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

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ISSN: 2056-9890

(3S,4R,4aS,7aR,12bS)-3-Cyclo­propyl­meth­yl-4a,9-dihy­dr­oxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octa­hydro-1H-4,12-methano-1-benzofuro[3,2-e]isoquinolin-3-ium 2,2,2-tri­fluoro­acetate methanol solvate

aBeijing Institute of Pharmacology and Toxicology, Beijing, 100850, People's Republic of China
*Correspondence e-mail: hapwave@yahoo.cn

(Received 2 October 2010; accepted 13 October 2010; online 20 October 2010)

In the title compound, C21H26F3NO6+·CF3COO·CH3OH or S-MNTX·CF3COO·CH3OH (MNTX = methyl­naltrexone), the conformation of the polycyclic backbone of the noroxy­morphone skeleton can be simplified in terms of the angles between the least-squares planes of these rings. The dihedral angle between the cyclohexene and piperidine rings is 84.5 (6)°, while the dihedral angles between the planes of cyclohexane ring and the benzene, cyclohexene and piperidine rings, respectively, are 85.8 (6),80.0  (7) and 10.3 (7)°. In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds. The trifluoro­acetate F atoms are disordered in a 0.710 (14):0.710 (14) ratio. The absolute stereochemistry was inferred from the use of (4R,4aS,7aR,12bS)-3-(cyclo­propyl­meth­yl)-4a,9-dihy­droxy-2,3,4,4a,5,6-hexa­hydro-1H-4,12-meth­ano­benzofuro[3,2-e]isoquinolin-7(7aH)-one as one of the starting materials.

Related literature

For general background to methyl­naltrexone (MNTX) bromide and R-MNTX, see: Crabtree (1984[Crabtree, B. L. (1984). Clin Pharm. 3, 273-280.]); Doshan & Perez (2006[Doshan, H. D. & Perez, J. (2006). WO Patent, WO 2006127899.]). For the bioactivity and synthesis of S-MNTX, see: Wagoner et al. (2006[Wagoner, H., Sanghvi, S. P., Boyd, T. A., Verbicky, C. & Andruski, S. (2006). WO Patent WO2006127898.]).

[Scheme 1]

Experimental

Crystal data
  • C21H26NO4+·C2F3O2·CH4O

  • Mr = 501.49

  • Orthorhombic, P 21 21 21

  • a = 9.404 (2) Å

  • b = 12.526 (3) Å

  • c = 19.693 (5) Å

  • V = 2319.8 (10) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.12 mm−1

  • T = 113 K

  • 0.20 × 0.18 × 0.14 mm

Data collection
  • Rigaku Saturn CCD area detector diffractometer

  • Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005[Rigaku/MSC (2005). CrystalClear. Rigaku/MSC,The Woodlands Texas, USA.]) Tmin = 0.976, Tmax = 0.983

  • 16033 measured reflections

  • 2336 independent reflections

  • 2261 reflections with I > 2σ(I)

  • Rint = 0.030

Refinement
  • R[F2 > 2σ(F2)] = 0.032

  • wR(F2) = 0.079

  • S = 1.07

  • 2336 reflections

  • 349 parameters

  • 66 restraints

  • H-atom parameters constrained

  • Δρmax = 0.22 e Å−3

  • Δρmin = −0.19 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1⋯O5i 0.84 1.79 2.622 (2) 170
O4—H4⋯O7ii 0.84 1.86 2.685 (2) 169
O7—H7A⋯O6ii 0.84 1.88 2.698 (2) 166
Symmetry codes: (i) [-x+2, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]; (ii) [-x+1, y+{\script{1\over 2}}, -z+{\script{1\over 2}}].

Data collection: CrystalClear (Rigaku/MSC, 2005[Rigaku/MSC (2005). CrystalClear. Rigaku/MSC,The Woodlands Texas, USA.]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: XCIF in SHELXTL.

Supporting information


Comment top

Methylnaltrexone (MNTX) is a quaternary derivative of the pure opioid antagonist naltrexone, which is a chiral molecule and the quaternary nitrogen can be in R or S configuration. R-MNTX bromide, as a peripheral opioid antagonist, has been used in clinic to refrain from addiction caused by meconium drugs. However, it has been found surprisingly that S-MNTX exhibited opioid agonist activity (Wagoner et al., 2006). In this paper, we report the synthesis and crystal structure of the title compound 2,2,2-trifluoroacetate of S-MNTX.

