research communications
of an apremilast ethanol hemisolvate hemihydrate solvatomorph
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
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 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.
Keywords: apremilast; PDE4; psoriatic arthritis; crystal structure; hydrogen bonding; solvatomorph.
CCDC reference: 1504229
1. Chemical context
Analogues of thalidomide have been reported to possibly enhance tumor necrosis factor alpha (TNFα) inhibitory activity (Corral et al., 1996; Muller et al., 1996) and phosphodiesterase type 4 (PD4) inhibition (Muller et al., 1998), hence showing potential for the treatment of inflammatory diseases (de Brito et al., 1997). 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; Man et al., 2009; Duplantier et al., 1996). In our previous studies, we reported three solvatomorphs of AP with ethyl acetate, toluene and dichloromethane, respectively (Wu et al., 2017). 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 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.
2. Structural commentary
The title solvatomorph (I) crystallizes in the same (P41212) as the other three structurally characterized solvatomorphs of ethyl acetate, toluene and dichloromethane (Wu et al., 2017). The structures of the molecular components of (I) are shown in Fig. 1. The 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, emphasizing the positions of the solvent molecules in the 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). 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).
3. Supramolecular features
An extensive network of intermolecular hydrogen-bonding interactions exists in the , 2–4; Table 1). 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) by C—H⋯O hydrogen bonds, and a zipper-like chain including R22(18) motifs (Fig. 4) is formed parallel to the a axis by additional C—H··O hydrogen bonds.
(Figs. 14. Synthesis and crystallization
AP was prepared according to a literature protocol (Muller et al., 2006, 2008a,b). 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) 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 . 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).
details are summarized in Table 2
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Supporting information
