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

Yoann Rousselin; Hugo Laureano; Alexandre Clavel

doi:10.1107/S1600536813030377

. 2013 Nov 20;69(Pt 12):o1794–o1795. doi: 10.1107/S1600536813030377

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

Yoann Rousselin ^a,^*, Hugo Laureano ^b, Alexandre Clavel ^b

PMCID: PMC4004435 PMID: 24860291

Abstract

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.

Related literature

For the synthesis of the enantiopure title product, see: Jas et al. (2011 ▶). For studies of related isomers, see: Cini et al. (1990 ▶); Tuchalski et al. (2006 ▶, 2008 ▶); Rousselin et al. (2012 ▶). for the monoclinic polymorph, see: Peeters et al. (1993 ▶). The title compound is a key intermediate in the synthesis of the beta blocker dl-nebivolol [systematic name: 1-(6-fluorochroman-2-yl)-{[2-(6-fluorochroman-2-yl)-2-hydroxy-ethyl]amino}ethanol. For the pharmacological properties of nebivolol, see: Van Lommen et al. (1990 ▶). For puckering parameters, see: Cremer & Pople (1975 ▶). For background to polymorphism, see: Bernstein (2002 ▶).

Experimental

Crystal data

C₁₈H₂₁FNO₂ ⁺·Br⁻
M _r = 382.27
Triclinic,
a = 4.9248 (2) Å
b = 5.5117 (2) Å
c = 16.3894 (7) Å
α = 83.721 (2)°
β = 89.038 (2)°
γ = 86.765 (2)°
V = 441.48 (3) Å³
Z = 1
Mo Kα₁ radiation
μ = 2.35 mm⁻¹
T = 115 K
0.25 × 0.2 × 0.2 mm

Data collection

Nonius KappaCCD diffractometer with APEXII detector
Absorption correction: multi-scan (SADABS; Bruker, 2012 ▶) T _min = 0.61, T _max = 0.74
10328 measured reflections
3903 independent reflections
3886 reflections with I > 2σ(I)
R _int = 0.020

Refinement

R[F ² > 2σ(F ²)] = 0.021
wR(F ²) = 0.052
S = 1.11
3903 reflections
210 parameters
3 restraints
H-atom parameters constrained
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)

Data collection: APEX2 (Bruker, 2012 ▶); cell refinement: SAINT (Bruker, 2012 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536813030377/gw2140sup1.cif

e-69-o1794-sup1.cif^{(320.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813030377/gw2140Isup2.hkl

e-69-o1794-Isup2.hkl^{(214.1KB, hkl)}

Click here for additional data file.^{(4.6KB, cdx)}

Supplementary material file. DOI: 10.1107/S1600536813030377/gw2140Isup3.cdx

Click here for additional data file.^{(6.5KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813030377/gw2140Isup4.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯Br1ⁱ	0.99	2.40	3.306 (2)	152
N1—H1B⋯Br1ⁱⁱ	0.99	2.30	3.258 (2)	162
O2—H2A⋯Br1ⁱ	0.84	2.47	3.2198 (19)	149

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

We thank Ms Marie-Jose Penouilh for the NMR spectra and for ESI mass spectra.

supplementary crystallographic information

1. 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).

2. Experimental

3. Synthesis and crystallization

2-chloro-1-(6-fluoro-chroman-2-yl)-1-ethanol were prepared as enantiopure products in order to obtain the 2-benzylamino-1-(6-fluoro-chroman-2-yl)-1-ethanol by addition of benzylamine (Jas et al. (2011)). A subsequent addition of (R)-2-chloro-1-((S)-6-fluoro-chroman-2-yl)-1-ethanol would then be used to yield the corresponding protected nebivolol. The crude 2-benzylamino-1-(6-fluoro-chroman-2-yl)-1-ethanol was then recrystallized at 60°C in a mixture of ethanol and aqueous hydrobromic acid.

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.

(S)-2-benzylamino-1-((R)-6-fluoro-chroman-2-yl)-1-ethanol characterization:

δ(¹H, DMSO-d6, 300 MHz, ppm): 1.69 (1H, m); 2.04 (2H, m); 2.58 (1H, m); 2.74 (3H, m); 3.65 – 3.78 (1H, m); 3.73 (2H, s); 3.88 (1H, m); 5.00 (1H, bs); 6.68 (1H, m); 6.88 (2H, m); 7.17 – 7.37 (5H, m).

δ(¹³C DMSO-d6, 75.47 MHz, ppm): 22.1; 23.8; 51.3; 53.0; 70.7; 77.3; 113.5 (d, 22.5 Hz); 115.2 (d, 22.5 Hz); 117.2 (d, 8.3 Hz); 123.8 (d, 7.5 Hz); 126.4; 127.8; 128.0; 140.9; 150.6 (d, 2.3 Hz); 155.7 (d, 234 Hz).

HRMS (ESI) for C₁₈H₂₁FNO₂[M+H]⁺ m/z =302.15508, found m/z = 302.1537.

IR (cm^-1) 3137, 2821, 1489, 1215, 810.

4. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. Anisotropic thermal parameters were used for non-hydrogen atoms. All H atoms, on carbon atom or oxygen atom, were placed at calculated positions using a riding model with C—H = 1 Å (methine), 0.99 Å (methylene), 0.95 Å (aromatic), N—H = 0.99 Å or O—H = 0.84 Å with Uiso(H) = 1.2Ueq(CH), Uiso(H) = 1.2Ueq(CH₂), Uiso(H) = 1.2Ueq(NH) or Uiso(H) = 1.5Ueq(OH). TWIN/BASF refinement type was used to determine absolute configuration from anomalous scattering using the Flack method.

5. Results and discussion

The asymmetric unit of the title compound, C₁₈H₂₁FNO₂⁺.Br^-, contains one molecule. Contrary to the previous structure (Peeters et al., 1993) which crystallized in monoclinic with P2₁ 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.