organic compounds
(S,S,S,S)-Nebivolol hydrochloride hemihydrate
aUniversite de Bourgogne, ICMUB–UMR6302, 9 avenue Alain Savary, 21000 Dijon, France, and bCordenPharma–Synkem, 47 rue de Longvic, 21301, Chenove, France
*Correspondence e-mail: yoann.rousselin@u-bourgogne.fr
The 22H26F2NO4+·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).
of the title hydrated salt, CRelated literature
For the synthesis of the enantiopure title product, see: Jas et al. (2011). For a study of related isomers, see: Cini et al. (1990); Peeters et al. (1993); Tuchalski et al. (2006, 2008). For pharmacological properties of nebivolol, see: Van Lommen et al., (1990). For distance computations in water molecules, see: Stewart (2009). For puckering parameters, see: Cremer & Pople, (1975).
Experimental
Crystal data
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Data collection
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Data collection: COLLECT (Nonius, 1998); cell DENZO (Otwinowski & Minor, 1997); data reduction: DENZO; program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012).
Supporting information
10.1107/S1600536812045813/jj2154sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: 10.1107/S1600536812045813/jj2154Isup2.hkl
Supporting information file. DOI: 10.1107/S1600536812045813/jj2154Isup3.cml
(R)-2-chloro-1-((S)-6-fluoro-chroman-2-yl)-1-ethanol was prepared as an
product in order to obtain the nebivolol isomer.[Jas et al. (2011)] A subsequent addition of benzylamine and (R)-2-chloro-1-((S)-6-fluoro-chroman-2-yl)-1-ethanol was then used to yield the corresponding protected nebivolol. (S,S,S,S)-nebivolol hydrochloride was isolated hereafter (Fig. 3).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 H2O, calcd %C 55.29 %H 6.33 %N 2.93, found %C 55.62 %H 6.48 %N 3.52.
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 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 Uiso(H) = 1.2Ueq(C). H atoms on nitrogen atoms and water molecule were located in the Fourier difference maps. Their positional parameters were either refined freely with Uiso(H) = 1.5Ueq(N) or Uiso(H) = 1.5Ueq(O).
TWIN/BASF
type was used to determine from using the Flack method.Data collection: COLLECT (Nonius, 1998); cell
DENZO (Otwinowski & Minor, 1997); data reduction: DENZO (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92, (Altomare et al., 1993); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012).Fig. 1. View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms. | |
