research communications
Febuxostat ethanol monosolvate
aUniversity of Innsbruck, Institute of Pharmacy, Innrain 52, 6020 Innsbruck, Austria, bUniversity of Innsbruck, Institute of Mineralogy and Petrography, Innrain 52, 6020 Innsbruck, Austria, and cSandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
*Correspondence e-mail: thomas.gelbrich@uibk.ac.at
The title compound, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethanol monosolvate, C16H16N2O3S·C2H6O, (I), displays intermolecular O—H⋯O and O—H⋯N bonds in which the carboxyl group of the febuxostat molecule and the hydroxyl group of the ethanol molecule serve as hydrogen-bond donor sites. These interactions result in a helical hydrogen-bonded chain structure. The title structure is isostructural with a previously reported methanol analogue.
Keywords: crystal structure; solvate; pharmaceuticals; hydrogen bonding; isostructural.
CCDC reference: 2000973
1. Chemical context
Febuxostat is a novel, small-molecule, non-purine-selective inhibitor of xanthine oxidase developed for the treatment of chronic gout and hyperuricemia, via oral administration (Pascual et al., 2009; Gray & Walters-Smith, 2011; Kataoka et al., 2015). This drug is currently marketed by Takeda Pharmaceuticals Inc. under the trade name Uloric. Matsumoto et al. (1999) disclosed the existence of five solid forms of febuxostat, i.e. of the anhydrous forms A, B and C, a methanol solvate D and a hemihydrate G. The crystal structures of two polymorphs were reported by Maddileti et al. (2013) and Yadav et al. (2017). Additionally, solvate structures containing the febuxostat molecule and methanol (Jiang et al., 2011), acetic acid (Wu et al., 2015) or pyrdine (Zhu et al., 2009) have been described.
The current study was carried out as part of an investigation with the aim of establishing a modified synthetic route for febuxostat (Lutra et al., 2012), avoiding harsh conditions, toxic reagents to form the thioamide and the highly toxic One of the key aspects of the novel route of synthesis was the introduction of a modified version of the Duff reaction (Duff & Bills, 1932, 1934) in the first step, which finally resulted in improved overall yields compared to the original synthesis by Hasegawa (1998).
2. Structural commentary
The febuxostat molecule (Fig. 1) is essentially planar. This is illustrated by the fact that the mean plane defined by all its non-H atoms, except for C22 of the isobutyl group, results in a root-mean-square deviation for the 21 fitted atoms of only 0.0890 Å. Atom C22 is located at a distance of 1.498 (3) Å from this mean plane. All bond lengths and angles are in good agreement with the geometrical characteristics of previously determined febuxostat structures (see below). The relative mutual orientation of the CN substituent at the phenyl ring and the Me group at the thiazole ring is characterized by the torsion angle S1—C2—C6—C7 of −6.5 (3)°. This torsion is also defined as τ in the Scheme. The isobutoxy group adopts the expected extended chain geometry with C9—O18—C19—C20 = 175.3 (2)° and O18—C19—C20—C21 = 170.7 (2)°.
3. Supramolecular features
The carboxyl group of the febuxostat molecule is linked to the OH group of an EtOH molecule via an O23—H23⋯N3(−x + 1, y + , −z + 1) interaction. The hydroxy group of the solvent additionally serves as a hydrogen-bond donor group for an O14—H14⋯O23(x − 1, y, z) bond to a second febuxostat molecule (see Table 1). Together, these two interactions result in a hydrogen-bonded chain composed of alternating febuxostat and ethanol molecules that displays a 21 symmetry and propagates parallel to the b axis (Fig. 2). The same hydrogen-bonded structure is also present in the analogous MeOH solvate of febuxostat, first reported (at 296 K) by Jiang et al. (2011) and redetermined by us at 173 K as part of this study (Gelbrich et al., 2020a). Indeed, a comparison with the program XPac (Gelbrich & Hursthouse, 2005) reveals that the EtOH and MeOH solvates are isostructural. The comparison of corresponding geometrical parameters generated from the complete set of 22 non-H atomic positions in the febuxostat molecule resulted in a dissimilarity index (Gelbrich et al., 2012) of x = 3.3, which indicates a high agreement of the febuxostat packing in the EtOH and MeOH solvates.