In the crystal structure of the title compound (Fig.1), C24H30F3NO7, the conformation of the polycyclic backbone of the noroxymorphone skeleton can be simplified in terms of the angles between the least-squares planes of these rings. Ring A is defined by atoms C1—C6, ring B by atoms C4/C5/C11/C12/C15/C16, ring C by atoms C7—C12, and ring D by atoms C11—C14/ C16/N1. The angle between the rings B and D is 84.5 (6)°. The angle between the planes of ring C and ring A/B/D is respectively 85.8 (6)/80.0 (7)/10.3 (7)°. The structure displays O—H···O hydrogen bonding (Table 1, Fig. 2). The structure exhibits disorder.

Related literature top

For general background to methylnaltrexone (MNTX) bromide and R-MNTX, see: Crabtree (1984); Doshan et al. (2006). For the bioactivity and synthesis of S-MNTX, see: Wagoner et al. (2006).

Experimental top

A solution of(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy- 2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH) -one(10 g, 29.4 mmol) and MeI(34 g) in 1-methyl-2-pyrrolidinone(100 mL) was stirred at 140 K for 10 h. The solvent was removed under pressure and the residue was purified by preparative reverse phase column (Waters C18) chromatography using water-methanol-TFA(74.8:25:0.2) as eluent. Two products were isolated. Colorless single crystals of the title compound were obtained from the methanol-water solution.

Refinement top

All H atoms were placed in calculated positions with C—H distances ranging from 0.95 to 1.00 Å and included in the refinement in riding-model approximation with Uiso = 1.2Ueq (1.5Ueq for methyl) of the carrier atom. In the absence of significant anomalous scattering effects, Friedel pairs were merged; the absolute configuration was inferred from the synthesis.

Structure description top

Methylnaltrexone (MNTX) is a quaternary derivative of the pure opioid antagonist naltrexone, which is a chiral molecule and the quaternary nitrogen can be in R or S configuration. R-MNTX bromide, as a peripheral opioid antagonist, has been used in clinic to refrain from addiction caused by meconium drugs. However, it has been found surprisingly that S-MNTX exhibited opioid agonist activity (Wagoner et al., 2006). In this paper, we report the synthesis and crystal structure of the title compound 2,2,2-trifluoroacetate of S-MNTX.

In the crystal structure of the title compound (Fig.1), C24H30F3NO7, the conformation of the polycyclic backbone of the noroxymorphone skeleton can be simplified in terms of the angles between the least-squares planes of these rings. Ring A is defined by atoms C1—C6, ring B by atoms C4/C5/C11/C12/C15/C16, ring C by atoms C7—C12, and ring D by atoms C11—C14/ C16/N1. The angle between the rings B and D is 84.5 (6)°. The angle between the planes of ring C and ring A/B/D is respectively 85.8 (6)/80.0 (7)/10.3 (7)°. The structure displays O—H···O hydrogen bonding (Table 1, Fig. 2). The structure exhibits disorder.

For general background to methylnaltrexone (MNTX) bromide and R-MNTX, see: Crabtree (1984); Doshan et al. (2006). For the bioactivity and synthesis of S-MNTX, see: Wagoner et al. (2006).

