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

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

Dabigatran etexilate tetra­hydrate

aState Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Centre for New Drug Safety Assessment and Research, Tianjin 300193, People's Republic of China, and bGraduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, People's Republic of China
*Correspondence e-mail: xiupingshen@yahoo.com

(Received 3 November 2012; accepted 12 November 2012; online 17 November 2012)

In the title compound, C34H41N7O5·4H2O (systematic name: ethyl 3-{[2-({4-[(Z)-amino­(hexyl­oxycarbonyl­imino)­meth­yl]anilino}meth­yl)-1-meth­yl­benzimidazole-5-carbon­yl]pyridin-2-yl­amino}­propano­ate tetra­hydrate), the benzene and pyridine rings form dihedral angles of 5.4 (1) and 43.8 (1)°, respectively, with the benzimidazole mean plane. The terminal butyl group is disordered over two conformations in a 0.756 (10):0.244 (10) ratio. There is an intramolecular N—H⋯O hydrogen bond present. In the crystal, the water mol­ecules are involved in the formation of O—H⋯O, O—H⋯N and N—H⋯O hydrogen bonds, which link the components into layers parallel to the ab plane.

Related literature

For background to the anti­coagulant drug dabigatran etexil­ate, see: Nagarakanti & Ellis (2012[Nagarakanti, R. & Ellis, C. R. (2012). Clin. Ther. 34, 2051-2060.]); Van Ryn et al. (2010[Van Ryn, J., Stangier, J., Haertter, S., Liesenfeld, K. H., Wienen, W., Feuring, M. & Clemens, A. (2010). Thromb. Haemost. 103, 1116-1127.]).

[Scheme 1]

Experimental

Crystal data
  • C34H41N7O5·4H2O

  • Mr = 699.80

  • Triclinic, [P \overline 1]

  • a = 9.1140 (13) Å

  • b = 10.9700 (14) Å

  • c = 18.3830 (17) Å

  • α = 88.51 (1)°

  • β = 85.455 (9)°

  • γ = 83.034 (12)°

  • V = 1818.4 (4) Å3

  • Z = 2

  • Mo Kα radiation

  • μ = 0.09 mm−1

  • T = 113 K

  • 0.22 × 0.20 × 0.18 mm

Data collection
  • Rigaku Saturn 724 CCD area-detector diffractometer

  • Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2009[Rigaku/MSC (2009). CrystalClear. Rigaku/MSC, The Woodlands, Texas, USA.]) Tmin = 0.980, Tmax = 0.983

  • 23569 measured reflections

  • 8627 independent reflections

  • 5187 reflections with I > 2σ(I)

  • Rint = 0.036

Refinement
  • R[F2 > 2σ(F2)] = 0.039

  • wR(F2) = 0.103

  • S = 0.96

  • 8627 reflections

  • 513 parameters

  • 40 restraints

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

  • Δρmax = 0.42 e Å−3

  • Δρmin = −0.37 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N1—H1⋯O7i 0.896 (17) 1.980 (18) 2.8468 (16) 162.5 (15)
N1—H2⋯O1 0.902 (15) 1.931 (16) 2.6281 (16) 132.7 (13)
O6—H8⋯N5 0.912 (19) 1.88 (2) 2.7938 (16) 176.3 (16)
O6—H16⋯O3ii 0.84 (2) 2.00 (2) 2.8373 (15) 172.1 (18)
O7—H17⋯O8 0.861 (19) 1.954 (19) 2.8061 (16) 170.2 (18)
O7—H18⋯O9 0.881 (18) 1.871 (19) 2.7513 (15) 176.5 (17)
O9—H20⋯N2 0.93 (2) 2.00 (2) 2.9226 (16) 168.8 (19)
O9—H20⋯O2 0.93 (2) 2.43 (2) 3.1126 (14) 129.6 (16)
O9—H24⋯N7iii 0.844 (19) 2.050 (19) 2.8918 (16) 175.5 (18)
O8—H25⋯O6 0.84 (2) 2.04 (2) 2.8689 (17) 171 (2)
O8—H32⋯O6iii 0.94 (2) 1.89 (2) 2.8291 (17) 175.3 (17)
Symmetry codes: (i) x-1, y, z; (ii) -x+1, -y+2, -z+2; (iii) -x+1, -y+1, -z+2.

Data collection: CrystalClear (Rigaku/MSC, 2009[Rigaku/MSC (2009). 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: SHELXTL.

Supporting information


Comment top

Dabigatran etexilate is an oral anticoagulant drug (Nagarakanti & Ellis 2012; Van Ryn et al., 2010). During our study on this drug, we obtained the single crystals of its tetrahydrate, which provides a valuable insight into the crystal structure of this drug.

In the title compound (Fig. 1), the benzene and pyridine rings form dihedral angles of 5.4 (1) and 43.8 (1)°, respectively, with the benzimidazole mean plane. The terminal butyl group is disordered over two conformations in a ratio 0.756 (1):0.244 (1). The crystalline water molecules are involved in formation of O—H···O, O—H···N and N—H···O hydrogen bonds (Table 1), which link all moieties into layers parallel to the ab plane.

Related literature top

For background to the anticoagulant drug dabigatran etexilate, see: Nagarakanti & Ellis (2012); Van Ryn et al. (2010).