4. Database survey
Table 2 displays those entries in the Cambridge Structural Database (version 5.41, November 2019; Groom et al., 2016) that relate to crystal structures containing the febuxostat molecule. The febuxostat geometries in most of these structures are in good agreement with the parameters of (I), i.e. the torsion τ (see Scheme) typically adopts a value close to 0°. However, an opposite geometry with τ values close to 180° has been reported for the polymorphs Q and H1, a with 4-aminobenzoic acid and a 2-(pyridin-2-ylamino)pyridinium salt.
5. Synthesis and crystallization
5.1. Synthesis
The preparation of febuxostat was carried out according to the scheme in Fig. 3 in a modified procedure based on the original synthesis by Hasegawa (1998).
5.1.1. Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (3)
Ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (2, 10.0 g) and hexamethylenetetramine (5.86 g) were added to trifluoroacetic acid (100 ml). The reaction mixture was heated to reflux under stirring for 40 h, and trifluoroacetic acid was distilled out. The obtained residue was cooled to 298 K, water (200 ml) was added slowly, and the slurry was stirred for 4 h. After filtration, the product was washed and dried under vacuum to give 9.60 g of 3.
5.1.2. Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (4)
Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate (3, 350 g), potassium carbonate (332 g) and isobutyl bromide (330 g) were added to DMF (1.75 1). The reaction mixture was heated to 383±3 K and stirred for 4 h. The reaction mixture was cooled to 298 K, and water (0.50 l) was added slowly. The slurry was stirred for 2 h. After filtration, the product was washed and dried under vacuum to give 389 g of 4. 1H NMR (CDCl3), 400 MHz): δ = 1.079–1.101 (d, 6H), 1.366–1.413 (t, 3H), 2.185–2.230 (m, 1H), 2.769 (s, 3H), 3.914–3.935 (d, 2H), 4.316–4.387 (q, 2H), 7.045–7.074 (d, 1H), 8.188–8.225 (dd, 1H), 8.353–8.361 (d, 1H).
5.1.3. Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (5)
Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (4, 350 g), sodium formate (123 g) and hydroxylamine hydrochloride (84 g) were successively added to formic acid (1.4 l). The reaction mixture was heated to reflux and stirred for 5 h to complete the reaction. The reaction solution was cooled to 298 K, and water (2.8 l) was slowly added. After stirring for approximately 1 h, the slurry was filtered, the product was washed with water and dried under vacuum to give 321 g of 5. 1H NMR (CDCl3), 400 MHz): δ = 1.053–1.104 (d, 6H), 1.368–1.463 (t, 3H), 2.164–2.225 (m, 1H), 2.768 (s, 3H), 3.890–3.911 (d, 2H), 4.324–4.395 (q, 2H), 6.998–7.027 (d, 1H), 8 8.188–8.225 (dd, 1H), 8.353–8.361 (d, 1H).
5.1.4. 2-(3-Cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole carboxylic acid (1)
Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (5, 250 g) and potassium carbonate (200 g) were successively added to a mixture of MeOH (7.5 l) and water (250 ml). To complete the reaction, the solution was heated to reflux for 3 h under stirring. The clear solution was cooled, and vacuum was applied to distil out the solvent below 313 K. Water (5 l) was added to the residue. After stirring, EtOAc (2.5 l) was added. The solution was stirred, and the layers were separated. The pH of the aqueous solution was adjusted to 2.5±0.2 by adding diluted hydrochloric acid solution at 313 K. After stirring for 1 h, the slurry was filtered, and the product was washed with water and dried under vacuum to give 215 g of 1.
6. Refinement
Crystal data, data collection and structure . All H atoms were identified in difference maps. Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip (C—H = 0.98 Å), and their Uiso parameters were set to 1.5Ueq(C) of the parent carbon atom. H atoms bonded to secondary CH2 (C—H = 0.99 Å) or tertiary CH (C—H = 0.99 Å) carbon atoms and H atoms bonded to C atoms in aromatic rings (C—H = 0.95 Å) were positioned geometrically and refined with Uiso set to 1.2Ueq(C) of the parent carbon atom. H atoms in OH groups were identified in difference maps, refined with a distance restraint [O—H = 0.84 (2) Å] and a free Uiso parameter. Two outliers (4) and (,,2) were omitted in the final cycles of refinement.
