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COMMUNICATIONS
ISSN: 2056-9890

Crystal structure of (S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phen­yl]oxazolidin-5-yl}meth­yl)thio­phene-2-carboxamide

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aChemistry Department, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China, and bInstitute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China
*Correspondence e-mail: huxiurong@zju.edu.cn

Edited by D.-J. Xu, Zhejiang University (Yuquan Campus), China (Received 29 November 2017; accepted 13 December 2017; online 1 January 2018)

The asymmetric unit of the crystal of the title compound (common name rivaroxaban), C19H18ClN3O5, contains two rivaroxaban mol­ecules with different conformations; the C—C—N—C torsion angles between the oxazolidine and thio­phene rings are −171.1 (7) and −106.8 (9)° in the two independent mol­ecules. In the crystal, classical N—H⋯O hydrogen bonds and weak C—H⋯O hydrogen bonds link the mol­ecules into a three-dimensional supra­molecular architecture.

1. Chemical context

At present, the incidence of thromboic disease is extremely high; this is mainly caused by vascular endothelial injury, increased blood coagulation, increased platelet number and decreased anti­coagulant activity (Lassila, 2012[Lassila, R. (2012). Scand. J. Surg. 101, 94-99.]). In anti­coagulants, warfarin and heparin have dominated the market, but they have some defects such as making making patients bleed easily and be prone to thrombocytopenia and osteoporosis (Mega & Carreras, 2012[Mega, J. & Carreras, E. T. (2012). J. Hematology Am. Soc. Hematol. Educ. Program. 2012, 547-552.]). In recent years, factor Xa inhibitors, the new type of anti­coagulant drugs, have received more and more attention, and rivaroxaban is a representative drug of factor Xa inhibitors (Goel & Srivathsan, 2012[Goel, R. & Srivathsan, K. (2012). Curr. Cardiol. Rev. 8, 158-165.]).

[Scheme 1]

Rivaroxaban is a novel oral direct factor Xa inhibitor that inhibits factor Xa selectively, thereby prolongs prothrombin time and reduces thrombin generation (Ansell, 2007[Ansell (2007). J. Thromb. Haemost. 5 (Suppl. 1), 60-64.]). It does not have a direct effect on thrombin but it inhibits the formation of thrombin by inhibiting factor Xa activity, which impedes the formation of fibrin in turn and ultimately inhibits thrombus formation and enlargement (Perzborn et al., 2005[Perzborn, E., Strassburger, J., Wilmen, A., Pohlmann, J., Roehrig, S., Schlemmer, K. & Straub, A. (2005). J. Thromb. Haemost. 3, 514-521.]). In 2011, rivaroxaban was approved by the US Food and Drug Administration (FDA) for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. The patent WO2007039132 (Ludescher et al., 2012[Ludescher, J, Ziegert-Knepper, R. E., Pichler, A., Sturm, H. Griesser, U. & Haddow, M. (2012). Patent WO2007039132.]) concerned crystalline form I, form II, form III, the amorphous form, the hydrate, the NMP solvate and the THF clathrate of rivaroxaban. However, there are few reports on the single-crystal structure of rivaroxaban. As part of our ongoing structural studies of pharmaceutical compounds, the crystal structure of rivaroxaban is presented here.

2. Structural commentary

The mol­ecular structure of the title compound is shown in Fig. 1[link]. The asymmetric unit contains two mol­ecules with different conformations. In the N-methyl­formamide moieties of mol­ecules A and B, the C7—C6—N1—C5 torsion angles are −171.1 (7) and −106.8 (9)°, respectively (Table 1[link]). The oxazolidine ring of mol­ecule A is almost planar [the maximum deviation is 0.048 (6) Å for the O2A atom], whereas the oxazolidine ring of mol­ecule B displays an envelope conformation with atom C8B as the flap. The morpholine rings of the two mol­ecules display similar twisted boat conformations. Atoms O4 and C17 deviate from the C16/N3/C19/C18 mean plane by 0.230 (2) and 0.517 (2) Å, respectively, in mol­ecule A and by 0.290 (2) and 0.489 (2) Å in mol­ecule B.

Table 1
Selected torsion angles (°)

C3A—C4A—C5A—O1A 172.0 (10) C7A—C6A—N1A—C5A −171.1 (7)
C3B—C4B—C5B—O1B −169.2 (9) O1B—C5B—N1B—C6B 10.8 (13)
O1A—C5A—N1A—C6A −4.0 (13) C4B—C5B—N1B—C6B −166.0 (7)
C4A—C5A—N1A—C6A 176.0 (6) C7B—C6B—N1B—C5B −106.8 (9)
[Figure 1]
Figure 1
The mol­ecular structure of the title compound,showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level. H atoms are shown as small circles of arbitrary radii.

3. Supra­molecular features

In the crystal, N—H⋯O hydrogen bonds (Table 2[link], Fig. 2[link]) link the independent mol­ecules A and B into dimers, and weak C—H⋯O hydrogen bonds link the dimers to form a three-dimensional supra­molecular architecture (Table 2[link]).

