organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

(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

(Received 1 October 2012; accepted 6 November 2012; online 14 November 2012)

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).

Related literature

For the synthesis of the enanti­opure title product, see: Jas et al. (2011[Jas, G., Freifeld, I. & Kesseler, K. (2011). Patent WO 2011091968 (Corden PharmaChem GmbH).]). For a study of related isomers, see: Cini et al. (1990[Cini, M., Crotti, P. & Macchia, F. (1990). Tetrahedron Lett. 31, 4661-4664.]); Peeters et al. (1993[Peeters, O. M., Blaton, N. M. & De Ranter, C. J. (1993). Acta Cryst. C49, 2154-2157.]); Tuchalski et al. (2006[Tuchalski, G., Emmerling, F., Groger, K., Hansicke, A., Nagel, T. & Reck, G. (2006). J. Mol. Struct. 800, 28-44.], 2008[Tuchalski, G., Hänsicke, A., Reck, G. & Emmerling, F. (2008). Acta Cryst. E64, o54.]). For pharmacological properties of nebivolol, see: Van Lommen et al., (1990[Van Lommen, G. R. E., de Bruyn, M. F. L. & Schroven, M. F. J. (1990). J. Pharm. Belg. 45, 355-360.]). For distance computations in water mol­ecules, see: Stewart (2009[Stewart, J. P. (2009). MOPAC2009. Stewart Computational Chemistry. Available from: http://OpenMOPAC.net.]). For puckering parameters, see: Cremer & Pople, (1975[Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354-1358.]).

[Scheme 1]

Experimental

Crystal data
  • C22H26F2NO4+·Cl·0.5H2O

  • Mr = 450.89

  • Orthorhombic, P 21 21 21

  • a = 7.5173 (3) Å

  • b = 8.1495 (3) Å

  • c = 34.1660 (11) Å

  • V = 2093.09 (13) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.23 mm−1

  • T = 115 K

  • 0.10 × 0.07 × 0.02 mm

Data collection
  • Nonius Kappa APEXII diffractometer

  • 4782 measured reflections

  • 4782 independent reflections

  • 4271 reflections with I > 2σ(I)

  • Rint = 0.000

Refinement
  • R[F2 > 2σ(F2)] = 0.072

  • wR(F2) = 0.137

  • S = 1.27

  • 4782 reflections

  • 290 parameters

  • 3 restraints

  • H atoms treated by a mixture of independent and constrained refinement

  • Δρmax = 0.43 e Å−3

  • Δρmin = −0.31 e Å−3

  • Absolute structure: Flack (2003[Flack, H. D. (2003). Helv. Chim. Acta, 86, 905-921.]), 1998 Friedel pairs

  • Flack parameter: 0.02 (12)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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-{\script{3\over 2}}, -z+{\script{3\over 2}}]; (ii) x-1, y-1, z; (iii) [-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]; (iv) [-x+1, y+{\script{3\over 2}}, -z+{\script{3\over 2}}].

Data collection: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: DENZO (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO; program(s) used to solve structure: SIR92 (Altomare et al., 1993[Altomare, A., Cascarano, G., Giacovazzo, C. & Guagliardi, A. (1993). J. Appl. Cryst. 26, 343-350.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]); software used to prepare material for publication: WinGX (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]).

Supporting information


Comment top

(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).

Related literature top

For synthesis of an enantiopure 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 top

(R)-2-chloro-1-((S)-6-fluoro-chroman-2-yl)-1-ethanol was prepared as an enantiopure 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.

Refinement top

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 refinement type was used to determine absolute configuration from anomalous scattering using the Flack method.

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: 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).