Computing details top

Data collection: CrystalClear (Rigaku/MSC, 2005); cell refinement: CrystalClear (Rigaku/MSC, 2005); data reduction: CrystalClear (Rigaku/MSC, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXL97 (Sheldrick, 2008); software used to prepare material for publication: XCIF in SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound, showing 50% displacement ellipsoids.
[Figure 2] Fig. 2. A partial packing diagram of title compound.
(3S,4R,4aS,7aR,12bS)-3-Cyclopropylmethyl- 4a,9-dihydroxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12- methano-1-benzofuro[3,2-e]isoquinolin-3-ium 2,2,2-trifluoroacetate methanol solvate top
Crystal data top
C21H26NO4+·C2F3O2·CH4OF(000) = 1056
Mr = 501.49Dx = 1.436 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 8884 reflections
a = 9.404 (2) Åθ = 1.6–27.9°
b = 12.526 (3) ŵ = 0.12 mm1
c = 19.693 (5) ÅT = 113 K
V = 2319.8 (10) Å3Prism, colorless
Z = 40.20 × 0.18 × 0.14 mm
Data collection top
Rigaku Saturn CCD area detector
diffractometer
2336 independent reflections
Radiation source: fine-focus sealed tube2261 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.030
Detector resolution: 14.63 pixels mm-1θmax = 25.0°, θmin = 1.9°
ω and φ scansh = 119
Absorption correction: multi-scan
CrystalClear (Rigaku/MSC, 2005)
k = 1413
Tmin = 0.976, Tmax = 0.983l = 2323
16033 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.032Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.079H-atom parameters constrained
S = 1.07 w = 1/[σ2(Fo2) + (0.051P)2 + 0.2916P]
where P = (Fo2 + 2Fc2)/3
2336 reflections(Δ/σ)max < 0.001
349 parametersΔρmax = 0.22 e Å3
66 restraintsΔρmin = 0.19 e Å3
Crystal data top
C21H26NO4+·C2F3O2·CH4OV = 2319.8 (10) Å3
Mr = 501.49Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 9.404 (2) ŵ = 0.12 mm1
b = 12.526 (3) ÅT = 113 K
c = 19.693 (5) Å0.20 × 0.18 × 0.14 mm
Data collection top
Rigaku Saturn CCD area detector
diffractometer
2336 independent reflections
Absorption correction: multi-scan
CrystalClear (Rigaku/MSC, 2005)
2261 reflections with I > 2σ(I)
Tmin = 0.976, Tmax = 0.983Rint = 0.030
16033 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.03266 restraints
wR(F2) = 0.079H-atom parameters constrained
S = 1.07Δρmax = 0.22 e Å3
2336 reflectionsΔρmin = 0.19 e Å3
349 parameters
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 > 2sigma(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. Mo Ka measured Friedel data cannot be used to determine absolute structure in a light atom study.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
O11.33431 (18)0.71301 (14)0.23591 (8)0.0281 (4)
H11.37090.71680.19710.042*
O21.14964 (17)0.71503 (13)0.35444 (7)0.0233 (4)
O31.0961 (2)0.92317 (15)0.35475 (11)0.0430 (5)
O40.69083 (18)0.71936 (12)0.41814 (7)0.0239 (4)
