with an additional π-system anchored to the distal nitrogen atom of the piperazine ring system by a suitable spacer (Capuano et al., 2003). The NH of the central seven-membered ring of clozapine has been isosterically replaced with oxygen, and the adjacent benzene ring replaced with a pyridine ring. This structural class, known as 'pyridobenzoxazepine', has been previously investigated by Liegeois et al., with particular interest to the compound 8-chloro-5-(4-methylpiperazin-1-yl)-11H-pyrido[2,3-b] [1,5]benzoxazepine (also known as JL13), which is currently being clinically evaluated. This alternative tricyclic nucleus is predicted to enhance aqueous solubility and bioavailability compared to previously published compounds. Additionally, isosteric replacement of NH for O in structurally related compounds has been shown to significantly reduce their oxidative sensitivity towards neutrophils, and therefore lessen their hematotoxic potential (Mouithys-Mickalad et al., 2001; Liegeois et al., 2000; Liegeois et al., 1997).

Our interest in the crystal structure of (I) was to examine the geometries of the piperazine ring and the tricyclic nucleus relative to clozapine. The crystal contains two crystallographically independent, but virtually identical molecules. The title compound (I) exhibits the characteristic buckled conformation of the pyridobenzoxazepine nucleus with the central seven-membered heterocycle in a classical boat conformation. The dihedral angle between the planes of the aromatic rings (defined as the obtuse angle subtended by the plane normals) are 112.40 (5)° (molecule 1) and 109.06 (6)° (molecule 2), which are comparable to 114° observed for JL13 (Dupont & Liégeois, 2003) and 115° observed for the prototypical atypical antipsychotic, clozapine (Petcher & Weber, 1976). The dihedral angles between the plane of the four C atoms in the piperazine ring and the chloro-substituted and pyridyl rings are 25.5 (1)° and 43.43 (6)° (molecule 1) and 26.39 (6)° and 45.42 (7)°, respectively (for clozapine, the angles are 40.5° and 31.8°, respectively (Petcher & Weber, 1976)); a consequence of the planarity of the piperazine nitrogen in the amidine moiety and the partial double bond character of N1—C12 (1.297 (3) Å and N5—C36 1.301 (2) Å. The piperazine ring adopts an almost perfect chair conformation with the phenethyl substituent assuming an equatorial orientation, by virtue of the sp2-like nature of the piperazine nitrogen atoms. No significant interactions between molecules of the title compound were observed.

Related literature top

For related literature see: Andreasen et al. (1994, 2000); Dupont & Liégeois (2003); Petcher & Weber (1976); Capuano et al. (1999,2002, 2003, 2006); Gerlach (1991); Gerson & Meltzer (1992); Liegeois et al. (1994, 1997, 2000); Mouithys-Mickalad et al. (2001); Vom (2006).

Experimental top

The title compound (I) was synthesized (Vom, 2006) from the tricyclic lactam, 8-chlorobenzo[b]pyrido[3,2-f][1,4]oxazepin- 5(6H)-one (Liegeois et al., 1994), and the monosubstituted piperazine, 1-phenethylpiperazine (Capuano et al., 2003), in the presence of a Lewis acid, (TiCl4). A stirred solution of 1-phenethylpiperazine (1.00 g, 5.28 mmol) in anhydrous 1,4-dioxane (5 ml) under nitrogen was treated with a solution of titanium tetrachloride in dry toluene (1M, 1.1 ml, 1.1 mmol). The mixture was warmed to 50–55 °C to which a hot solution of the tricyclic lactam (250 mg, 1.01 mmol) in anhydrous dioxane (20 ml) was added. The reaction mixture was heated at reflux for 4 h after which time it was then cooled and evaporated to dryness in vacuo. The resulting yellow/brown residue was partitioned between sodium hydroxide solution (1M, 50 mL) and ethyl acetate (50 ml). The organic layer was removed and the aqueous phase was further extracted with ethyl acetate (3x50 ml). The combined organic fractions were washed with water (50 ml), dried over anhydrous sodium sulfate, and then evaporated to dryness. The resulting residue was purified by flash chromatography (ethyl acetate:methanol 97.5:2.5) and the major product evaporated to dryness. The product was recrystallized from dichloromethane/hexane as pale yellow prisms (216 mg, 51%), which were suitable for X-ray diffraction studies (mp 428 K (softens) 433 K (melts)). IR νmax 1599, 1583, 1549 cm-1. 1H NMR (CDCl3) δ 2.70–2.75 (6H, m, H3', H5', H2''), 2.86–2.91 (2H, m, H1''), 3.64 (4H, br s, H2',H6'), 6.97 (1H, dd, J = 8.5, 2.5 Hz,H9), 7.14–7.32 (8H, m, H3, H7, H10, H2''', H3''', H4''', H5''', H6'''), 7.73 (1H, dd, J 7.5, 2.0 Hz, H4), 8.43 (1H, dd, J 5.0, 2.0 Hz, H2). 13C NMR (CDCl3) δ 33.0 (CH2), 46.9 (CH2), 52.7 (CH2), 60.1 (CH2), 117.6 (Cq), 121.7 (CH), 122.3 (CH), 124.5 (CH), 126.4 (CH), 126.7 (CH), 128.6 (2 x CH), 131.0 (Cq), 139.5 (Cq), 140.7 (Cq), 148.4 (Cq), 151.6 (CH), 157.9 (Cq), 164.2 (Cq). ESI MS (20 V) m/z 421 (M[37Cl]H+, 36%), 419 (M[35Cl]H+, 100%). ESI high resolution MS: Found m/z 419.1630. Calcd. for C24H23ClN4O: m/z 419.1633.