Fig. 2. View of the hydrogen-bonding and weak intermolecular interactions in (I). Dashed lines indicate O—H···O hydrogen-bonds and weak N—H···O, N—H···Cl, O—H···Cl, O—H···O and O—H···Cl intermolecular interactions. | |
Fig. 3. Synthesis of the title compound, (I). |
C22H26F2NO4+·Cl−·0.5H2O | F(000) = 948 |
Mr = 450.89 | Dx = 1.431 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 2753 reflections |
a = 7.5173 (3) Å | θ = 1.0–27.5° |
b = 8.1495 (3) Å | µ = 0.23 mm−1 |
c = 34.1660 (11) Å | T = 115 K |
V = 2093.09 (13) Å3 | Needle, colourless |
Z = 4 | 0.10 × 0.07 × 0.02 mm |
Nonius Kappa APEXII diffractometer | 4271 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.000 |
Horizonally mounted graphite crystal monochromator | θmax = 27.5°, θmin = 2.6° |
Detector resolution: 9 pixels mm-1 | h = −9→9 |
CCD rotation images, thick slices scans | k = −10→10 |
4782 measured reflections | l = −43→44 |
4782 independent reflections |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.072 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.137 | w = 1/[σ2(Fo2) + (0.P)2 + 4.746P] where P = (Fo2 + 2Fc2)/3 |
S = 1.27 | (Δ/σ)max < 0.001 |
4782 reflections | Δρmax = 0.43 e Å−3 |
290 parameters | Δρmin = −0.31 e Å−3 |
3 restraints | Absolute structure: Flack (2003), 1998 Friedel pairs |
0 constraints | Absolute structure parameter: 0.02 (12) |
Primary atom site location: structure-invariant direct methods |
C22H26F2NO4+·Cl−·0.5H2O | V = 2093.09 (13) Å3 |
Mr = 450.89 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 7.5173 (3) Å | µ = 0.23 mm−1 |
b = 8.1495 (3) Å | T = 115 K |
c = 34.1660 (11) Å | 0.10 × 0.07 × 0.02 mm |
Nonius Kappa APEXII diffractometer | 4271 reflections with I > 2σ(I) |
4782 measured reflections | Rint = 0.000 |
4782 independent reflections |
R[F2 > 2σ(F2)] = 0.072 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.137 | Δρmax = 0.43 e Å−3 |
S = 1.27 | Δρmin = −0.31 e Å−3 |
4782 reflections | Absolute structure: Flack (2003), 1998 Friedel pairs |
290 parameters | Absolute structure parameter: 0.02 (12) |
3 restraints |
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.1H and 13C 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. (S,S,S,S)-Nebivolol hydrochloride characterization: δ(1H, DMSO-d6, 500 MHz, p.p.m.): 1.77 (2H, m); 1.95 (2H, m); 2.78 (4H, m); 3.21 (4H, m); 4.00 (2H, m); 4.14 (2H, m); 5.79 (2H, bs); 6.76 (2H, dd); 6.92 (4H, m); 8.58 (2H, bs). δ(13C DMSO-d6, 125.76 MHz, p.p.m.): 22.2; 24.1; 49.5; 67.4; 76.8; 113.6 (23.7); 115.2 (22.5); 117.4 (7.5); 123.7 (7.5); 150.5; 155.9 (235.0). [α]29D69.6° (c =0.1, THF/water = 4/1) HRMS (ESI) calcd for C22H25F2NO4[M+H]+ m/z = 406.18244, found m/z = 406.18222. IR (cm-1) 3381, 1492, 1215, 812. |