Figures top
[Figure 1] Fig. 1. View of the molecular structure of (I) with 50% probability displacement ellipsoids for the non-hydrogen atoms.
[Figure 2] 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.
[Figure 3] Fig. 3. Synthesis of the title compound, (I).
(S,S,S,S)-bis[2-(6-fluoro-3,4- dihydro-2H-1-benzopyran-2-yl)-2-hydroxyethyl]ammonium chloride hemihydrate top
Crystal data top
C22H26F2NO4+·Cl·0.5H2OF(000) = 948
Mr = 450.89Dx = 1.431 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 2753 reflections
a = 7.5173 (3) Åθ = 1.0–27.5°
b = 8.1495 (3) ŵ = 0.23 mm1
c = 34.1660 (11) ÅT = 115 K
V = 2093.09 (13) Å3Needle, colourless
Z = 40.10 × 0.07 × 0.02 mm
Data collection top
Nonius Kappa APEXII
diffractometer
4271 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.000
Horizonally mounted graphite crystal monochromatorθmax = 27.5°, θmin = 2.6°
Detector resolution: 9 pixels mm-1h = 99
CCD rotation images, thick slices scansk = 1010
4782 measured reflectionsl = 4344
4782 independent reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.072H 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 reflectionsΔρmax = 0.43 e Å3
290 parametersΔρmin = 0.31 e Å3
3 restraintsAbsolute structure: Flack (2003), 1998 Friedel pairs
0 constraintsAbsolute structure parameter: 0.02 (12)
Primary atom site location: structure-invariant direct methods
Crystal data top
C22H26F2NO4+·Cl·0.5H2OV = 2093.09 (13) Å3
Mr = 450.89Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 7.5173 (3) ŵ = 0.23 mm1
b = 8.1495 (3) ÅT = 115 K
c = 34.1660 (11) Å0.10 × 0.07 × 0.02 mm
Data collection top
Nonius Kappa APEXII
diffractometer
4271 reflections with I > 2σ(I)
4782 measured reflectionsRint = 0.000
4782 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.072H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.137Δρmax = 0.43 e Å3
S = 1.27Δρmin = 0.31 e Å3
4782 reflectionsAbsolute structure: Flack (2003), 1998 Friedel pairs
290 parametersAbsolute structure parameter: 0.02 (12)
3 restraints
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
C10.4811 (6)0.0821 (5)0.97619 (12)0.0242 (9)
C20.3245 (6)0.1358 (5)0.96076 (12)0.0243 (9)
H20.23680.18330.97730.029*
C30.2926 (5)0.1210 (5)0.92044 (12)0.0211 (8)
C40.4248 (5)0.0511 (5)0.89753 (11)0.0199 (8)
C50.5850 (5)0.0016 (5)0.91376 (12)0.0230 (8)
H50.67480.04360.89740.028*
C60.6152 (5)0.0173 (5)0.95347 (12)0.0264 (9)
H60.72500.01560.96480.032*
C70.1216 (5)0.1825 (5)0.90272 (12)0.0237 (8)
H7A0.09000.28960.91450.028*
H7B0.02450.10410.90850.028*
C80.1409 (6)0.2016 (5)0.85853 (11)0.0209 (8)
H8A0.02200.21490.84650.025*
H8B0.21190.30080.85260.025*
C90.2313 (5)0.0525 (5)0.84167 (11)0.0212 (8)
H90.15930.04680.84830.025*