CCDC reference: 1504229
https://doi.org/10.1107/S2056989017006661/wm5386sup1.cif
contains datablock I. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017006661/wm5386Isup2.hkl
Data collection: APEX2 (Bruker, 2009); cell
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).C22H24N2O7S·0.5C2H6O·0.5H2O | Dx = 1.295 Mg m−3 |
Mr = 492.53 | Mo Kα radiation, λ = 0.71073 Å |
Tetragonal, P41212 | Cell parameters from 2016 reflections |
a = 12.9905 (18) Å | θ = 2–20° |
c = 29.942 (6) Å | µ = 0.18 mm−1 |
V = 5052.8 (17) Å3 | T = 298 K |
Z = 8 | Block, colourless |
F(000) = 2080 | 0.3 × 0.3 × 0.2 mm |
Bruker P4 diffractometer | θmax = 24.9°, θmin = 1.7° |
ω scans | h = 0→15 |
9575 measured reflections | k = 0→15 |
4390 independent reflections | l = −35→35 |
2811 reflections with I > 2σ(I) | 1 standard reflections every 60 reflections |
Rint = 0.079 | intensity decay: 1% |
Refinement on F2 | Hydrogen site location: mixed |
Least-squares matrix: full | H-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 = 1.05 | Δρmax = 0.62 e Å−3 |
4390 reflections | Δρmin = −0.30 e Å−3 |
329 parameters | Absolute structure: Flack x determined using 833 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013) |
30 restraints | Absolute structure parameter: 0.15 (8) |
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. |
x | y | z | Uiso*/Ueq | Occ. (<1) | |
S1 | 0.89768 (15) | 0.65667 (14) | 0.46183 (6) | 0.0537 (5) | |
O3 | 0.9782 (4) | 0.7422 (4) | 0.33313 (15) | 0.0565 (12) | |
O6 | 1.2492 (4) | 1.0317 (4) | 0.51740 (15) | 0.0650 (15) | |
O5 | 0.8948 (4) | 0.9600 (4) | 0.44709 (16) | 0.0618 (14) | |
O1 | 0.8059 (4) | 0.7045 (4) | 0.44502 (17) | 0.0690 (14) | |
O2 | 0.9386 (4) | 0.5729 (4) | 0.43657 (18) | 0.0728 (16) | |
O4 | 0.6990 (5) | 0.8281 (4) | 0.21258 (18) | 0.0774 (16) | |
O7 | 1.3846 (4) | 1.0504 (4) | 0.45344 (16) | 0.0660 (14) | |
N1 | 0.9578 (4) | 0.8403 (4) | 0.39684 (16) | 0.0425 (12) | |
N2 | 0.8221 (4) | 0.8054 (5) | 0.26522 (17) | 0.0544 (15) | |
H2 | 0.8764 | 0.7699 | 0.2710 | 0.065* | |
C3 | 0.9329 (5) | 0.8089 (5) | 0.3537 (2) | 0.0418 (14) | |
C2 | 1.0379 (5) | 0.7928 (5) | 0.4242 (2) | 0.0441 (15) | |
H2A | 1.0637 | 0.7333 | 0.4075 | 0.053* | |
C12 | 0.8912 (5) | 0.9175 (5) | 0.4107 (2) | 0.0487 (16) | |
C11 | 0.8173 (5) | 0.9376 (5) | 0.3739 (2) | 0.0452 (15) | |