Experimental top

5.00 g (10 mmol) of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)- 1H-benzo[d]imidazole-5-carboxamido)propanoate was dissolved in 40 ml of THF and 10 ml of water, and 8.29 (60 mmol) of potassium carbonate was added. The mixture was stirred at room temperature for 20 min, followed by dropwise addition of 3.29 g (20 mmol) of n-hexyl chloroformate. The reaction mixture was stirred at room temperature until the reaction completed (typical 4–6 h). The reaction mixture was diluted with 100 ml of dichloromethane, washed with saturated brine, dried over sodium sulfate and evaporated on a rotary evaporator to afford the crude product as a white solid. The crude product was triturated with ethyl acetate/petroleum ether (1/2) to yield the pure product as a white solid. Single crystals suitable for X-ray diffraction were obtained through slow evaporation of a solution of the pure title compound in ethyl acetate/petroleum ether (1/2 by volume).

Refinement top

N- and O-bound H atoms were located on a difference map and isotropically refined. C-bound H atoms were geometrically positioned (C–H = 0.95–0.99 Å), and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2–1.5Ueq(C).

Computing details top

Data collection: CrystalClear (Rigaku/MSC, 2009); cell refinement: CrystalClear (Rigaku/MSC, 2009); data reduction: CrystalClear (Rigaku/MSC, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. View of the title compound showing the atomic numbering and 40% probability displacement ellipsoids. For the disordered atoms, only major parts are shown.
Ethyl 3-{[2-({4-[(Z)-amino(hexyloxycarbonylimino)methyl]anilino}methyl)-1- methylbenzimidazole-5-carbonyl]pyridin-2-ylamino}propanoate tetrahydrate top
Crystal data top
C34H41N7O5·4H2OZ = 2
Mr = 699.80F(000) = 748
Triclinic, P1Dx = 1.278 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 9.1140 (13) ÅCell parameters from 6648 reflections
b = 10.9700 (14) Åθ = 1.9–27.9°
c = 18.3830 (17) ŵ = 0.09 mm1
α = 88.51 (1)°T = 113 K
β = 85.455 (9)°Prism, colourless
γ = 83.034 (12)°0.22 × 0.20 × 0.18 mm
V = 1818.4 (4) Å3
Data collection top
Rigaku Saturn 724 CCD area-detector
diffractometer
8627 independent reflections
Radiation source: rotating anode5187 reflections with I > 2σ(I)
Multilayer monochromatorRint = 0.036
Detector resolution: 14.222 pixels mm-1θmax = 27.9°, θmin = 1.9°
ω and ϕ scansh = 1111
Absorption correction: multi-scan
(CrystalClear; Rigaku/MSC, 2009)
k = 1414
Tmin = 0.980, Tmax = 0.983l = 2424
23569 measured 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)] = 0.039H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.103 w = 1/[σ2(Fo2) + (0.0522P)2]
where P = (Fo2 + 2Fc2)/3
S = 0.96(Δ/σ)max = 0.003
8627 reflectionsΔρmax = 0.42 e Å3
513 parametersΔρmin = 0.37 e Å3
40 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0080 (11)
Crystal data top
C34H41N7O5·4H2Oγ = 83.034 (12)°
Mr = 699.80V = 1818.4 (4) Å3
Triclinic, P1Z = 2
a = 9.1140 (13) ÅMo Kα radiation
b = 10.9700 (14) ŵ = 0.09 mm1
c = 18.3830 (17) ÅT = 113 K
α = 88.51 (1)°0.22 × 0.20 × 0.18 mm
β = 85.455 (9)°
Data collection top
Rigaku Saturn 724 CCD area-detector
diffractometer
8627 independent reflections
Absorption correction: multi-scan
(CrystalClear; Rigaku/MSC, 2009)
5187 reflections with I > 2σ(I)
Tmin = 0.980, Tmax = 0.983Rint = 0.036
23569 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.03940 restraints
wR(F2) = 0.103H atoms treated by a mixture of independent and constrained refinement
S = 0.96Δρmax = 0.42 e Å3
8627 reflectionsΔρmin = 0.37 e Å3
513 parameters
Special details top

