research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

Crystal structure of an apremilast ethanol hemisolvate hemihydrate solvatomorph

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aSpringPharma Tech Co. Ltd, Weidi Road 9, 210046 Nanjing, People's Republic of China, and bJiangSu Center for Safety Evaluation of Drugs, Majia Street 26, 210009 Nanjing, People's Republic of China
*Correspondence e-mail: wuyundeng@hotmail.com

Edited by M. Weil, Vienna University of Technology, Austria (Received 18 April 2017; accepted 3 May 2017; online 9 May 2017)

The title compound, C22H24N2O7S·0.5C2H5OH·0.5H2O {systematic name: (S)-4-acetamido-2-[1-(3-eth­oxy-4-meth­oxy­phen­yl)-2-(methyl­sulfon­yl)eth­yl]iso­indo­line-1,3-dione ethanol hemisolvate hemihydrate}, is a novel solvatomorph of apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The asymmetric unit contains one mol­ecule of AP and disordered mol­ecules of ethanol and water, both with half occupancy. The dihedral angle between the planes of the phenyl ring and the iso­indole ring is 67.9 (2)°. Extensive intra- and inter­molecular hydrogen bonds help to stabilize the mol­ecular conformation and sustain the crystal packing.

1. Chemical context

Analogues of thalidomide have been reported to possibly enhance tumor necrosis factor alpha (TNFα) inhibitory activity (Corral et al., 1996[Corral, L. G., Muller, G. W., Moreira, A. L., Chen, Y., Wu, M., Stirling, D. I. & Kaplan, G. (1996). Mol. Med. 2, 506-515.]; Muller et al., 1996[Muller, G. W., Corral, L. G., Shire, M. G., Wang, H., Moreira, A. L., Kaplan, G. & Stirling, D. I. (1996). J. Med. Chem. 39, 3238-3240.]) and phospho­diesterase type 4 (PD4) inhibition (Muller et al., 1998[Muller, G. W., Shire, M. G., Wong, L. M., Corral, L. G., Patterson, R. T., Chen, Y. & Stirling, D. I. (1998). Bioorg. Med. Chem. Lett. 8, 2669-2674.]), hence showing potential for the treatment of inflammatory diseases (de Brito et al., 1997[Brito, F. de, Souness, J. E. & Warne, P. J. (1997). Emerg. Drugs, 2, 249-268.]). Among these substances are phen­ethyl­sulfones substituted in the α position to the phenyl group with a 1-oxoisoindoline or 1,3-dioxoisoindoline group that can reduce the levels of TNFα in a mammal. Typical embodiments are (S)-2-[1-(3-eth­oxy-4-meth­oxy­phen­yl)-2-(meth­yl­sulfon­yl)eth­yl]-4-acetamido­isoindoline-1,3-dione] with the generic name apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis (Gottlieb et al., 2008[Gottlieb, A. B., Strober, B., Krueger, J. G., Rohane, P., Zeldis, J. B., Hu, C. C. & Kipnis, C. (2008). Curr. Med. Res. Opin. 24, 1529-1538.]; Man et al., 2009[Man, H. W., Schafer, P., Wong, L. M., Patterson, R. T., Corral, L. G., Raymon, H., Blease, K., Leisten, J., Shirley, M. A., Tang, Y., Babusis, D. M., Chen, R., Stirling, D. & Muller, G. W. (2009). J. Med. Chem. 52, 1522-1524.]; Duplantier et al., 1996[Duplantier, A. J., Biggers, M. S., Chambers, R. J., Cheng, J. B., Cooper, K., Damon, D. B., Eggler, J. F., Kraus, K. G., Marfat, A., Masamune, H., Pillar, J. S., Shirley, J. T., Umland, J. P. & Watson, J. W. (1996). J. Med. Chem. 39, 120-125.]). In our previous studies, we reported three solvatomorphs of AP with ethyl acetate, toluene and di­chloro­methane, respectively (Wu et al., 2017[Wu, Y.-D., Zhang, X.-L., Liu, X.-H., Xu, J., Zhang, M., Shen, K., Zhang, S.-H., He, Y.-M., Ma, Y. & Zhang, A.-H. (2017). Acta Cryst. C73, 305-313.]). However, these three solvates exhibit toxicity, in particular the solvates of toluene and di­chloro­methane, which clearly limits the possibility of these compounds being developed into drugs. In a continuation of our work, a novel solvatomorph of AP with ethanol and water solvents in the molar ratio 1:0.5:0.5 was prepared and its crystal structure determined. This solvatomorph of AP appears to be suitable for development into a powerful drug, showing much lower toxicity than the solvatomorphs of ethyl acetate, toluene and di­chloro­methane.