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N1A—H1A⋯O3B 0.86 2.16 3.008 (11) 169
N1B—H1B⋯O3A 0.86 2.22 3.016 (11) 153
C3A—H3A⋯O3B 0.93 2.48 3.357 (11) 157
C6B—H6B1⋯O5Ai 0.97 2.41 3.227 (10) 141
C7A—H7A⋯O5Bii 0.98 2.41 3.288 (8) 149
C8A—H8A2⋯O1Biii 0.97 2.52 3.459 (11) 163
C8B—H8B1⋯O1Aiv 0.97 2.15 2.961 (12) 140
Symmetry codes: (i) x-1, y, z; (ii) x+1, y, z; (iii) x, y+1, z; (iv) x, y-1, z.
[Figure 2]
Figure 2
The supermolecular structure showing the inter­molecular inter­actions (Table 2[link]) as dashed lines.

4. Hirshfeld surface analysis

The Hirshfeld surface of a mol­ecule in a crystal is constructed by calculating the spherical atom electron densities. On the dnorm surface, when inter­molecular contacts are shorter than the sum of van der Waals radii, they are highlighted in red, longer contacts in blue and contacts around the sum of van der Waals radii in white. The Hirshfeld surface analyses and two-dimensional fingerprint plots for the title compound were generated by CrystalExplorer (Wolff et al., 2013[Wolff, S., Grimwood, D., McKinnon, J., Turner, M., Jayatilaka, D. & Spackman, M. (2013). CrystalExplorer. University of Western Australia, Perth, Australia.]), and are illustrated in Figs. 3[link] and 4[link], respectively.

[Figure 3]
Figure 3
Plots of dnorm mapped on the Hirshfeld surfaces of the title compound showing the N—H⋯O hydrogen bonds.
[Figure 4]
Figure 4
The two-dimensional fingerprint of title compound showing contributions from different contacts.

The light-red spots on the Hirshfeld surface are the results of N—H⋯O, C—H⋯O and C—Cl⋯O inter­actions (Fig. 3[link]). The H⋯H contacts, which comprise 27% of the total Hirshfeld surface area, appear in the central region of the fingerprint plot (Fig. 3[link]b). The O⋯H/H⋯O inter­actions (22.4%), which are the most significant inter­molecular inter­actions and link the mol­ecular dimers into infinite chains along the b axis, appear as two obvious spikes (Fig. 3[link]c). At the top left (di < de) and bottom right (di > de) of the fingerprint plot, there are characteristic `wings' that are identified resulting from the C⋯H/H⋯C inter­actions (18.7%) shown in Fig. 3[link]d.

5. Synthesis and crystallization

The crude product was supplied by the Zhejiang Huadong Pharmaceutical Co., Ltd. It was recrystallized from methanol solution, giving colourless crystals suitable for X-ray diffraction.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. N-bound atoms H1A and H1B were found in difference-Fourier maps, but placed in calculated positions with N—H = 0.86 Å and refined as riding with Uiso(H) = 1.2Ueq(N). All other H atoms were placed in calculated positions with C—H = 0.93–0.98 Å and included in the refinement in a riding model, with Uiso(H) = 1.2 or 1.5Ueq(carrier atom).

Table 3
Experimental details

Crystal data
Chemical formula C19H18ClN3O5S
Mr 435.87
Crystal system, space group Triclinic, P1
Temperature (K) 296
a, b, c (Å) 9.0184 (6), 10.9980 (8), 11.2386 (8)
α, β, γ (°) 63.426 (2), 74.414 (3), 78.144 (2)
V3) 955.56 (12)
Z 2
Radiation type Mo Kα
μ (mm−1) 0.35
Crystal size (mm) 0.39 × 0.27 × 0.06
 
Data collection
Diffractometer Rigaku R-AXIS RAPID
Absorption correction Multi-scan (ABSCOR; Higashi, 1995[Higashi, T. (1995). ABSCOR. Program for Absorption Correction. Rigaku Corporation, Tokyo, Japan.])
Tmin, Tmax 0.868, 0.979
No. of measured, independent and observed [I > 2σ(I)] reflections 8375, 6267, 3981
Rint 0.043
(sin θ/λ)max−1) 0.617
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.045, 0.149, 1.00
No. of reflections 6267
No. of parameters 524
No. of restraints 3
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.33, −0.48
Absolute structure Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 2519 Friedel pairs
Absolute structure parameter −0.07 (13)
Computer programs: PROCESS-AUTO (Rigaku, 2006[Rigaku (2006). PROCESS-AUTO. Rigaku Corporation, Tokyo, Japan.]), CrystalStructure (Rigaku, 2007[Rigaku (2007). CrystalStructure. Rigaku, Tokyo, Japan.]), SHELXS97 and SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), ORTEP-3 for Windows (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]) and WinGX and DIAMOND (Brandenburg & Putz, 2006[Brandenburg, K. & Putz, H. (2006). DIAMOND. Crystal ImpactGbR, Bonn, Germany.]).

Supporting information


Computing details top

Data collection: PROCESS-AUTO (Rigaku, 2006); cell refinement: PROCESS-AUTO (Rigaku, 2006); data reduction: CrystalStructure (Rigaku, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and DIAMOND (Brandenburg & Putz, 2006); software used to prepare material for publication: WinGX (Farrugia, 2012).