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)
O10.07658 (10)0.08373 (9)0.62025 (5)0.0267 (2)
O20.17115 (10)0.05322 (9)0.62048 (5)0.0270 (2)
O30.42751 (11)1.14550 (9)1.09974 (5)0.0287 (2)
O40.04154 (11)1.24401 (10)1.31026 (6)0.0381 (3)
O50.17441 (10)1.34627 (9)1.37972 (5)0.0279 (2)
O60.39167 (12)0.67342 (10)0.95328 (6)0.0275 (2)
O70.50826 (11)0.30578 (10)0.79165 (6)0.0295 (3)
O80.44104 (13)0.41395 (12)0.92879 (7)0.0384 (3)
O90.35290 (12)0.12591 (10)0.74559 (6)0.0312 (3)
N10.20452 (13)0.22911 (11)0.72416 (7)0.0235 (3)
N20.05361 (12)0.18903 (10)0.69881 (6)0.0203 (3)
N30.03535 (13)0.61137 (11)0.93156 (7)0.0240 (3)
N40.10668 (11)0.85922 (10)1.05945 (6)0.0183 (2)
N50.12518 (11)0.79155 (10)1.01673 (6)0.0192 (2)
N60.35894 (11)1.13593 (10)1.22064 (6)0.0189 (2)
N70.60387 (12)1.13966 (10)1.25116 (6)0.0224 (3)
C10.06690 (14)0.24665 (12)0.73487 (7)0.0181 (3)
C20.04330 (14)0.33887 (11)0.78872 (7)0.0176 (3)
C30.09907 (14)0.37209 (12)0.79453 (7)0.0203 (3)
H30.18040.33180.76530.024*
C40.12344 (14)0.46122 (12)0.84135 (7)0.0212 (3)
H40.22120.48140.84430.025*
C50.00592 (14)0.52322 (12)0.88503 (7)0.0187 (3)
C60.13680 (14)0.49039 (12)0.88028 (7)0.0215 (3)
H60.21800.53070.90950.026*
C70.15985 (14)0.39941 (12)0.83304 (7)0.0213 (3)
H70.25710.37770.83070.026*
C80.03660 (15)0.10830 (12)0.64545 (7)0.0206 (3)
C90.17173 (15)0.03820 (13)0.56542 (8)0.0270 (3)
H9A0.12700.00050.52160.032*
H9B0.11330.10430.58420.032*
C100.33034 (16)0.09023 (14)0.54624 (8)0.0337 (4)
H10A0.37660.11340.59050.040*0.756 (10)
H10B0.38200.02750.52220.040*0.756 (10)
H10C0.37090.12810.58910.040*0.244 (10)
H10D0.38630.02400.53120.040*0.244 (10)
C110.3481 (5)0.1909 (4)0.4920 (3)0.0363 (10)0.756 (10)
H11A0.30060.15950.44750.044*0.756 (10)
H11B0.29390.25850.51250.044*0.756 (10)
C120.5069 (4)0.2433 (3)0.4700 (2)0.0317 (8)0.756 (10)
H12A0.55800.26570.51480.038*0.756 (10)
H12B0.55780.17820.44400.038*0.756 (10)
C130.5237 (4)0.3553 (4)0.4216 (2)0.0413 (9)0.756 (10)
H13A0.47650.42240.44760.050*0.756 (10)
H13B0.47240.33450.37660.050*0.756 (10)
C140.6862 (7)0.3987 (8)0.4014 (5)0.0448 (5)0.756 (10)
H14A0.73450.33060.37880.067*0.756 (10)
H14B0.69410.46630.36690.067*0.756 (10)
H14C0.73470.42730.44540.067*0.756 (10)
C11'0.3396 (14)0.2118 (12)0.5051 (9)0.0363 (10)0.244 (10)
H11C0.28940.27200.53600.044*0.244 (10)
H11D0.28710.19730.46000.044*0.244 (10)
C12'0.4992 (14)0.2644 (12)0.4854 (7)0.0317 (8)0.244 (10)
H12C0.56310.19900.49090.038*0.244 (10)
H12D0.52700.33040.52130.038*0.244 (10)
C13'0.5337 (14)0.3157 (13)0.4106 (6)0.0413 (9)0.244 (10)
H13C0.53480.24700.37460.050*0.244 (10)
H13D0.45420.36460.39930.050*0.244 (10)
C14'0.683 (2)0.397 (2)0.4025 (14)0.0448 (5)0.244 (10)
H14D0.71210.41040.35060.067*0.244 (10)
H14E0.67370.47580.42740.067*0.244 (10)
H14F0.75820.35590.42430.067*0.244 (10)
C150.08019 (14)0.68470 (12)0.97473 (7)0.0200 (3)
H15A0.13290.63081.00900.024*
H15B0.15280.72680.94230.024*
C160.01657 (14)0.77783 (12)1.01663 (7)0.0183 (3)
C170.01616 (14)0.93177 (12)1.09055 (7)0.0179 (3)
C180.12911 (14)0.88895 (11)1.06367 (7)0.0174 (3)
C190.24838 (14)0.94473 (12)1.08399 (7)0.0194 (3)
H190.34690.91771.06550.023*
C200.21816 (14)1.04163 (12)1.13237 (7)0.0194 (3)
C210.07151 (15)1.08313 (12)1.15878 (7)0.0210 (3)
H210.05451.14961.19170.025*
C220.04793 (15)1.02964 (12)1.13805 (7)0.0209 (3)
H220.14681.05831.15540.025*
