Crystal structure of levomepromazine maleate

In the crystal, enantiomerically pure (S)-3-(2-methoxyphenothiazin-10-yl)-N,N,2-trimethylpropanaminium hydrogen maleate, also known as levomepromazine maleate, forms a three-dimensional supramolecular network through N—H⋯O, C—H⋯O and C—H⋯π interactions. The asymmetric unit comprises two slightly conformationally different levomepromazine cations and two hydrogen maleate anions.


Chemical context
Levomepromazine maleate is a type of tranquilizer that is widely used as an important active pharmaceutical ingredient (API). As a typical N-substituted phenothiazine antipsychotic, this API is able to block a variety of receptors. For example, levomepromazine is used for treating schizophrenia (Froimowitz & Cody, 1993). The levomepromazine molecule is chiral and the (R)-(À) enantiomer is the medically active form. It is worth noting that the neutral (R)-levomepromazine molecule corresponds to the (S)-levomepromazine cation formed by protonation of its tertiary amino group, according to the Cahn-Ingold-Prelog (CIP) convention. The crystal structure of neutral (R)-levomepromazine has been reported previously, including the determination of its absolute configuration (Sato et al.). As (R)-levomepromazine is generally sold in the form of its maleate salt, we report here the crystal structure of this compound and compare the conformation of neutral levomepromazine with those of its cationic forms.

Structural commentary
The asymmetric unit of the title compound comprises two levomepromazine cations and two hydrogen maleate anions ISSN 2056-9890 ( Fig. 1). The nitrogen atoms N18 and N48 are protonated, thus the cations contain a tertiary amine group. The main difference in the cationic structures results from the different orientation of the methoxy substituent of the phenothiazine ring system, as illustrated in Fig. 2a where superposition of the two cations is presented. The root-mean-square deviation measuring the average distance between the atoms of the superimposed molecules is 0.509 Å and the maximum distance between the methoxy carbon atoms is 2.980 (4) Å . The phenothiazine groups are similarly bent along the N-S line with dihedral angles between the benzene rings of 42.51 (17) and 43.71 (18) ; these values are close to the analogous dihedral angles in the neutral levomepromazine molecule [41.24 at room temperature (MPZPAM; Sato et al., 1980) and 43.09 at 121 K (Dahl et al., 1982)].
The conformation of the investigated levomepromazine hydrogen maleate salt was compared with that of neutral levomepromazin (MPZPAM) and with the closely related compound 3-(2-methoxy-10-phenothiazinyl)-N,N-dimethylpropanaminium hydrogen maleate, in which the propyl side chain is non-methylated (MAPTML10; Marsau & Gauthier, 1973) (see Fig. 2b). Molecules MPZPAM and MAPTML10 were inverted to obtain the same conformation for the phenothiazine rings (which resulted in the opposite enantiomer for MPZPAM). It can be seen that the main difference is in the torsion angle around the N10-C15 bond and the conformation of the side chain. For MPZPAM, the phenothiazine ring could be fully superimposed with the phenothiazine ring of the title compound, but the propyl side chains differ in the configuration and orientation of their aminomethyl groups. In the non-methylated derivative MAPTML10, the heterocyclic ring system is significantly closer to being flat (the dihedral angle between the benzene rings is 21.74 ), while the aliphatic chain bends to the opposite site of the phenothiazine ring in comparison with the title compound.
The planar structure of the hydrogen maleate anions is stabilized by very strong intramolecular O-HÁ Á ÁO hydrogen bonds between the carboxylic and carboxylate groups, as is often observed for these anions (Table 1, Fig. 3).

Supramolecular features
The crystal structure of the title compound features strong N-HÁ Á ÁO hydrogen bonds and several weak C-HÁ Á ÁO interactions ( The molecular structure of the title compound, showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The asymmetric unit contains two organic salt molecules. H atoms have been omitted for clarity.

Figure 2
Conformational comparison of (a) the two levomepromazine molecules in the asymmetric unit of the title structure, and (b) one of the levomepromazines from the title structure (gray) compared with neutral dimorphic levomepromazine (green, MPZPAM) as well as the nonmethylated derivative (purple, MAPTML10). Table 1 Hydrogen-bond geometry (Å , ).
with the protonated amino groups of the levomepromazine cations by strong N-HÁ Á ÁO interactions (Fig. 3). The methoxy groups of the levomepromazine cations differ in their intermolecular interactions. In one, the methoxy methyl group is involved in a C-HÁ Á Á interaction to the aromatic ring of a neighbouring levomepromazine cation [C23-H23CÁ Á ÁCg(C31-C36), Table 1]. The same methyl group forms an additional hydrogen bond to a methoxy O atom of the other symmetry-independent levomepromazine cation (C23-H23AÁ Á ÁO52, Fig. 4). There are numerous C-HÁ Á ÁO interactions between the hydrogen maleate anions and the levomepromazine C-H groups, assisting the assembly of the crystal components in the bc plane (Table 1, Fig. 4).

Synthesis and crystallization
The title compound was obtained from EGIS Pharmaceuticals Private Limited Company and used without further purification. The compound was enantiomerically pure, its melting point is 457-459 K. Colorless single crystals were obtained by slow evaporation of the solvent from an ethyl acetate solution over one week. Crystal packing along the bc plane showing the N-HÁ Á ÁO and C-HÁ Á ÁO interactions as turquoise lines.

Figure 3
The view of the columnar structure arrangement extending along the a axis showing the C-HÁ Á ÁO and C-HÁ Á Á interactions as turquoise lines.

Refinement
Crystal data, data collection and details of the structure refinement are summarized in Table 2. The 13 missing reflections were found to be obstructed by the beamstop. All H atoms were located in difference electron-density maps. Hydrogen atoms were included in the structure-factor calculations but they were not refined; their positions were calculated with C-H = 0.95-1.00 Å and they were allowed to ride on their parent atoms, with U iso (H) = 1.2U eq (C) for aromatic, methylene and methine and U iso (H) = 1.5U eq (C) for methyl protons. The absolute configuration around the C16 and C46 atoms in the title compound ( Fig. 1) were determined to be S from anomalous dispersion effects.   et al., 2006) and PLATON (Spek, 2009).

(-)-(S)-3-(2-Methoxyphenothiazin-10-yl)-N,N,2-trimethylpropanaminium hydrogen maleate
Crystal data Special details 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.