(S)-5-Chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl}methyl)thiophene-2-carboxamide top
Crystal data top
C19H18ClN3O5SZ = 2
Mr = 435.87F(000) = 452
Triclinic, P1Dx = 1.515 Mg m3
Hall symbol: P 1Mo Kα radiation, λ = 0.71073 Å
a = 9.0184 (6) ÅCell parameters from 6182 reflections
b = 10.9980 (8) Åθ = 3.3–27.5°
c = 11.2386 (8) ŵ = 0.35 mm1
α = 63.426 (2)°T = 296 K
β = 74.414 (3)°Platelet, colorless
γ = 78.144 (2)°0.39 × 0.27 × 0.06 mm
V = 955.56 (12) Å3
Data collection top
Rigaku R-AXIS RAPID
diffractometer
6267 independent reflections
Radiation source: rotating anode3981 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.043
Detector resolution: 10.00 pixels mm-1θmax = 26.0°, θmin = 3.3°
ω scansh = 1110
Absorption correction: multi-scan
(ABSCOR; Higashi, 1995)
k = 1313
Tmin = 0.868, Tmax = 0.979l = 1312
8375 measured reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.045 w = 1/[σ2(Fo2) + (0.0576P)2 + 0.9688P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.149(Δ/σ)max < 0.001
S = 1.00Δρmax = 0.33 e Å3
6267 reflectionsΔρmin = 0.47 e Å3
524 parametersExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
3 restraintsExtinction coefficient: 0.0153 (18)
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), 2519 Friedel pairs
Secondary atom site location: difference Fourier mapAbsolute structure parameter: 0.07 (13)
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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C1A0.1583 (9)1.0666 (8)0.2283 (8)0.0439 (19)
C2A0.0913 (9)0.9526 (9)0.2067 (9)0.055 (2)
H2A0.13180.91370.16540.066*
C3A0.0484 (9)0.9019 (8)0.2560 (8)0.049 (2)
H3A0.10970.82510.24960.059*
C4A0.0845 (9)0.9721 (8)0.3113 (8)0.044 (2)
C5A0.2153 (9)0.9561 (8)0.3737 (8)0.046 (2)
C6A0.4500 (8)0.8320 (8)0.4481 (8)0.0536 (19)
H6A10.41730.82270.54100.064*
H6A20.50240.91430.39460.064*
C7A0.5590 (6)0.7108 (6)0.4437 (6)0.0432 (14)
H7A0.58440.71520.35150.052*
C8A0.7087 (8)0.6965 (8)0.4921 (7)0.0468 (18)
H8A10.79860.70550.41930.056*
H8A20.70490.76450.52590.056*
C9A0.5857 (9)0.4996 (8)0.6187 (8)0.0426 (18)
C10A0.8327 (8)0.5027 (8)0.6745 (7)0.0371 (17)
C11A0.9704 (8)0.5597 (9)0.6184 (8)0.051 (2)
H11A0.98420.63190.53270.061*
C12A1.0901 (9)0.5086 (9)0.6909 (8)0.052 (2)
H12A1.18320.54790.65380.063*
C13A1.0706 (9)0.4001 (8)0.8169 (7)0.0405 (19)
C14A0.9315 (9)0.3423 (9)0.8685 (8)0.048 (2)
H14A0.91830.26730.95210.058*
C15A0.8124 (9)0.3937 (8)0.7984 (7)0.0425 (18)
H15A0.71920.35460.83500.051*
C16A1.2171 (11)0.4524 (11)0.9410 (11)0.067 (3)
H16A1.12060.50140.96640.080*
H16B1.28220.51850.86650.080*
C17A1.2969 (10)0.3788 (11)1.0610 (9)0.065 (3)
H17A1.32590.44491.08370.078*
H17B1.22700.32131.13930.078*
C18A1.3869 (11)0.1916 (9)1.0115 (10)0.059 (2)
H18A1.35340.12081.10080.071*
H18B1.47910.15310.96710.071*
C19A1.2629 (9)0.2279 (9)0.9317 (8)0.048 (2)
C1B1.0264 (9)0.0628 (8)0.7509 (8)0.0427 (19)
C2B0.9694 (9)0.0466 (9)0.7726 (9)0.052 (2)