C13 | 1.1290 (5) | 0.8638 (5) | 0.4319 (2) | 0.0455 (16) | |
C14 | 1.1440 (5) | 0.9163 (5) | 0.4720 (2) | 0.0512 (17) | |
H14 | 1.0952 | 0.9100 | 0.4945 | 0.061* | |
C4 | 0.8437 (5) | 0.8713 (5) | 0.3392 (2) | 0.0451 (16) | |
C8 | 0.7059 (5) | 0.9390 (5) | 0.2964 (3) | 0.0572 (18) | |
H8 | 0.6670 | 0.9408 | 0.2703 | 0.069* | |
C5 | 0.7893 (5) | 0.8709 (5) | 0.2996 (2) | 0.0477 (16) | |
C1 | 0.9941 (5) | 0.7515 (5) | 0.4684 (2) | 0.0467 (15) | |
H1A | 0.9657 | 0.8086 | 0.4853 | 0.056* | |
H1B | 1.0501 | 0.7225 | 0.4858 | 0.056* | |
C20 | 1.2874 (5) | 0.9370 (6) | 0.4048 (2) | 0.0575 (18) | |
H20 | 1.3353 | 0.9435 | 0.3819 | 0.069* | |
C6 | 0.7810 (7) | 0.7888 (6) | 0.2243 (2) | 0.0599 (19) | |
C18 | 1.3020 (5) | 0.9885 (5) | 0.4443 (3) | 0.0533 (18) | |
C15 | 1.2291 (5) | 0.9771 (5) | 0.4791 (2) | 0.0504 (17) | |
C21 | 1.2011 (6) | 0.8752 (5) | 0.3988 (2) | 0.0571 (19) | |
H21 | 1.1921 | 0.8409 | 0.3718 | 0.069* | |
C10 | 0.7368 (5) | 1.0042 (6) | 0.3713 (3) | 0.0585 (18) | |
H10 | 0.7199 | 1.0481 | 0.3947 | 0.070* | |
C16 | 1.1741 (5) | 1.0248 (6) | 0.5523 (2) | 0.065 (2) | |
H16A | 1.1668 | 0.9539 | 0.5619 | 0.078* | |
H16B | 1.1078 | 1.0488 | 0.5417 | 0.078* | |
C9 | 0.6809 (6) | 1.0032 (6) | 0.3313 (3) | 0.067 (2) | |
H9 | 0.6249 | 1.0473 | 0.3282 | 0.081* | |
C7 | 0.8411 (6) | 0.7188 (7) | 0.1951 (2) | 0.076 (2) | |
H7A | 0.9067 | 0.7050 | 0.2086 | 0.114* | |
H7B | 0.8513 | 0.7508 | 0.1665 | 0.114* | |
H7C | 0.8043 | 0.6553 | 0.1912 | 0.114* | |
C22 | 0.8740 (7) | 0.6177 (7) | 0.5166 (2) | 0.083 (3) | |
H22A | 0.8596 | 0.6769 | 0.5347 | 0.124* | |
H22B | 0.9334 | 0.5827 | 0.5281 | 0.124* | |
H22C | 0.8159 | 0.5720 | 0.5171 | 0.124* | |
C19 | 1.4549 (6) | 1.0668 (8) | 0.4174 (3) | 0.086 (3) | |
H19A | 1.4204 | 1.1022 | 0.3936 | 0.128* | |
H19B | 1.4798 | 1.0017 | 0.4068 | 0.128* | |
H19C | 1.5118 | 1.1076 | 0.4277 | 0.128* | |
C17 | 1.2096 (8) | 1.0901 (9) | 0.5904 (3) | 0.104 (4) | |
H17A | 1.2163 | 1.1602 | 0.5807 | 0.157* | |
H17B | 1.2750 | 1.0656 | 0.6009 | 0.157* | |
H17C | 1.1602 | 1.0866 | 0.6142 | 0.157* | |
O8 | 0.4584 (16) | 0.3998 (17) | 0.4571 (7) | 0.177 (8) | 0.5 |
H8A | 0.5022 | 0.4544 | 0.4613 | 0.265* | 0.5 |
C23 | 0.3896 (19) | 0.3736 (17) | 0.4889 (8) | 0.108 (7) | 0.5 |
H23A | 0.3470 | 0.4341 | 0.4933 | 0.130* | 0.5 |
H23B | 0.4291 | 0.3653 | 0.5161 | 0.130* | 0.5 |