H40.64110.77350.42650.036*
N10.6598 (2)0.54016 (14)0.31973 (9)0.0224 (4)
C11.1913 (3)0.70077 (18)0.22998 (12)0.0238 (5)
C21.1185 (3)0.69242 (18)0.16778 (12)0.0258 (6)
H21.17190.69380.12680.031*
C30.9710 (3)0.68222 (18)0.16386 (12)0.0255 (5)
H30.92630.67880.12060.031*
C40.8880 (3)0.67693 (18)0.22272 (12)0.0230 (5)
C50.9618 (3)0.68362 (17)0.28299 (11)0.0215 (5)
C61.1068 (3)0.69866 (18)0.28753 (11)0.0219 (5)
C71.0192 (3)0.74854 (18)0.38813 (11)0.0228 (5)
H71.02360.73370.43800.027*
C80.9985 (3)0.86850 (19)0.37436 (12)0.0271 (6)
C90.8483 (3)0.90873 (18)0.38089 (13)0.0286 (6)
H9A0.84480.98590.37020.034*
H9B0.81440.89870.42810.034*
C100.7521 (3)0.84654 (17)0.33149 (12)0.0244 (5)
H10A0.65440.87590.33290.029*
H10B0.78870.85390.28460.029*
C110.7500 (3)0.72831 (18)0.35199 (11)0.0211 (5)
C120.9008 (3)0.68246 (18)0.35386 (11)0.0211 (5)
C130.8942 (3)0.56643 (18)0.38041 (12)0.0222 (5)
H13A0.99180.53750.38440.027*
H13B0.85030.56560.42610.027*
C140.8082 (3)0.49697 (17)0.33281 (12)0.0240 (5)
H14A0.80040.42440.35250.029*
H14B0.85920.49090.28900.029*
C150.7269 (3)0.6745 (2)0.22605 (12)0.0258 (6)
H15A0.69210.61530.19710.031*
H15B0.68960.74190.20690.031*
C160.6658 (3)0.65996 (17)0.29849 (11)0.0225 (5)
H160.56580.68710.29780.027*
C170.5940 (3)0.4752 (2)0.26332 (12)0.0293 (6)
H17A0.66260.46740.22620.044*
H17B0.50870.51150.24650.044*
H17C0.56810.40450.28060.044*
C180.5687 (3)0.52023 (18)0.38352 (12)0.0238 (5)
H18A0.57180.44310.39440.029*
H18B0.61180.55920.42210.029*
C190.4160 (3)0.55373 (18)0.37701 (12)0.0239 (5)
H190.39970.62890.36180.029*
C200.3038 (3)0.4746 (2)0.35699 (13)0.0328 (6)
H20A0.22310.50070.32930.039*
H20B0.33450.40070.34680.039*
C210.3133 (3)0.51176 (19)0.42924 (12)0.0307 (6)
H21A0.35000.46080.46340.037*
H21B0.23860.56080.44600.037*
F10.4670 (15)0.2811 (8)0.5019 (7)0.042 (3)0.290 (14)
F20.475 (2)0.1198 (14)0.5336 (8)0.066 (4)0.290 (14)
F30.3034 (9)0.1836 (19)0.4686 (7)0.089 (4)0.290 (14)
F1'0.4075 (11)0.2763 (4)0.4989 (4)0.083 (2)0.710 (14)
F2'0.5213 (9)0.1381 (6)0.5325 (3)0.0609 (17)0.710 (14)
F3'0.3205 (5)0.1191 (5)0.4841 (2)0.0727 (15)0.710 (14)
O50.5400 (2)0.24675 (13)0.38094 (8)0.0294 (4)
O60.5533 (2)0.07136 (14)0.40010 (9)0.0396 (5)
C220.5196 (3)0.16372 (19)0.41422 (11)0.0256 (5)
C230.4420 (4)0.1785 (2)0.48217 (14)0.0434 (8)
O70.4835 (2)0.37757 (13)0.04273 (8)0.0277 (4)
H7A0.45930.43830.05660.042*
C240.6210 (3)0.3522 (2)0.06831 (13)0.0371 (7)
H24A0.68530.41260.06060.056*
H24B0.65770.28900.04490.056*
H24C0.61460.33770.11710.056*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0234 (10)0.0354 (9)0.0255 (8)0.0008 (8)0.0021 (8)0.0017 (8)
O20.0218 (9)0.0265 (9)0.0216 (7)0.0015 (7)0.0026 (7)0.0008 (7)
O30.0314 (11)0.0279 (10)0.0698 (14)0.0053 (9)0.0018 (11)0.0055 (9)
O40.0282 (10)0.0202 (8)0.0232 (7)0.0036 (7)0.0025 (7)0.0021 (6)