Refinement top

All H atoms for the primary molecules were initially located in the difference Fourier map but were placed in geometrically idealized positions and constrained to ride on their parent atoms with C—H distances in the range 0.95–1.00 Å and Uiso(H) = 1.2–1.5 Ueq(C).

Computing details top

Data collection: COLLECT (Bruker, 2000); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: X-SEED (Barbour, 2001); software used to prepare material for publication: CIFTAB (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. Molecular diagram of one of the crystallographically independent molecules of the title compound. Displacement ellipsoids are drawn at the 50% probability level.
8-Chloro-5-(4-phenethylpiperazin-1-yl)pyrido[2,3-b][1,5]benzoxazepine top
Crystal data top
C24H23ClN4OZ = 4
Mr = 418.91F(000) = 880
Triclinic, P1Dx = 1.322 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 9.9253 (2) ÅCell parameters from 25726 reflections
b = 15.0549 (3) Åθ = 1.5–27.5°
c = 15.9996 (3) ŵ = 0.21 mm1
α = 107.774 (2)°T = 123 K
β = 95.487 (1)°Prismatic, pale yellow
γ = 108.783 (1)°0.30 × 0.25 × 0.20 mm
V = 2104.93 (8) Å3
Data collection top
Nonius KappaCCD
diffractometer
6353 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.084
Graphite monochromatorθmax = 27.5°, θmin = 1.5°
1 deg frames in ϕ and ω scansh = 1212
25726 measured reflectionsk = 1919
9532 independent reflectionsl = 1620
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.055Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.158H-atom parameters constrained
S = 1.00 w = 1/[σ2(Fo2) + (0.086P)2]
where P = (Fo2 + 2Fc2)/3
9532 reflections(Δ/σ)max = 0.002
541 parametersΔρmax = 0.48 e Å3
0 restraintsΔρmin = 0.32 e Å3
Crystal data top
C24H23ClN4Oγ = 108.783 (1)°
Mr = 418.91V = 2104.93 (8) Å3
Triclinic, P1Z = 4
a = 9.9253 (2) ÅMo Kα radiation
b = 15.0549 (3) ŵ = 0.21 mm1
c = 15.9996 (3) ÅT = 123 K
α = 107.774 (2)°0.30 × 0.25 × 0.20 mm
β = 95.487 (1)°
Data collection top
Nonius KappaCCD
diffractometer
6353 reflections with I > 2σ(I)
25726 measured reflectionsRint = 0.084
9532 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0550 restraints
wR(F2) = 0.158H-atom parameters constrained
S = 1.00Δρmax = 0.48 e Å3
9532 reflectionsΔρmin = 0.32 e Å3
541 parameters
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Cl10.43755 (6)1.38055 (4)1.08930 (3)0.03010 (15)
Cl20.12302 (6)0.14811 (4)0.23248 (3)0.03132 (15)
O10.82246 (16)1.34506 (11)0.83292 (9)0.0255 (3)
O20.04349 (15)0.18117 (10)0.58032 (8)0.0248 (3)
N10.55743 (18)1.17733 (13)0.80785 (10)0.0223 (4)
N21.02695 (19)1.32173 (13)0.88624 (11)0.0265 (4)
N30.59265 (18)1.05244 (13)0.69781 (10)0.0245 (4)
