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

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.

As part of an antipsychotic drug discovery program, we report the crystal structure of the title compound, C 24 H 23 ClN 4 O. 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 2phenyl-ethyl substituent assuming an equatorial orientation. There are two crystallographically independent, but virtually identical, molecules in the asymmetric unit.
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(Capuano et al., , 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)-11Hpyrido[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 sevenmembered 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 supplementary materials sup-2 assuming an equatorial orientation, by virtue of the sp 2 -like nature of the piperazine nitrogen atoms. No significant interactions between molecules of the title compound were observed.

Experimental
The title compound (I) was synthesized (Vom, 2006) (Liegeois et al., 1994), and the monosubstituted piperazine, 1-phenethylpiperazine (Capuano et al., 2003), in the presence of a Lewis acid, (TiCl 4 ). 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 ν max 1599, 1583,

Refinement
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 U iso (H) = 1.2-1.5 U eq (C). Fig. 1. Molecular diagram of one of the crystallographically independent molecules of the title compound. Displacement ellipsoids are drawn at the 50% probability level.