l-Nebiviololinium chloride dihydrate

The hydrochloride salt of chiral l-nebivolol {systematic name: (+)−(R,S,S,S)-bis[2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl]ammonium chloride dihydrate}, C22H26F2NO4 +·Cl−·2H2O, was obtained by chiral liquid chromatography as a dihydrate. The pyran rings adopt half-chair conformations. Hydrogen bonds between the cation, anions and water molecules contribute to the formation of layers parallel to the ac plane.


S1. Comment
L-Nebivolol is one enantiomer of the active pharmaceutical ingredient DL-nebivolol. DL-Nebivolol is a β-blocker of the third generation exhibiting a unique activity profile (van Lommen, et al., 1990). Here we report the title compound, (I), the hydrochloride salt of L-nebivolol, obtained by chiral liquid chromatography.
The overall shape of the cation in (I) is strongly influenced by the conformation of the bridging C-C-N-C-C chain between the two benzopyran moieties. This conformation is stabilized by two intramolecular N-H···O hydrogen bonds, depicted in Figure 1. Two non-classical C-H···O intramolecular hydrogen bonds align the torsion angles C2-C3-C5 -O6 and C2′-C3′-C5′-O6′ in a synclinal (sc) arrangement. The length of the bridging chain defined by the distance between the carbon atoms C5 and C5′ amounts to 7.434 (2) Å. O6 and O6′ are in cis-position. The average C-N, C-C and C-O distances in the title compound ( Fig. 1) are in good agreement with those in other nebivolol derivatives (Peeters et al., 1993;Tuchalski et al., 2006). Figure 2 shows the packing in (I). Like in the other nebivolol isomers the molecular packing of l-nebivolol is directed by classical intermolecular hydrogen bonds. Nine unique hydrogen bonds between nitrogen and hydroxyl groups, nitrogen and water molecules, hydroxyl groups and water molecules, hydroxyl groups and chlorine as well as between water and chlorine can be observed (Table 1). Together, these result in layers propagating in (010).

S2. Experimental
The title compound was synthesized by a subsequent ring-opening addition reaction (Cini et al., 1990) of two different oxiran isomers with benzylamine leading to the individual benzyl-nebivolol isomers endowed with 4 chiral centers. The L-nebivolol isomer was isolated after hydrogenation and preparative chiral chromatography as its corresponding hydrochloride.
Colourless needles of (I) were grown by solvent evaporation from ethanol/ethyl acetate (1:1 v/v) at room temperature.

S3. Refinement
The water H atoms were located in a difference map and their positions were freely refined with U iso (H) = 1.5U eq (O).
The other hydrogen atoms were located in difference maps, repositioned with idealized geometry (C-H = 0.93-0.97 Å, N-H = 0.89 Å, O-H = 0.82 Å) and refined as riding with U iso (H) = 1.2U eq (parent atom).  View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms.

Figure 2
View of the layers array of (I), formed via hydrogen-bonding interactions (indicated by green lines).  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.