N40.47574 (18)0.86689 (13)0.54748 (10)0.0252 (4)
N50.05941 (18)0.35809 (13)0.53319 (10)0.0224 (4)
N60.13408 (19)0.17182 (13)0.67722 (10)0.0245 (4)
N70.10986 (18)0.48198 (12)0.67195 (10)0.0221 (4)
N80.11770 (18)0.67465 (12)0.77966 (10)0.0219 (4)
C10.6055 (2)1.26737 (16)0.88188 (12)0.0217 (4)
C20.5157 (2)1.27768 (16)0.94409 (12)0.0230 (4)
H20.43271.22170.94000.028*
C30.5486 (2)1.36993 (16)1.01146 (12)0.0238 (5)
C40.6674 (2)1.45349 (16)1.01968 (13)0.0279 (5)
H40.68621.51631.06540.034*
C50.7592 (2)1.44418 (16)0.95978 (13)0.0276 (5)
H50.84231.50050.96460.033*
C60.7283 (2)1.35212 (16)0.89302 (12)0.0230 (4)
C70.8879 (2)1.28001 (16)0.84410 (12)0.0228 (4)
C81.0898 (2)1.25901 (17)0.89859 (13)0.0280 (5)
H81.18901.28710.92930.034*
C91.0194 (2)1.15579 (17)0.86940 (12)0.0260 (5)
H91.06891.11450.88000.031*
C100.8740 (2)1.11413 (16)0.82406 (12)0.0226 (4)
H100.82241.04360.80290.027*
C110.8060 (2)1.17713 (15)0.81026 (12)0.0209 (4)
C120.6466 (2)1.13941 (15)0.77075 (12)0.0208 (4)
C130.6737 (2)1.03001 (16)0.62703 (12)0.0262 (5)
H13A0.77971.06290.65300.031*
H13B0.65061.05670.58040.031*
C140.4348 (2)1.00197 (16)0.66368 (14)0.0295 (5)
H14A0.40211.02850.61930.035*
H14B0.38381.01480.71370.035*
C150.6332 (2)0.91819 (16)0.58523 (13)0.0266 (5)
H15A0.68700.90360.53700.032*
H15B0.66170.89240.63130.032*
C160.3981 (2)0.88978 (16)0.61953 (13)0.0277 (5)
H16A0.42380.86300.66550.033*
H16B0.29190.85580.59460.033*
C170.4348 (2)0.75783 (16)0.50652 (13)0.0283 (5)
H17A0.32730.72520.49320.034*
H17B0.47530.73360.55020.034*
C180.4887 (3)0.72652 (17)0.42041 (14)0.0345 (6)
H18A0.44130.74500.37460.041*
H18B0.59510.76340.43230.041*
C190.4567 (2)0.61571 (17)0.38432 (13)0.0270 (5)
C200.5436 (2)0.57522 (18)0.42136 (13)0.0321 (5)
H200.62270.61830.47080.039*
C210.5179 (3)0.47376 (19)0.38809 (15)0.0398 (6)
H210.58090.44820.41330.048*
C220.4013 (3)0.40982 (19)0.31860 (17)0.0458 (7)
H220.38280.33990.29610.055*
C230.3108 (3)0.4477 (2)0.28147 (15)0.0447 (7)
H230.22940.40370.23380.054*
C240.3391 (2)0.55034 (19)0.31401 (14)0.0367 (6)
H240.27730.57600.28780.044*
C250.0493 (2)0.26283 (15)0.47717 (12)0.0209 (4)
C260.0878 (2)0.25284 (16)0.39394 (12)0.0233 (4)
H260.12930.31070.37890.028*
C270.0653 (2)0.15853 (16)0.33345 (12)0.0235 (5)
C280.0012 (2)0.07163 (16)0.35102 (13)0.0251 (5)
H280.01740.00760.30730.030*
C290.0354 (2)0.08040 (16)0.43400 (12)0.0238 (5)
H290.07810.02210.44830.029*
C300.0094 (2)0.17435 (15)0.49555 (12)0.0226 (4)
C310.0867 (2)0.22962 (16)0.64466 (12)0.0225 (4)
C320.2615 (2)0.21837 (17)0.73820 (13)0.0273 (5)
H320.29870.17890.76290.033*
C330.3407 (2)0.32015 (16)0.76676 (12)0.0244 (5)
H330.42990.34970.81000.029*
C340.2875 (2)0.37851 (16)0.73110 (12)0.0222 (4)
H340.33990.44880.74950.027*