N10.0229 (11)0.0168 (9)0.0277 (9)0.0008 (8)0.0040 (9)0.0001 (8)
C10.0260 (14)0.0194 (11)0.0261 (12)0.0008 (10)0.0017 (11)0.0020 (9)
C20.0320 (15)0.0229 (12)0.0226 (11)0.0019 (11)0.0019 (11)0.0003 (9)
C30.0309 (15)0.0247 (12)0.0209 (11)0.0000 (11)0.0041 (11)0.0008 (9)
C40.0256 (14)0.0199 (11)0.0235 (11)0.0009 (10)0.0051 (10)0.0022 (10)
C50.0248 (13)0.0171 (11)0.0227 (11)0.0026 (9)0.0011 (10)0.0007 (9)
C60.0253 (13)0.0186 (11)0.0218 (11)0.0008 (10)0.0042 (10)0.0020 (9)
C70.0249 (13)0.0220 (12)0.0217 (10)0.0016 (10)0.0003 (10)0.0008 (9)
C80.0302 (15)0.0212 (12)0.0300 (12)0.0018 (11)0.0025 (11)0.0005 (10)
C90.0313 (14)0.0187 (11)0.0358 (12)0.0012 (10)0.0042 (12)0.0008 (10)
C100.0246 (13)0.0193 (11)0.0293 (12)0.0046 (10)0.0027 (11)0.0033 (9)
C110.0233 (12)0.0194 (11)0.0207 (11)0.0005 (10)0.0003 (10)0.0027 (9)
C120.0237 (13)0.0189 (11)0.0206 (10)0.0001 (10)0.0029 (10)0.0015 (9)
C130.0219 (13)0.0198 (11)0.0248 (11)0.0031 (10)0.0021 (10)0.0041 (9)
C140.0223 (13)0.0183 (11)0.0312 (12)0.0040 (10)0.0014 (10)0.0018 (10)
C150.0275 (14)0.0269 (12)0.0230 (12)0.0003 (10)0.0062 (10)0.0033 (10)
C160.0228 (14)0.0184 (11)0.0263 (11)0.0027 (10)0.0034 (11)0.0045 (9)
C170.0321 (15)0.0276 (12)0.0283 (12)0.0040 (12)0.0054 (11)0.0035 (10)
C180.0257 (14)0.0180 (11)0.0276 (11)0.0012 (10)0.0019 (10)0.0026 (9)
C190.0256 (14)0.0179 (11)0.0283 (12)0.0001 (10)0.0005 (11)0.0012 (10)
C200.0259 (14)0.0303 (13)0.0423 (14)0.0000 (12)0.0022 (12)0.0062 (11)
C210.0289 (15)0.0276 (13)0.0356 (13)0.0007 (11)0.0013 (12)0.0049 (10)
F10.074 (7)0.034 (4)0.018 (3)0.021 (4)0.007 (4)0.009 (3)
F20.113 (9)0.032 (5)0.052 (5)0.002 (6)0.045 (5)0.027 (4)
F30.050 (5)0.135 (9)0.081 (6)0.003 (6)0.019 (4)0.017 (6)
F1'0.148 (6)0.048 (2)0.054 (3)0.054 (3)0.053 (4)0.0154 (19)
F2'0.111 (5)0.048 (3)0.0238 (17)0.001 (3)0.002 (2)0.0139 (14)
F3'0.056 (2)0.091 (3)0.071 (2)0.001 (2)0.0386 (18)0.004 (2)
O50.0351 (10)0.0234 (9)0.0296 (8)0.0029 (8)0.0043 (8)0.0007 (7)
O60.0551 (13)0.0242 (9)0.0396 (10)0.0061 (9)0.0149 (10)0.0008 (8)
C220.0264 (14)0.0245 (12)0.0260 (12)0.0028 (11)0.0020 (11)0.0010 (10)
C230.060 (2)0.0361 (16)0.0343 (15)0.0108 (15)0.0087 (15)0.0001 (12)
O70.0292 (10)0.0231 (8)0.0308 (9)0.0009 (8)0.0008 (8)0.0004 (7)
C240.0328 (16)0.0426 (16)0.0361 (14)0.0019 (13)0.0040 (13)0.0039 (12)
Geometric parameters (Å, º) top
O1—C11.359 (3)C13—H13B0.9900
O1—H10.8400C14—H14A0.9900
O2—C61.393 (3)C14—H14B0.9900
O2—C71.456 (3)C15—C161.549 (3)
O3—C81.209 (3)C15—H15A0.9900
O4—C111.421 (3)C15—H15B0.9900
O4—H40.8400C16—H161.0000
N1—C171.510 (3)C17—H17A0.9800
N1—C141.519 (3)C17—H17B0.9800
N1—C181.541 (3)C17—H17C0.9800
N1—C161.559 (3)C18—C191.501 (3)
C1—C61.384 (3)C18—H18A0.9900
C1—C21.407 (3)C18—H18B0.9900
C2—C31.395 (4)C19—C201.501 (3)
C2—H20.9500C19—C211.506 (3)
C3—C41.399 (3)C19—H191.0000