C230.26885 (14)0.86874 (13)1.07118 (8)0.0249 (3)
H23A0.31030.84801.02610.030*
H23B0.30810.95291.08480.030*
H23C0.29640.81171.11040.030*
C240.34361 (14)1.10995 (12)1.14951 (7)0.0201 (3)
C250.47803 (14)1.20529 (12)1.23399 (7)0.0189 (3)
C260.45451 (15)1.33195 (12)1.23265 (8)0.0236 (3)
H260.36271.37451.22000.028*
C270.56949 (15)1.39514 (13)1.25036 (8)0.0267 (3)
H270.55771.48241.25040.032*
C280.70211 (15)1.32896 (13)1.26806 (8)0.0259 (3)
H280.78281.37001.28000.031*
C290.71403 (15)1.20250 (13)1.26791 (7)0.0244 (3)
H290.80471.15751.28030.029*
C300.30221 (15)1.06478 (12)1.28412 (7)0.0219 (3)
H30A0.37660.99401.29410.026*
H30B0.21051.03221.27220.026*
C310.26932 (15)1.14206 (13)1.35196 (7)0.0244 (3)
H31A0.23901.08911.39350.029*
H31B0.36111.17491.36360.029*
C320.14955 (15)1.24727 (14)1.34383 (7)0.0250 (3)
C330.06161 (17)1.45193 (14)1.37596 (9)0.0335 (4)
H33A0.03441.43151.39900.040*
H33B0.04831.47641.32450.040*
C340.11330 (19)1.55442 (14)1.41568 (9)0.0388 (4)
H34A0.12761.52861.46630.047*
H34B0.03881.62671.41500.047*
H34C0.20731.57491.39170.047*
H10.2851 (19)0.2647 (16)0.7500 (10)0.050 (5)*
H20.2158 (17)0.1769 (14)0.6885 (9)0.033 (4)*
H50.1212 (17)0.6292 (14)0.9290 (8)0.034 (5)*
H80.307 (2)0.7148 (16)0.9744 (10)0.055 (6)*
H160.442 (2)0.7259 (17)0.9336 (10)0.057 (6)*
H170.482 (2)0.3315 (17)0.8352 (11)0.059 (6)*
H180.455 (2)0.2495 (17)0.7780 (10)0.053 (6)*
H200.263 (3)0.145 (2)0.7243 (12)0.085 (7)*
H240.367 (2)0.0486 (17)0.7441 (10)0.051 (6)*
H250.431 (2)0.4908 (19)0.9311 (11)0.068 (7)*
H320.502 (2)0.3853 (17)0.9665 (11)0.061 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0211 (5)0.0330 (6)0.0271 (5)0.0033 (4)0.0044 (4)0.0115 (4)
O20.0199 (5)0.0321 (6)0.0289 (5)0.0010 (4)0.0004 (4)0.0144 (5)
O30.0310 (6)0.0362 (6)0.0221 (5)0.0181 (5)0.0004 (4)0.0038 (4)
O40.0240 (6)0.0475 (7)0.0435 (7)0.0025 (5)0.0132 (5)0.0163 (6)
O50.0264 (5)0.0280 (6)0.0297 (6)0.0008 (4)0.0064 (4)0.0042 (5)
O60.0232 (6)0.0238 (6)0.0345 (6)0.0029 (5)0.0040 (5)0.0018 (5)
O70.0228 (5)0.0303 (6)0.0367 (7)0.0089 (5)0.0025 (5)0.0116 (5)
O80.0460 (7)0.0293 (7)0.0413 (7)0.0022 (6)0.0193 (6)0.0113 (6)
O90.0274 (6)0.0215 (6)0.0468 (7)0.0018 (5)0.0143 (5)0.0088 (5)
N10.0188 (6)0.0264 (7)0.0262 (7)0.0043 (5)0.0017 (5)0.0116 (6)
N20.0185 (6)0.0215 (6)0.0212 (6)0.0016 (5)0.0024 (5)0.0059 (5)
N30.0166 (6)0.0257 (7)0.0309 (7)0.0055 (5)0.0013 (5)0.0107 (5)
N40.0158 (5)0.0206 (6)0.0196 (6)0.0059 (5)0.0013 (4)0.0028 (5)
N50.0189 (6)0.0190 (6)0.0205 (6)0.0036 (5)0.0030 (5)0.0022 (5)
N60.0169 (6)0.0213 (6)0.0200 (6)0.0065 (5)0.0029 (4)0.0028 (5)
N70.0189 (6)0.0220 (6)0.0268 (6)0.0024 (5)0.0039 (5)0.0039 (5)
C10.0186 (7)0.0169 (7)0.0190 (7)0.0029 (5)0.0023 (5)0.0010 (5)
C20.0191 (7)0.0160 (6)0.0180 (6)0.0027 (5)0.0033 (5)0.0003 (5)
C30.0168 (6)0.0220 (7)0.0213 (7)0.0005 (6)0.0012 (5)0.0027 (6)
C40.0151 (6)0.0236 (7)0.0258 (7)0.0052 (6)0.0032 (5)0.0016 (6)
C50.0206 (7)0.0167 (7)0.0195 (7)0.0034 (5)0.0042 (5)0.0020 (5)
C60.0179 (7)0.0214 (7)0.0248 (7)0.0014 (6)0.0004 (6)0.0069 (6)
C70.0170 (7)0.0218 (7)0.0261 (7)0.0054 (6)0.0026 (6)0.0028 (6)
C80.0204 (7)0.0207 (7)0.0207 (7)0.0032 (6)0.0005 (6)0.0012 (6)
C90.0268 (8)0.0300 (8)0.0240 (7)0.0000 (6)0.0027 (6)0.0123 (6)
C100.0250 (8)0.0403 (9)0.0347 (9)0.0004 (7)0.0018 (7)0.0148 (7)
C110.0340 (10)0.0424 (17)0.031 (2)0.0088 (11)0.0096 (11)0.0134 (16)