H2B1.01630.08290.81210.062*
C3B0.8282 (10)0.1024 (10)0.7290 (9)0.054 (2)
H3B0.77240.18120.73520.065*
C4B0.7817 (9)0.0297 (8)0.6767 (8)0.0427 (19)
C5B0.6395 (9)0.0457 (9)0.6254 (8)0.047 (2)
C6B0.3859 (8)0.1766 (7)0.5957 (8)0.056 (2)
H6B10.31740.20910.66060.068*
H6B20.35730.08780.61680.068*
C7B0.3595 (7)0.2715 (6)0.4581 (6)0.0417 (13)
H7B0.41970.23670.39110.050*
C8B0.1891 (8)0.2963 (7)0.4524 (9)0.052 (2)
H8B10.16330.24060.41540.062*
H8B20.12380.27860.54140.062*
C9B0.2926 (8)0.5022 (9)0.3553 (7)0.0397 (18)
C10B0.0478 (8)0.5025 (8)0.2993 (7)0.0347 (16)
C11B0.0894 (9)0.4413 (8)0.3481 (8)0.0444 (19)
H11B0.10050.36370.42970.053*
C12B0.2088 (9)0.4918 (9)0.2796 (8)0.049 (2)
H12B0.29860.44780.31440.059*
C13B0.1964 (9)0.6065 (8)0.1604 (8)0.0391 (18)
C14B0.0649 (8)0.6727 (8)0.1093 (7)0.0392 (17)
H14B0.05780.75200.02920.047*
C15B0.0591 (8)0.6212 (8)0.1778 (7)0.0367 (17)
H15B0.14850.66580.14250.044*
C16B0.3420 (11)0.5655 (11)0.0280 (11)0.069 (3)
H16C0.39880.49120.09980.083*
H16D0.24240.52660.00610.083*
C17B0.4295 (10)0.6406 (12)0.0841 (10)0.065 (3)
H17C0.36740.70690.16160.078*
H17D0.45430.57720.11260.078*
C18B0.5312 (10)0.8161 (9)0.0125 (9)0.056 (2)
H18C0.62370.84800.03780.067*
H18D0.50270.89170.09960.067*
C19B0.4012 (9)0.7757 (9)0.0650 (8)0.0437 (19)
N1A0.3152 (7)0.8431 (7)0.3946 (7)0.0498 (17)
H1A0.29990.77880.37690.060*
N2A0.7116 (7)0.5601 (7)0.5999 (6)0.0372 (14)
N3A1.1862 (8)0.3562 (7)0.8972 (7)0.0432 (15)
N1B0.5436 (7)0.1595 (7)0.6146 (7)0.0532 (17)
H1B0.57670.22500.61920.064*
N2B0.1756 (6)0.4401 (6)0.3618 (6)0.0368 (14)
N3B0.3186 (7)0.6567 (7)0.0831 (6)0.0409 (15)
O1A0.2326 (8)1.0454 (7)0.4062 (8)0.084 (2)
O2A0.4876 (6)0.5867 (5)0.5382 (6)0.0555 (15)
O3A0.5553 (7)0.3836 (6)0.6960 (6)0.0604 (16)
O4A1.4274 (7)0.2998 (7)1.0281 (7)0.0691 (19)
O5A1.2297 (8)0.1426 (7)0.9017 (6)0.0673 (17)
O1B0.6129 (7)0.0440 (6)0.6016 (7)0.0673 (17)
O2B0.3984 (6)0.4081 (6)0.4212 (6)0.0482 (13)
O3B0.3058 (7)0.6245 (6)0.3060 (6)0.0541 (14)
O4B0.5669 (7)0.7076 (7)0.0354 (6)0.0594 (16)
O5B0.3806 (7)0.8525 (6)0.1100 (6)0.0622 (16)
S1A0.0530 (2)1.1087 (2)0.3076 (2)0.0611 (6)
S1B0.9128 (2)0.1087 (2)0.6818 (2)0.0563 (6)
Cl1A0.3274 (2)1.1591 (2)0.1863 (2)0.0640 (6)
Cl1B1.1962 (2)0.1602 (2)0.7917 (2)0.0675 (7)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C1A0.037 (4)0.045 (5)0.042 (4)0.002 (4)0.016 (3)0.008 (4)
C2A0.054 (5)0.043 (5)0.064 (5)0.001 (4)0.017 (4)0.019 (4)
C3A0.040 (4)0.034 (4)0.072 (5)0.015 (3)0.030 (4)0.018 (4)
C4A0.041 (5)0.038 (5)0.054 (4)0.005 (4)0.019 (4)0.016 (4)
C5A0.040 (4)0.036 (4)0.067 (5)0.000 (3)0.023 (4)0.021 (4)
C6A0.044 (4)0.049 (4)0.081 (5)0.002 (3)0.028 (4)0.031 (4)
C7A0.041 (3)0.043 (3)0.043 (3)0.002 (2)0.015 (3)0.013 (3)
C8A0.039 (4)0.044 (4)0.050 (4)0.001 (3)0.021 (3)0.008 (3)
C9A0.056 (5)0.025 (4)0.048 (4)0.014 (3)0.030 (4)0.013 (3)
C10A0.034 (4)0.041 (4)0.042 (4)0.006 (3)0.014 (3)0.023 (4)
C11A0.032 (4)0.064 (6)0.047 (4)0.013 (4)0.011 (3)0.009 (4)