details are summarized in Table 3
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Supporting information
CCDC reference: 2000973
https://doi.org/10.1107/S2056989020006076/fy2145sup1.cif
contains datablock I. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020006076/fy2145Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S2056989020006076/fy2145Isup3.cml
Data collection: CrysAlis PRO (Rigaku OD, 2015); cell
CrysAlis PRO (Rigaku OD, 2015); data reduction: CrysAlis PRO (Rigaku OD, 2015); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014/6 (Sheldrick, 2015b); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2020); software used to prepare material for publication: PLATON (Spek, 2020) and publCIF (Westrip, 2010).C16H16N2O3S·C2H6O | F(000) = 384 |
Mr = 362.43 | Dx = 1.351 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
a = 4.7274 (2) Å | Cell parameters from 2681 reflections |
b = 17.7820 (5) Å | θ = 2.3–28.6° |
c = 10.7340 (4) Å | µ = 0.21 mm−1 |
β = 98.994 (4)° | T = 173 K |
V = 891.23 (6) Å3 | Prism, colourless |
Z = 2 | 0.40 × 0.40 × 0.36 mm |
Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini ultra diffractometer | 3070 independent reflections |
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source | 2917 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.028 |
Detector resolution: 10.3575 pixels mm-1 | θmax = 27.1°, θmin = 1.9° |
ω scans | h = −5→6 |
Absorption correction: multi-scan CrysAlisPro (Rigaku OD, 2015) | k = −17→22 |
Tmin = 0.760, Tmax = 1.000 | l = −12→13 |
6054 measured reflections |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: mixed |
R[F2 > 2σ(F2)] = 0.030 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.077 | w = 1/[σ2(Fo2) + (0.0439P)2 + 0.0696P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max < 0.001 |
3070 reflections | Δρmax = 0.26 e Å−3 |
238 parameters | Δρmin = −0.17 e Å−3 |
3 restraints | Absolute structure: Flack x determined using 1046 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013). |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −0.02 (4) |
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 | ||
S1 | 0.32087 (12) | 0.17683 (3) | 0.31163 (5) | 0.02221 (15) | |
C2 | 0.3894 (5) | 0.08540 (14) | 0.3610 (2) | 0.0195 (5) | |
N3 | 0.2673 (4) | 0.06576 (12) | 0.45794 (18) | 0.0199 (4) | |
C4 | 0.1127 (5) | 0.12385 (14) | 0.4979 (2) | 0.0210 (5) | |
C5 | 0.1165 (5) | 0.18918 (14) | 0.4308 (2) | 0.0209 (5) | |
C6 | 0.5737 (5) | 0.03525 (14) | 0.3007 (2) | 0.0188 (5) | |
C7 | 0.6801 (5) | 0.05673 (15) | 0.1922 (2) | 0.0211 (5) | |
H7 | 0.6309 | 0.1045 | 0.1555 | 0.025* | |
C8 | 0.8571 (5) | 0.00904 (14) | 0.1371 (2) | 0.0208 (5) | |
C9 | 0.9280 (5) | −0.06253 (15) | 0.1882 (2) | 0.0207 (5) | |
C10 | 0.8252 (5) | −0.08344 (15) | 0.2980 (2) | 0.0231 (5) | |
H10 | 0.8757 | −0.1309 | 0.3357 | 0.028* | |