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. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
C1 | 0.4811 (6) | 0.0821 (5) | 0.97619 (12) | 0.0242 (9) | |
C2 | 0.3245 (6) | 0.1358 (5) | 0.96076 (12) | 0.0243 (9) | |
H2 | 0.2368 | 0.1833 | 0.9773 | 0.029* | |
C3 | 0.2926 (5) | 0.1210 (5) | 0.92044 (12) | 0.0211 (8) | |
C4 | 0.4248 (5) | 0.0511 (5) | 0.89753 (11) | 0.0199 (8) | |
C5 | 0.5850 (5) | 0.0016 (5) | 0.91376 (12) | 0.0230 (8) | |
H5 | 0.6748 | −0.0436 | 0.8974 | 0.028* | |
C6 | 0.6152 (5) | 0.0173 (5) | 0.95347 (12) | 0.0264 (9) | |
H6 | 0.7250 | −0.0156 | 0.9648 | 0.032* | |
C7 | 0.1216 (5) | 0.1825 (5) | 0.90272 (12) | 0.0237 (8) | |
H7A | 0.0900 | 0.2896 | 0.9145 | 0.028* | |
H7B | 0.0245 | 0.1041 | 0.9085 | 0.028* | |
C8 | 0.1409 (6) | 0.2016 (5) | 0.85853 (11) | 0.0209 (8) | |
H8A | 0.0220 | 0.2149 | 0.8465 | 0.025* | |
H8B | 0.2119 | 0.3008 | 0.8526 | 0.025* | |
C9 | 0.2313 (5) | 0.0525 (5) | 0.84167 (11) | 0.0212 (8) | |
H9 | 0.1593 | −0.0468 | 0.8483 | 0.025* | |
C10 | 0.2528 (6) | 0.0615 (5) | 0.79760 (12) | 0.0202 (8) | |
H10 | 0.1331 | 0.0811 | 0.7857 | 0.024* | |
C11 | 0.3266 (6) | −0.0984 (5) | 0.78125 (11) | 0.0217 (9) | |
H11A | 0.4582 | −0.0942 | 0.7813 | 0.026* | |
H11B | 0.2890 | −0.1909 | 0.7981 | 0.026* | |
C12 | 0.3360 (5) | −0.0161 (5) | 0.70943 (11) | 0.0200 (8) | |
H12A | 0.4675 | −0.0160 | 0.7110 | 0.024* | |
H12B | 0.2934 | 0.0975 | 0.7135 | 0.024* | |
C13 | 0.2764 (5) | −0.0781 (5) | 0.66940 (12) | 0.0195 (8) | |
H13 | 0.1450 | −0.0604 | 0.6676 | 0.023* | |
C14 | 0.3619 (5) | 0.0185 (5) | 0.63636 (11) | 0.0190 (7) | |
H14 | 0.3190 | 0.1345 | 0.6377 | 0.023* | |
C15 | 0.3219 (5) | −0.0488 (4) | 0.59603 (11) | 0.0202 (8) | |
H15A | 0.1915 | −0.0528 | 0.5920 | 0.024* | |
H15B | 0.3688 | −0.1619 | 0.5938 | 0.024* | |
C16 | 0.4070 (5) | 0.0597 (5) | 0.56468 (12) | 0.0219 (9) | |
H16A | 0.4128 | −0.0016 | 0.5397 | 0.026* | |
H16B | 0.3319 | 0.1580 | 0.5605 | 0.026* | |
C17 | 0.5927 (5) | 0.1131 (5) | 0.57633 (12) | 0.0194 (8) | |
C18 | 0.7062 (6) | 0.1889 (5) | 0.54997 (12) | 0.0224 (9) | |
H18 | 0.6683 | 0.2080 | 0.5238 | 0.027* | |
C19 | 0.8729 (6) | 0.2363 (5) | 0.56154 (12) | 0.0253 (9) | |