C24 | 0.319 (3) | 0.287 (3) | 0.4878 (12) | 0.164 (13) | 0.5 |
H24A | 0.3262 | 0.2506 | 0.4601 | 0.247* | 0.5 |
H24B | 0.2492 | 0.3117 | 0.4904 | 0.247* | 0.5 |
H24C | 0.3334 | 0.2412 | 0.5122 | 0.247* | 0.5 |
O9 | 0.6400 (13) | 0.5606 (12) | 0.4753 (9) | 0.192 (11) | 0.5 |
H9A | 0.6367 | 0.6301 | 0.4706 | 0.289* | 0.5 |
H9B | 0.7011 | 0.5451 | 0.4635 | 0.289* | 0.5 |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0592 (11) | 0.0558 (11) | 0.0461 (9) | −0.0131 (9) | −0.0010 (8) | 0.0016 (8) |
O3 | 0.057 (3) | 0.067 (3) | 0.045 (3) | 0.013 (2) | 0.002 (2) | −0.015 (2) |
O6 | 0.060 (3) | 0.082 (4) | 0.053 (3) | −0.023 (3) | 0.007 (2) | −0.021 (3) |
O5 | 0.081 (3) | 0.062 (3) | 0.043 (3) | 0.003 (3) | 0.006 (2) | −0.014 (2) |
O1 | 0.058 (3) | 0.083 (4) | 0.066 (3) | −0.008 (3) | −0.010 (3) | 0.005 (3) |
O2 | 0.085 (4) | 0.058 (3) | 0.076 (4) | −0.012 (3) | 0.002 (3) | −0.017 (3) |
O4 | 0.079 (4) | 0.092 (4) | 0.062 (3) | 0.015 (3) | −0.021 (3) | −0.006 (3) |
O7 | 0.054 (3) | 0.080 (4) | 0.064 (3) | −0.019 (3) | 0.007 (3) | −0.004 (3) |
N1 | 0.049 (3) | 0.043 (3) | 0.036 (3) | 0.000 (3) | 0.004 (2) | −0.007 (2) |
N2 | 0.057 (4) | 0.064 (4) | 0.043 (3) | 0.015 (3) | −0.006 (3) | −0.008 (3) |
C3 | 0.042 (3) | 0.046 (4) | 0.037 (3) | −0.003 (3) | 0.009 (3) | −0.002 (3) |
C2 | 0.049 (4) | 0.048 (4) | 0.035 (3) | 0.000 (3) | 0.000 (3) | −0.005 (3) |
C12 | 0.059 (4) | 0.045 (4) | 0.041 (4) | −0.010 (3) | 0.008 (3) | −0.003 (3) |
C11 | 0.048 (4) | 0.043 (4) | 0.044 (4) | −0.002 (3) | 0.008 (3) | −0.006 (3) |
C13 | 0.047 (4) | 0.045 (4) | 0.044 (4) | 0.000 (3) | 0.003 (3) | 0.000 (3) |
C14 | 0.051 (4) | 0.052 (4) | 0.051 (4) | −0.008 (3) | 0.013 (3) | −0.004 (3) |
C4 | 0.051 (4) | 0.042 (4) | 0.042 (4) | −0.006 (3) | 0.011 (3) | −0.001 (3) |
C8 | 0.054 (4) | 0.054 (4) | 0.063 (5) | 0.003 (4) | −0.005 (4) | −0.003 (4) |
C5 | 0.050 (4) | 0.046 (4) | 0.048 (4) | −0.001 (3) | 0.003 (3) | 0.001 (3) |
C1 | 0.049 (4) | 0.050 (4) | 0.040 (3) | −0.007 (3) | −0.001 (3) | −0.004 (3) |
C20 | 0.051 (4) | 0.069 (5) | 0.053 (4) | −0.007 (4) | 0.013 (4) | 0.006 (4) |
C6 | 0.070 (5) | 0.068 (5) | 0.042 (4) | −0.008 (4) | −0.001 (4) | 0.002 (4) |
C18 | 0.046 (4) | 0.055 (4) | 0.059 (4) | −0.005 (4) | 0.002 (3) | 0.003 (3) |
C15 | 0.041 (4) | 0.055 (4) | 0.055 (4) | −0.003 (3) | −0.001 (3) | −0.003 (3) |