C350.1563 (2)0.33270 (15)0.66807 (12)0.0205 (4)
C360.0998 (2)0.38808 (15)0.62012 (12)0.0211 (4)
C370.0757 (2)0.50015 (15)0.76178 (12)0.0235 (5)
H37A0.10460.45670.78950.028*
H37B0.03050.48300.75640.028*
C380.0800 (2)0.54901 (15)0.62959 (12)0.0246 (5)
H38A0.02600.53460.61700.029*
H38B0.11260.53840.57200.029*
C390.1557 (2)0.60878 (15)0.82070 (12)0.0238 (5)
H39A0.12990.62060.88030.029*
H39B0.26210.62460.82950.029*
C400.1610 (2)0.65674 (15)0.69272 (12)0.0230 (4)
H40A0.26720.67150.70230.028*
H40B0.14060.70270.66490.028*
C410.1924 (2)0.78003 (15)0.83789 (12)0.0251 (5)
H41A0.18260.82310.80350.030*
H41B0.29740.79350.85540.030*
C420.1336 (2)0.80871 (16)0.92268 (13)0.0273 (5)
H42A0.03020.79970.90560.033*
H42B0.13790.76330.95560.033*
C430.2189 (2)0.91604 (16)0.98384 (12)0.0245 (5)
C440.3466 (2)0.93923 (17)1.04455 (13)0.0263 (5)
H440.38090.88751.04600.032*
C450.4243 (2)1.03739 (17)1.10308 (13)0.0286 (5)
H450.51021.05201.14490.034*
C460.3771 (2)1.11341 (17)1.10059 (13)0.0313 (5)
H460.43001.18031.14070.038*
C470.2520 (2)1.09162 (17)1.03929 (13)0.0302 (5)
H470.21991.14391.03660.036*
C480.1736 (2)0.99370 (16)0.98195 (13)0.0279 (5)
H480.08730.97940.94060.033*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0300 (3)0.0328 (3)0.0256 (3)0.0151 (2)0.0060 (2)0.0043 (2)
Cl20.0398 (3)0.0298 (3)0.0227 (3)0.0145 (3)0.0059 (2)0.0056 (2)
O10.0273 (8)0.0225 (8)0.0304 (8)0.0101 (7)0.0088 (6)0.0127 (6)
O20.0203 (7)0.0238 (8)0.0245 (7)0.0041 (6)0.0025 (5)0.0060 (6)
N10.0191 (9)0.0228 (10)0.0223 (8)0.0083 (8)0.0006 (6)0.0050 (7)
N20.0218 (9)0.0254 (10)0.0269 (9)0.0048 (8)0.0048 (7)0.0062 (7)
N30.0176 (9)0.0247 (10)0.0246 (9)0.0065 (8)0.0023 (7)0.0020 (7)
N40.0220 (9)0.0218 (10)0.0260 (9)0.0075 (8)0.0031 (7)0.0020 (7)
N50.0236 (9)0.0216 (10)0.0213 (8)0.0098 (8)0.0010 (7)0.0060 (7)
N60.0314 (10)0.0224 (10)0.0240 (9)0.0136 (8)0.0074 (7)0.0100 (7)
N70.0289 (10)0.0198 (9)0.0201 (8)0.0131 (8)0.0030 (7)0.0071 (7)
N80.0252 (9)0.0193 (9)0.0227 (8)0.0101 (8)0.0032 (7)0.0083 (7)
C10.0212 (10)0.0249 (11)0.0203 (10)0.0126 (9)0.0013 (7)0.0073 (8)
C20.0211 (11)0.0236 (11)0.0233 (10)0.0090 (9)0.0012 (8)0.0083 (8)
C30.0265 (11)0.0286 (12)0.0199 (10)0.0161 (10)0.0038 (8)0.0076 (8)
C40.0350 (13)0.0218 (12)0.0249 (11)0.0137 (10)0.0007 (9)0.0042 (8)
C50.0301 (12)0.0199 (11)0.0304 (11)0.0074 (9)0.0017 (9)0.0090 (9)
C60.0237 (11)0.0255 (12)0.0234 (10)0.0125 (9)0.0030 (8)0.0107 (8)
C70.0230 (11)0.0232 (11)0.0226 (10)0.0087 (9)0.0055 (8)0.0086 (8)
C80.0207 (11)0.0389 (14)0.0228 (10)0.0115 (10)0.0030 (8)0.0088 (9)
C90.0236 (11)0.0329 (13)0.0245 (10)0.0143 (10)0.0051 (8)0.0101 (9)
C100.0239 (11)0.0225 (11)0.0213 (10)0.0087 (9)0.0077 (8)0.0068 (8)