C20 | 0.9358 (5) | 0.2098 (5) | 0.59908 (12) | 0.0213 (8) | |
H20 | 1.0528 | 0.2418 | 0.6063 | 0.026* | |
C21 | 0.8238 (5) | 0.1355 (5) | 0.62564 (12) | 0.0192 (8) | |
H21 | 0.8637 | 0.1160 | 0.6516 | 0.023* | |
C22 | 0.6531 (5) | 0.0890 (4) | 0.61476 (11) | 0.0192 (8) | |
N1 | 0.2609 (5) | −0.1263 (4) | 0.74016 (10) | 0.0207 (7) | |
H1N | 0.279 (6) | −0.221 (6) | 0.7347 (13) | 0.025* | |
H2N | 0.130 (6) | −0.109 (5) | 0.7406 (13) | 0.025* | |
O1 | 0.4083 (3) | 0.0325 (3) | 0.85757 (8) | 0.0220 (6) | |
O2 | 0.3686 (4) | 0.1925 (3) | 0.78601 (8) | 0.0220 (6) | |
H2A | 0.3087 | 0.2783 | 0.7825 | 0.033* | |
O3 | 0.3073 (4) | −0.2506 (3) | 0.66653 (9) | 0.0226 (6) | |
H3 | 0.4166 | −0.2696 | 0.6690 | 0.034* | |
O4 | 0.5511 (3) | 0.0167 (4) | 0.64353 (7) | 0.0209 (6) | |
O5 | 0.8099 (7) | 0.8960 (7) | 0.82485 (16) | 0.0209 (12)* | 0.50 |
H1O | 0.760 (10) | 0.996 (5) | 0.8325 (18) | 0.025* | 0.50 |
H2O | 0.824 (11) | 0.901 (9) | 0.7977 (7) | 0.025* | 0.50 |
F1 | 0.5065 (4) | 0.0952 (3) | 1.01561 (7) | 0.0378 (7) | |
F2 | 0.9814 (3) | 0.3121 (3) | 0.53516 (7) | 0.0337 (6) | |
Cl1 | 0.85980 (12) | 0.99394 (12) | 0.73521 (3) | 0.0246 (2) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.033 (2) | 0.021 (2) | 0.019 (2) | −0.0051 (18) | −0.0096 (17) | 0.0018 (16) |
C2 | 0.036 (2) | 0.0172 (19) | 0.020 (2) | −0.0008 (17) | 0.0037 (18) | −0.0013 (15) |
C3 | 0.025 (2) | 0.0158 (18) | 0.023 (2) | −0.0002 (16) | −0.0034 (16) | 0.0046 (16) |
C4 | 0.024 (2) | 0.0164 (18) | 0.0198 (19) | −0.0042 (15) | −0.0027 (15) | 0.0023 (15) |
C5 | 0.0254 (19) | 0.0154 (17) | 0.028 (2) | 0.0006 (18) | −0.0029 (15) | 0.0023 (18) |
C6 | 0.024 (2) | 0.024 (2) | 0.031 (2) | −0.0009 (19) | −0.0112 (17) | 0.0044 (18) |
C7 | 0.018 (2) | 0.024 (2) | 0.029 (2) | 0.0042 (17) | 0.0013 (17) | −0.0008 (17) |
C8 | 0.0175 (18) | 0.0185 (18) | 0.027 (2) | 0.0024 (17) | −0.0047 (17) | −0.0017 (16) |
C9 | 0.023 (2) | 0.0177 (19) | 0.022 (2) | −0.0029 (16) | −0.0046 (17) | 0.0019 (16) |
C10 | 0.022 (2) | 0.0140 (18) | 0.025 (2) | −0.0036 (16) | −0.0039 (16) | 0.0000 (16) |
C11 | 0.032 (2) | 0.0145 (18) | 0.0186 (19) | −0.0021 (17) | −0.0033 (17) | −0.0001 (15) |
C12 | 0.0174 (18) | 0.0167 (18) | 0.0258 (19) | −0.0008 (17) | −0.0019 (15) | 0.0033 (16) |
C13 | 0.0170 (19) | 0.0147 (19) | 0.027 (2) | 0.0007 (15) | 0.0007 (16) | −0.0004 (16) |
C14 | 0.0148 (16) | 0.0154 (17) | 0.0267 (18) | 0.0022 (16) | −0.0023 (15) | 0.0022 (16) |
C15 | 0.0172 (19) | 0.0176 (18) | 0.026 (2) | 0.0001 (15) | −0.0010 (16) | −0.0018 (16) |