C12A0.033 (4)0.050 (5)0.058 (5)0.004 (3)0.008 (4)0.010 (4)
C13A0.033 (4)0.049 (5)0.042 (4)0.006 (3)0.017 (3)0.020 (4)
C14A0.052 (5)0.042 (4)0.047 (4)0.001 (4)0.015 (4)0.016 (4)
C15A0.038 (4)0.048 (5)0.044 (4)0.009 (3)0.017 (3)0.015 (4)
C16A0.067 (6)0.073 (6)0.092 (7)0.013 (5)0.050 (5)0.051 (6)
C17A0.057 (5)0.091 (7)0.066 (6)0.004 (5)0.027 (5)0.046 (5)
C18A0.061 (5)0.053 (6)0.071 (5)0.014 (4)0.032 (4)0.031 (5)
C19A0.045 (4)0.046 (5)0.052 (4)0.008 (4)0.021 (4)0.019 (4)
C1B0.032 (4)0.046 (5)0.041 (4)0.001 (3)0.016 (3)0.008 (4)
C2B0.039 (4)0.062 (6)0.067 (5)0.003 (4)0.028 (4)0.029 (5)
C3B0.052 (5)0.060 (6)0.065 (5)0.000 (4)0.027 (4)0.033 (5)
C4B0.034 (4)0.037 (5)0.057 (5)0.001 (3)0.021 (4)0.015 (4)
C5B0.038 (4)0.045 (5)0.053 (5)0.006 (4)0.019 (3)0.014 (4)
C6B0.035 (4)0.042 (4)0.080 (5)0.004 (3)0.025 (4)0.011 (4)
C7B0.041 (3)0.036 (3)0.055 (4)0.001 (2)0.024 (3)0.020 (3)
C8B0.047 (4)0.031 (4)0.080 (5)0.002 (3)0.033 (4)0.017 (4)
C9B0.024 (3)0.055 (5)0.048 (4)0.011 (3)0.010 (3)0.024 (4)
C10B0.027 (3)0.035 (4)0.050 (4)0.001 (3)0.016 (3)0.021 (4)
C11B0.046 (4)0.035 (4)0.046 (4)0.000 (3)0.021 (3)0.006 (3)
C12B0.034 (4)0.054 (5)0.065 (5)0.009 (3)0.023 (4)0.021 (4)
C13B0.036 (4)0.037 (4)0.053 (4)0.006 (3)0.022 (3)0.023 (4)
C14B0.036 (4)0.038 (4)0.043 (4)0.000 (3)0.018 (3)0.011 (3)
C15B0.032 (4)0.035 (4)0.038 (4)0.004 (3)0.010 (3)0.009 (3)
C16B0.064 (5)0.066 (6)0.111 (8)0.023 (5)0.054 (6)0.058 (6)
C17B0.051 (5)0.095 (7)0.076 (6)0.000 (5)0.031 (5)0.053 (6)
C18B0.047 (5)0.053 (5)0.056 (5)0.002 (4)0.020 (4)0.011 (4)
C19B0.034 (4)0.049 (5)0.047 (4)0.005 (3)0.013 (3)0.019 (4)
N1A0.044 (4)0.037 (4)0.076 (4)0.008 (3)0.027 (3)0.027 (3)
N2A0.028 (3)0.037 (3)0.041 (3)0.000 (2)0.014 (2)0.010 (3)
N3A0.041 (3)0.045 (4)0.053 (4)0.010 (3)0.026 (3)0.025 (3)
N1B0.039 (4)0.042 (4)0.071 (4)0.001 (3)0.032 (3)0.008 (3)
N2B0.034 (3)0.035 (3)0.049 (3)0.002 (2)0.024 (3)0.016 (3)
N3B0.040 (3)0.046 (4)0.050 (4)0.003 (3)0.028 (3)0.024 (3)
O1A0.074 (4)0.074 (5)0.153 (6)0.024 (3)0.068 (4)0.076 (5)
O2A0.053 (3)0.031 (3)0.079 (4)0.002 (2)0.045 (3)0.003 (3)
O3A0.060 (3)0.041 (4)0.082 (4)0.011 (3)0.039 (3)0.011 (3)
O4A0.049 (4)0.084 (5)0.081 (4)0.005 (3)0.030 (3)0.035 (4)
O5A0.070 (4)0.055 (4)0.088 (4)0.006 (3)0.036 (3)0.034 (3)
O1B0.069 (4)0.054 (4)0.107 (5)0.006 (3)0.047 (3)0.046 (4)
O2B0.041 (3)0.045 (3)0.066 (3)0.004 (2)0.027 (2)0.020 (3)
O3B0.057 (3)0.037 (3)0.071 (3)0.004 (2)0.035 (3)0.013 (3)
O4B0.046 (3)0.066 (4)0.073 (4)0.004 (3)0.034 (3)0.027 (3)
O5B0.068 (4)0.051 (4)0.078 (4)0.014 (3)0.037 (3)0.032 (3)
S1A0.0506 (12)0.0551 (14)0.0912 (17)0.0171 (10)0.0335 (12)0.0409 (14)
S1B0.0468 (12)0.0469 (13)0.0783 (15)0.0098 (9)0.0291 (10)0.0255 (12)
Cl1A0.0391 (11)0.0656 (16)0.0746 (14)0.0071 (10)0.0234 (11)0.0167 (12)
Cl1B0.0391 (11)0.0587 (15)0.0823 (15)0.0071 (10)0.0275 (11)0.0062 (12)
Geometric parameters (Å, º) top
C1A—C2A1.371 (11)C1B—S1B1.703 (9)
C1A—Cl1A1.704 (8)C1B—Cl1B1.722 (8)