C110.0182 (10)0.0226 (11)0.0196 (9)0.0062 (9)0.0036 (7)0.0061 (8)
C120.0187 (10)0.0229 (11)0.0216 (10)0.0078 (9)0.0025 (7)0.0097 (8)
C130.0233 (11)0.0273 (12)0.0226 (10)0.0048 (9)0.0039 (8)0.0067 (9)
C140.0189 (11)0.0278 (13)0.0330 (11)0.0094 (9)0.0001 (8)0.0000 (9)
C150.0211 (11)0.0295 (13)0.0248 (10)0.0084 (9)0.0046 (8)0.0048 (9)
C160.0174 (10)0.0268 (12)0.0308 (11)0.0070 (9)0.0025 (8)0.0017 (9)
C170.0268 (12)0.0231 (12)0.0284 (11)0.0069 (10)0.0066 (9)0.0026 (9)
C180.0446 (15)0.0251 (13)0.0303 (12)0.0113 (11)0.0112 (10)0.0061 (9)
C190.0288 (12)0.0280 (12)0.0220 (10)0.0088 (10)0.0110 (8)0.0061 (9)
C200.0304 (13)0.0361 (14)0.0253 (11)0.0086 (11)0.0085 (9)0.0079 (9)
C210.0511 (16)0.0411 (16)0.0432 (14)0.0258 (13)0.0256 (12)0.0227 (12)
C220.0585 (18)0.0264 (14)0.0490 (15)0.0109 (13)0.0326 (13)0.0077 (11)
C230.0328 (14)0.0386 (16)0.0348 (13)0.0027 (12)0.0079 (10)0.0077 (11)
C240.0261 (12)0.0428 (15)0.0320 (12)0.0101 (11)0.0045 (9)0.0044 (10)
C250.0196 (10)0.0216 (11)0.0201 (10)0.0096 (9)0.0023 (7)0.0053 (8)
C260.0236 (11)0.0228 (11)0.0232 (10)0.0093 (9)0.0008 (8)0.0088 (8)
C270.0254 (11)0.0282 (12)0.0165 (9)0.0128 (9)0.0002 (8)0.0057 (8)
C280.0262 (11)0.0209 (11)0.0237 (10)0.0108 (9)0.0023 (8)0.0021 (8)
C290.0189 (10)0.0201 (11)0.0268 (11)0.0039 (9)0.0033 (8)0.0068 (8)
C300.0193 (10)0.0248 (12)0.0208 (10)0.0080 (9)0.0007 (7)0.0057 (8)
C310.0227 (11)0.0250 (12)0.0197 (10)0.0094 (9)0.0061 (8)0.0070 (8)
C320.0337 (12)0.0309 (13)0.0257 (11)0.0193 (10)0.0081 (9)0.0132 (9)
C330.0222 (11)0.0309 (12)0.0226 (10)0.0119 (9)0.0037 (8)0.0110 (9)
C340.0223 (11)0.0237 (11)0.0203 (10)0.0086 (9)0.0056 (8)0.0073 (8)
C350.0211 (10)0.0215 (11)0.0209 (10)0.0097 (9)0.0057 (7)0.0080 (8)
C360.0171 (10)0.0214 (11)0.0240 (10)0.0067 (9)0.0029 (7)0.0079 (8)
C370.0273 (11)0.0219 (11)0.0251 (10)0.0120 (9)0.0087 (8)0.0097 (8)
C380.0321 (12)0.0222 (11)0.0207 (10)0.0137 (10)0.0005 (8)0.0072 (8)
C390.0276 (11)0.0241 (12)0.0210 (10)0.0120 (9)0.0048 (8)0.0073 (8)
C400.0272 (11)0.0234 (11)0.0211 (10)0.0117 (9)0.0047 (8)0.0093 (8)
C410.0273 (12)0.0214 (11)0.0257 (10)0.0091 (9)0.0040 (8)0.0075 (8)
C420.0294 (12)0.0228 (12)0.0272 (11)0.0085 (10)0.0074 (8)0.0062 (9)
C430.0273 (12)0.0263 (12)0.0206 (10)0.0111 (10)0.0078 (8)0.0074 (8)
C440.0285 (12)0.0297 (13)0.0278 (11)0.0144 (10)0.0100 (8)0.0146 (9)
C450.0247 (12)0.0361 (14)0.0237 (10)0.0091 (10)0.0051 (8)0.0112 (9)
C460.0299 (13)0.0275 (13)0.0290 (11)0.0078 (10)0.0084 (9)0.0026 (9)
C470.0346 (13)0.0259 (12)0.0301 (11)0.0152 (10)0.0064 (9)0.0059 (9)
C480.0292 (12)0.0265 (12)0.0273 (11)0.0122 (10)0.0030 (8)0.0077 (9)
Geometric parameters (Å, º) top
Cl1—C31.745 (2)C18—H18A0.9900
Cl2—C271.7442 (19)C18—H18B0.9900
O1—C71.381 (2)C19—C201.388 (3)