C100.2528 (6)0.0615 (5)0.79760 (12)0.0202 (8)
H100.13310.08110.78570.024*
C110.3266 (6)0.0984 (5)0.78125 (11)0.0217 (9)
H11A0.45820.09420.78130.026*
H11B0.28900.19090.79810.026*
C120.3360 (5)0.0161 (5)0.70943 (11)0.0200 (8)
H12A0.46750.01600.71100.024*
H12B0.29340.09750.71350.024*
C130.2764 (5)0.0781 (5)0.66940 (12)0.0195 (8)
H130.14500.06040.66760.023*
C140.3619 (5)0.0185 (5)0.63636 (11)0.0190 (7)
H140.31900.13450.63770.023*
C150.3219 (5)0.0488 (4)0.59603 (11)0.0202 (8)
H15A0.19150.05280.59200.024*
H15B0.36880.16190.59380.024*
C160.4070 (5)0.0597 (5)0.56468 (12)0.0219 (9)
H16A0.41280.00160.53970.026*
H16B0.33190.15800.56050.026*
C170.5927 (5)0.1131 (5)0.57633 (12)0.0194 (8)
C180.7062 (6)0.1889 (5)0.54997 (12)0.0224 (9)
H180.66830.20800.52380.027*
C190.8729 (6)0.2363 (5)0.56154 (12)0.0253 (9)
C200.9358 (5)0.2098 (5)0.59908 (12)0.0213 (8)
H201.05280.24180.60630.026*
C210.8238 (5)0.1355 (5)0.62564 (12)0.0192 (8)
H210.86370.11600.65160.023*
C220.6531 (5)0.0890 (4)0.61476 (11)0.0192 (8)
N10.2609 (5)0.1263 (4)0.74016 (10)0.0207 (7)
H1N0.279 (6)0.221 (6)0.7347 (13)0.025*
H2N0.130 (6)0.109 (5)0.7406 (13)0.025*
O10.4083 (3)0.0325 (3)0.85757 (8)0.0220 (6)
O20.3686 (4)0.1925 (3)0.78601 (8)0.0220 (6)
H2A0.30870.27830.78250.033*
O30.3073 (4)0.2506 (3)0.66653 (9)0.0226 (6)
H30.41660.26960.66900.034*
O40.5511 (3)0.0167 (4)0.64353 (7)0.0209 (6)
O50.8099 (7)0.8960 (7)0.82485 (16)0.0209 (12)*0.50
H1O0.760 (10)0.996 (5)0.8325 (18)0.025*0.50
H2O0.824 (11)0.901 (9)0.7977 (7)0.025*0.50
F10.5065 (4)0.0952 (3)1.01561 (7)0.0378 (7)
F20.9814 (3)0.3121 (3)0.53516 (7)0.0337 (6)
Cl10.85980 (12)0.99394 (12)0.73521 (3)0.0246 (2)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.033 (2)0.021 (2)0.019 (2)0.0051 (18)0.0096 (17)0.0018 (16)
C20.036 (2)0.0172 (19)0.020 (2)0.0008 (17)0.0037 (18)0.0013 (15)
C30.025 (2)0.0158 (18)0.023 (2)0.0002 (16)0.0034 (16)0.0046 (16)
C40.024 (2)0.0164 (18)0.0198 (19)0.0042 (15)0.0027 (15)0.0023 (15)
C50.0254 (19)0.0154 (17)0.028 (2)0.0006 (18)0.0029 (15)0.0023 (18)
C60.024 (2)0.024 (2)0.031 (2)0.0009 (19)0.0112 (17)0.0044 (18)
C70.018 (2)0.024 (2)0.029 (2)0.0042 (17)0.0013 (17)0.0008 (17)
C80.0175 (18)0.0185 (18)0.027 (2)0.0024 (17)0.0047 (17)0.0017 (16)
C90.023 (2)0.0177 (19)0.022 (2)0.0029 (16)0.0046 (17)0.0019 (16)
C100.022 (2)0.0140 (18)0.025 (2)0.0036 (16)0.0039 (16)0.0000 (16)
C110.032 (2)0.0145 (18)0.0186 (19)0.0021 (17)0.0033 (17)0.0001 (15)
C120.0174 (18)0.0167 (18)0.0258 (19)0.0008 (17)0.0019 (15)0.0033 (16)
C130.0170 (19)0.0147 (19)0.027 (2)0.0007 (15)0.0007 (16)0.0004 (16)
C140.0148 (16)0.0154 (17)0.0267 (18)0.0022 (16)0.0023 (15)0.0022 (16)
C150.0172 (19)0.0176 (18)0.026 (2)0.0001 (15)0.0010 (16)0.0018 (16)
C160.022 (2)0.022 (2)0.0214 (19)0.0020 (16)0.0040 (16)0.0003 (16)