C11 | 0.6499 (5) | −0.03524 (14) | 0.3523 (2) | 0.0225 (5) | |
H11 | 0.5797 | −0.0505 | 0.4266 | 0.027* | |
C12 | −0.0406 (5) | 0.11107 (16) | 0.6073 (2) | 0.0269 (6) | |
H12A | 0.0985 | 0.1093 | 0.6852 | 0.040* | |
H12B | −0.1448 | 0.0633 | 0.5962 | 0.040* | |
H12C | −0.1761 | 0.1522 | 0.6125 | 0.040* | |
C13 | −0.0224 (5) | 0.26111 (15) | 0.4499 (2) | 0.0234 (5) | |
O14 | 0.0142 (5) | 0.31184 (12) | 0.36340 (19) | 0.0339 (5) | |
H14 | −0.062 (8) | 0.3537 (16) | 0.375 (4) | 0.072 (13)* | |
O15 | −0.1558 (4) | 0.27251 (11) | 0.53494 (18) | 0.0345 (5) | |
C16 | 0.9755 (6) | 0.03373 (15) | 0.0278 (2) | 0.0259 (6) | |
N17 | 1.0707 (5) | 0.05481 (15) | −0.0569 (2) | 0.0387 (6) | |
O18 | 1.0943 (4) | −0.10584 (10) | 0.12590 (16) | 0.0248 (4) | |
C19 | 1.1767 (5) | −0.17866 (15) | 0.1797 (2) | 0.0227 (5) | |
H19A | 1.0042 | −0.2076 | 0.1919 | 0.027* | |
H19B | 1.2988 | −0.1724 | 0.2627 | 0.027* | |
C20 | 1.3396 (5) | −0.22023 (14) | 0.0906 (2) | 0.0236 (5) | |
H20 | 1.4987 | −0.1875 | 0.0709 | 0.028* | |
C21 | 1.4684 (6) | −0.29130 (17) | 0.1579 (3) | 0.0327 (6) | |
H21A | 1.5817 | −0.2775 | 0.2390 | 0.049* | |
H21B | 1.5919 | −0.3164 | 0.1054 | 0.049* | |
H21C | 1.3139 | −0.3254 | 0.1722 | 0.049* | |
C22 | 1.1480 (7) | −0.24066 (17) | −0.0320 (3) | 0.0336 (6) | |
H22A | 1.0040 | −0.2773 | −0.0148 | 0.050* | |
H22B | 1.2643 | −0.2625 | −0.0907 | 0.050* | |
H22C | 1.0519 | −0.1953 | −0.0694 | 0.050* | |
O23 | 0.7299 (4) | 0.43799 (11) | 0.37730 (18) | 0.0347 (5) | |
H23 | 0.741 (8) | 0.4681 (18) | 0.437 (3) | 0.053 (11)* | |
C24 | 0.4973 (6) | 0.45692 (16) | 0.2805 (3) | 0.0347 (7) | |
H24A | 0.5205 | 0.5091 | 0.2515 | 0.042* | |
H24B | 0.3143 | 0.4538 | 0.3142 | 0.042* | |
C25 | 0.4914 (7) | 0.40395 (19) | 0.1727 (3) | 0.0440 (8) | |
H25A | 0.4835 | 0.3521 | 0.2031 | 0.066* | |
H25B | 0.6647 | 0.4107 | 0.1343 | 0.066* | |
H25C | 0.3222 | 0.4141 | 0.1097 | 0.066* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0281 (3) | 0.0153 (3) | 0.0243 (3) | 0.0024 (3) | 0.0077 (2) | 0.0010 (3) |
C2 | 0.0205 (11) | 0.0154 (12) | 0.0214 (11) | −0.0005 (9) | −0.0003 (10) | −0.0001 (10) |
N3 | 0.0210 (10) | 0.0168 (11) | 0.0219 (10) | −0.0017 (8) | 0.0028 (8) | −0.0008 (8) |
C4 | 0.0212 (12) | 0.0173 (12) | 0.0234 (12) | −0.0013 (10) | −0.0002 (10) | −0.0031 (10) |
C5 | 0.0207 (11) | 0.0209 (14) | 0.0211 (11) | −0.0028 (10) | 0.0034 (9) | −0.0034 (10) |
C6 | 0.0199 (11) | 0.0149 (12) | 0.0211 (11) | 0.0003 (10) | 0.0014 (9) | −0.0033 (9) |
C7 | 0.0237 (12) | 0.0146 (12) | 0.0244 (12) | −0.0014 (10) | 0.0018 (10) | 0.0006 (10) |
C8 | 0.0231 (12) | 0.0164 (12) | 0.0225 (12) | −0.0018 (10) | 0.0025 (10) | −0.0008 (10) |
C9 | 0.0233 (12) | 0.0167 (12) | 0.0223 (12) | −0.0004 (10) | 0.0040 (10) | −0.0033 (10) |
C10 | 0.0303 (14) | 0.0151 (13) | 0.0240 (12) | 0.0027 (10) | 0.0046 (10) | 0.0029 (10) |