O1—C61.408 (2)C19—C241.389 (3)
O2—C311.393 (2)C20—C211.381 (3)
O2—C301.410 (2)C20—H200.9500
N1—C121.297 (3)C21—C221.373 (4)
N1—C11.401 (2)C21—H210.9500
N2—C71.326 (3)C22—C231.386 (4)
N2—C81.338 (3)C22—H220.9500
N3—C121.363 (2)C23—C241.392 (3)
N3—C141.466 (3)C23—H230.9500
N3—C131.469 (2)C24—H240.9500
N4—C161.463 (2)C25—C261.398 (3)
N4—C171.467 (3)C25—C301.405 (3)
N4—C151.470 (3)C26—C271.385 (3)
N5—C361.301 (2)C26—H260.9500
N5—C251.406 (2)C27—C281.385 (3)
N6—C311.320 (3)C28—C291.389 (3)
N6—C321.348 (3)C28—H280.9500
N7—C361.369 (3)C29—C301.379 (3)
N7—C381.462 (3)C29—H290.9500
N7—C371.472 (2)C31—C351.390 (3)
N8—C411.464 (2)C32—C331.380 (3)
N8—C391.466 (3)C32—H320.9500
N8—C401.467 (2)C33—C341.387 (3)
C1—C61.402 (3)C33—H330.9500
C1—C21.405 (3)C34—C351.391 (3)
C2—C31.387 (3)C34—H340.9500
C2—H20.9500C35—C361.486 (3)
C3—C41.380 (3)C37—C391.508 (3)
C4—C51.391 (3)C37—H37A0.9900
C4—H40.9500C37—H37B0.9900
C5—C61.384 (3)C38—C401.517 (3)
C5—H50.9500C38—H38A0.9900
C7—C111.395 (3)C38—H38B0.9900
C8—C91.384 (3)C39—H39A0.9900
C8—H80.9500C39—H39B0.9900
C9—C101.393 (3)C40—H40A0.9900
C9—H90.9500C40—H40B0.9900
C10—C111.384 (3)C41—C421.524 (3)
C10—H100.9500C41—H41A0.9900
C11—C121.495 (3)C41—H41B0.9900
C13—C151.506 (3)C42—C431.510 (3)
C13—H13A0.9900C42—H42A0.9900
C13—H13B0.9900C42—H42B0.9900
C14—C161.520 (3)C43—C481.388 (3)
C14—H14A0.9900C43—C441.394 (3)
C14—H14B0.9900C44—C451.392 (3)
C15—H15A0.9900C44—H440.9500
C15—H15B0.9900C45—C461.379 (3)
C16—H16A0.9900C45—H450.9500
C16—H16B0.9900C46—C471.386 (3)
C17—C181.521 (3)C46—H460.9500
C17—H17A0.9900C47—C481.385 (3)
C17—H17B0.9900C47—H470.9500
C18—C191.501 (3)C48—H480.9500
C7—O1—C6108.51 (15)C21—C22—C23119.7 (2)
C31—O2—C30107.85 (14)C21—C22—H22120.1
C12—N1—C1122.45 (17)C23—C22—H22120.1
C7—N2—C8116.26 (19)C22—C23—C24120.0 (2)
C12—N3—C14119.65 (17)C22—C23—H23120.0
C12—N3—C13122.36 (17)C24—C23—H23120.0
C14—N3—C13111.97 (15)C19—C24—C23120.8 (2)
C16—N4—C17109.81 (16)C19—C24—H24119.6
C16—N4—C15108.62 (15)C23—C24—H24119.6
C17—N4—C15111.58 (17)C26—C25—C30117.01 (18)
C36—N5—C25121.46 (18)C26—C25—N5118.53 (18)
C31—N6—C32116.07 (18)C30—C25—N5124.21 (17)
C36—N7—C38120.12 (15)C27—C26—C25119.9 (2)
C36—N7—C37120.21 (17)C27—C26—H26120.0
C38—N7—C37112.65 (16)C25—C26—H26120.0
C41—N8—C39110.58 (15)C26—C27—C28122.30 (19)
C41—N8—C40110.43 (16)C26—C27—Cl2119.27 (17)
C39—N8—C40107.81 (16)C28—C27—Cl2118.42 (15)
N1—C1—C6124.50 (18)C27—C28—C29118.42 (18)
N1—C1—C2117.77 (18)C27—C28—H28120.8
C6—C1—C2117.31 (18)C29—C28—H28120.8
C3—C2—C1119.8 (2)C30—C29—C28119.5 (2)
C3—C2—H2120.1C30—C29—H29120.3
C1—C2—H2120.1C28—C29—H29120.3
C4—C3—C2122.16 (19)C29—C30—C25122.73 (18)
C4—C3—Cl1118.81 (15)C29—C30—O2118.25 (18)