C120.0310 (10)0.0351 (15)0.0277 (18)0.0004 (11)0.0002 (11)0.0059 (12)
C130.0365 (11)0.039 (2)0.0472 (16)0.0086 (16)0.0096 (10)0.0161 (16)
C140.0372 (10)0.0537 (13)0.0410 (11)0.0068 (8)0.0023 (8)0.0127 (9)
C11'0.0340 (10)0.0424 (17)0.031 (2)0.0088 (11)0.0096 (11)0.0134 (16)
C12'0.0310 (10)0.0351 (15)0.0277 (18)0.0004 (11)0.0002 (11)0.0059 (12)
C13'0.0365 (11)0.039 (2)0.0472 (16)0.0086 (16)0.0096 (10)0.0161 (16)
C14'0.0372 (10)0.0537 (13)0.0410 (11)0.0068 (8)0.0023 (8)0.0127 (9)
C150.0202 (7)0.0187 (7)0.0221 (7)0.0051 (6)0.0025 (5)0.0027 (6)
C160.0203 (7)0.0172 (7)0.0179 (6)0.0036 (6)0.0024 (5)0.0007 (5)
C170.0186 (7)0.0179 (7)0.0182 (6)0.0059 (5)0.0031 (5)0.0006 (5)
C180.0186 (6)0.0159 (6)0.0179 (6)0.0024 (5)0.0020 (5)0.0006 (5)
C190.0165 (6)0.0208 (7)0.0213 (7)0.0031 (5)0.0029 (5)0.0002 (6)
C200.0215 (7)0.0190 (7)0.0189 (7)0.0063 (6)0.0043 (5)0.0012 (5)
C210.0240 (7)0.0194 (7)0.0204 (7)0.0041 (6)0.0022 (6)0.0044 (6)
C220.0174 (7)0.0237 (7)0.0218 (7)0.0030 (6)0.0010 (5)0.0042 (6)
C230.0173 (7)0.0318 (8)0.0269 (8)0.0078 (6)0.0000 (6)0.0059 (6)
C240.0184 (7)0.0197 (7)0.0225 (7)0.0027 (6)0.0020 (5)0.0031 (6)
C250.0163 (6)0.0223 (7)0.0187 (7)0.0040 (6)0.0019 (5)0.0041 (6)
C260.0209 (7)0.0221 (7)0.0277 (8)0.0009 (6)0.0041 (6)0.0007 (6)
C270.0283 (8)0.0196 (7)0.0332 (8)0.0063 (6)0.0031 (6)0.0028 (6)
C280.0221 (7)0.0271 (8)0.0303 (8)0.0080 (6)0.0044 (6)0.0057 (6)
C290.0176 (7)0.0284 (8)0.0281 (8)0.0037 (6)0.0051 (6)0.0040 (6)
C300.0203 (7)0.0235 (7)0.0229 (7)0.0060 (6)0.0028 (6)0.0001 (6)
C310.0211 (7)0.0318 (8)0.0213 (7)0.0061 (6)0.0042 (6)0.0006 (6)
C320.0203 (7)0.0345 (8)0.0209 (7)0.0067 (6)0.0001 (6)0.0049 (6)
C330.0331 (9)0.0330 (9)0.0335 (9)0.0036 (7)0.0078 (7)0.0015 (7)
C340.0444 (10)0.0295 (9)0.0431 (10)0.0031 (8)0.0084 (8)0.0015 (8)
Geometric parameters (Å, º) top
O1—C81.2251 (15)C12—H12A0.9900
O2—C81.3510 (15)C12—H12B0.9900
O2—C91.4425 (15)C13—C141.520 (5)
O3—C241.2316 (16)C13—H13A0.9900
O4—C321.2071 (16)C13—H13B0.9900
O5—C321.3367 (16)C14—H14A0.9800
O5—C331.4571 (17)C14—H14B0.9800
O6—H80.912 (19)C14—H14C0.9800
O6—H160.84 (2)C11'—C12'1.519 (9)
O7—H170.861 (19)C11'—H11C0.9900
O7—H180.881 (18)C11'—H11D0.9900
O8—H250.84 (2)C12'—C13'1.495 (9)
O8—H320.94 (2)C12'—H12C0.9900
O9—H200.93 (2)C12'—H12D0.9900
O9—H240.844 (19)C13'—C14'1.530 (9)
N1—C11.3223 (16)C13'—H13C0.9900
N1—H10.896 (17)C13'—H13D0.9900
N1—H20.902 (15)C14'—H14D0.9800
N2—C11.3354 (16)C14'—H14E0.9800
N2—C81.3688 (16)C14'—H14F0.9800
N3—C51.3713 (16)C15—C161.4928 (17)
N3—C151.4426 (17)C15—H15A0.9900
N3—H50.826 (15)C15—H15B0.9900
N4—C161.3593 (16)C17—C221.3901 (17)
N4—C171.3780 (15)C17—C181.4054 (17)
N4—C231.4680 (16)C18—C191.3904 (17)
N5—C161.3188 (16)C19—C201.3914 (18)
N5—C181.3963 (15)C19—H190.9500
N6—C241.3669 (16)C20—C211.4109 (18)
N6—C251.4386 (16)C20—C241.4985 (17)
N6—C301.4810 (17)C21—C221.3809 (17)
N7—C251.3337 (17)C21—H210.9500
N7—C291.3438 (16)C22—H220.9500
C1—C21.4794 (17)C23—H23A0.9800
C2—C71.3975 (18)C23—H23B0.9800
C2—C31.4023 (17)C23—H23C0.9800
C3—C41.3685 (17)C25—C261.3798 (18)
C3—H30.9500C26—C271.3881 (18)
C4—C51.4036 (18)C26—H260.9500
C4—H40.9500C27—C281.390 (2)
C5—C61.4010 (18)C27—H270.9500
C6—C71.3854 (17)C28—C291.3784 (19)
C6—H60.9500C28—H280.9500
C7—H70.9500C29—H290.9500
C9—C101.5064 (19)C30—C311.5159 (18)
C9—H9A0.9900C30—H30A0.9900
C9—H9B0.9900C30—H30B0.9900
C10—C111.494 (3)C31—C321.502 (2)