[Scheme 1]

2. Structural commentary

The title solvatomorph (I)[link] crystallizes in the same space group (P41212) as the other three structurally characterized solvatomorphs of ethyl acetate, toluene and di­chloro­methane (Wu et al., 2017[Wu, Y.-D., Zhang, X.-L., Liu, X.-H., Xu, J., Zhang, M., Shen, K., Zhang, S.-H., He, Y.-M., Ma, Y. & Zhang, A.-H. (2017). Acta Cryst. C73, 305-313.]). The structures of the mol­ecular components of (I)[link] are shown in Fig. 1[link]. The asymmetric unit comprises one mol­ecule of AP and one solvent mol­ecule each of ethanol and water, both being disordered about a twofold rotation axis (occupancy for both solvent mol­ecules = 0.5). A space-filling drawing of the structure is given in Fig. 2[link], emphasizing the positions of the solvent mol­ecules in the crystal structure. The bond lengths and angles in the AP mol­ecule are in normal ranges and very similar to those in the previous three solvatomorphs (Wu et al., 2017[Wu, Y.-D., Zhang, X.-L., Liu, X.-H., Xu, J., Zhang, M., Shen, K., Zhang, S.-H., He, Y.-M., Ma, Y. & Zhang, A.-H. (2017). Acta Cryst. C73, 305-313.]). The same applies to the dihedral angle between the phenyl (C13–C20) and iso­indole (C3–C5/C8–C12/N1) rings, which is 67.9 (2)° in the title structure. The conformation of the AP mol­ecule is stabilized by several intra­molecular hydrogen bonds of types N—H⋯O and C—H⋯O (Table 1[link]).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N2—H2⋯O3 0.86 2.31 2.986 (7) 136
O8—H8A⋯O9 0.92 2.30 3.20 (3) 166
O9—H9B⋯O1 0.89 2.54 2.994 (17) 112
C8—H8⋯O4 0.93 2.30 2.894 (9) 121
C1—H1A⋯O5 0.97 2.45 3.068 (8) 121
C1—H1A⋯O5i 0.97 2.32 3.172 (8) 147
C1—H1B⋯O4ii 0.97 2.56 3.524 (9) 172
C14—H14⋯O5i 0.93 2.49 3.415 (8) 178
C19—H19C⋯O4iii 0.96 2.61 3.567 (10) 173
C20—H20⋯O2ii 0.93 2.46 3.370 (9) 166
C22—H22C⋯O3iv 0.96 2.44 3.088 (9) 124
C22—H22C⋯O9 0.96 2.61 3.36 (2) 136
Symmetry codes: (i) y, x, -z+1; (ii) [x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+{\script{3\over 4}}]; (iii) [-y+{\script{5\over 2}}, x+{\script{1\over 2}}, z+{\script{1\over 4}}]; (iv) [-y+{\script{3\over 2}}, x-{\script{1\over 2}}, z+{\script{1\over 4}}].
[Figure 1]
Figure 1
The structures of the mol­ecular components in (I)[link]. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines.
[Figure 2]
Figure 2
The unit cell of (I)[link], with the solvent mol­ecules shown in space-filling mode. [See Table 1[link] for symmetry codes.]