C3—H30.9500C20—C211.500 (4)
C4—C51.378 (3)C20—H20A0.9900
C4—C151.517 (4)C20—H20B0.9900
C5—C61.380 (4)C21—H21A0.9900
C5—C121.509 (3)C21—H21B0.9900
C7—C81.539 (3)F1—C231.363 (9)
C7—C121.543 (3)F2—C231.290 (10)
C7—H71.0000F3—C231.332 (8)
C8—C91.505 (4)F1'—C231.309 (6)
C9—C101.540 (3)F2'—C231.340 (5)
C9—H9A0.9900F3'—C231.364 (5)
C9—H9B0.9900O5—C221.244 (3)
C10—C111.535 (3)O6—C221.231 (3)
C10—H10A0.9900C22—C231.536 (4)
C10—H10B0.9900O7—C241.423 (3)
C11—C121.530 (3)O7—H7A0.8400
C11—C161.572 (3)C24—H24A0.9800
C12—C131.546 (3)C24—H24B0.9800
C13—C141.513 (3)C24—H24C0.9800
C13—H13A0.9900
C1—O1—H1109.5C4—C15—H15A108.7
C6—O2—C7103.31 (17)C16—C15—H15A108.7
C11—O4—H4109.5C4—C15—H15B108.7
C17—N1—C14108.01 (18)C16—C15—H15B108.7
C17—N1—C18106.54 (18)H15A—C15—H15B107.6
C14—N1—C18108.35 (16)C15—C16—N1111.92 (18)
C17—N1—C16109.65 (17)C15—C16—C11111.50 (19)
C14—N1—C16110.83 (18)N1—C16—C11111.26 (17)
C18—N1—C16113.25 (17)C15—C16—H16107.3
O1—C1—C6120.0 (2)N1—C16—H16107.3
O1—C1—C2124.4 (2)C11—C16—H16107.3
C6—C1—C2115.6 (2)N1—C17—H17A109.5
C3—C2—C1122.6 (2)N1—C17—H17B109.5
C3—C2—H2118.7H17A—C17—H17B109.5
C1—C2—H2118.7N1—C17—H17C109.5
C2—C3—C4120.9 (2)H17A—C17—H17C109.5
C2—C3—H3119.6H17B—C17—H17C109.5
C4—C3—H3119.6C19—C18—N1114.64 (19)
C5—C4—C3115.4 (2)C19—C18—H18A108.6
C5—C4—C15117.9 (2)N1—C18—H18A108.6
C3—C4—C15126.5 (2)C19—C18—H18B108.6
C4—C5—C6124.2 (2)N1—C18—H18B108.6
C4—C5—C12127.2 (2)H18A—C18—H18B107.6
C6—C5—C12108.5 (2)C20—C19—C18120.7 (2)
C5—C6—C1121.1 (2)C20—C19—C2159.85 (16)
C5—C6—O2111.5 (2)C18—C19—C21117.2 (2)
C1—C6—O2127.3 (2)C20—C19—H19115.8
O2—C7—C8107.92 (18)C18—C19—H19115.8
O2—C7—C12104.70 (17)C21—C19—H19115.8
C8—C7—C12110.80 (19)C21—C20—C1960.24 (16)
O2—C7—H7111.1C21—C20—H20A117.7
C8—C7—H7111.1C19—C20—H20A117.7
C12—C7—H7111.1C21—C20—H20B117.7
O3—C8—C9123.4 (2)C19—C20—H20B117.7
O3—C8—C7120.9 (2)H20A—C20—H20B114.9
C9—C8—C7115.5 (2)C20—C21—C1959.91 (17)
C8—C9—C10109.13 (19)C20—C21—H21A117.8
C8—C9—H9A109.9C19—C21—H21A117.8
C10—C9—H9A109.9C20—C21—H21B117.8
C8—C9—H9B109.9C19—C21—H21B117.8
C10—C9—H9B109.9H21A—C21—H21B114.9
H9A—C9—H9B108.3O6—C22—O5128.8 (2)
C11—C10—C9109.23 (19)O6—C22—C23115.6 (2)
C11—C10—H10A109.8O5—C22—C23115.5 (2)
C9—C10—H10A109.8F2—C23—F1'113.3 (10)
C11—C10—H10B109.8F2—C23—F3114.8 (10)
C9—C10—H10B109.8F1'—C23—F376.3 (7)
H10A—C10—H10B108.3F2—C23—F2'21.5 (8)
O4—C11—C12108.15 (18)F1'—C23—F2'107.8 (5)
O4—C11—C10108.80 (18)F3—C23—F2'135.3 (8)
C12—C11—C10110.9 (2)F2—C23—F1105.8 (11)
O4—C11—C16111.95 (18)F1'—C23—F124.3 (6)
C12—C11—C16106.19 (18)F3—C23—F1100.4 (9)
C10—C11—C16110.83 (18)F2'—C23—F192.8 (7)
C5—C12—C11109.05 (19)F2—C23—F3'82.5 (8)
C5—C12—C797.19 (19)F1'—C23—F3'107.2 (4)
C11—C12—C7118.55 (19)F3—C23—F3'38.0 (8)
C5—C12—C13109.71 (18)F2'—C23—F3'103.9 (4)
C11—C12—C13108.87 (19)F1—C23—F3'130.6 (6)