C10—C11'1.540 (9)C31—H31A0.9900
C10—H10A0.9601C31—H31B0.9900
C10—H10B0.9600C33—C341.498 (2)
C10—H10C0.9601C33—H33A0.9900
C10—H10D0.9601C33—H33B0.9900
C11—C121.519 (3)C34—H34A0.9800
C11—H11A0.9900C34—H34B0.9800
C11—H11B0.9900C34—H34C0.9800
C12—C131.522 (4)
C8—O2—C9116.08 (10)C13'—C12'—C11'116.6 (9)
C32—O5—C33115.53 (11)C13'—C12'—H12C108.1
H8—O6—H16107.3 (16)C11'—C12'—H12C108.1
H17—O7—H18113.2 (17)C13'—C12'—H12D108.1
H25—O8—H32105.7 (17)C11'—C12'—H12D108.1
H20—O9—H24103.2 (16)H12C—C12'—H12D107.3
C1—N1—H1124.5 (10)C12'—C13'—C14'112.8 (9)
C1—N1—H2116.5 (10)C12'—C13'—H13C109.0
H1—N1—H2119.1 (14)C14'—C13'—H13C109.0
C1—N2—C8119.06 (11)C12'—C13'—H13D109.0
C5—N3—C15122.41 (11)C14'—C13'—H13D109.0
C5—N3—H5116.9 (10)H13C—C13'—H13D107.8
C15—N3—H5120.0 (10)C13'—C14'—H14D109.5
C16—N4—C17106.66 (10)C13'—C14'—H14E109.5
C16—N4—C23127.23 (11)H14D—C14'—H14E109.5
C17—N4—C23126.11 (11)C13'—C14'—H14F109.5
C16—N5—C18104.75 (10)H14D—C14'—H14F109.5
C24—N6—C25116.67 (10)H14E—C14'—H14F109.5
C24—N6—C30124.33 (10)N3—C15—C16110.61 (11)
C25—N6—C30115.31 (10)N3—C15—H15A109.5
C25—N7—C29117.00 (12)C16—C15—H15A109.5
N1—C1—N2124.48 (12)N3—C15—H15B109.5
N1—C1—C2118.39 (12)C16—C15—H15B109.5
N2—C1—C2117.10 (11)H15A—C15—H15B108.1
C7—C2—C3117.59 (11)N5—C16—N4113.56 (11)
C7—C2—C1122.34 (11)N5—C16—C15125.99 (12)
C3—C2—C1120.02 (11)N4—C16—C15120.45 (11)
C4—C3—C2121.45 (12)N4—C17—C22131.62 (12)
C4—C3—H3119.3N4—C17—C18105.80 (10)
C2—C3—H3119.3C22—C17—C18122.57 (11)
C3—C4—C5120.90 (12)C19—C18—N5130.40 (12)
C3—C4—H4119.6C19—C18—C17120.36 (11)
C5—C4—H4119.6N5—C18—C17109.23 (10)
N3—C5—C6122.64 (12)C18—C19—C20117.59 (12)
N3—C5—C4119.02 (12)C18—C19—H19121.2
C6—C5—C4118.33 (11)C20—C19—H19121.2
C7—C6—C5120.21 (12)C19—C20—C21121.15 (11)
C7—C6—H6119.9C19—C20—C24118.17 (12)
C5—C6—H6119.9C21—C20—C24120.35 (11)
C6—C7—C2121.51 (12)C22—C21—C20121.72 (12)
C6—C7—H7119.2C22—C21—H21119.1
C2—C7—H7119.2C20—C21—H21119.1
O1—C8—O2120.94 (11)C21—C22—C17116.59 (12)
O1—C8—N2129.76 (12)C21—C22—H22121.7
O2—C8—N2109.30 (11)C17—C22—H22121.7
O2—C9—C10107.93 (11)N4—C23—H23A109.5
O2—C9—H9A110.1N4—C23—H23B109.5
C10—C9—H9A110.1H23A—C23—H23B109.5
O2—C9—H9B110.1N4—C23—H23C109.5
C10—C9—H9B110.1H23A—C23—H23C109.5
H9A—C9—H9B108.4H23B—C23—H23C109.5
C11—C10—C9114.1 (2)O3—C24—N6121.11 (11)
C11—C10—C11'12.7 (8)O3—C24—C20120.02 (12)
C9—C10—C11'111.3 (5)N6—C24—C20118.82 (11)
C11—C10—H10A113.1N7—C25—C26124.33 (12)
C9—C10—H10A108.8N7—C25—N6115.85 (11)
C11'—C10—H10A103.9C26—C25—N6119.71 (12)
C11—C10—H10B103.7C25—C26—C27117.78 (13)
C9—C10—H10B108.9C25—C26—H26121.1
C11'—C10—H10B115.7C27—C26—H26121.1
H10A—C10—H10B107.9C26—C27—C28119.05 (13)
C11—C10—H10C104.4C26—C27—H27120.5
C9—C10—H10C108.9C28—C27—H27120.5
C11'—C10—H10C94.3C29—C28—C27118.55 (13)
H10A—C10—H10C10.7C29—C28—H28120.7
H10B—C10—H10C117.0C27—C28—H28120.7
C11—C10—H10D112.7N7—C29—C28123.29 (13)
C9—C10—H10D108.7N7—C29—H29118.4
C11'—C10—H10D124.1C28—C29—H29118.4
H10A—C10—H10D98.3N6—C30—C31112.12 (11)
H10B—C10—H10D10.7N6—C30—H30A109.2
H10C—C10—H10D107.9C31—C30—H30A109.2
C10—C11—C12115.4 (3)N6—C30—H30B109.2
C10—C11—H11A108.4C31—C30—H30B109.2
C12—C11—H11A108.4H30A—C30—H30B107.9
C10—C11—H11B108.4C32—C31—C30113.14 (11)
C12—C11—H11B108.4C32—C31—H31A109.0
H11A—C11—H11B107.5C30—C31—H31A109.0
C11—C12—C13115.1 (3)C32—C31—H31B109.0
C11—C12—H12A108.5C30—C31—H31B109.0
C13—C12—H12A108.5H31A—C31—H31B107.8