C2—C3—Cl1119.03 (17)C25—C30—O2119.02 (17)
C3—C4—C5118.86 (19)N6—C31—C35125.67 (19)
C3—C4—H4120.6N6—C31—O2116.04 (18)
C5—C4—H4120.6C35—C31—O2118.28 (18)
C6—C5—C4119.4 (2)N6—C32—C33123.6 (2)
C6—C5—H5120.3N6—C32—H32118.2
C4—C5—H5120.3C33—C32—H32118.2
C5—C6—C1122.44 (19)C32—C33—C34118.69 (19)
C5—C6—O1118.19 (19)C32—C33—H33120.7
C1—C6—O1119.34 (17)C34—C33—H33120.7
N2—C7—O1116.16 (19)C33—C34—C35119.05 (19)
N2—C7—C11125.0 (2)C33—C34—H34120.5
O1—C7—C11118.86 (18)C35—C34—H34120.5
N2—C8—C9124.1 (2)C31—C35—C34116.89 (19)
N2—C8—H8117.9C31—C35—C36120.65 (17)
C9—C8—H8117.9C34—C35—C36122.14 (19)
C8—C9—C10118.2 (2)N5—C36—N7119.44 (19)
C8—C9—H9120.9N5—C36—C35124.18 (18)
C10—C9—H9120.9N7—C36—C35115.85 (16)
C11—C10—C9119.0 (2)N7—C37—C39110.22 (16)
C11—C10—H10120.5N7—C37—H37A109.6
C9—C10—H10120.5C39—C37—H37A109.6
C10—C11—C7117.41 (18)N7—C37—H37B109.6
C10—C11—C12122.08 (19)C39—C37—H37B109.6
C7—C11—C12120.12 (19)H37A—C37—H37B108.1
N1—C12—N3119.41 (18)N7—C38—C40108.73 (15)
N1—C12—C11123.82 (17)N7—C38—H38A109.9
N3—C12—C11116.22 (17)C40—C38—H38A109.9
N3—C13—C15109.85 (17)N7—C38—H38B109.9
N3—C13—H13A109.7C40—C38—H38B109.9
C15—C13—H13A109.7H38A—C38—H38B108.3
N3—C13—H13B109.7N8—C39—C37110.54 (16)
C15—C13—H13B109.7N8—C39—H39A109.5
H13A—C13—H13B108.2C37—C39—H39A109.5
N3—C14—C16109.06 (17)N8—C39—H39B109.5
N3—C14—H14A109.9C37—C39—H39B109.5
C16—C14—H14A109.9H39A—C39—H39B108.1
N3—C14—H14B109.9N8—C40—C38111.45 (16)
C16—C14—H14B109.9N8—C40—H40A109.3
H14A—C14—H14B108.3C38—C40—H40A109.3
N4—C15—C13111.03 (18)N8—C40—H40B109.3
N4—C15—H15A109.4C38—C40—H40B109.3
C13—C15—H15A109.4H40A—C40—H40B108.0
N4—C15—H15B109.4N8—C41—C42113.44 (17)
C13—C15—H15B109.4N8—C41—H41A108.9
H15A—C15—H15B108.0C42—C41—H41A108.9
N4—C16—C14112.14 (18)N8—C41—H41B108.9
N4—C16—H16A109.2C42—C41—H41B108.9
C14—C16—H16A109.2H41A—C41—H41B107.7
N4—C16—H16B109.2C43—C42—C41112.03 (17)
C14—C16—H16B109.2C43—C42—H42A109.2
H16A—C16—H16B107.9C41—C42—H42A109.2
N4—C17—C18113.11 (18)C43—C42—H42B109.2
N4—C17—H17A109.0C41—C42—H42B109.2
C18—C17—H17A109.0H42A—C42—H42B107.9
N4—C17—H17B109.0C48—C43—C44118.2 (2)
C18—C17—H17B109.0C48—C43—C42121.78 (19)
H17A—C17—H17B107.8C44—C43—C42120.0 (2)
C19—C18—C17111.98 (18)C45—C44—C43120.7 (2)
C19—C18—H18A109.2C45—C44—H44119.7
C17—C18—H18A109.2C43—C44—H44119.7
C19—C18—H18B109.2C46—C45—C44120.2 (2)
C17—C18—H18B109.2C46—C45—H45119.9
H18A—C18—H18B107.9C44—C45—H45119.9
C20—C19—C24117.9 (2)C45—C46—C47119.6 (2)
C20—C19—C18120.6 (2)C45—C46—H46120.2
C24—C19—C18121.5 (2)C47—C46—H46120.2
C21—C20—C19121.6 (2)C48—C47—C46120.1 (2)
C21—C20—H20119.2C48—C47—H47119.9
C19—C20—H20119.2C46—C47—H47119.9
C22—C21—C20120.0 (3)C47—C48—C43121.1 (2)
C22—C21—H21120.0C47—C48—H48119.4
C20—C21—H21120.0C43—C48—H48119.4

