A triclinic polymorph of (−)-(S)-N-benzyl-2-[(R)-6-fluorochroman-2-yl]-2-hydroxyethanaminium bromide

The title salt, C18H21FNO2 +·Br−, determined at 115 K, crystallizes in the triclinic space group P1. The previously reported polymorph occurs in the monoclinic space group P21 and has two independent molecules in the asymmetric unit [Peeters et al. (1993 ▶). Acta Cryst. C49, 2157–2160]. In the title molecule, the pyran rings adopt half-chair conformations. The absolute configuration is S for the hydroxy-bearing C atom and R for the asymmetric C atom in the dihydropyran unit. In the crystal, the components are linked by N—H⋯Br and O—H⋯Br hydrogen bonds, forming chains along the c-axis direction. The crystal studied was refined as an inversion twin.

The title salt, C 18 H 21 FNO 2 + ÁBr À , determined at 115 K, crystallizes in the triclinic space group P1. The previously reported polymorph occurs in the monoclinic space group P2 1 and has two independent molecules in the asymmetric unit [Peeters et al. (1993). Acta Cryst. C49, 2157-2160]. In the title molecule, the pyran rings adopt half-chair conformations. The absolute configuration is S for the hydroxy-bearing C atom and R for the asymmetric C atom in the dihydropyran unit. In the crystal, the components are linked by N-HÁ Á ÁBr and O-HÁ Á ÁBr hydrogen bonds, forming chains along the c-axis direction. The crystal studied was refined as an inversion twin.
We thank Ms Marie-Jose Penouilh for the NMR spectra and for ESI mass spectra.

Introduction
The asymmetric unit of title compound is a key building block for the synthesis of dl-nebivolol. This active pharmaceutical ingredient is a highly cardioselective vasodilatory β-receptor blocker used in treatment of hypertension.
The chemical structure of nebivolol contains four asymmetric carbon atoms (chiral centers), the combination of all the centers results in 16 theoretical isomers and the total number of isomeric structures is reduced to 10 due to the symmetry plane through the N atom of the molecule. All isomeric structures are currently known (Tuchalski et al. (2006), Rousselin et al. (2012). This paper confirms absolute configuration of one possible amino intermediate formed during the synthesis of dl-nebivolol. This structure is a polymorphic form (Bernstein, 2002) of a previous structure determined by Peeters et al. (1993).
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.
1H and 13C NMR measurements were performed in deuterated DMSO on Bruker Avance III, recorded at 300 MHz and 75.5 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
Crystal data, data collection and structure refinement details are summarized in Table 1 TWIN/BASF refinement type was used to determine absolute configuration from anomalous scattering using the Flack method.

Results and discussion
The asymmetric unit of the title compound, C 18 H 21 FNO 2 + .Br -, contains one molecule. Contrary to the previous structure (Peeters et al., 1993) which crystallized in monoclinic with P2 1 symmetry, we found a polymophic form which crystallize in triclinic with P1 symmetry. The overlay of the molecules obtained in two different crystal systems clearly shows that they possess the same conformation with RMSD of 0.1329 Å, 0.1088 Å and a maximum deviation of 0.2823 Å, 0.1789 Å. The pyran rings adopt half-chair conformations with total puckering amplitutdes QT of 0.5041 (28) (with Θ = 129.10 (33)° and φ = 84.59 (39)°) (Cremer & Pople, (1975)). The protonation of the amine is confimed by the distance C11-N1 and C12-N1 of 1.502 (3) and 1.513 (4) respectively. The structure is stabilized by a network of hydrogen bonds between N, O and Br atoms. The absolute configuration is R for the asymmetric C atom in the dihydropyran ring and S for the hydroxyl-bearing C atom. Chains are formed in the c axis.
Concerning the crystal packing features, each aromatic group are parallel unlike the previously determined structure (Peeters et al., 1993) wherein aromatic rings between two adjacent molecules possess dihedral angle close to 35° and 55° respectively.

Figure 1
View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms.   Packing features in (I). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.37 e Å −3 Δρ min = −0.18 e Å −3 Absolute structure: Flack (1983); refined as an inversion twin Absolute structure parameter: 0.013 (7) Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refined as a 2-component inversion twin.