C21 | 0.063 (5) | 0.065 (5) | 0.043 (4) | −0.006 (4) | 0.005 (3) | −0.006 (3) |
C10 | 0.059 (5) | 0.053 (4) | 0.063 (5) | 0.010 (4) | 0.009 (4) | −0.010 (4) |
C16 | 0.044 (4) | 0.090 (6) | 0.062 (5) | −0.006 (4) | 0.004 (3) | −0.021 (4) |
C9 | 0.053 (5) | 0.059 (5) | 0.090 (6) | 0.011 (4) | 0.007 (4) | −0.001 (4) |
C7 | 0.079 (5) | 0.098 (6) | 0.051 (4) | 0.024 (5) | −0.009 (4) | −0.017 (4) |
C22 | 0.102 (7) | 0.096 (7) | 0.050 (5) | −0.029 (5) | 0.010 (4) | 0.017 (4) |
C19 | 0.062 (5) | 0.123 (8) | 0.072 (6) | −0.027 (5) | 0.004 (4) | 0.023 (5) |
C17 | 0.086 (7) | 0.148 (9) | 0.079 (7) | −0.024 (7) | 0.014 (5) | −0.052 (6) |
O8 | 0.161 (12) | 0.190 (14) | 0.180 (14) | 0.097 (10) | −0.023 (11) | 0.023 (12) |
C23 | 0.110 (11) | 0.086 (10) | 0.129 (13) | 0.061 (8) | −0.053 (9) | 0.002 (10) |
C24 | 0.179 (19) | 0.150 (17) | 0.16 (2) | 0.014 (15) | −0.043 (16) | −0.010 (15) |
O9 | 0.126 (14) | 0.125 (14) | 0.33 (3) | −0.030 (11) | 0.032 (16) | 0.084 (16) |
S1—O1 | 1.436 (5) | C20—H20 | 0.9300 |
S1—O2 | 1.428 (6) | C20—C18 | 1.372 (10) |
S1—C1 | 1.768 (6) | C20—C21 | 1.390 (10) |
S1—C22 | 1.744 (7) | C6—C7 | 1.485 (10) |
O3—C3 | 1.214 (7) | C18—C15 | 1.417 (10) |
O6—C15 | 1.373 (8) | C21—H21 | 0.9300 |
O6—C16 | 1.433 (8) | C10—H10 | 0.9300 |
O5—C12 | 1.221 (7) | C10—C9 | 1.400 (11) |
O4—C6 | 1.232 (9) | C16—H16A | 0.9700 |
O7—C18 | 1.368 (8) | C16—H16B | 0.9700 |
O7—C19 | 1.430 (9) | C16—C17 | 1.495 (11) |
N1—C3 | 1.394 (8) | C9—H9 | 0.9300 |
N1—C2 | 1.461 (8) | C7—H7A | 0.9601 |
N1—C12 | 1.388 (8) | C7—H7B | 0.9599 |
N2—H2 | 0.8600 | C7—H7C | 0.9602 |
N2—C5 | 1.401 (8) | C22—H22A | 0.9600 |
N2—C6 | 1.353 (9) | C22—H22B | 0.9600 |
C3—C4 | 1.478 (9) | C22—H22C | 0.9600 |
C2—H2A | 0.9800 | C19—H19A | 0.9600 |
C2—C13 | 1.518 (9) | C19—H19B | 0.9600 |
C2—C1 | 1.539 (8) | C19—H19C | 0.9600 |
C12—C11 | 1.485 (9) | C17—H17A | 0.9600 |
C11—C4 | 1.392 (8) | C17—H17B | 0.9600 |
C11—C10 | 1.360 (9) | C17—H17C | 0.9600 |
C13—C14 | 1.394 (9) | O8—H8A | 0.9182 |
C13—C21 | 1.372 (9) | O8—C23 | 1.35 (2) |
C14—H14 | 0.9300 | C23—H23A | 0.9700 |
C14—C15 | 1.375 (9) | C23—H23B | 0.9700 |
C4—C5 | 1.381 (9) | C23—C24 | 1.46 (2) |
C8—H8 | 0.9300 | C24—H24A | 0.9600 |
C8—C5 | 1.401 (9) | C24—H24B | 0.9600 |
C8—C9 | 1.377 (10) | C24—H24C | 0.9600 |
C1—H1A | 0.9700 | O9—H9A | 0.9150 |
C1—H1B | 0.9700 | O9—H9B | 0.8918 |
