Redetermination of loperamide monohydrate

The structure of the title compound {systematic name: 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide monohydrate}, C29H33ClN2O2·H2O, has been redetermined at 170 (2) K. The redetermination is of significantly higher precision than the previous structure determination at room temperature and includes the H-atom coordinates that were not included in the previous report [Germain et al. (1977 ▶). Acta Cryst. B33, 942–944]. It consists of a piperidin-1-yl ring in a distorted chair conformation, with the N,N-dimethyl-α,α-diphenylbutyramide and the 4-chlorophenyl and hydroxy groups bonded in para positions and an external water molecule within the asymmetric unit. The dihedral angles between the mean plane of the piperidine ring and the 4-chlorophenyl and two benzene rings are 83.4 (5), 76.4 (2) and 85.9 (2)°, respectively. The two benzene rings are inclined to one another by 50.8 (6)°. In the crystal, molecules are linked by O—H⋯O and O—H⋯N hydrogen bonds and weak C—H⋯O intermolecular interactions, forming an infinite two-dimensional network along [110].

The structure of the title compound {systematic name: 4-[4-(4chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide monohydrate}, C 29 H 33 ClN 2 O 2 ÁH 2 O, has been redetermined at 170 (2) K. The redetermination is of significantly higher precision than the previous structure determination at room temperature and includes the H-atom coordinates that were not included in the previous report [Germain et al. (1977). Acta Cryst. B33, [942][943][944]. It consists of a piperidin-1-yl ring in a distorted chair conformation, with the N,N-dimethyl-,-diphenylbutyramide and the 4-chlorophenyl and hydroxy groups bonded in para positions and an external water molecule within the asymmetric unit. The dihedral angles between the mean plane of the piperidine ring and the 4-chlorophenyl and two benzene rings are 83.4 (5), 76.4 (2) and 85.9 (2) , respectively. The two benzene rings are inclined to one another by 50.8 (6) . In the crystal, molecules are linked by O-HÁ Á ÁO and O-HÁ Á ÁN hydrogen bonds and weak C-HÁ Á ÁO intermolecular interactions, forming an infinite two-dimensional network along [110].
ASD and HSY thank the University of Mysore for research facilities and R. L. Fine Chem, Bangalore, India, for the gift sample. JPJ acknowledges the NSF-MRI program (grant No. CHE1039027) for funds to purchase the X-ray diffractometer.

Comment
Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Loperamide is a synthetic piperidine derivative, an opioid drug effective against diarrhea resulting from gastroenteritis or inflammatory bowel disease. Loperamide is an opioid-receptor agonist and acts on the µ-opioid receptors in the myenteric plexus of the large intestine; by itself it does not affect the central nervous system like other opioids. A review of its pharmacological properties and therapeutic efficacy in diarrhoea is reported (Heel et al., 1978). The crystal structures of loperamide hydrochloride tetrahydrate (Caira et al., 1995) and loperamide N-oxide hydrate (Peeters et al., 1996) have been reported. The crystal structure of the title compound was first reported [Germain, et al. (1977) Acta Cryst. B33, 942-944] with an R value of 9% at room temperature. The present paper is a redetermination of the title compound,  (Table 1) forming an infinite 2-D network along [110].

Experimental
The title compound was obtained as a gift sample from R. L. Fine Chem, Bangalore. X-ray quality crystals were obtained by slow evaporation of dimethylformamide solution (m.p.: 403-407 K).

Refinement
H1w, H2w and H2O were located by a difference map and refined isotropically. Ow1 with H1w and H2w were set to DFIX = 0.85 (2)Å, while Hw1 and Hw2 were set to 1.35 (2)Å. H20 with O2 was set to 0.82 (2)Å. All of the remaining H atoms were placed in their calculated positions and then refined using the riding model with Atom-H lengths of 0.93Å (CH), 0.96Å (CH 2 ) or 0.97Å (CH 3 ). Isotropic displacement parameters for these atoms were set to 1.18-1.21 (CH, CH 2 ) or 1.49-1.50 (CH 3 ) times U eq of the parent atom.

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.
Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.