C11—C12—H12B108.5O4—C32—O5123.06 (14)
C13—C12—H12B108.5O4—C32—C31124.96 (13)
H12A—C12—H12B107.5O5—C32—C31111.97 (11)
C14—C13—C12110.9 (4)O5—C33—C34107.38 (12)
C14—C13—H13A109.5O5—C33—H33A110.2
C12—C13—H13A109.5C34—C33—H33A110.2
C14—C13—H13B109.5O5—C33—H33B110.2
C12—C13—H13B109.5C34—C33—H33B110.2
H13A—C13—H13B108.0H33A—C33—H33B108.5
C12'—C11'—C10111.6 (9)C33—C34—H34A109.5
C12'—C11'—H11C109.3C33—C34—H34B109.5
C10—C11'—H11C109.3H34A—C34—H34B109.5
C12'—C11'—H11D109.3C33—C34—H34C109.5
C10—C11'—H11D109.3H34A—C34—H34C109.5
H11C—C11'—H11D108.0H34B—C34—H34C109.5
C8—N2—C1—N11.9 (2)C23—N4—C17—C18179.88 (12)
C8—N2—C1—C2176.19 (12)C16—N5—C18—C19179.11 (14)
N1—C1—C2—C76.0 (2)C16—N5—C18—C170.32 (14)
N2—C1—C2—C7175.86 (12)N4—C17—C18—C19179.02 (12)
N1—C1—C2—C3171.36 (12)C22—C17—C18—C190.2 (2)
N2—C1—C2—C36.82 (19)N4—C17—C18—N50.08 (14)
C7—C2—C3—C40.6 (2)C22—C17—C18—N5179.18 (12)
C1—C2—C3—C4176.89 (13)N5—C18—C19—C20179.84 (13)
C2—C3—C4—C50.4 (2)C17—C18—C19—C201.16 (19)
C15—N3—C5—C65.5 (2)C18—C19—C20—C211.1 (2)
C15—N3—C5—C4175.89 (12)C18—C19—C20—C24174.58 (12)
C3—C4—C5—N3179.58 (13)C19—C20—C21—C220.1 (2)
C3—C4—C5—C60.9 (2)C24—C20—C21—C22173.45 (13)
N3—C5—C6—C7179.07 (13)C20—C21—C22—C170.8 (2)
C4—C5—C6—C70.4 (2)N4—C17—C22—C21179.80 (13)
C5—C6—C7—C20.5 (2)C18—C17—C22—C210.7 (2)
C3—C2—C7—C61.0 (2)C25—N6—C24—O30.57 (19)
C1—C2—C7—C6176.37 (13)C30—N6—C24—O3157.83 (13)
C9—O2—C8—O12.42 (19)C25—N6—C24—C20177.95 (11)
C9—O2—C8—N2177.92 (11)C30—N6—C24—C2024.79 (19)
C1—N2—C8—O15.4 (2)C19—C20—C24—O348.24 (19)
C1—N2—C8—O2174.95 (11)C21—C20—C24—O3125.29 (15)
C8—O2—C9—C10178.74 (12)C19—C20—C24—N6134.35 (13)
O2—C9—C10—C11177.3 (3)C21—C20—C24—N652.12 (18)
O2—C9—C10—C11'163.8 (8)C29—N7—C25—C260.2 (2)
C9—C10—C11—C12178.5 (2)C29—N7—C25—N6176.35 (11)
C11'—C10—C11—C12101 (3)C24—N6—C25—N795.43 (15)
C10—C11—C12—C13173.3 (5)C30—N6—C25—N763.90 (15)
C11—C12—C13—C14178.7 (5)C24—N6—C25—C2688.23 (15)
C11—C10—C11'—C12'75 (3)C30—N6—C25—C26112.44 (14)
C9—C10—C11'—C12'179.8 (9)N7—C25—C26—C270.0 (2)
C10—C11'—C12'—C13'137.5 (15)N6—C25—C26—C27176.00 (12)
C11'—C12'—C13'—C14'164.4 (16)C25—C26—C27—C280.4 (2)
C5—N3—C15—C16176.57 (12)C26—C27—C28—C290.5 (2)
C18—N5—C16—N40.46 (15)C25—N7—C29—C280.0 (2)
C18—N5—C16—C15179.85 (13)C27—C28—C29—N70.3 (2)
C17—N4—C16—N50.41 (15)C24—N6—C30—C31153.22 (12)
C23—N4—C16—N5179.89 (12)C25—N6—C30—C3149.24 (15)
C17—N4—C16—C15179.87 (12)N6—C30—C31—C3262.82 (15)
C23—N4—C16—C150.2 (2)C33—O5—C32—O40.0 (2)
N3—C15—C16—N51.54 (19)C33—O5—C32—C31178.75 (12)
N3—C15—C16—N4178.13 (12)C30—C31—C32—O436.1 (2)
C16—N4—C17—C22179.36 (14)C30—C31—C32—O5145.15 (12)
C23—N4—C17—C220.9 (2)C32—O5—C33—C34176.98 (12)
C16—N4—C17—C180.18 (14)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O7i0.896 (17)1.980 (18)2.8468 (16)162.5 (15)
N1—H2···O10.902 (15)1.931 (16)2.6281 (16)132.7 (13)
O6—H8···N50.912 (19)1.88 (2)2.7938 (16)176.3 (16)
O6—H16···O3ii0.84 (2)2.00 (2)2.8373 (15)172.1 (18)
O7—H17···O80.861 (19)1.954 (19)2.8061 (16)170.2 (18)
O7—H18···O90.881 (18)1.871 (19)2.7513 (15)176.5 (17)
O9—H20···N20.93 (2)2.00 (2)2.9226 (16)168.8 (19)
O9—H20···O20.93 (2)2.43 (2)3.1126 (14)129.6 (16)
O9—H24···N7iii0.844 (19)2.050 (19)2.8918 (16)175.5 (18)
O8—H25···O60.84 (2)2.04 (2)2.8689 (17)171 (2)
O8—H32···O6iii0.94 (2)1.89 (2)2.8291 (17)175.3 (17)
Symmetry codes: (i) x1, y, z; (ii) x+1, y+2, z+2; (iii) x+1, y+1, z+2.