C16 | 0.022 (2) | 0.022 (2) | 0.0214 (19) | 0.0020 (16) | −0.0040 (16) | −0.0003 (16) |
C17 | 0.021 (2) | 0.0139 (17) | 0.0232 (19) | 0.0040 (15) | 0.0006 (16) | −0.0033 (15) |
C18 | 0.026 (2) | 0.0177 (19) | 0.023 (2) | 0.0032 (17) | 0.0046 (17) | 0.0000 (16) |
C19 | 0.024 (2) | 0.023 (2) | 0.028 (2) | 0.0026 (19) | 0.0091 (19) | 0.0013 (18) |
C20 | 0.0179 (19) | 0.0192 (19) | 0.027 (2) | −0.0015 (16) | −0.0005 (16) | −0.0034 (17) |
C21 | 0.0170 (19) | 0.0158 (18) | 0.025 (2) | 0.0044 (15) | 0.0020 (16) | −0.0004 (15) |
C22 | 0.0209 (19) | 0.0123 (17) | 0.0243 (19) | 0.0022 (16) | 0.0019 (17) | −0.0018 (15) |
N1 | 0.0265 (18) | 0.0151 (16) | 0.0207 (18) | −0.0058 (15) | −0.0025 (15) | −0.0021 (14) |
O1 | 0.0213 (14) | 0.0252 (15) | 0.0193 (13) | 0.0044 (12) | −0.0030 (11) | 0.0007 (12) |
O2 | 0.0263 (15) | 0.0118 (12) | 0.0280 (15) | −0.0005 (12) | −0.0028 (13) | 0.0022 (11) |
O3 | 0.0255 (15) | 0.0145 (13) | 0.0279 (15) | 0.0006 (11) | 0.0013 (13) | −0.0016 (12) |
O4 | 0.0178 (13) | 0.0246 (14) | 0.0204 (13) | −0.0001 (12) | −0.0017 (10) | 0.0044 (12) |
F1 | 0.0514 (18) | 0.0392 (15) | 0.0229 (13) | 0.0007 (14) | −0.0093 (13) | −0.0011 (12) |
F2 | 0.0313 (14) | 0.0413 (15) | 0.0285 (14) | −0.0062 (12) | 0.0108 (12) | 0.0057 (12) |
Cl1 | 0.0251 (4) | 0.0197 (4) | 0.0289 (5) | 0.0010 (4) | −0.0055 (4) | −0.0040 (4) |
C1—C2 | 1.362 (6) | C12—H12B | 0.9900 |
C1—F1 | 1.365 (5) | C13—O3 | 1.429 (5) |
C1—C6 | 1.377 (6) | C13—C14 | 1.519 (5) |
C2—C3 | 1.403 (6) | C13—H13 | 1.0000 |
C2—H2 | 0.9500 | C14—O4 | 1.443 (4) |
C3—C4 | 1.387 (6) | C14—C15 | 1.513 (5) |
C3—C7 | 1.507 (6) | C14—H14 | 1.0000 |
C4—O1 | 1.379 (5) | C15—C16 | 1.529 (5) |
C4—C5 | 1.386 (5) | C15—H15A | 0.9900 |
C5—C6 | 1.382 (5) | C15—H15B | 0.9900 |
C5—H5 | 0.9500 | C16—C17 | 1.516 (5) |
C6—H6 | 0.9500 | C16—H16A | 0.9900 |
C7—C8 | 1.525 (5) | C16—H16B | 0.9900 |
C7—H7A | 0.9900 | C17—C18 | 1.386 (6) |
C7—H7B | 0.9900 | C17—C22 | 1.403 (5) |
C8—C9 | 1.506 (5) | C18—C19 | 1.370 (6) |
C8—H8A | 0.9900 | C18—H18 | 0.9500 |
C8—H8B | 0.9900 | C19—F2 | 1.364 (5) |
C9—O1 | 1.446 (5) | C19—C20 | 1.384 (6) |
C9—C10 | 1.516 (5) | C20—C21 | 1.378 (6) |
C9—H9 | 1.0000 | C20—H20 | 0.9500 |
C10—O2 | 1.433 (5) | C21—C22 | 1.389 (5) |
C10—C11 | 1.523 (5) | C21—H21 | 0.9500 |
C10—H10 | 1.0000 | C22—O4 | 1.379 (5) |
C11—N1 | 1.505 (5) | N1—H1N | 0.80 (5) |
C11—H11A | 0.9900 | N1—H2N | 1.00 (5) |
C11—H11B | 0.9900 | O2—H2A | 0.8400 |
C12—N1 | 1.492 (5) | O3—H3 | 0.8400 |