3. Supra­molecular features

An extensive network of inter­molecular hydrogen-bonding inter­actions exists in the crystal structure (Figs. 1[link], 2[link]–4; Table 1[link]). The water mol­ecule (O9) is hydrogen-bonded to the AP mol­ecule by C22—H22C⋯O9 and O9—H9B⋯O1 inter­actions and likewise is bonded by an O8—H8A⋯O9 inter­action to the ethanol solvent mol­ecule. As well as these hydrogen bonds involving the solvent mol­ecules, there are inter­actions between AP mol­ecules. Two AP mol­ecules are arranged into a dimer with an R21(7) motif (Fig. 3[link]) by C—H⋯O hydrogen bonds, and a zipper-like chain including R22(18) motifs (Fig. 4[link]) is formed parallel to the a axis by additional C—H··O hydrogen bonds.

[Figure 3]
Figure 3
(AP)2 dimers with an R21(7) motif formed by C—H⋯O hydrogen bonds. [See Table 1[link] for symmetry code.]
[Figure 4]
Figure 4
C1—H1B⋯O4ii and C20—H20⋯O2ii hydrogen bonds incorporating R22(18) motifs expand the structure parallel to the a-axis direction. [See Table 1[link] for symmetry codes.]

4. Synthesis and crystallization

AP was prepared according to a literature protocol (Muller et al., 2006[Muller, G. W., Schafer, P. & Rohane, P. (2006). US Patent No. 2006183787.], 2008a[Muller, G. W., Schafer, P. H., Man, H. W. & Ge, C. (2008a). US Patent No. 7427638.],b[Muller, G. W., Schafer, P. H., Man, H.-W., Ge, C. & Xu, J. (2008b). WO Patent No. 2009120167.]). A 100 ml round-bottomed flask equipped with a magnetic stirring bar was charged with a solution of (S)-1-(3-eth­oxy-4-meth­oxy­phen­yl)-2-methyl­sulfonyl­ethan­amine N-acetyl leucine salt (5.0 g, 11.2 mmol, 1.0 eq) and 3-acetamido­phthalic anhydride (2.42 g, 11.8 mmol, 1.05 eq) to which glacial acetic acid (50 ml) was added. The mixture was refluxed for 16 h and then cooled to room temperature. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (2 × 50 ml), saturated aqueous sodium bicarbonate (2 × 50 ml), brine (2 × 50 ml), and dried over anhydrous sodium sulfate. The solvents were evaporated in vacuo, and the obtained AP recrystallized from an ethanol/acetone mixture (2:1, v/v). Single crystals of (I)[link] were obtained by slow evaporation of an AP-saturated solution from an N,N-di­methyl­formamide/ethanol/water mixture (1:10:2, v/v/v), at room temperature over 90 days.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. Hydrogen atoms bound to nitro­gen or carbon atoms were placed in calculated positions (N—H = 0.87, C—H = 0.93–0.98 Å) and constrained to ride on their carrier atoms [Uiso(H) = 1.2Ueq(C,N) or 1.5Ueq(Cmeth­yl)]. Hydrogen atoms bound to oxygen atoms were deduced from difference-Fourier maps and their positions relative to donor and possible acceptor atoms. They were refined with Uiso(H) = 1.5Ueq(O). The solvent ethanol and water mol­ecules are disordered about a twofold rotation axis and were refined with an occupancy of 0.5. To get reasonable shape and displacement parameters for both mol­ecules, they were treated with DFIX, RIGU and ISOR restraints in SHELXL2014 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]).

Table 2
Experimental details

Crystal data
Chemical formula C22H24N2O7S·0.5C2H6O·0.5H2O
Mr 492.53
Crystal system, space group Tetragonal, P41212
Temperature (K) 298
a, c (Å) 12.9905 (18), 29.942 (6)
V3) 5052.8 (17)
Z 8
Radiation type Mo Kα
μ (mm−1) 0.18
Crystal size (mm) 0.3 × 0.3 × 0.2
 
Data collection
Diffractometer Bruker P4
No. of measured, independent and observed [I > 2σ(I)] reflections 9575, 4390, 2811
Rint 0.079
(sin θ/λ)max−1) 0.592
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.066, 0.183, 1.05
No. of reflections 4390
No. of parameters 329
No. of restraints 30
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.62, −0.30
Absolute structure Flack x determined using 833 quotients [(I+)−(I)]/[(I+)+(I)] (Parsons et al., 2013[Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249-259.])
Absolute structure parameter 0.15 (8)
Computer programs: APEX2 and SAINT (Bruker, 2009[Bruker (2009). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL2014 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]) and OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]).