Experimental details

Crystal data
Chemical formulaC24H23ClN4O
Mr418.91
Crystal system, space groupTriclinic, P1
Temperature (K)123
a, b, c (Å)9.9253 (2), 15.0549 (3), 15.9996 (3)
α, β, γ (°)107.774 (2), 95.487 (1), 108.783 (1)
V3)2104.93 (8)
Z4
Radiation typeMo Kα
µ (mm1)0.21
Crystal size (mm)0.30 × 0.25 × 0.20
Data collection
DiffractometerNonius KappaCCD
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
25726, 9532, 6353
Rint0.084
(sin θ/λ)max1)0.650
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.055, 0.158, 1.00
No. of reflections9532
No. of parameters541
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.48, 0.32

Computer programs: COLLECT (Bruker, 2000), DENZO-SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), X-SEED (Barbour, 2001), CIFTAB (Sheldrick, 2008).

 

Acknowledgements

We acknowledge support from Monash University and the Australian Research Council

References

First citationAndreasen, N. C. (2000). Brain Res. Brain Res. Rev. 31, 106–112.  Web of Science CrossRef PubMed CAS Google Scholar
First citationAndreasen, N. C., Nopoulos, P., Schultz, S., Miller, D., Gupta, S., Swayze, V. & Flaum, M. (1994). Acta Psychiatr. Scand. Suppl. 384, 51–59.  CrossRef CAS PubMed Web of Science Google Scholar
First citationBarbour, L. J. (2001). J. Supramol. Chem. 1, 189–191.  CrossRef CAS Google Scholar
First citationBruker (2000). COLLECT. Bruker AXS BV, Delft, The Netherlands.  Google Scholar
First citationCapuano, B. (1999). Molecules, 4, 329-332.  Web of Science CrossRef CAS Google Scholar
First citationCapuano, B., Crosby, I. T., Forsyth, C. M., Lloyd, E. J., Vom, A. & Yuriev, E. (2006). Acta Cryst. E62, o5434–o5436.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationCapuano, B., Crosby, I. T., Lloyd, E. J. & Taylor, D. A. (2002). Aust. J. Chem. 55, 565–576.  Web of Science CrossRef CAS Google Scholar
First citationCapuano, B., Crosby, I. T., Lloyd, E. J. & Taylor, D. A. (2003). Aust. J. Chem. 56, 875–886.  Web of Science CrossRef CAS Google Scholar
First citationDupont, L. & Liégeois, J.-F. (2003). Acta Cryst. E59, o1962–o1963.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationGerlach, J. (1991). Schizophr. Bull. 17, 289–309.  CrossRef PubMed CAS Web of Science Google Scholar
First citationGerson, S. L. & Meltzer, H. (1992). Drug Safety, 7 (Suppl. 1), 17–25.  Google Scholar
First citationLiégeois, J.-F., Mouithys-Mickalad, A., Bruhwyler, J., Petit, C., Kauffmann, J. M. & Lamy, M. (1997). Biochem. Biophys. Res. Commun. 238, 252–255.  PubMed Web of Science Google Scholar
First citationLiégeois, J.-F., Rogistert, F. A., Bruhwyler, J., Damas, J., Nguyen, T. P., Inarejos, M.-O., Chleide, E. M. G., Mercier, M. G. A. & Delarget, J. E. (1994). J. Med. Chem. 37, 519–525.  CrossRef CAS PubMed Web of Science Google Scholar
First citationLiégeois, J.-F., Zahid, N., Bruhwyler, J. & Uetrecht, J. (2000). Arch. Pharm. Wienheim, Ger. 333, 63–67.  Google Scholar
First citationMouithys-Mickalad, A., Kauffmann, J. M., Petit, C., Bruhwyler, J., Liao, Y., Wikstrom, H., Damas, J., Delarge, J., Deby-Dupont, G., Geczy, J. & Liegeois, J.-F. (2001). J. Med. Chem. 44, 769–776.  Web of Science CrossRef PubMed CAS Google Scholar
First citationOtwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.  Google Scholar
First citationPetcher, T. J. & Weber, H.-P. (1976). J. Chem. Soc. Perkin Trans. 2, pp. 1415–1420.  CSD CrossRef Web of Science Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationVom, A. (2006). Honours Thesis, Monash University (Parkville), Victoria, Australia.  Google Scholar

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Volume 64| Part 10| October 2008| Pages o1865-o1866
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