O1—S1—C1 | 109.0 (3) | C20—C18—C15 | 119.4 (6) |
O1—S1—C22 | 108.0 (4) | O6—C15—C14 | 125.3 (6) |
O2—S1—O1 | 117.0 (3) | O6—C15—C18 | 115.7 (6) |
O2—S1—C1 | 109.1 (3) | C14—C15—C18 | 118.9 (6) |
O2—S1—C22 | 110.0 (4) | C13—C21—C20 | 121.3 (6) |
C22—S1—C1 | 102.8 (4) | C13—C21—H21 | 119.3 |
C15—O6—C16 | 116.6 (5) | C20—C21—H21 | 119.3 |
C18—O7—C19 | 115.9 (6) | C11—C10—H10 | 121.9 |
C3—N1—C2 | 124.2 (5) | C11—C10—C9 | 116.3 (6) |
C12—N1—C3 | 110.2 (5) | C9—C10—H10 | 121.9 |
C12—N1—C2 | 125.5 (5) | O6—C16—H16A | 110.1 |
C5—N2—H2 | 115.3 | O6—C16—H16B | 110.1 |
C6—N2—H2 | 114.8 | O6—C16—C17 | 108.2 (6) |
C6—N2—C5 | 129.9 (6) | H16A—C16—H16B | 108.4 |
O3—C3—N1 | 124.4 (6) | C17—C16—H16A | 110.1 |
O3—C3—C4 | 128.5 (6) | C17—C16—H16B | 110.1 |
N1—C3—C4 | 107.0 (5) | C8—C9—C10 | 122.2 (7) |
N1—C2—H2A | 106.9 | C8—C9—H9 | 118.9 |
N1—C2—C13 | 112.7 (5) | C10—C9—H9 | 118.9 |
N1—C2—C1 | 111.5 (5) | C6—C7—H7A | 109.4 |
C13—C2—H2A | 106.9 | C6—C7—H7B | 109.4 |
C13—C2—C1 | 111.6 (5) | C6—C7—H7C | 109.6 |
C1—C2—H2A | 106.9 | H7A—C7—H7B | 109.5 |
O5—C12—N1 | 124.8 (6) | H7A—C7—H7C | 109.5 |
O5—C12—C11 | 127.4 (6) | H7B—C7—H7C | 109.4 |
N1—C12—C11 | 107.9 (5) | S1—C22—H22A | 109.5 |
C4—C11—C12 | 106.6 (6) | S1—C22—H22B | 109.5 |
C10—C11—C12 | 130.7 (6) | S1—C22—H22C | 109.5 |
C10—C11—C4 | 122.7 (6) | H22A—C22—H22B | 109.5 |
C14—C13—C2 | 122.5 (5) | H22A—C22—H22C | 109.5 |
C21—C13—C2 | 119.2 (6) | H22B—C22—H22C | 109.5 |
C21—C13—C14 | 118.3 (6) | O7—C19—H19A | 109.5 |
C13—C14—H14 | 119.1 | O7—C19—H19B | 109.5 |
C15—C14—C13 | 121.8 (6) | O7—C19—H19C | 109.5 |
C15—C14—H14 | 119.1 | H19A—C19—H19B | 109.5 |
C11—C4—C3 | 108.3 (6) | H19A—C19—H19C | 109.5 |
C5—C4—C3 | 130.6 (6) | H19B—C19—H19C | 109.5 |
C5—C4—C11 | 121.1 (6) | C16—C17—H17A | 109.5 |
C5—C8—H8 | 119.6 | C16—C17—H17B | 109.5 |
C9—C8—H8 | 119.6 | C16—C17—H17C | 109.5 |
C9—C8—C5 | 120.8 (7) | H17A—C17—H17B | 109.5 |
N2—C5—C8 | 124.6 (6) | H17A—C17—H17C | 109.5 |
C4—C5—N2 | 118.5 (6) | H17B—C17—H17C | 109.5 |
C4—C5—C8 | 116.9 (6) | C23—O8—H8A | 120.7 |
S1—C1—H1A | 108.7 | O8—C23—H23A | 105.6 |
S1—C1—H1B | 108.7 | O8—C23—H23B | 105.6 |
C2—C1—S1 | 114.1 (4) | O8—C23—C24 | 127 (3) |
C2—C1—H1A | 108.7 | H23A—C23—H23B | 106.1 |
C2—C1—H1B | 108.7 | C24—C23—H23A | 105.6 |
H1A—C1—H1B | 107.6 | C24—C23—H23B | 105.6 |
C18—C20—H20 | 119.8 | C23—C24—H24A | 109.5 |