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(S)-4-Acetamido-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione ethanol hemisolvate hemihydrate top
Crystal data top
C22H24N2O7S·0.5C2H6O·0.5H2ODx = 1.295 Mg m3
Mr = 492.53Mo Kα radiation, λ = 0.71073 Å
Tetragonal, P41212Cell parameters from 2016 reflections
a = 12.9905 (18) Åθ = 2–20°
c = 29.942 (6) ŵ = 0.18 mm1
V = 5052.8 (17) Å3T = 298 K
Z = 8Block, colourless
F(000) = 20800.3 × 0.3 × 0.2 mm
Data collection top
Bruker P4
diffractometer
θmax = 24.9°, θmin = 1.7°
ω scansh = 015
9575 measured reflectionsk = 015
4390 independent reflectionsl = 3535
2811 reflections with I > 2σ(I)1 standard reflections every 60 reflections
Rint = 0.079 intensity decay: 1%
Refinement top
Refinement on F2Hydrogen site location: mixed
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.066 w = 1/[σ2(Fo2) + (0.0992P)2]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.183(Δ/σ)max < 0.001
S = 1.05Δρmax = 0.62 e Å3
4390 reflectionsΔρmin = 0.30 e Å3
329 parametersAbsolute structure: Flack x determined using 833 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
30 restraintsAbsolute structure parameter: 0.15 (8)
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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
S10.89768 (15)0.65667 (14)0.46183 (6)0.0537 (5)
O30.9782 (4)0.7422 (4)0.33313 (15)0.0565 (12)
O61.2492 (4)1.0317 (4)0.51740 (15)0.0650 (15)
O50.8948 (4)0.9600 (4)0.44709 (16)0.0618 (14)
O10.8059 (4)0.7045 (4)0.44502 (17)0.0690 (14)
O20.9386 (4)0.5729 (4)0.43657 (18)0.0728 (16)
O40.6990 (5)0.8281 (4)0.21258 (18)0.0774 (16)
O71.3846 (4)1.0504 (4)0.45344 (16)0.0660 (14)
N10.9578 (4)0.8403 (4)0.39684 (16)0.0425 (12)
N20.8221 (4)0.8054 (5)0.26522 (17)0.0544 (15)
H20.87640.76990.27100.065*
C30.9329 (5)0.8089 (5)0.3537 (2)0.0418 (14)
C21.0379 (5)0.7928 (5)0.4242 (2)0.0441 (15)
H2A1.06370.73330.40750.053*
C120.8912 (5)0.9175 (5)0.4107 (2)0.0487 (16)
C110.8173 (5)0.9376 (5)0.3739 (2)0.0452 (15)
C131.1290 (5)0.8638 (5)0.4319 (2)0.0455 (16)
C141.1440 (5)0.9163 (5)0.4720 (2)0.0512 (17)
H141.09520.91000.49450.061*
C40.8437 (5)0.8713 (5)0.3392 (2)0.0451 (16)
C80.7059 (5)0.9390 (5)0.2964 (3)0.0572 (18)
H80.66700.94080.27030.069*