C1A—S1A1.707 (9)C2B—C3B1.408 (12)
C2A—C3A1.420 (12)C2B—H2B0.9300
C2A—H2A0.9300C3B—C4B1.361 (12)
C3A—C4A1.315 (12)C3B—H3B0.9300
C3A—H3A0.9300C4B—C5B1.491 (12)
C4A—C5A1.471 (12)C4B—S1B1.714 (8)
C4A—S1A1.733 (8)C5B—O1B1.213 (10)
C5A—O1A1.239 (10)C5B—N1B1.344 (10)
C5A—N1A1.344 (10)C6B—N1B1.456 (10)
C6A—N1A1.456 (10)C6B—C7B1.480 (9)
C6A—C7A1.496 (8)C6B—H6B10.9700
C6A—H6A10.9700C6B—H6B20.9700
C6A—H6A20.9700C7B—O2B1.460 (8)
C7A—O2A1.451 (7)C7B—C8B1.518 (9)
C7A—C8A1.540 (9)C7B—H7B0.9800
C7A—H7A0.9800C8B—N2B1.449 (9)
C8A—N2A1.447 (9)C8B—H8B10.9700
C8A—H8A10.9700C8B—H8B20.9700
C8A—H8A20.9700C9B—O3B1.222 (9)
C9A—O3A1.217 (9)C9B—N2B1.340 (9)
C9A—O2A1.351 (9)C9B—O2B1.348 (9)
C9A—N2A1.353 (10)C10B—C11B1.390 (11)
C10A—C15A1.367 (10)C10B—C15B1.402 (10)
C10A—C11A1.370 (11)C10B—N2B1.404 (10)
C10A—N2A1.425 (10)C11B—C12B1.370 (11)
C11A—C12A1.399 (12)C11B—H11B0.9300
C11A—H11A0.9300C12B—C13B1.365 (11)
C12A—C13A1.379 (11)C12B—H12B0.9300
C12A—H12A0.9300C13B—C14B1.371 (11)
C13A—C14A1.386 (11)C13B—N3B1.453 (10)
C13A—N3A1.429 (11)C14B—C15B1.405 (10)
C14A—C15A1.379 (11)C14B—H14B0.9300
C14A—H14A0.9300C15B—H15B0.9300
C15A—H15A0.9300C16B—N3B1.465 (11)
C16A—N3A1.448 (11)C16B—C17B1.492 (13)
C16A—C17A1.516 (12)C16B—H16C0.9700
C16A—H16A0.9700C16B—H16D0.9700
C16A—H16B0.9700C17B—O4B1.413 (10)
C17A—O4A1.382 (10)C17B—H17C0.9700
C17A—H17A0.9700C17B—H17D0.9700
C17A—H17B0.9700C18B—O4B1.439 (11)
C18A—O4A1.413 (11)C18B—C19B1.523 (12)
C18A—C19A1.500 (12)C18B—H18C0.9700
C18A—H18A0.9700C18B—H18D0.9700
C18A—H18B0.9700C19B—O5B1.225 (10)
C19A—O5A1.240 (11)C19B—N3B1.323 (9)
C19A—N3A1.369 (10)N1A—H1A0.8600
C1B—C2B1.309 (11)N1B—H1B0.8600
C2A—C1A—Cl1A126.4 (7)O1B—C5B—N1B123.9 (9)
C2A—C1A—S1A112.0 (6)O1B—C5B—C4B119.9 (8)
Cl1A—C1A—S1A121.6 (5)N1B—C5B—C4B116.1 (8)
C1A—C2A—C3A110.7 (8)N1B—C6B—C7B115.4 (6)
C1A—C2A—H2A124.6N1B—C6B—H6B1108.4
C3A—C2A—H2A124.6C7B—C6B—H6B1108.4
C4A—C3A—C2A114.8 (8)N1B—C6B—H6B2108.4
C4A—C3A—H3A122.6C7B—C6B—H6B2108.4
C2A—C3A—H3A122.6H6B1—C6B—H6B2107.5
C3A—C4A—C5A132.7 (7)O2B—C7B—C6B111.0 (6)
C3A—C4A—S1A111.3 (7)O2B—C7B—C8B102.7 (5)
C5A—C4A—S1A116.0 (6)C6B—C7B—C8B111.7 (6)
O1A—C5A—N1A120.8 (8)O2B—C7B—H7B110.4
O1A—C5A—C4A120.5 (8)C6B—C7B—H7B110.4
N1A—C5A—C4A118.7 (7)C8B—C7B—H7B110.4
N1A—C6A—C7A110.4 (6)N2B—C8B—C7B101.2 (5)
N1A—C6A—H6A1109.6N2B—C8B—H8B1111.5
C7A—C6A—H6A1109.6C7B—C8B—H8B1111.5
N1A—C6A—H6A2109.6N2B—C8B—H8B2111.5
C7A—C6A—H6A2109.6C7B—C8B—H8B2111.5
H6A1—C6A—H6A2108.1H8B1—C8B—H8B2109.3
O2A—C7A—C6A109.4 (5)O3B—C9B—N2B128.6 (8)
O2A—C7A—C8A104.3 (5)O3B—C9B—O2B121.8 (7)
C6A—C7A—C8A113.4 (6)N2B—C9B—O2B109.6 (7)
O2A—C7A—H7A109.9C11B—C10B—C15B117.5 (7)
C6A—C7A—H7A109.9C11B—C10B—N2B121.1 (7)
C8A—C7A—H7A109.9C15B—C10B—N2B121.1 (7)
N2A—C8A—C7A103.1 (6)C12B—C11B—C10B122.0 (7)
N2A—C8A—H8A1111.1C12B—C11B—H11B119.0
C7A—C8A—H8A1111.1C10B—C11B—H11B119.0
N2A—C8A—H8A2111.1C11B—C12B—C13B120.2 (7)
C7A—C8A—H8A2111.1C11B—C12B—H12B119.9
H8A1—C8A—H8A2109.1C13B—C12B—H12B119.9