C18—C20—C21 | 120.3 (6) | C23—C24—H24B | 109.5 |
C21—C20—H20 | 119.8 | C23—C24—H24C | 109.5 |
O4—C6—N2 | 122.3 (7) | H24A—C24—H24B | 109.5 |
O4—C6—C7 | 122.7 (7) | H24A—C24—H24C | 109.5 |
N2—C6—C7 | 115.1 (7) | H24B—C24—H24C | 109.5 |
O7—C18—C20 | 124.7 (6) | H9A—O9—H9B | 101.7 |
O7—C18—C15 | 116.0 (6) | ||
O3—C3—C4—C11 | 179.6 (6) | C12—C11—C10—C9 | −179.1 (7) |
O3—C3—C4—C5 | −0.2 (11) | C11—C4—C5—N2 | 177.4 (6) |
O5—C12—C11—C4 | 179.6 (6) | C11—C4—C5—C8 | −1.0 (10) |
O5—C12—C11—C10 | −1.3 (12) | C11—C10—C9—C8 | −0.4 (11) |
O1—S1—C1—C2 | −71.1 (6) | C13—C2—C1—S1 | −173.0 (4) |
O2—S1—C1—C2 | 57.7 (6) | C13—C14—C15—O6 | 179.5 (7) |
O7—C18—C15—O6 | 1.6 (9) | C13—C14—C15—C18 | 1.6 (10) |
O7—C18—C15—C14 | 179.7 (6) | C14—C13—C21—C20 | 0.2 (10) |
N1—C3—C4—C11 | −0.2 (7) | C4—C11—C10—C9 | −0.2 (10) |
N1—C3—C4—C5 | 180.0 (6) | C5—N2—C6—O4 | −5.0 (12) |
N1—C2—C13—C14 | 102.5 (7) | C5—N2—C6—C7 | 175.8 (7) |
N1—C2—C13—C21 | −79.2 (7) | C5—C8—C9—C10 | 0.3 (12) |
N1—C2—C1—S1 | 60.1 (6) | C1—C2—C13—C14 | −23.8 (9) |
N1—C12—C11—C4 | −0.3 (7) | C1—C2—C13—C21 | 154.5 (6) |
N1—C12—C11—C10 | 178.8 (7) | C20—C18—C15—O6 | −179.6 (6) |
C3—N1—C2—C13 | 111.8 (6) | C20—C18—C15—C14 | −1.5 (10) |
C3—N1—C2—C1 | −121.8 (6) | C6—N2—C5—C4 | 177.9 (7) |
C3—N1—C12—O5 | −179.8 (6) | C6—N2—C5—C8 | −3.9 (12) |
C3—N1—C12—C11 | 0.1 (7) | C18—C20—C21—C13 | −0.1 (11) |
C3—C4—C5—N2 | −2.9 (11) | C15—O6—C16—C17 | −179.4 (7) |
C3—C4—C5—C8 | 178.7 (6) | C21—C13—C14—C15 | −1.0 (10) |
C2—N1—C3—O3 | −3.8 (9) | C21—C20—C18—O7 | 179.5 (7) |
C2—N1—C3—C4 | 176.1 (5) | C21—C20—C18—C15 | 0.8 (11) |
C2—N1—C12—O5 | 4.3 (10) | C10—C11—C4—C3 | −178.9 (6) |
C2—N1—C12—C11 | −175.8 (5) | C10—C11—C4—C5 | 0.9 (10) |
C2—C13—C14—C15 | 177.3 (6) | C16—O6—C15—C14 | −0.5 (10) |
C2—C13—C21—C20 | −178.2 (6) | C16—O6—C15—C18 | 177.4 (6) |
C12—N1—C3—O3 | −179.8 (6) | C9—C8—C5—N2 | −177.9 (7) |
C12—N1—C3—C4 | 0.1 (6) | C9—C8—C5—C4 | 0.4 (10) |
C12—N1—C2—C13 | −72.8 (7) | C22—S1—C1—C2 | 174.5 (5) |
C12—N1—C2—C1 | 53.6 (8) | C19—O7—C18—C20 | 4.8 (10) |
C12—C11—C4—C3 | 0.3 (7) | C19—O7—C18—C15 | −176.4 (7) |
C12—C11—C4—C5 | −179.9 (6) |
D—H···A | D—H | H···A | D···A | 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+1/2, −y+3/2, −z+3/4; (iii) −y+5/2, x+1/2, z+1/4; (iv) −y+3/2, x−1/2, z+1/4. |
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