C50.7893 (5)0.8709 (5)0.2996 (2)0.0477 (16)
C10.9941 (5)0.7515 (5)0.4684 (2)0.0467 (15)
H1A0.96570.80860.48530.056*
H1B1.05010.72250.48580.056*
C201.2874 (5)0.9370 (6)0.4048 (2)0.0575 (18)
H201.33530.94350.38190.069*
C60.7810 (7)0.7888 (6)0.2243 (2)0.0599 (19)
C181.3020 (5)0.9885 (5)0.4443 (3)0.0533 (18)
C151.2291 (5)0.9771 (5)0.4791 (2)0.0504 (17)
C211.2011 (6)0.8752 (5)0.3988 (2)0.0571 (19)
H211.19210.84090.37180.069*
C100.7368 (5)1.0042 (6)0.3713 (3)0.0585 (18)
H100.71991.04810.39470.070*
C161.1741 (5)1.0248 (6)0.5523 (2)0.065 (2)
H16A1.16680.95390.56190.078*
H16B1.10781.04880.54170.078*
C90.6809 (6)1.0032 (6)0.3313 (3)0.067 (2)
H90.62491.04730.32820.081*
C70.8411 (6)0.7188 (7)0.1951 (2)0.076 (2)
H7A0.90670.70500.20860.114*
H7B0.85130.75080.16650.114*
H7C0.80430.65530.19120.114*
C220.8740 (7)0.6177 (7)0.5166 (2)0.083 (3)
H22A0.85960.67690.53470.124*
H22B0.93340.58270.52810.124*
H22C0.81590.57200.51710.124*
C191.4549 (6)1.0668 (8)0.4174 (3)0.086 (3)
H19A1.42041.10220.39360.128*
H19B1.47981.00170.40680.128*
H19C1.51181.10760.42770.128*
C171.2096 (8)1.0901 (9)0.5904 (3)0.104 (4)
H17A1.21631.16020.58070.157*
H17B1.27501.06560.60090.157*
H17C1.16021.08660.61420.157*
O80.4584 (16)0.3998 (17)0.4571 (7)0.177 (8)0.5
H8A0.50220.45440.46130.265*0.5
C230.3896 (19)0.3736 (17)0.4889 (8)0.108 (7)0.5
H23A0.34700.43410.49330.130*0.5
H23B0.42910.36530.51610.130*0.5
C240.319 (3)0.287 (3)0.4878 (12)0.164 (13)0.5
H24A0.32620.25060.46010.247*0.5
H24B0.24920.31170.49040.247*0.5
H24C0.33340.24120.51220.247*0.5
O90.6400 (13)0.5606 (12)0.4753 (9)0.192 (11)0.5
H9A0.63670.63010.47060.289*0.5
H9B0.70110.54510.46350.289*0.5
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0592 (11)0.0558 (11)0.0461 (9)0.0131 (9)0.0010 (8)0.0016 (8)
O30.057 (3)0.067 (3)0.045 (3)0.013 (2)0.002 (2)0.015 (2)
O60.060 (3)0.082 (4)0.053 (3)0.023 (3)0.007 (2)0.021 (3)
O50.081 (3)0.062 (3)0.043 (3)0.003 (3)0.006 (2)0.014 (2)
O10.058 (3)0.083 (4)0.066 (3)0.008 (3)0.010 (3)0.005 (3)
O20.085 (4)0.058 (3)0.076 (4)0.012 (3)0.002 (3)0.017 (3)
O40.079 (4)0.092 (4)0.062 (3)0.015 (3)0.021 (3)0.006 (3)
O70.054 (3)0.080 (4)0.064 (3)0.019 (3)0.007 (3)0.004 (3)
N10.049 (3)0.043 (3)0.036 (3)0.000 (3)0.004 (2)0.007 (2)