O3A—C9A—O2A120.6 (8)C12B—C13B—C14B120.2 (7)
O3A—C9A—N2A128.2 (8)C12B—C13B—N3B120.7 (7)
O2A—C9A—N2A111.1 (7)C14B—C13B—N3B119.1 (7)
C15A—C10A—C11A120.9 (8)C13B—C14B—C15B120.2 (7)
C15A—C10A—N2A121.0 (7)C13B—C14B—H14B119.9
C11A—C10A—N2A118.1 (7)C15B—C14B—H14B119.9
C10A—C11A—C12A119.6 (8)C10B—C15B—C14B119.9 (7)
C10A—C11A—H11A120.2C10B—C15B—H15B120.0
C12A—C11A—H11A120.2C14B—C15B—H15B120.0
C13A—C12A—C11A120.2 (8)N3B—C16B—C17B111.0 (8)
C13A—C12A—H12A119.9N3B—C16B—H16C109.4
C11A—C12A—H12A119.9C17B—C16B—H16C109.4
C12A—C13A—C14A118.6 (8)N3B—C16B—H16D109.4
C12A—C13A—N3A120.5 (8)C17B—C16B—H16D109.4
C14A—C13A—N3A120.8 (7)H16C—C16B—H16D108.0
C15A—C14A—C13A121.4 (8)O4B—C17B—C16B108.2 (7)
C15A—C14A—H14A119.3O4B—C17B—H17C110.1
C13A—C14A—H14A119.3C16B—C17B—H17C110.1
C10A—C15A—C14A119.3 (8)O4B—C17B—H17D110.1
C10A—C15A—H15A120.3C16B—C17B—H17D110.1
C14A—C15A—H15A120.3H17C—C17B—H17D108.4
N3A—C16A—C17A110.6 (8)O4B—C18B—C19B114.2 (7)
N3A—C16A—H16A109.5O4B—C18B—H18C108.7
C17A—C16A—H16A109.5C19B—C18B—H18C108.7
N3A—C16A—H16B109.5O4B—C18B—H18D108.7
C17A—C16A—H16B109.5C19B—C18B—H18D108.7
H16A—C16A—H16B108.1H18C—C18B—H18D107.6
O4A—C17A—C16A109.3 (7)O5B—C19B—N3B123.4 (8)
O4A—C17A—H17A109.8O5B—C19B—C18B118.8 (8)
C16A—C17A—H17A109.8N3B—C19B—C18B117.7 (8)
O4A—C17A—H17B109.8C5A—N1A—C6A118.4 (7)
C16A—C17A—H17B109.8C5A—N1A—H1A120.8
H17A—C17A—H17B108.3C6A—N1A—H1A120.8
O4A—C18A—C19A116.1 (8)C9A—N2A—C10A126.5 (7)
O4A—C18A—H18A108.3C9A—N2A—C8A111.0 (6)
C19A—C18A—H18A108.3C10A—N2A—C8A122.5 (6)
O4A—C18A—H18B108.3C19A—N3A—C13A120.9 (8)
C19A—C18A—H18B108.3C19A—N3A—C16A121.8 (7)
H18A—C18A—H18B107.4C13A—N3A—C16A117.3 (7)
O5A—C19A—N3A121.9 (8)C5B—N1B—C6B122.7 (8)
O5A—C19A—C18A120.5 (8)C5B—N1B—H1B118.7
N3A—C19A—C18A117.6 (8)C6B—N1B—H1B118.7
C2B—C1B—S1B113.9 (6)C9B—N2B—C10B126.6 (7)
C2B—C1B—Cl1B125.4 (7)C9B—N2B—C8B111.3 (6)
S1B—C1B—Cl1B120.6 (5)C10B—N2B—C8B121.9 (6)
C1B—C2B—C3B111.7 (8)C19B—N3B—C13B121.8 (7)
C1B—C2B—H2B124.1C19B—N3B—C16B123.4 (7)
C3B—C2B—H2B124.1C13B—N3B—C16B114.7 (7)
C4B—C3B—C2B113.3 (8)C9A—O2A—C7A109.8 (6)
C4B—C3B—H3B123.3C17A—O4A—C18A110.9 (8)
C2B—C3B—H3B123.3C9B—O2B—C7B109.4 (5)
C3B—C4B—C5B132.1 (8)C17B—O4B—C18B110.3 (7)
C3B—C4B—S1B110.3 (6)C1A—S1A—C4A91.2 (4)
C5B—C4B—S1B117.5 (6)C1B—S1B—C4B90.7 (4)
Cl1A—C1A—C2A—C3A179.5 (6)C15A—C10A—N2A—C9A18.4 (11)
S1A—C1A—C2A—C3A0.4 (9)C11A—C10A—N2A—C9A161.4 (8)
C1A—C2A—C3A—C4A0.2 (11)C15A—C10A—N2A—C8A160.6 (7)
C2A—C3A—C4A—C5A180.0 (9)C11A—C10A—N2A—C8A19.5 (10)
C2A—C3A—C4A—S1A0.1 (10)C7A—C8A—N2A—C9A1.0 (8)
C3A—C4A—C5A—O1A172.0 (10)C7A—C8A—N2A—C10A179.8 (6)
S1A—C4A—C5A—O1A8.1 (12)O5A—C19A—N3A—C13A4.1 (12)
C3A—C4A—C5A—N1A8.0 (15)C18A—C19A—N3A—C13A177.6 (8)
S1A—C4A—C5A—N1A171.9 (6)O5A—C19A—N3A—C16A175.3 (9)
N1A—C6A—C7A—O2A67.0 (8)C18A—C19A—N3A—C16A2.9 (12)
N1A—C6A—C7A—C8A177.1 (6)C12A—C13A—N3A—C19A117.5 (9)
O2A—C7A—C8A—N2A5.4 (7)C14A—C13A—N3A—C19A67.9 (10)
C6A—C7A—C8A—N2A124.3 (6)C12A—C13A—N3A—C16A63.0 (11)
C15A—C10A—C11A—C12A2.2 (13)C14A—C13A—N3A—C16A111.6 (10)