C12—C13 | 1.525 (5) | O5—H1O | 0.94 (2) |
C12—H12A | 0.9900 | O5—H2O | 0.93 (2) |
C2—C1—F1 | 118.5 (4) | O3—C13—C14 | 113.0 (3) |
C2—C1—C6 | 122.5 (4) | O3—C13—C12 | 109.9 (3) |
F1—C1—C6 | 118.9 (4) | C14—C13—C12 | 111.8 (3) |
C1—C2—C3 | 120.0 (4) | O3—C13—H13 | 107.3 |
C1—C2—H2 | 120.0 | C14—C13—H13 | 107.3 |
C3—C2—H2 | 120.0 | C12—C13—H13 | 107.3 |
C4—C3—C2 | 117.9 (4) | O4—C14—C15 | 110.3 (3) |
C4—C3—C7 | 121.4 (4) | O4—C14—C13 | 106.6 (3) |
C2—C3—C7 | 120.7 (4) | C15—C14—C13 | 113.9 (3) |
O1—C4—C5 | 116.2 (4) | O4—C14—H14 | 108.6 |
O1—C4—C3 | 122.6 (4) | C15—C14—H14 | 108.6 |
C5—C4—C3 | 121.1 (4) | C13—C14—H14 | 108.6 |
C6—C5—C4 | 120.6 (4) | C14—C15—C16 | 110.2 (3) |
C6—C5—H5 | 119.7 | C14—C15—H15A | 109.6 |
C4—C5—H5 | 119.7 | C16—C15—H15A | 109.6 |
C1—C6—C5 | 117.9 (4) | C14—C15—H15B | 109.6 |
C1—C6—H6 | 121.0 | C16—C15—H15B | 109.6 |
C5—C6—H6 | 121.0 | H15A—C15—H15B | 108.1 |
C3—C7—C8 | 110.5 (3) | C17—C16—C15 | 111.5 (3) |
C3—C7—H7A | 109.5 | C17—C16—H16A | 109.3 |
C8—C7—H7A | 109.5 | C15—C16—H16A | 109.3 |
C3—C7—H7B | 109.5 | C17—C16—H16B | 109.3 |
C8—C7—H7B | 109.5 | C15—C16—H16B | 109.3 |
H7A—C7—H7B | 108.1 | H16A—C16—H16B | 108.0 |
C9—C8—C7 | 109.8 (3) | C18—C17—C22 | 118.1 (4) |
C9—C8—H8A | 109.7 | C18—C17—C16 | 121.6 (4) |
C7—C8—H8A | 109.7 | C22—C17—C16 | 120.2 (4) |
C9—C8—H8B | 109.7 | C19—C18—C17 | 120.1 (4) |
C7—C8—H8B | 109.7 | C19—C18—H18 | 120.0 |
H8A—C8—H8B | 108.2 | C17—C18—H18 | 120.0 |
O1—C9—C8 | 111.3 (3) | F2—C19—C18 | 119.0 (4) |
O1—C9—C10 | 106.3 (3) | F2—C19—C20 | 118.6 (4) |
C8—C9—C10 | 112.9 (3) | C18—C19—C20 | 122.4 (4) |
O1—C9—H9 | 108.8 | C21—C20—C19 | 118.0 (4) |
C8—C9—H9 | 108.8 | C21—C20—H20 | 121.0 |
C10—C9—H9 | 108.8 | C19—C20—H20 | 121.0 |
O2—C10—C9 | 112.0 (3) | C20—C21—C22 | 120.6 (4) |
O2—C10—C11 | 108.3 (3) | C20—C21—H21 | 119.7 |
C9—C10—C11 | 111.2 (3) | C22—C21—H21 | 119.7 |
O2—C10—H10 | 108.4 | O4—C22—C21 | 116.1 (3) |
C9—C10—H10 | 108.4 | O4—C22—C17 | 123.2 (4) |
C11—C10—H10 | 108.4 | C21—C22—C17 | 120.7 (4) |
N1—C11—C10 | 110.6 (3) | C12—N1—C11 | 116.2 (3) |
N1—C11—H11A | 109.5 | C12—N1—H1N | 110 (3) |
C10—C11—H11A | 109.5 | C11—N1—H1N | 108 (3) |
N1—C11—H11B | 109.5 | C12—N1—H2N | 107 (3) |
C10—C11—H11B | 109.5 | C11—N1—H2N | 107 (3) |
H11A—C11—H11B | 108.1 | H1N—N1—H2N | 108 (4) |
N1—C12—C13 | 108.7 (3) | C4—O1—C9 | 116.2 (3) |
N1—C12—H12A | 109.9 | C10—O2—H2A | 109.5 |
C13—C12—H12A | 109.9 | C13—O3—H3 | 109.5 |
N1—C12—H12B | 109.9 | C22—O4—C14 | 115.0 (3) |