N20.057 (4)0.064 (4)0.043 (3)0.015 (3)0.006 (3)0.008 (3)
C30.042 (3)0.046 (4)0.037 (3)0.003 (3)0.009 (3)0.002 (3)
C20.049 (4)0.048 (4)0.035 (3)0.000 (3)0.000 (3)0.005 (3)
C120.059 (4)0.045 (4)0.041 (4)0.010 (3)0.008 (3)0.003 (3)
C110.048 (4)0.043 (4)0.044 (4)0.002 (3)0.008 (3)0.006 (3)
C130.047 (4)0.045 (4)0.044 (4)0.000 (3)0.003 (3)0.000 (3)
C140.051 (4)0.052 (4)0.051 (4)0.008 (3)0.013 (3)0.004 (3)
C40.051 (4)0.042 (4)0.042 (4)0.006 (3)0.011 (3)0.001 (3)
C80.054 (4)0.054 (4)0.063 (5)0.003 (4)0.005 (4)0.003 (4)
C50.050 (4)0.046 (4)0.048 (4)0.001 (3)0.003 (3)0.001 (3)
C10.049 (4)0.050 (4)0.040 (3)0.007 (3)0.001 (3)0.004 (3)
C200.051 (4)0.069 (5)0.053 (4)0.007 (4)0.013 (4)0.006 (4)
C60.070 (5)0.068 (5)0.042 (4)0.008 (4)0.001 (4)0.002 (4)
C180.046 (4)0.055 (4)0.059 (4)0.005 (4)0.002 (3)0.003 (3)
C150.041 (4)0.055 (4)0.055 (4)0.003 (3)0.001 (3)0.003 (3)
C210.063 (5)0.065 (5)0.043 (4)0.006 (4)0.005 (3)0.006 (3)
C100.059 (5)0.053 (4)0.063 (5)0.010 (4)0.009 (4)0.010 (4)
C160.044 (4)0.090 (6)0.062 (5)0.006 (4)0.004 (3)0.021 (4)
C90.053 (5)0.059 (5)0.090 (6)0.011 (4)0.007 (4)0.001 (4)
C70.079 (5)0.098 (6)0.051 (4)0.024 (5)0.009 (4)0.017 (4)
C220.102 (7)0.096 (7)0.050 (5)0.029 (5)0.010 (4)0.017 (4)
C190.062 (5)0.123 (8)0.072 (6)0.027 (5)0.004 (4)0.023 (5)
C170.086 (7)0.148 (9)0.079 (7)0.024 (7)0.014 (5)0.052 (6)
O80.161 (12)0.190 (14)0.180 (14)0.097 (10)0.023 (11)0.023 (12)
C230.110 (11)0.086 (10)0.129 (13)0.061 (8)0.053 (9)0.002 (10)
C240.179 (19)0.150 (17)0.16 (2)0.014 (15)0.043 (16)0.010 (15)
O90.126 (14)0.125 (14)0.33 (3)0.030 (11)0.032 (16)0.084 (16)
Geometric parameters (Å, º) top
S1—O11.436 (5)C20—H200.9300
S1—O21.428 (6)C20—C181.372 (10)
S1—C11.768 (6)C20—C211.390 (10)
S1—C221.744 (7)C6—C71.485 (10)
O3—C31.214 (7)C18—C151.417 (10)
O6—C151.373 (8)C21—H210.9300
O6—C161.433 (8)C10—H100.9300
O5—C121.221 (7)C10—C91.400 (11)
O4—C61.232 (9)C16—H16A0.9700
O7—C181.368 (8)C16—H16B0.9700
O7—C191.430 (9)C16—C171.495 (11)
N1—C31.394 (8)C9—H90.9300
N1—C21.461 (8)C7—H7A0.9601
N1—C121.388 (8)C7—H7B0.9599
N2—H20.8600C7—H7C0.9602
N2—C51.401 (8)C22—H22A0.9600
N2—C61.353 (9)C22—H22B0.9600
C3—C41.478 (9)C22—H22C0.9600
C2—H2A0.9800C19—H19A0.9600
C2—C131.518 (9)C19—H19B0.9600
C2—C11.539 (8)C19—H19C0.9600