Experimental details

Crystal data
Chemical formulaC34H41N7O5·4H2O
Mr699.80
Crystal system, space groupTriclinic, P1
Temperature (K)113
a, b, c (Å)9.1140 (13), 10.9700 (14), 18.3830 (17)
α, β, γ (°)88.51 (1), 85.455 (9), 83.034 (12)
V3)1818.4 (4)
Z2
Radiation typeMo Kα
µ (mm1)0.09
Crystal size (mm)0.22 × 0.20 × 0.18
Data collection
DiffractometerRigaku Saturn 724 CCD area-detector
diffractometer
Absorption correctionMulti-scan
(CrystalClear; Rigaku/MSC, 2009)
Tmin, Tmax0.980, 0.983
No. of measured, independent and
observed [I > 2σ(I)] reflections
23569, 8627, 5187
Rint0.036
(sin θ/λ)max1)0.658
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.039, 0.103, 0.96
No. of reflections8627
No. of parameters513
No. of restraints40
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.42, 0.37

Computer programs: CrystalClear (Rigaku/MSC, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O7i0.896 (17)1.980 (18)2.8468 (16)162.5 (15)
N1—H2···O10.902 (15)1.931 (16)2.6281 (16)132.7 (13)
O6—H8···N50.912 (19)1.88 (2)2.7938 (16)176.3 (16)
O6—H16···O3ii0.84 (2)2.00 (2)2.8373 (15)172.1 (18)
O7—H17···O80.861 (19)1.954 (19)2.8061 (16)170.2 (18)
O7—H18···O90.881 (18)1.871 (19)2.7513 (15)176.5 (17)
O9—H20···N20.93 (2)2.00 (2)2.9226 (16)168.8 (19)
O9—H20···O20.93 (2)2.43 (2)3.1126 (14)129.6 (16)
O9—H24···N7iii0.844 (19)2.050 (19)2.8918 (16)175.5 (18)
O8—H25···O60.84 (2)2.04 (2)2.8689 (17)171 (2)
O8—H32···O6iii0.94 (2)1.89 (2)2.8291 (17)175.3 (17)
Symmetry codes: (i) x1, y, z; (ii) x+1, y+2, z+2; (iii) x+1, y+1, z+2.
 

References

First citationNagarakanti, R. & Ellis, C. R. (2012). Clin. Ther. 34, 2051–2060.  Web of Science CrossRef CAS PubMed
First citationRigaku/MSC (2009). CrystalClear. Rigaku/MSC, The Woodlands, Texas, USA.
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals
First citationVan Ryn, J., Stangier, J., Haertter, S., Liesenfeld, K. H., Wienen, W., Feuring, M. & Clemens, A. (2010). Thromb. Haemost. 103, 1116–1127.  Web of Science CrossRef CAS PubMed

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