C13—C12—H12B | 109.9 | H1O—O5—H2O | 107 (3) |
H12A—C12—H12B | 108.3 | ||
F1—C1—C2—C3 | −178.7 (4) | C12—C13—C14—C15 | 174.2 (3) |
C6—C1—C2—C3 | 2.2 (6) | O4—C14—C15—C16 | −62.4 (4) |
C1—C2—C3—C4 | −0.1 (6) | C13—C14—C15—C16 | 177.8 (3) |
C1—C2—C3—C7 | −178.9 (4) | C14—C15—C16—C17 | 41.5 (4) |
C2—C3—C4—O1 | −179.2 (4) | C15—C16—C17—C18 | 169.2 (4) |
C7—C3—C4—O1 | −0.4 (6) | C15—C16—C17—C22 | −11.9 (5) |
C2—C3—C4—C5 | −1.7 (6) | C22—C17—C18—C19 | 0.7 (6) |
C7—C3—C4—C5 | 177.1 (4) | C16—C17—C18—C19 | 179.7 (4) |
O1—C4—C5—C6 | 179.1 (4) | C17—C18—C19—F2 | −179.3 (4) |
C3—C4—C5—C6 | 1.5 (6) | C17—C18—C19—C20 | 0.8 (6) |
C2—C1—C6—C5 | −2.4 (6) | F2—C19—C20—C21 | 178.9 (3) |
F1—C1—C6—C5 | 178.5 (4) | C18—C19—C20—C21 | −1.2 (6) |
C4—C5—C6—C1 | 0.5 (6) | C19—C20—C21—C22 | 0.1 (6) |
C4—C3—C7—C8 | −16.2 (5) | C20—C21—C22—O4 | −179.6 (3) |
C2—C3—C7—C8 | 162.5 (4) | C20—C21—C22—C17 | 1.5 (6) |
C3—C7—C8—C9 | 45.4 (5) | C18—C17—C22—O4 | 179.2 (3) |
C7—C8—C9—O1 | −61.5 (4) | C16—C17—C22—O4 | 0.3 (6) |
C7—C8—C9—C10 | 179.1 (3) | C18—C17—C22—C21 | −1.8 (6) |
O1—C9—C10—O2 | −57.6 (4) | C16—C17—C22—C21 | 179.2 (3) |
C8—C9—C10—O2 | 64.6 (4) | C13—C12—N1—C11 | 171.7 (3) |
O1—C9—C10—C11 | 63.8 (4) | C10—C11—N1—C12 | 70.9 (4) |
C8—C9—C10—C11 | −174.0 (3) | C5—C4—O1—C9 | 168.0 (3) |
O2—C10—C11—N1 | −86.3 (4) | C3—C4—O1—C9 | −14.4 (5) |
C9—C10—C11—N1 | 150.1 (3) | C8—C9—O1—C4 | 45.4 (4) |
N1—C12—C13—O3 | −48.4 (4) | C10—C9—O1—C4 | 168.7 (3) |
N1—C12—C13—C14 | −174.6 (3) | C21—C22—O4—C14 | 160.5 (3) |
O3—C13—C14—O4 | −72.2 (4) | C17—C22—O4—C14 | −20.5 (5) |
C12—C13—C14—O4 | 52.3 (4) | C15—C14—O4—C22 | 51.4 (4) |
O3—C13—C14—C15 | 49.7 (4) | C13—C14—O4—C22 | 175.5 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···Cl1i | 0.80 (5) | 2.75 (5) | 3.333 (4) | 131 (4) |
N1—H2N···Cl1ii | 1.00 (5) | 2.20 (5) | 3.175 (4) | 165 (4) |
O2—H2A···Cl1iii | 0.84 | 2.25 | 3.084 (3) | 172 |
O3—H3···O2iii | 0.84 | 2.25 | 2.963 (4) | 143 |
O3—H3···O1iii | 0.84 | 2.27 | 2.893 (4) | 131 |
O5—H1O···O3iv | 0.94 (2) | 2.12 (3) | 3.026 (6) | 161 (6) |
O5—H2O···Cl1 | 0.93 (2) | 2.28 (3) | 3.187 (6) | 163 (6) |
Symmetry codes: (i) −x+1, y−3/2, −z+3/2; (ii) x−1, y−1, z; (iii) −x+1, y−1/2, −z+3/2; (iv) −x+1, y+3/2, −z+3/2. |
Experimental details
Crystal data | |
Chemical formula | C22H26F2NO4+·Cl−·0.5H2O |
Mr | 450.89 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 115 |
a, b, c (Å) | 7.5173 (3), 8.1495 (3), 34.1660 (11) |
V (Å3) | 2093.09 (13) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.23 |