C7—C12—C13112.68 (19)F2—C23—C22120.1 (9)
C14—C13—C12110.65 (19)F1'—C23—C22116.7 (4)
C14—C13—H13A109.5F3—C23—C22107.3 (5)
C12—C13—H13A109.5F2'—C23—C22109.5 (4)
C14—C13—H13B109.5F1—C23—C22106.3 (7)
C12—C13—H13B109.5F3'—C23—C22110.9 (3)
H13A—C13—H13B108.1C24—O7—H7A109.5
C13—C14—N1113.03 (18)O7—C24—H24A109.5
C13—C14—H14A109.0O7—C24—H24B109.5
N1—C14—H14A109.0H24A—C24—H24B109.5
C13—C14—H14B109.0O7—C24—H24C109.5
N1—C14—H14B109.0H24A—C24—H24C109.5
H14A—C14—H14B107.8H24B—C24—H24C109.5
C4—C15—C16114.4 (2)
O1—C1—C2—C3178.6 (2)C8—C7—C12—C579.5 (2)
C6—C1—C2—C30.2 (3)O2—C7—C12—C11152.89 (18)
C1—C2—C3—C41.7 (4)C8—C7—C12—C1136.8 (3)
C2—C3—C4—C50.7 (3)O2—C7—C12—C1378.3 (2)
C2—C3—C4—C15175.0 (2)C8—C7—C12—C13165.6 (2)
C3—C4—C5—C62.4 (3)C5—C12—C13—C1456.7 (3)
C15—C4—C5—C6172.4 (2)C11—C12—C13—C1462.5 (2)
C3—C4—C5—C12178.7 (2)C7—C12—C13—C14163.8 (2)
C15—C4—C5—C123.9 (4)C12—C13—C14—N155.1 (2)
C4—C5—C6—C14.6 (4)C17—N1—C14—C13170.77 (19)
C12—C5—C6—C1178.6 (2)C18—N1—C14—C1374.2 (2)
C4—C5—C6—O2172.8 (2)C16—N1—C14—C1350.6 (2)
C12—C5—C6—O24.0 (3)C5—C4—C15—C1610.2 (3)
O1—C1—C6—C5178.3 (2)C3—C4—C15—C16175.7 (2)
C2—C1—C6—C53.3 (3)C4—C15—C16—N184.1 (3)
O1—C1—C6—O24.7 (4)C4—C15—C16—C1141.3 (3)
C2—C1—C6—O2173.7 (2)C17—N1—C16—C1547.7 (3)
C7—O2—C6—C520.5 (2)C14—N1—C16—C1571.5 (2)
C7—O2—C6—C1156.8 (2)C18—N1—C16—C15166.53 (19)
C6—O2—C7—C881.9 (2)C17—N1—C16—C11173.2 (2)
C6—O2—C7—C1236.2 (2)C14—N1—C16—C1154.0 (2)
O2—C7—C8—O317.3 (3)C18—N1—C16—C1168.0 (3)
C12—C7—C8—O3131.4 (2)O4—C11—C16—C15177.34 (18)
O2—C7—C8—C9157.47 (19)C12—C11—C16—C1564.8 (2)
C12—C7—C8—C943.4 (3)C10—C11—C16—C1555.7 (3)
O3—C8—C9—C10116.4 (3)O4—C11—C16—N156.9 (2)
C7—C8—C9—C1058.2 (3)C12—C11—C16—N160.9 (2)
C8—C9—C10—C1163.6 (2)C10—C11—C16—N1178.62 (19)
C9—C10—C11—O462.3 (2)C17—N1—C18—C1961.0 (2)
C9—C10—C11—C1256.5 (2)C14—N1—C18—C19176.99 (18)
C9—C10—C11—C16174.2 (2)C16—N1—C18—C1959.6 (3)
C4—C5—C12—C1128.4 (3)N1—C18—C19—C2095.2 (2)
C6—C5—C12—C11148.30 (19)N1—C18—C19—C21164.64 (19)
C4—C5—C12—C7152.0 (2)C18—C19—C20—C21105.7 (3)
C6—C5—C12—C724.7 (2)C18—C19—C21—C20111.4 (2)
C4—C5—C12—C1390.8 (3)O6—C22—C23—F235.2 (10)
C6—C5—C12—C1392.5 (2)O5—C22—C23—F2144.7 (10)
O4—C11—C12—C5175.83 (18)O6—C22—C23—F1'178.7 (6)
C10—C11—C12—C565.0 (2)O5—C22—C23—F1'1.3 (7)
C16—C11—C12—C555.5 (2)O6—C22—C23—F398.2 (11)
O4—C11—C12—C774.4 (2)O5—C22—C23—F381.8 (11)
C10—C11—C12—C744.8 (3)O6—C22—C23—F2'55.9 (5)
C16—C11—C12—C7165.30 (19)O5—C22—C23—F2'124.1 (4)
O4—C11—C12—C1356.1 (2)O6—C22—C23—F1155.0 (6)
C10—C11—C12—C13175.36 (17)O5—C22—C23—F125.0 (7)
C16—C11—C12—C1364.2 (2)O6—C22—C23—F3'58.1 (4)
O2—C7—C12—C536.6 (2)O5—C22—C23—F3'121.9 (4)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O5i0.841.792.622 (2)170
O4—H4···O7ii0.841.862.685 (2)169
O7—H7A···O6ii0.841.882.698 (2)166
Symmetry codes: (i) x+2, y+1/2, z+1/2; (ii) x+1, y+1/2, z+1/2.