C11 | 0.0259 (13) | 0.0200 (13) | 0.0219 (12) | 0.0001 (11) | 0.0045 (10) | −0.0006 (10) |
C12 | 0.0309 (14) | 0.0218 (14) | 0.0296 (13) | 0.0002 (11) | 0.0095 (11) | −0.0001 (11) |
C13 | 0.0255 (12) | 0.0192 (13) | 0.0245 (13) | −0.0024 (11) | 0.0006 (11) | −0.0046 (10) |
O14 | 0.0474 (12) | 0.0196 (10) | 0.0387 (11) | 0.0099 (9) | 0.0189 (9) | 0.0045 (9) |
O15 | 0.0518 (12) | 0.0232 (10) | 0.0327 (10) | 0.0046 (9) | 0.0191 (9) | −0.0043 (8) |
C16 | 0.0314 (13) | 0.0166 (13) | 0.0305 (14) | 0.0045 (11) | 0.0072 (12) | −0.0009 (11) |
N17 | 0.0512 (15) | 0.0318 (15) | 0.0377 (13) | 0.0033 (12) | 0.0210 (12) | 0.0081 (12) |
O18 | 0.0328 (9) | 0.0175 (9) | 0.0260 (9) | 0.0062 (8) | 0.0105 (8) | 0.0031 (7) |
C19 | 0.0267 (13) | 0.0162 (13) | 0.0259 (12) | 0.0018 (10) | 0.0068 (10) | 0.0024 (10) |
C20 | 0.0264 (12) | 0.0172 (13) | 0.0292 (13) | 0.0025 (10) | 0.0108 (11) | 0.0018 (10) |
C21 | 0.0333 (14) | 0.0225 (14) | 0.0452 (16) | 0.0077 (12) | 0.0146 (13) | 0.0072 (13) |
C22 | 0.0447 (16) | 0.0284 (16) | 0.0290 (14) | −0.0006 (13) | 0.0099 (12) | −0.0043 (12) |
O23 | 0.0465 (12) | 0.0218 (10) | 0.0345 (11) | 0.0092 (9) | 0.0025 (9) | −0.0071 (9) |
C24 | 0.0395 (16) | 0.0237 (15) | 0.0416 (16) | 0.0086 (13) | 0.0078 (13) | −0.0036 (12) |
C25 | 0.0536 (19) | 0.0343 (18) | 0.0424 (17) | 0.0044 (15) | 0.0020 (15) | −0.0067 (14) |
S1—C2 | 1.725 (3) | O14—H14 | 0.84 (2) |
S1—C5 | 1.733 (2) | C16—N17 | 1.139 (3) |
C2—N3 | 1.313 (3) | O18—C19 | 1.446 (3) |
C2—C6 | 1.466 (3) | C19—C20 | 1.511 (3) |
N3—C4 | 1.372 (3) | C19—H19A | 0.9900 |
C4—C5 | 1.369 (4) | C19—H19B | 0.9900 |
C4—C12 | 1.491 (3) | C20—C22 | 1.520 (4) |
C5—C13 | 1.467 (4) | C20—C21 | 1.534 (4) |
C6—C7 | 1.393 (3) | C20—H20 | 1.0000 |
C6—C11 | 1.395 (3) | C21—H21A | 0.9800 |
C7—C8 | 1.387 (3) | C21—H21B | 0.9800 |
C7—H7 | 0.9500 | C21—H21C | 0.9800 |
C8—C9 | 1.406 (4) | C22—H22A | 0.9800 |
C8—C16 | 1.444 (4) | C22—H22B | 0.9800 |
C9—O18 | 1.350 (3) | C22—H22C | 0.9800 |
C9—C10 | 1.394 (3) | O23—C24 | 1.430 (4) |
C10—C11 | 1.383 (4) | O23—H23 | 0.83 (2) |
C10—H10 | 0.9500 | C24—C25 | 1.489 (4) |
C11—H11 | 0.9500 | C24—H24A | 0.9900 |
C12—H12A | 0.9800 | C24—H24B | 0.9900 |
C12—H12B | 0.9800 | C25—H25A | 0.9800 |
C12—H12C | 0.9800 | C25—H25B | 0.9800 |
C13—O15 | 1.205 (3) | C25—H25C | 0.9800 |
C13—O14 | 1.325 (3) | ||
C2—S1—C5 | 89.55 (12) | N17—C16—C8 | 178.3 (3) |
N3—C2—C6 | 123.6 (2) | C9—O18—C19 | 117.03 (18) |
N3—C2—S1 | 114.17 (18) | O18—C19—C20 | 108.51 (19) |
C6—C2—S1 | 122.25 (18) | O18—C19—H19A | 110.0 |
C2—N3—C4 | 111.7 (2) | C20—C19—H19A | 110.0 |
C5—C4—N3 | 115.0 (2) | O18—C19—H19B | 110.0 |
C5—C4—C12 | 126.3 (2) | C20—C19—H19B | 110.0 |
N3—C4—C12 | 118.7 (2) | H19A—C19—H19B | 108.4 |
C4—C5—C13 | 128.6 (2) | C19—C20—C22 | 111.8 (2) |
C4—C5—S1 | 109.62 (19) | C19—C20—C21 | 108.0 (2) |