Crystal size (mm) | 0.10 × 0.07 × 0.02 |
Data collection | |
Diffractometer | Nonius Kappa APEXII diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4782, 4782, 4271 |
Rint | 0.000 |
(sin θ/λ)max (Å−1) | 0.649 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.072, 0.137, 1.27 |
No. of reflections | 4782 |
No. of parameters | 290 |
No. of restraints | 3 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.43, −0.31 |
Absolute structure | Flack (2003), 1998 Friedel pairs |
Absolute structure parameter | 0.02 (12) |
Computer programs: COLLECT (Nonius, 1998), DENZO (Otwinowski & Minor, 1997), SIR92, (Altomare et al., 1993), SHELXL97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 2012), WinGX (Farrugia, 2012).
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1N···Cl1i | 0.80 (5) | 2.75 (5) | 3.333 (4) | 131 (4) |
N1—H2N···Cl1ii | 1.00 (5) | 2.20 (5) | 3.175 (4) | 165 (4) |
O2—H2A···Cl1iii | 0.84 | 2.25 | 3.084 (3) | 172.0 |
O3—H3···O2iii | 0.84 | 2.25 | 2.963 (4) | 142.7 |
O3—H3···O1iii | 0.84 | 2.27 | 2.893 (4) | 131.1 |
O5—H1O···O3iv | 0.94 (2) | 2.12 (3) | 3.026 (6) | 161 (6) |
O5—H2O···Cl1 | 0.93 (2) | 2.28 (3) | 3.187 (6) | 163 (6) |
Symmetry codes: (i) −x+1, y−3/2, −z+3/2; (ii) x−1, y−1, z; (iii) −x+1, y−1/2, −z+3/2; (iv) −x+1, y+3/2, −z+3/2. |
Acknowledgements
We thank Ms Marie-José Penouilh for the NMR spectra and for ESI mass spectra. This study was co-financed by OSEO Burgundy and the European Regional Development Fund.
References
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(S,S,S,S)-Nebivolol is one isomer of the active pharmaceutical ingredient dl-nebivolol which 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 stereoisomers and the total number of isomeric structures is reduced to 10 due to the symmetry plane through the N atom of the molecule. 9 of 10 isomeric structures are known and well described [Tuchalski et al. (2006)], here we report the last unknown structure of the title compound, (I), C22H26F2NO4+Cl-.0.5H2O, the hydrochloride salt of (S,S,S,S)-nebivolol, obtained by total enantio selective synthesis.
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 QT 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)). Like other nebivolol isomers, crystal packing in (I) is stabilized by classical O—H···O hydrogen bonds as well as weak N—H···O, N—H···Cl, O—H···Cl, O—H···O and O—H···Cl intermolecular interactions (Fig. 2, Table 1) producing layers along (010).