N2A—C10A—C11A—C12A178.0 (8)C17A—C16A—N3A—C19A19.1 (12)
C10A—C11A—C12A—C13A1.1 (13)C17A—C16A—N3A—C13A160.4 (7)
C11A—C12A—C13A—C14A1.0 (12)O1B—C5B—N1B—C6B10.8 (13)
C11A—C12A—C13A—N3A173.7 (8)C4B—C5B—N1B—C6B166.0 (7)
C12A—C13A—C14A—C15A2.0 (12)C7B—C6B—N1B—C5B106.8 (9)
N3A—C13A—C14A—C15A172.7 (8)O3B—C9B—N2B—C10B7.6 (12)
C11A—C10A—C15A—C14A1.2 (12)O2B—C9B—N2B—C10B176.3 (6)
N2A—C10A—C15A—C14A179.0 (7)O3B—C9B—N2B—C8B168.0 (8)
C13A—C14A—C15A—C10A1.0 (12)O2B—C9B—N2B—C8B8.1 (8)
N3A—C16A—C17A—O4A54.0 (11)C11B—C10B—N2B—C9B157.4 (7)
O4A—C18A—C19A—O5A173.5 (8)C15B—C10B—N2B—C9B29.2 (11)
O4A—C18A—C19A—N3A8.2 (11)C11B—C10B—N2B—C8B17.8 (11)
S1B—C1B—C2B—C3B1.8 (10)C15B—C10B—N2B—C8B155.6 (7)
Cl1B—C1B—C2B—C3B179.5 (6)C7B—C8B—N2B—C9B20.0 (8)
C1B—C2B—C3B—C4B1.1 (11)C7B—C8B—N2B—C10B164.2 (6)
C2B—C3B—C4B—C5B176.6 (8)O5B—C19B—N3B—C13B0.8 (12)
C2B—C3B—C4B—S1B0.1 (10)C18B—C19B—N3B—C13B177.4 (7)
C3B—C4B—C5B—O1B169.2 (9)O5B—C19B—N3B—C16B179.3 (9)
S1B—C4B—C5B—O1B7.1 (11)C18B—C19B—N3B—C16B2.5 (12)
C3B—C4B—C5B—N1B7.7 (13)C12B—C13B—N3B—C19B114.8 (9)
S1B—C4B—C5B—N1B176.0 (6)C14B—C13B—N3B—C19B67.9 (10)
N1B—C6B—C7B—O2B59.1 (9)C12B—C13B—N3B—C16B65.2 (10)
N1B—C6B—C7B—C8B173.0 (6)C14B—C13B—N3B—C16B112.2 (9)
O2B—C7B—C8B—N2B23.1 (7)C17B—C16B—N3B—C19B18.5 (13)
C6B—C7B—C8B—N2B142.1 (6)C17B—C16B—N3B—C13B161.5 (8)
C15B—C10B—C11B—C12B1.5 (11)O3A—C9A—O2A—C7A172.5 (7)
N2B—C10B—C11B—C12B172.1 (7)N2A—C9A—O2A—C7A8.0 (8)
C10B—C11B—C12B—C13B0.8 (13)C6A—C7A—O2A—C9A129.8 (6)
C11B—C12B—C13B—C14B0.7 (12)C8A—C7A—O2A—C9A8.2 (8)
C11B—C12B—C13B—N3B176.6 (7)C16A—C17A—O4A—C18A67.0 (11)
C12B—C13B—C14B—C15B1.4 (11)C19A—C18A—O4A—C17A44.0 (11)
N3B—C13B—C14B—C15B175.9 (7)O3B—C9B—O2B—C7B175.1 (6)
C11B—C10B—C15B—C14B0.8 (10)N2B—C9B—O2B—C7B8.5 (7)
N2B—C10B—C15B—C14B172.8 (7)C6B—C7B—O2B—C9B139.8 (6)
C13B—C14B—C15B—C10B0.6 (11)C8B—C7B—O2B—C9B20.3 (7)
N3B—C16B—C17B—O4B53.3 (11)C16B—C17B—O4B—C18B68.4 (10)
O4B—C18B—C19B—O5B167.4 (7)C19B—C18B—O4B—C17B46.9 (9)
O4B—C18B—C19B—N3B10.9 (10)C2A—C1A—S1A—C4A0.4 (7)
O1A—C5A—N1A—C6A4.0 (13)Cl1A—C1A—S1A—C4A179.5 (5)
C4A—C5A—N1A—C6A176.0 (6)C3A—C4A—S1A—C1A0.2 (7)
C7A—C6A—N1A—C5A171.1 (7)C5A—C4A—S1A—C1A179.8 (6)
O3A—C9A—N2A—C10A4.6 (13)C2B—C1B—S1B—C4B1.6 (7)
O2A—C9A—N2A—C10A174.9 (6)Cl1B—C1B—S1B—C4B179.4 (5)
O3A—C9A—N2A—C8A176.3 (8)C3B—C4B—S1B—C1B0.9 (7)
O2A—C9A—N2A—C8A4.2 (8)C5B—C4B—S1B—C1B178.0 (6)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1A—H1A···O3B0.862.163.008 (11)169
N1B—H1B···O3A0.862.223.016 (11)153
C3A—H3A···O3B0.932.483.357 (11)157
C6B—H6B1···O5Ai0.972.413.227 (10)141
C7A—H7A···O5Bii0.982.413.288 (8)149
C8A—H8A2···O1Biii0.972.523.459 (11)163
C8B—H8B1···O1Aiv0.972.152.961 (12)140
Symmetry codes: (i) x1, y, z; (ii) x+1, y, z; (iii) x, y+1, z; (iv) x, y1, z.
 

Acknowledgements

The authors thank the Zhejiang Jingxin Pharmaceutical Co. Ltd for support in the form of raw materials.

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