C13—C5—S1 | 121.80 (19) | C22—C20—C21 | 110.5 (2) |
C7—C6—C11 | 118.3 (2) | C19—C20—H20 | 108.9 |
C7—C6—C2 | 121.3 (2) | C22—C20—H20 | 108.9 |
C11—C6—C2 | 120.4 (2) | C21—C20—H20 | 108.9 |
C8—C7—C6 | 120.7 (2) | C20—C21—H21A | 109.5 |
C8—C7—H7 | 119.7 | C20—C21—H21B | 109.5 |
C6—C7—H7 | 119.7 | H21A—C21—H21B | 109.5 |
C7—C8—C9 | 120.6 (2) | C20—C21—H21C | 109.5 |
C7—C8—C16 | 119.8 (2) | H21A—C21—H21C | 109.5 |
C9—C8—C16 | 119.6 (2) | H21B—C21—H21C | 109.5 |
O18—C9—C10 | 125.0 (2) | C20—C22—H22A | 109.5 |
O18—C9—C8 | 116.4 (2) | C20—C22—H22B | 109.5 |
C10—C9—C8 | 118.6 (2) | H22A—C22—H22B | 109.5 |
C11—C10—C9 | 120.1 (2) | C20—C22—H22C | 109.5 |
C11—C10—H10 | 119.9 | H22A—C22—H22C | 109.5 |
C9—C10—H10 | 119.9 | H22B—C22—H22C | 109.5 |
C10—C11—C6 | 121.6 (2) | C24—O23—H23 | 111 (3) |
C10—C11—H11 | 119.2 | O23—C24—C25 | 109.5 (2) |
C6—C11—H11 | 119.2 | O23—C24—H24A | 109.8 |
C4—C12—H12A | 109.5 | C25—C24—H24A | 109.8 |
C4—C12—H12B | 109.5 | O23—C24—H24B | 109.8 |
H12A—C12—H12B | 109.5 | C25—C24—H24B | 109.8 |
C4—C12—H12C | 109.5 | H24A—C24—H24B | 108.2 |
H12A—C12—H12C | 109.5 | C24—C25—H25A | 109.5 |
H12B—C12—H12C | 109.5 | C24—C25—H25B | 109.5 |
O15—C13—O14 | 123.9 (2) | H25A—C25—H25B | 109.5 |
O15—C13—C5 | 123.5 (2) | C24—C25—H25C | 109.5 |
O14—C13—C5 | 112.7 (2) | H25A—C25—H25C | 109.5 |
C13—O14—H14 | 113 (3) | H25B—C25—H25C | 109.5 |
D—H···A | D—H | H···A | D···A | D—H···A |
O23—H23···N3i | 0.83 (2) | 2.07 (2) | 2.878 (3) | 162 (4) |
O14—H14···O23ii | 0.84 (2) | 1.80 (2) | 2.631 (3) | 170 (4) |
Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) x−1, y, z. |
Form | CSD | τ (°) | Ref. |
Polymorph Q | HIQQAB | -174.1 | Maddileti et al. (2013) |
Polymorph H1 | HIQQAB02 | 177.9 | Yadav et al. (2017) |
-1.2 | |||
MeOH solvate (173 K) | CCDC 1981184 | 5.6 | Gelbrich et al. (2020a) |
MeOH solvate (296 K) | UREQOY | 5.0 | Jiang et al. (2011) |
EtOH solvate (I) | – | 4.5 | This study |
Acetic acid solvate (173 K) | CCDC 1981185 | -2.8 | Gelbrich et al. (2020b) |
Acetic acid solvate (296 K) | XULRUT | -3.2 | Wu et al. (2015) |
Pyridine solvate | PUHGUV | 2.7 | Zhu et al. (2009) |
Acetamide co-crystal | HIQQEF | -6.9 | Maddileti et al. (2013) |
Nicotinamide co-crystal | HIQQIJ | 0.7 | Maddileti et al. (2013) |
4-Aminobenzoic acid co-crystal | HIQQOP | -176.9 | Maddileti et al. (2013) |
Urea co-crystal | HIQQUV | 4.4 | Maddileti et al. (2013) |
Isonicotinamide co-crystal | OYADAV | -3.8 | Kang et al. (2017) |
2-Methyl-1H-imidazole salt | FAMQIW | -19.4 | Zhang & Zhang (2017) |
13.4 | |||
Imidazole salt monohydrate | KIPMAA | -5.7 | Gao et al. (2019) |
2-(Pyridin-2-ylamino)pyridinium salt | FAMQOC | -174.5 | Zhang & Zhang (2017) |
References
Duff, J. C. & Bills, E. J. (1932). J. Chem. Soc. pp. 1987–1988. CrossRef Google Scholar
Duff, J. C. & Bills, E. J. (1934). J. Chem. Soc. pp. 1305–1308. CrossRef Google Scholar