C12—C111.485 (9)C17—H17A0.9600
C11—C41.392 (8)C17—H17B0.9600
C11—C101.360 (9)C17—H17C0.9600
C13—C141.394 (9)O8—H8A0.9182
C13—C211.372 (9)O8—C231.35 (2)
C14—H140.9300C23—H23A0.9700
C14—C151.375 (9)C23—H23B0.9700
C4—C51.381 (9)C23—C241.46 (2)
C8—H80.9300C24—H24A0.9600
C8—C51.401 (9)C24—H24B0.9600
C8—C91.377 (10)C24—H24C0.9600
C1—H1A0.9700O9—H9A0.9150
C1—H1B0.9700O9—H9B0.8918
O1—S1—C1109.0 (3)C20—C18—C15119.4 (6)
O1—S1—C22108.0 (4)O6—C15—C14125.3 (6)
O2—S1—O1117.0 (3)O6—C15—C18115.7 (6)
O2—S1—C1109.1 (3)C14—C15—C18118.9 (6)
O2—S1—C22110.0 (4)C13—C21—C20121.3 (6)
C22—S1—C1102.8 (4)C13—C21—H21119.3
C15—O6—C16116.6 (5)C20—C21—H21119.3
C18—O7—C19115.9 (6)C11—C10—H10121.9
C3—N1—C2124.2 (5)C11—C10—C9116.3 (6)
C12—N1—C3110.2 (5)C9—C10—H10121.9
C12—N1—C2125.5 (5)O6—C16—H16A110.1
C5—N2—H2115.3O6—C16—H16B110.1
C6—N2—H2114.8O6—C16—C17108.2 (6)
C6—N2—C5129.9 (6)H16A—C16—H16B108.4
O3—C3—N1124.4 (6)C17—C16—H16A110.1
O3—C3—C4128.5 (6)C17—C16—H16B110.1
N1—C3—C4107.0 (5)C8—C9—C10122.2 (7)
N1—C2—H2A106.9C8—C9—H9118.9
N1—C2—C13112.7 (5)C10—C9—H9118.9
N1—C2—C1111.5 (5)C6—C7—H7A109.4
C13—C2—H2A106.9C6—C7—H7B109.4
C13—C2—C1111.6 (5)C6—C7—H7C109.6
C1—C2—H2A106.9H7A—C7—H7B109.5
O5—C12—N1124.8 (6)H7A—C7—H7C109.5
O5—C12—C11127.4 (6)H7B—C7—H7C109.4
N1—C12—C11107.9 (5)S1—C22—H22A109.5
C4—C11—C12106.6 (6)S1—C22—H22B109.5
C10—C11—C12130.7 (6)S1—C22—H22C109.5
C10—C11—C4122.7 (6)H22A—C22—H22B109.5
C14—C13—C2122.5 (5)H22A—C22—H22C109.5
C21—C13—C2119.2 (6)H22B—C22—H22C109.5
C21—C13—C14118.3 (6)O7—C19—H19A109.5
C13—C14—H14119.1O7—C19—H19B109.5
C15—C14—C13121.8 (6)O7—C19—H19C109.5
C15—C14—H14119.1H19A—C19—H19B109.5
C11—C4—C3108.3 (6)H19A—C19—H19C109.5
C5—C4—C3130.6 (6)H19B—C19—H19C109.5
C5—C4—C11121.1 (6)C16—C17—H17A109.5
C5—C8—H8119.6C16—C17—H17B109.5
C9—C8—H8119.6C16—C17—H17C109.5
C9—C8—C5120.8 (7)H17A—C17—H17B109.5
N2—C5—C8124.6 (6)H17A—C17—H17C109.5
C4—C5—N2118.5 (6)H17B—C17—H17C109.5
C4—C5—C8116.9 (6)C23—O8—H8A120.7
S1—C1—H1A108.7O8—C23—H23A105.6
S1—C1—H1B108.7O8—C23—H23B105.6
C2—C1—S1114.1 (4)O8—C23—C24127 (3)
C2—C1—H1A108.7H23A—C23—H23B106.1
C2—C1—H1B108.7C24—C23—H23A105.6
H1A—C1—H1B107.6C24—C23—H23B105.6
C18—C20—H20119.8C23—C24—H24A109.5
C18—C20—C21120.3 (6)C23—C24—H24B109.5