Experimental details

Crystal data
Chemical formulaC21H26NO4+·C2F3O2·CH4O
Mr501.49
Crystal system, space groupOrthorhombic, P212121
Temperature (K)113
a, b, c (Å)9.404 (2), 12.526 (3), 19.693 (5)
V3)2319.8 (10)
Z4
Radiation typeMo Kα
µ (mm1)0.12
Crystal size (mm)0.20 × 0.18 × 0.14
Data collection
DiffractometerRigaku Saturn CCD area detector
Absorption correctionMulti-scan
CrystalClear (Rigaku/MSC, 2005)
Tmin, Tmax0.976, 0.983
No. of measured, independent and
observed [I > 2σ(I)] reflections
16033, 2336, 2261
Rint0.030
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.032, 0.079, 1.07
No. of reflections2336
No. of parameters349
No. of restraints66
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.22, 0.19

Computer programs: CrystalClear (Rigaku/MSC, 2005), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), XCIF in SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O5i0.841.792.622 (2)170.2
O4—H4···O7ii0.841.862.685 (2)169.4
O7—H7A···O6ii0.841.882.698 (2)165.9
Symmetry codes: (i) x+2, y+1/2, z+1/2; (ii) x+1, y+1/2, z+1/2.
 

Acknowledgements

This work was supported by the National Science Foundation of China and grant No. 2009ZX09501-005.

References

First citationCrabtree, B. L. (1984). Clin Pharm. 3, 273–280.  CAS PubMed Web of Science Google Scholar
First citationDoshan, H. D. & Perez, J. (2006). WO Patent, WO 2006127899.  Google Scholar
First citationRigaku/MSC (2005). CrystalClear. Rigaku/MSC,The Woodlands Texas, USA.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationWagoner, H., Sanghvi, S. P., Boyd, T. A., Verbicky, C. & Andruski, S. (2006). WO Patent WO2006127898.  Google Scholar

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