(S,S,S,S)-Nebivolol hydrochloride hemihydrate

The asymmetric unit of the title hydrated salt, C22H26F2NO4 +·Cl−·0.5H2O, consists of an (S,S,S,S)-nebivolol {nebivol = bis[2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl]ammonium} cation, a chloride anion and a half-occupancy water molecule. The dihedral angle between the mean planes of the benzene rings is 50.34 (12)°. The pyran rings adopt half-chair conformations. The crystal packing features O—H⋯O hydrogen bonds and weak N—H⋯Cl, O—H⋯Cl, and O—H⋯Cl interactions, producing layers along (010).


supplementary materials
The title compound is a salt consisting of a (S,S,S,S)-bis[2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl] ammonium cation, a chloride anion and a water molecule in the asymmetric unit (Fig. 1). The general shape of the cation is strongly influenced by the conformation of the diethylamine chain between the two fluorochroman moieties. The dihedral angle between the mean planes of the two aromatic benzene rings is 50.34 (12)°. Each of the two benzopyran moieties are non-coplanar. The two pyran rings adopt half-chair conformations with total puckering amplitutdes Q T of 0.480 (4) (with Θ = 50.5 (5)° and φ = 265.7 (6)°) and 0.489 (4) (with Θ = 129.5 (5)° and φ = 263.4 (6)°), respectively (Cremer & Pople, (1975)  Preparation of single cristal of (S,S,S,S)-nebivolol hydrochloride was performed according to procedure described by Tuchalski et al. for (R,R,R,R)-nebivolol isomer. The crude product was dissolved at 60 °C in a mixture of ethanol and ethyl acetate (1: 1). The clear solution slowly cooled down to room temperature and the solution left to stand at this temperature. The formation of crystals suitable for X-ray analysis was observed after 8 days. Elemental analysis for (S,S,S,S)-Nebivolol hydrochloride + 2 H 2 O, calcd %C 55.29 %H 6.33 %N 2.93, found %C 55.62 %H 6.48 %N 3.52.

Refinement
The site occupancy factor of the water molecule O5 was refined to close to 0.5. The occupancy was then fixed at 0.5.
The geometric parameters of water molecule were restrained by using DFIX restraints. The O-H and H-H distance were restrained to 0.96 (2) Å and 1.50 (2) Å respectively. These distances have been taken from a semi-empirical sup-2 . E68, o3352 geometry calculation using MOPAC2009 program (Stewart, 2009) to optimize the molecule with the Austin Model 1 (AM1) approximation All H atoms, on carbon atoms, were placed at calculated positions using a riding model with C-H = 0.95 Å (aromatic), 0.99 Å (methylene) or 1 Å (methine) with U iso (H) = 1.2U eq (C). H atoms on nitrogen atoms and water molecule were located in the Fourier difference maps. Their positional parameters were either refined freely with U iso (H) = 1.5U eq (N) or TWIN/BASF refinement type was used to determine absolute configuration from anomalous scattering using the Flack method.

Figure 1
View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms.   Synthesis of the title compound, (I).

Special details
Experimental. The X-ray, mass spectrometry and NMR analyzes was recorded in the "Pôle Chimie Moléculaire", the technological platform for chemical analysis and molecular synthesis (http://www.wpcm.fr) which relies on the Institute of the Molecular Chemistry of University of Burgundy and Welience"TM", a Burgundy University private subsidiary. The analytical results concerning identity (NMR and optical rotation) and purity (HPLC and chiral HPLC) are listed below. 1 H and 13 C NMR measurements were performed in deuterated DMSO on Bruker Avance III, recorded at 500 MHz and 125 MHz, respectively. DMSO-d6 has been used as internal reference. Chemical shifts (δ) and coupling constants are reported respectively in p.p.m. and hertz (Hz).The optical rotation was measured using a UV Visible Perkin Elmer Lambda 12, polarimeter at 589 nm. High-resolution mass spectrometry (HRMS) was performed in ESI a positive mode. The infrared spectrum (IR) was generated by ATR using a Spectrometer Infrared Avatar 370. A scan range of 4000 -400 cm -1 was used. 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 > σ(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.