Gao, L., Zhang, X.-R., Chen, Y.-F., Liao, Z.-L., Wang, Y.-Q. & Zou, X.-Y. (2019). J. Mol. Struct. 1176, 633–640. CSD CrossRef CAS Google Scholar
Gelbrich, T. & Hursthouse, M. B. (2005). CrystEngComm, 7, 324–336. Web of Science CrossRef CAS Google Scholar
Gelbrich, T., Kahlenberg, V., Adamer, V. & Griesser, U. J. (2020a). Private Communication (CCDC reference 1981184). CCDC, Cambridge, England. Google Scholar
Gelbrich, T., Kahlenberg, V., Adamer, V. & Griesser, U. J. (2020b). Private Communication (CCDC reference 1981185). CCDC, Cambridge, England. Google Scholar
Gelbrich, T., Threlfall, T. L. & Hursthouse, M. B. (2012). CrystEngComm, 14, 5454–5464. Web of Science CSD CrossRef CAS Google Scholar
Gray, C. L. & Walters-Smith, N. E. (2011). Am. J. Health Syst. Pharm. 68, 389–398. Web of Science CrossRef CAS PubMed Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Hasegawa, M. (1998). Heterocycles, 47, 857–864. CrossRef CAS Google Scholar
Jiang, Q.-Y., Qian, J.-J., Gu, J.-M., Tang, G.-P. & Hu, X.-R. (2011). Acta Cryst. E67, o1232. Web of Science CSD CrossRef IUCr Journals Google Scholar
Kang, Y., Gu, J. & Hu, X. (2017). J. Mol. Struct. 1130, 480–486. CSD CrossRef CAS Google Scholar
Kataoka, H., Yang, K. & Rock, K. L. (2015). Eur. J. Pharmacol. 746, 174–179. Web of Science CrossRef CAS PubMed Google Scholar
Lutra, P., Khan, R., Salunkhe, D. & Nasir, A. (2012). Int. Patent Appl. WO 2012131590 (A1). Google Scholar
Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235. Web of Science CrossRef CAS IUCr Journals Google Scholar
Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188–3196. Web of Science CSD CrossRef CAS Google Scholar
Matsumoto, K., Watanabe, K., Hiramatsu, T. & Kitamura, M. (1999). Int. Patent Appl. WO 1999065885 (A1). Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CrossRef CAS IUCr Journals Google Scholar
Pascual, E., Sivera, F., Yasothan, U. & Kirkpatrick, P. (2009). Nat. Rev. Drug Discov. 8, 191–192. Web of Science CrossRef PubMed CAS Google Scholar
Rigaku OD (2015). CrysAlis PRO. Rigaku Corporation, Tokyo, Japan. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spek, A. L. (2020). Acta Cryst. E76, 1–11. Web of Science CrossRef IUCr Journals Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
Wu, M., Hu, X.-R., Gu, J.-M. & Tang, G.-P. (2015). Acta Cryst. E71, o295–o296. CSD CrossRef IUCr Journals Google Scholar
Yadav, J. A., Khomane, K. S., Modi, S. R., Ugale, B., Yadav, R. N., Nagaraja, C. M., Kumar, N. & Bansal, A. K. (2017). Mol. Pharm. 14, 866–874. CSD CrossRef CAS PubMed Google Scholar
Zhang, X.-R. & Zhang, L. (2017). J. Mol. Struct. 1137, 328–334. CSD CrossRef CAS Google Scholar
Zhu, X., Wang, Y. & Lu, T. (2009). Acta Cryst. E65, o2603. Web of Science CSD CrossRef IUCr Journals Google Scholar
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