C21—C20—H20119.8C23—C24—H24C109.5
O4—C6—N2122.3 (7)H24A—C24—H24B109.5
O4—C6—C7122.7 (7)H24A—C24—H24C109.5
N2—C6—C7115.1 (7)H24B—C24—H24C109.5
O7—C18—C20124.7 (6)H9A—O9—H9B101.7
O7—C18—C15116.0 (6)
O3—C3—C4—C11179.6 (6)C12—C11—C10—C9179.1 (7)
O3—C3—C4—C50.2 (11)C11—C4—C5—N2177.4 (6)
O5—C12—C11—C4179.6 (6)C11—C4—C5—C81.0 (10)
O5—C12—C11—C101.3 (12)C11—C10—C9—C80.4 (11)
O1—S1—C1—C271.1 (6)C13—C2—C1—S1173.0 (4)
O2—S1—C1—C257.7 (6)C13—C14—C15—O6179.5 (7)
O7—C18—C15—O61.6 (9)C13—C14—C15—C181.6 (10)
O7—C18—C15—C14179.7 (6)C14—C13—C21—C200.2 (10)
N1—C3—C4—C110.2 (7)C4—C11—C10—C90.2 (10)
N1—C3—C4—C5180.0 (6)C5—N2—C6—O45.0 (12)
N1—C2—C13—C14102.5 (7)C5—N2—C6—C7175.8 (7)
N1—C2—C13—C2179.2 (7)C5—C8—C9—C100.3 (12)
N1—C2—C1—S160.1 (6)C1—C2—C13—C1423.8 (9)
N1—C12—C11—C40.3 (7)C1—C2—C13—C21154.5 (6)
N1—C12—C11—C10178.8 (7)C20—C18—C15—O6179.6 (6)
C3—N1—C2—C13111.8 (6)C20—C18—C15—C141.5 (10)
C3—N1—C2—C1121.8 (6)C6—N2—C5—C4177.9 (7)
C3—N1—C12—O5179.8 (6)C6—N2—C5—C83.9 (12)
C3—N1—C12—C110.1 (7)C18—C20—C21—C130.1 (11)
C3—C4—C5—N22.9 (11)C15—O6—C16—C17179.4 (7)
C3—C4—C5—C8178.7 (6)C21—C13—C14—C151.0 (10)
C2—N1—C3—O33.8 (9)C21—C20—C18—O7179.5 (7)
C2—N1—C3—C4176.1 (5)C21—C20—C18—C150.8 (11)
C2—N1—C12—O54.3 (10)C10—C11—C4—C3178.9 (6)
C2—N1—C12—C11175.8 (5)C10—C11—C4—C50.9 (10)
C2—C13—C14—C15177.3 (6)C16—O6—C15—C140.5 (10)
C2—C13—C21—C20178.2 (6)C16—O6—C15—C18177.4 (6)
C12—N1—C3—O3179.8 (6)C9—C8—C5—N2177.9 (7)
C12—N1—C3—C40.1 (6)C9—C8—C5—C40.4 (10)
C12—N1—C2—C1372.8 (7)C22—S1—C1—C2174.5 (5)
C12—N1—C2—C153.6 (8)C19—O7—C18—C204.8 (10)
C12—C11—C4—C30.3 (7)C19—O7—C18—C15176.4 (7)
C12—C11—C4—C5179.9 (6)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O30.862.312.986 (7)136
O8—H8A···O90.922.303.20 (3)166
O9—H9B···O10.892.542.994 (17)112
C8—H8···O40.932.302.894 (9)121
C1—H1A···O50.972.453.068 (8)121
C1—H1A···O5i0.972.323.172 (8)147
C1—H1B···O4ii0.972.563.524 (9)172
C14—H14···O5i0.932.493.415 (8)178
C19—H19C···O4iii0.962.613.567 (10)173
C20—H20···O2ii0.932.463.370 (9)166
C22—H22C···O3iv0.962.443.088 (9)124
C22—H22C···O90.962.613.36 (2)136
Symmetry codes: (i) y, x, z+1; (ii) x+1/2, y+3/2, z+3/4; (iii) y+5/2, x+1/2, z+1/4; (iv) y+3/2, x1/2, z+1/4.
 

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