C170.021 (2)0.0139 (17)0.0232 (19)0.0040 (15)0.0006 (16)0.0033 (15)
C180.026 (2)0.0177 (19)0.023 (2)0.0032 (17)0.0046 (17)0.0000 (16)
C190.024 (2)0.023 (2)0.028 (2)0.0026 (19)0.0091 (19)0.0013 (18)
C200.0179 (19)0.0192 (19)0.027 (2)0.0015 (16)0.0005 (16)0.0034 (17)
C210.0170 (19)0.0158 (18)0.025 (2)0.0044 (15)0.0020 (16)0.0004 (15)
C220.0209 (19)0.0123 (17)0.0243 (19)0.0022 (16)0.0019 (17)0.0018 (15)
N10.0265 (18)0.0151 (16)0.0207 (18)0.0058 (15)0.0025 (15)0.0021 (14)
O10.0213 (14)0.0252 (15)0.0193 (13)0.0044 (12)0.0030 (11)0.0007 (12)
O20.0263 (15)0.0118 (12)0.0280 (15)0.0005 (12)0.0028 (13)0.0022 (11)
O30.0255 (15)0.0145 (13)0.0279 (15)0.0006 (11)0.0013 (13)0.0016 (12)
O40.0178 (13)0.0246 (14)0.0204 (13)0.0001 (12)0.0017 (10)0.0044 (12)
F10.0514 (18)0.0392 (15)0.0229 (13)0.0007 (14)0.0093 (13)0.0011 (12)
F20.0313 (14)0.0413 (15)0.0285 (14)0.0062 (12)0.0108 (12)0.0057 (12)
Cl10.0251 (4)0.0197 (4)0.0289 (5)0.0010 (4)0.0055 (4)0.0040 (4)
Geometric parameters (Å, º) top
C1—C21.362 (6)C12—H12B0.9900
C1—F11.365 (5)C13—O31.429 (5)
C1—C61.377 (6)C13—C141.519 (5)
C2—C31.403 (6)C13—H131.0000
C2—H20.9500C14—O41.443 (4)
C3—C41.387 (6)C14—C151.513 (5)
C3—C71.507 (6)C14—H141.0000
C4—O11.379 (5)C15—C161.529 (5)
C4—C51.386 (5)C15—H15A0.9900
C5—C61.382 (5)C15—H15B0.9900
C5—H50.9500C16—C171.516 (5)
C6—H60.9500C16—H16A0.9900
C7—C81.525 (5)C16—H16B0.9900
C7—H7A0.9900C17—C181.386 (6)
C7—H7B0.9900C17—C221.403 (5)
C8—C91.506 (5)C18—C191.370 (6)
C8—H8A0.9900C18—H180.9500
C8—H8B0.9900C19—F21.364 (5)
C9—O11.446 (5)C19—C201.384 (6)
C9—C101.516 (5)C20—C211.378 (6)
C9—H91.0000C20—H200.9500
C10—O21.433 (5)C21—C221.389 (5)
C10—C111.523 (5)C21—H210.9500
C10—H101.0000C22—O41.379 (5)
C11—N11.505 (5)N1—H1N0.80 (5)
C11—H11A0.9900N1—H2N1.00 (5)
C11—H11B0.9900O2—H2A0.8400
C12—N11.492 (5)O3—H30.8400
C12—C131.525 (5)O5—H1O0.94 (2)
C12—H12A0.9900O5—H2O0.93 (2)
C2—C1—F1118.5 (4)O3—C13—C14113.0 (3)
C2—C1—C6122.5 (4)O3—C13—C12109.9 (3)
F1—C1—C6118.9 (4)C14—C13—C12111.8 (3)
C1—C2—C3120.0 (4)O3—C13—H13107.3
C1—C2—H2120.0C14—C13—H13107.3
C3—C2—H2120.0C12—C13—H13107.3
C4—C3—C2117.9 (4)O4—C14—C15110.3 (3)
C4—C3—C7121.4 (4)O4—C14—C13106.6 (3)
C2—C3—C7120.7 (4)C15—C14—C13113.9 (3)
O1—C4—C5116.2 (4)O4—C14—H14108.6
O1—C4—C3122.6 (4)C15—C14—H14108.6
C5—C4—C3121.1 (4)C13—C14—H14108.6
C6—C5—C4120.6 (4)C14—C15—C16110.2 (3)
C6—C5—H5119.7C14—C15—H15A109.6
C4—C5—H5119.7C16—C15—H15A109.6
C1—C6—C5117.9 (4)C14—C15—H15B109.6
C1—C6—H6121.0C16—C15—H15B109.6
C5—C6—H6121.0H15A—C15—H15B108.1
C3—C7—C8110.5 (3)C17—C16—C15111.5 (3)
C3—C7—H7A109.5C17—C16—H16A109.3
C8—C7—H7A109.5C15—C16—H16A109.3
C3—C7—H7B109.5C17—C16—H16B109.3
C8—C7—H7B109.5C15—C16—H16B109.3
H7A—C7—H7B108.1H16A—C16—H16B108.0
C9—C8—C7109.8 (3)C18—C17—C22118.1 (4)
C9—C8—H8A109.7C18—C17—C16121.6 (4)
C7—C8—H8A109.7C22—C17—C16120.2 (4)
C9—C8—H8B109.7C19—C18—C17120.1 (4)
C7—C8—H8B109.7C19—C18—H18120.0
H8A—C8—H8B108.2C17—C18—H18120.0
O1—C9—C8111.3 (3)F2—C19—C18119.0 (4)
O1—C9—C10106.3 (3)F2—C19—C20118.6 (4)
C8—C9—C10112.9 (3)C18—C19—C20122.4 (4)
O1—C9—H9108.8C21—C20—C19118.0 (4)
C8—C9—H9108.8C21—C20—H20121.0
C10—C9—H9108.8C19—C20—H20121.0
O2—C10—C9112.0 (3)C20—C21—C22120.6 (4)
O2—C10—C11108.3 (3)C20—C21—H21119.7
C9—C10—C11111.2 (3)C22—C21—H21119.7
O2—C10—H10108.4O4—C22—C21116.1 (3)
C9—C10—H10108.4O4—C22—C17123.2 (4)
C11—C10—H10108.4C21—C22—C17120.7 (4)
N1—C11—C10110.6 (3)C12—N1—C11116.2 (3)
N1—C11—H11A109.5C12—N1—H1N110 (3)
C10—C11—H11A109.5C11—N1—H1N108 (3)
N1—C11—H11B109.5C12—N1—H2N107 (3)
C10—C11—H11B109.5C11—N1—H2N107 (3)
H11A—C11—H11B108.1H1N—N1—H2N108 (4)
N1—C12—C13108.7 (3)C4—O1—C9116.2 (3)
N1—C12—H12A109.9C10—O2—H2A109.5
C13—C12—H12A109.9C13—O3—H3109.5
N1—C12—H12B109.9C22—O4—C14115.0 (3)
C13—C12—H12B109.9H1O—O5—H2O107 (3)
H12A—C12—H12B108.3
F1—C1—C2—C3178.7 (4)C12—C13—C14—C15174.2 (3)
C6—C1—C2—C32.2 (6)O4—C14—C15—C1662.4 (4)
C1—C2—C3—C40.1 (6)C13—C14—C15—C16177.8 (3)
C1—C2—C3—C7178.9 (4)C14—C15—C16—C1741.5 (4)
C2—C3—C4—O1179.2 (4)C15—C16—C17—C18169.2 (4)
C7—C3—C4—O10.4 (6)C15—C16—C17—C2211.9 (5)
C2—C3—C4—C51.7 (6)C22—C17—C18—C190.7 (6)
C7—C3—C4—C5177.1 (4)C16—C17—C18—C19179.7 (4)
O1—C4—C5—C6179.1 (4)C17—C18—C19—F2179.3 (4)
C3—C4—C5—C61.5 (6)C17—C18—C19—C200.8 (6)
C2—C1—C6—C52.4 (6)F2—C19—C20—C21178.9 (3)
F1—C1—C6—C5178.5 (4)C18—C19—C20—C211.2 (6)
C4—C5—C6—C10.5 (6)C19—C20—C21—C220.1 (6)
C4—C3—C7—C816.2 (5)C20—C21—C22—O4179.6 (3)
C2—C3—C7—C8162.5 (4)C20—C21—C22—C171.5 (6)
C3—C7—C8—C945.4 (5)C18—C17—C22—O4179.2 (3)
C7—C8—C9—O161.5 (4)C16—C17—C22—O40.3 (6)
C7—C8—C9—C10179.1 (3)C18—C17—C22—C211.8 (6)
O1—C9—C10—O257.6 (4)C16—C17—C22—C21179.2 (3)
C8—C9—C10—O264.6 (4)C13—C12—N1—C11171.7 (3)
O1—C9—C10—C1163.8 (4)C10—C11—N1—C1270.9 (4)
C8—C9—C10—C11174.0 (3)C5—C4—O1—C9168.0 (3)
O2—C10—C11—N186.3 (4)C3—C4—O1—C914.4 (5)
C9—C10—C11—N1150.1 (3)C8—C9—O1—C445.4 (4)
N1—C12—C13—O348.4 (4)C10—C9—O1—C4168.7 (3)
N1—C12—C13—C14174.6 (3)C21—C22—O4—C14160.5 (3)
O3—C13—C14—O472.2 (4)C17—C22—O4—C1420.5 (5)
C12—C13—C14—O452.3 (4)C15—C14—O4—C2251.4 (4)
O3—C13—C14—C1549.7 (4)C13—C14—O4—C22175.5 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1N···Cl1i0.80 (5)2.75 (5)3.333 (4)131 (4)
N1—H2N···Cl1ii1.00 (5)2.20 (5)3.175 (4)165 (4)
O2—H2A···Cl1iii0.842.253.084 (3)172
O3—H3···O2iii0.842.252.963 (4)143
O3—H3···O1iii0.842.272.893 (4)131
O5—H1O···O3iv0.94 (2)2.12 (3)3.026 (6)161 (6)
O5—H2O···Cl10.93 (2)2.28 (3)3.187 (6)163 (6)
Symmetry codes: (i) x+1, y3/2, z+3/2; (ii) x1, y1, z; (iii) x+1, y1/2, z+3/2; (iv) x+1, y+3/2, z+3/2.

Experimental details

Crystal data
Chemical formulaC22H26F2NO4+·Cl·0.5H2O
Mr450.89
Crystal system, space groupOrthorhombic, P212121
Temperature (K)115
a, b, c (Å)7.5173 (3), 8.1495 (3), 34.1660 (11)
V3)2093.09 (13)
Z4
Radiation typeMo Kα
µ (mm1)0.23
Crystal size (mm)0.10 × 0.07 × 0.02
Data collection
DiffractometerNonius Kappa APEXII
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
4782, 4782, 4271
Rint0.000
(sin θ/λ)max1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.072, 0.137, 1.27
No. of reflections4782
No. of parameters290
No. of restraints3
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.43, 0.31
Absolute structureFlack (2003), 1998 Friedel pairs
Absolute structure parameter0.02 (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).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1N···Cl1i0.80 (5)2.75 (5)3.333 (4)131 (4)
N1—H2N···Cl1ii1.00 (5)2.20 (5)3.175 (4)165 (4)
O2—H2A···Cl1iii0.842.253.084 (3)172.0
O3—H3···O2iii0.842.252.963 (4)142.7
O3—H3···O1iii0.842.272.893 (4)131.1
O5—H1O···O3iv0.94 (2)2.12 (3)3.026 (6)161 (6)
O5—H2O···Cl10.93 (2)2.28 (3)3.187 (6)163 (6)
Symmetry codes: (i) x+1, y3/2, z+3/2; (ii) x1, y1, z; (iii) x+1, y1/2, 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

First citationAltomare, A., Cascarano, G., Giacovazzo, C. & Guagliardi, A. (1993). J. Appl. Cryst. 26, 343–350.  CrossRef Web of Science IUCr Journals
First citationCini, M., Crotti, P. & Macchia, F. (1990). Tetrahedron Lett. 31, 4661–4664.
First citationCremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1358.  CrossRef CAS Web of Science
First citationFarrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.  Web of Science CrossRef CAS IUCr Journals
First citationFlack, H. D. (2003). Helv. Chim. Acta, 86, 905–921.  Web of Science CrossRef CAS
First citationJas, G., Freifeld, I. & Kesseler, K. (2011). Patent WO 2011091968 (Corden PharmaChem GmbH).
First citationNonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.
First citationOtwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.
First citationPeeters, O. M., Blaton, N. M. & De Ranter, C. J. (1993). Acta Cryst. C49, 2154–2157.  CSD CrossRef CAS Web of Science IUCr Journals
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals
First citationStewart, J. P. (2009). MOPAC2009. Stewart Computational Chemistry. Available from: http://OpenMOPAC.net.
First citationTuchalski, G., Emmerling, F., Groger, K., Hansicke, A., Nagel, T. & Reck, G. (2006). J. Mol. Struct. 800, 28–44.  Web of Science CSD CrossRef CAS
First citationTuchalski, G., Hänsicke, A., Reck, G. & Emmerling, F. (2008). Acta Cryst. E64, o54.  Web of Science CSD CrossRef IUCr Journals
First citationVan Lommen, G. R. E., de Bruyn, M. F. L. & Schroven, M. F. J. (1990). J. Pharm. Belg. 45, 355–360.  PubMed CAS

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds