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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 76| Part 6| June 2020| Pages 816-819
https://doi.org/10.1107/S2056989020006076

Febuxostat ethanol monosolvate

CROSSMARK_Color_square_no_text.svg
Thomas Gelbrich,a* Volker Kahlenberg,b Verena Adamer,c Sven Nerdingerc and Ulrich J. Griessera

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

Edited by L. Fabian, University of East Anglia, England (Received 20 February 2020; accepted 4 May 2020; online 12 May 2020)

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.

CCDC reference: 2000973

Similar articles

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[Pascual, E., Sivera, F., Yasothan, U. & Kirkpatrick, P. (2009). Nat. Rev. Drug Discov. 8, 191-192.]; Gray & Walters-Smith, 2011[Gray, C. L. & Walters-Smith, N. E. (2011). Am. J. Health Syst. Pharm. 68, 389-398.]; Kataoka et al., 2015[Kataoka, H., Yang, K. & Rock, K. L. (2015). Eur. J. Pharmacol. 746, 174-179.]). This drug is currently marketed by Takeda Pharmaceuticals Inc. under the trade name Uloric. Matsumoto et al. (1999[Matsumoto, K., Watanabe, K., Hiramatsu, T. & Kitamura, M. (1999). Int. Patent Appl. WO 1999065885 (A1).]) 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[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.]) and Yadav et al. (2017[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.]). Additionally, solvate structures containing the febuxostat mol­ecule and methanol (Jiang et al., 2011[Jiang, Q.-Y., Qian, J.-J., Gu, J.-M., Tang, G.-P. & Hu, X.-R. (2011). Acta Cryst. E67, o1232.]), acetic acid (Wu et al., 2015[Wu, M., Hu, X.-R., Gu, J.-M. & Tang, G.-P. (2015). Acta Cryst. E71, o295-o296.]) or pyrdine (Zhu et al., 2009[Zhu, X., Wang, Y. & Lu, T. (2009). Acta Cryst. E65, o2603.]) have been described.

[Scheme 1]

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[Lutra, P., Khan, R., Salunkhe, D. & Nasir, A. (2012). Int. Patent Appl. WO 2012131590 (A1).]), avoiding harsh conditions, toxic reagents to form the thio­amide and the highly toxic cyanides. 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[Duff, J. C. & Bills, E. J. (1932). J. Chem. Soc. pp. 1987-1988.], 1934[Duff, J. C. & Bills, E. J. (1934). J. Chem. Soc. pp. 1305-1308.]) in the first step, which finally resulted in improved overall yields compared to the original synthesis by Hasegawa (1998[Hasegawa, M. (1998). Heterocycles, 47, 857-864.]).

2. Structural commentary

The febuxostat mol­ecule (Fig. 1[link]) 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)°.

[Figure 1]
Figure 1
Asymmetric unit of (I)[link] with displacement ellipsoids drawn at the 50% probability level and hydrogen atoms drawn as spheres of arbitrary size.

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 + [{1\over 2}], −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[link]). 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[link]). 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[Jiang, Q.-Y., Qian, J.-J., Gu, J.-M., Tang, G.-P. & Hu, X.-R. (2011). Acta Cryst. E67, o1232.]) and redetermined by us at 173 K as part of this study (Gelbrich et al., 2020a[Gelbrich, T., Kahlenberg, V., Adamer, V. & Griesser, U. J. (2020a). Private Communication (CCDC reference 1981184). CCDC, Cambridge, England.]). Indeed, a comparison with the program XPac (Gelbrich & Hursthouse, 2005[Gelbrich, T. & Hursthouse, M. B. (2005). CrystEngComm, 7, 324-336.]) 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[Gelbrich, T., Threlfall, T. L. & Hursthouse, M. B. (2012). CrystEngComm, 14, 5454-5464.]) of x = 3.3, which indicates a high agreement of the febuxostat packing in the EtOH and MeOH solvates.

Table 1
Hydrogen-bond geometry (Å, °)

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+{\script{1\over 2}}, -z+1]; (ii) x-1, y, z.
[Figure 2]
Figure 2
Hydrogen-bonded layer structure of (I)[link], viewed along the a axis.

4. Database survey

Table 2[link] displays those entries in the Cambridge Structural Database (version 5.41, November 2019; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) 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)[link], 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 co-crystal with 4-amino­benzoic acid and a 2-(pyridin-2-yl­amino)­pyridinium salt.

Table 2
Conformation of febuxostat mol­ecules in polymorphs and multi-component structures, indicated by the torsion angle τ

Form CSD τ (°) Ref.
Polymorph Q HIQQAB −174.1 Maddileti et al. (2013[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.])
Polymorph H1 HIQQAB02 177.9 Yadav et al. (2017[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.])
    −1.2  
MeOH solvate (173 K) CCDC 1981184 5.6 Gelbrich et al. (2020a[Gelbrich, T., Kahlenberg, V., Adamer, V. & Griesser, U. J. (2020a). Private Communication (CCDC reference 1981184). CCDC, Cambridge, England.])
MeOH solvate (296 K) UREQOY 5.0 Jiang et al. (2011[Jiang, Q.-Y., Qian, J.-J., Gu, J.-M., Tang, G.-P. & Hu, X.-R. (2011). Acta Cryst. E67, o1232.])
EtOH solvate (I) – 4.5 This study
Acetic acid solvate (173 K) CCDC 1981185 −2.8 Gelbrich et al. (2020b[Gelbrich, T., Kahlenberg, V., Adamer, V. & Griesser, U. J. (2020b). Private Communication (CCDC reference 1981185). CCDC, Cambridge, England.])
Acetic acid solvate (296 K) XULRUT −3.2 Wu et al. (2015[Wu, M., Hu, X.-R., Gu, J.-M. & Tang, G.-P. (2015). Acta Cryst. E71, o295-o296.])
Pyridine solvate PUHGUV 2.7 Zhu et al. (2009[Zhu, X., Wang, Y. & Lu, T. (2009). Acta Cryst. E65, o2603.])
Acetamide co-crystal HIQQEF −6.9 Maddileti et al. (2013[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.])
Nicotinamide co-crystal HIQQIJ 0.7 Maddileti et al. (2013[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.])
4-Amino­benzoic acid co-crystal HIQQOP −176.9 Maddileti et al. (2013[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.])
Urea co-crystal HIQQUV 4.4 Maddileti et al. (2013[Maddileti, D., Jayabun, S. K. & Nangia, A. (2013). Cryst. Growth Des. 13, 3188-3196.])
Isonicotinamide co-crystal OYADAV −3.8 Kang et al. (2017[Kang, Y., Gu, J. & Hu, X. (2017). J. Mol. Struct. 1130, 480-486.])
2-Methyl-1H-imidazole salt FAMQIW −19.4 Zhang & Zhang (2017[Zhang, X.-R. & Zhang, L. (2017). J. Mol. Struct. 1137, 328-334.])
    13.4  
Imidazole salt monohydrate KIPMAA −5.7 Gao et al. (2019[Gao, L., Zhang, X.-R., Chen, Y.-F., Liao, Z.-L., Wang, Y.-Q. & Zou, X.-Y. (2019). J. Mol. Struct. 1176, 633-640.])
2-(Pyridin-2-yl­amino)­pyridinium salt FAMQOC −174.5 Zhang & Zhang (2017[Zhang, X.-R. & Zhang, L. (2017). J. Mol. Struct. 1137, 328-334.])

5. Synthesis and crystallization

5.1. Synthesis

The preparation of febuxostat was carried out according to the scheme in Fig. 3[link] in a modified procedure based on the original synthesis by Hasegawa (1998[Hasegawa, M. (1998). Heterocycles, 47, 857-864.]).

[Figure 3]
Figure 3
Synthetic scheme for the preparation of febuxostat (1).
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.

5.2. Crystallization

Febuxostat (1 g) was dissolved in ethanol (10 ml), which yielded a clear solution upon heating to 338 K. After filtration, the solution was allowed to cool to room temperature, and the subsequent crystallization resulted in febuxostat ethanol solvate.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. 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 ([\overline{4}][\overline{7}]4) and ([\overline{2}],[\overline{16}],2) were omitted in the final cycles of refinement.

Table 3
Experimental details

Crystal data
Chemical formula C16H16N2O3S·C2H6O
Mr 362.43
Crystal system, space group Monoclinic, P21
Temperature (K) 173
a, b, c (Å) 4.7274 (2), 17.7820 (5), 10.7340 (4)
β (°) 98.994 (4)
V (Å3) 891.23 (6)
Z 2
Radiation type Mo Kα
μ (mm−1) 0.21
Crystal size (mm) 0.40 × 0.40 × 0.36
 
Data collection
Diffractometer Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini ultra
Absorption correction Multi-scan (CrysAlis PRO; Rigaku OD, 2015[Rigaku OD (2015). CrysAlis PRO. Rigaku Corporation, Tokyo, Japan.])
Tmin, Tmax 0.760, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 6054, 3070, 2917
Rint 0.028
(sin θ/λ)max (Å−1) 0.641
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.030, 0.077, 1.04
No. of reflections 3070
No. of parameters 238
No. of restraints 3
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.26, −0.17
Absolute structure Flack x determined using 1046 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 −0.02 (4)
Computer programs: CrysAlis PRO (Rigaku OD, 2015[Rigaku OD (2015). CrysAlis PRO. Rigaku Corporation, Tokyo, Japan.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL2014/6 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), Mercury (Macrae et al., 2020[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.]), PLATON (Spek, 2020[Spek, A. L. (2020). Acta Cryst. E76, 1-11.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information

CCDC reference: 2000973

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989020006076/fy2145sup1.cif

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

checkCIF report


Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2015); cell refinement: 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).

2-[3-Cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethanol monosolvate top
Crystal data top
C16H16N2O3S·C2H6OF(000) = 384
Mr = 362.43Dx = 1.351 Mg m−3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
a = 4.7274 (2) ÅCell parameters from 2681 reflections
b = 17.7820 (5) Åθ = 2.3–28.6°
c = 10.7340 (4) ŵ = 0.21 mm−1
β = 98.994 (4)°T = 173 K
V = 891.23 (6) Å3Prism, colourless
Z = 20.40 × 0.40 × 0.36 mm
Data collection top
Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini ultra
diffractometer		3070 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source2917 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.028
Detector resolution: 10.3575 pixels mm-1θmax = 27.1°, θmin = 1.9°
ω scansh = −5→6
Absorption correction: multi-scan
CrysAlisPro (Rigaku OD, 2015)		k = −17→22
Tmin = 0.760, Tmax = 1.000l = −12→13
6054 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.030H 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 reflectionsΔρmax = 0.26 e Å−3
238 parametersΔρmin = −0.17 e Å−3
3 restraintsAbsolute structure: Flack x determined using 1046 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013).
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: −0.02 (4)
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*/Ueq
S10.32087 (12)0.17683 (3)0.31163 (5)0.02221 (15)
C20.3894 (5)0.08540 (14)0.3610 (2)0.0195 (5)
N30.2673 (4)0.06576 (12)0.45794 (18)0.0199 (4)
C40.1127 (5)0.12385 (14)0.4979 (2)0.0210 (5)
C50.1165 (5)0.18918 (14)0.4308 (2)0.0209 (5)
C60.5737 (5)0.03525 (14)0.3007 (2)0.0188 (5)
C70.6801 (5)0.05673 (15)0.1922 (2)0.0211 (5)
H70.63090.10450.15550.025*
C80.8571 (5)0.00904 (14)0.1371 (2)0.0208 (5)
C90.9280 (5)−0.06253 (15)0.1882 (2)0.0207 (5)
C100.8252 (5)−0.08344 (15)0.2980 (2)0.0231 (5)
H100.8757−0.13090.33570.028*
C110.6499 (5)−0.03524 (14)0.3523 (2)0.0225 (5)
H110.5797−0.05050.42660.027*
C12−0.0406 (5)0.11107 (16)0.6073 (2)0.0269 (6)
H12A0.09850.10930.68520.040*
H12B−0.14480.06330.59620.040*
H12C−0.17610.15220.61250.040*
C13−0.0224 (5)0.26111 (15)0.4499 (2)0.0234 (5)
O140.0142 (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)
C160.9755 (6)0.03373 (15)0.0278 (2)0.0259 (6)
N171.0707 (5)0.05481 (15)−0.0569 (2)0.0387 (6)
O181.0943 (4)−0.10584 (10)0.12590 (16)0.0248 (4)
C191.1767 (5)−0.17866 (15)0.1797 (2)0.0227 (5)
H19A1.0042−0.20760.19190.027*
H19B1.2988−0.17240.26270.027*
C201.3396 (5)−0.22023 (14)0.0906 (2)0.0236 (5)
H201.4987−0.18750.07090.028*
C211.4684 (6)−0.29130 (17)0.1579 (3)0.0327 (6)
H21A1.5817−0.27750.23900.049*
H21B1.5919−0.31640.10540.049*
H21C1.3139−0.32540.17220.049*
C221.1480 (7)−0.24066 (17)−0.0320 (3)0.0336 (6)
H22A1.0040−0.2773−0.01480.050*
H22B1.2643−0.2625−0.09070.050*
H22C1.0519−0.1953−0.06940.050*
O230.7299 (4)0.43799 (11)0.37730 (18)0.0347 (5)
H230.741 (8)0.4681 (18)0.437 (3)0.053 (11)*
C240.4973 (6)0.45692 (16)0.2805 (3)0.0347 (7)
H24A0.52050.50910.25150.042*
H24B0.31430.45380.31420.042*
C250.4914 (7)0.40395 (19)0.1727 (3)0.0440 (8)
H25A0.48350.35210.20310.066*
H25B0.66470.41070.13430.066*
H25C0.32220.41410.10970.066*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0281 (3)0.0153 (3)0.0243 (3)0.0024 (3)0.0077 (2)0.0010 (3)
C20.0205 (11)0.0154 (12)0.0214 (11)−0.0005 (9)−0.0003 (10)−0.0001 (10)
N30.0210 (10)0.0168 (11)0.0219 (10)−0.0017 (8)0.0028 (8)−0.0008 (8)
C40.0212 (12)0.0173 (12)0.0234 (12)−0.0013 (10)−0.0002 (10)−0.0031 (10)
C50.0207 (11)0.0209 (14)0.0211 (11)−0.0028 (10)0.0034 (9)−0.0034 (10)
C60.0199 (11)0.0149 (12)0.0211 (11)0.0003 (10)0.0014 (9)−0.0033 (9)
C70.0237 (12)0.0146 (12)0.0244 (12)−0.0014 (10)0.0018 (10)0.0006 (10)
C80.0231 (12)0.0164 (12)0.0225 (12)−0.0018 (10)0.0025 (10)−0.0008 (10)
C90.0233 (12)0.0167 (12)0.0223 (12)−0.0004 (10)0.0040 (10)−0.0033 (10)
C100.0303 (14)0.0151 (13)0.0240 (12)0.0027 (10)0.0046 (10)0.0029 (10)
C110.0259 (13)0.0200 (13)0.0219 (12)0.0001 (11)0.0045 (10)−0.0006 (10)
C120.0309 (14)0.0218 (14)0.0296 (13)0.0002 (11)0.0095 (11)−0.0001 (11)
C130.0255 (12)0.0192 (13)0.0245 (13)−0.0024 (11)0.0006 (11)−0.0046 (10)
O140.0474 (12)0.0196 (10)0.0387 (11)0.0099 (9)0.0189 (9)0.0045 (9)
O150.0518 (12)0.0232 (10)0.0327 (10)0.0046 (9)0.0191 (9)−0.0043 (8)
C160.0314 (13)0.0166 (13)0.0305 (14)0.0045 (11)0.0072 (12)−0.0009 (11)
N170.0512 (15)0.0318 (15)0.0377 (13)0.0033 (12)0.0210 (12)0.0081 (12)
O180.0328 (9)0.0175 (9)0.0260 (9)0.0062 (8)0.0105 (8)0.0031 (7)
C190.0267 (13)0.0162 (13)0.0259 (12)0.0018 (10)0.0068 (10)0.0024 (10)
C200.0264 (12)0.0172 (13)0.0292 (13)0.0025 (10)0.0108 (11)0.0018 (10)
C210.0333 (14)0.0225 (14)0.0452 (16)0.0077 (12)0.0146 (13)0.0072 (13)
C220.0447 (16)0.0284 (16)0.0290 (14)−0.0006 (13)0.0099 (12)−0.0043 (12)
O230.0465 (12)0.0218 (10)0.0345 (11)0.0092 (9)0.0025 (9)−0.0071 (9)
C240.0395 (16)0.0237 (15)0.0416 (16)0.0086 (13)0.0078 (13)−0.0036 (12)
C250.0536 (19)0.0343 (18)0.0424 (17)0.0044 (15)0.0020 (15)−0.0067 (14)
Geometric parameters (Å, º) top
S1—C21.725 (3)O14—H140.84 (2)
S1—C51.733 (2)C16—N171.139 (3)
C2—N31.313 (3)O18—C191.446 (3)
C2—C61.466 (3)C19—C201.511 (3)
N3—C41.372 (3)C19—H19A0.9900
C4—C51.369 (4)C19—H19B0.9900
C4—C121.491 (3)C20—C221.520 (4)
C5—C131.467 (4)C20—C211.534 (4)
C6—C71.393 (3)C20—H201.0000
C6—C111.395 (3)C21—H21A0.9800
C7—C81.387 (3)C21—H21B0.9800
C7—H70.9500C21—H21C0.9800
C8—C91.406 (4)C22—H22A0.9800
C8—C161.444 (4)C22—H22B0.9800
C9—O181.350 (3)C22—H22C0.9800
C9—C101.394 (3)O23—C241.430 (4)
C10—C111.383 (4)O23—H230.83 (2)
C10—H100.9500C24—C251.489 (4)
C11—H110.9500C24—H24A0.9900
C12—H12A0.9800C24—H24B0.9900
C12—H12B0.9800C25—H25A0.9800
C12—H12C0.9800C25—H25B0.9800
C13—O151.205 (3)C25—H25C0.9800
C13—O141.325 (3)
C2—S1—C589.55 (12)N17—C16—C8178.3 (3)
N3—C2—C6123.6 (2)C9—O18—C19117.03 (18)
N3—C2—S1114.17 (18)O18—C19—C20108.51 (19)
C6—C2—S1122.25 (18)O18—C19—H19A110.0
C2—N3—C4111.7 (2)C20—C19—H19A110.0
C5—C4—N3115.0 (2)O18—C19—H19B110.0
C5—C4—C12126.3 (2)C20—C19—H19B110.0
N3—C4—C12118.7 (2)H19A—C19—H19B108.4
C4—C5—C13128.6 (2)C19—C20—C22111.8 (2)
C4—C5—S1109.62 (19)C19—C20—C21108.0 (2)
C13—C5—S1121.80 (19)C22—C20—C21110.5 (2)
C7—C6—C11118.3 (2)C19—C20—H20108.9
C7—C6—C2121.3 (2)C22—C20—H20108.9
C11—C6—C2120.4 (2)C21—C20—H20108.9
C8—C7—C6120.7 (2)C20—C21—H21A109.5
C8—C7—H7119.7C20—C21—H21B109.5
C6—C7—H7119.7H21A—C21—H21B109.5
C7—C8—C9120.6 (2)C20—C21—H21C109.5
C7—C8—C16119.8 (2)H21A—C21—H21C109.5
C9—C8—C16119.6 (2)H21B—C21—H21C109.5
O18—C9—C10125.0 (2)C20—C22—H22A109.5
O18—C9—C8116.4 (2)C20—C22—H22B109.5
C10—C9—C8118.6 (2)H22A—C22—H22B109.5
C11—C10—C9120.1 (2)C20—C22—H22C109.5
C11—C10—H10119.9H22A—C22—H22C109.5
C9—C10—H10119.9H22B—C22—H22C109.5
C10—C11—C6121.6 (2)C24—O23—H23111 (3)
C10—C11—H11119.2O23—C24—C25109.5 (2)
C6—C11—H11119.2O23—C24—H24A109.8
C4—C12—H12A109.5C25—C24—H24A109.8
C4—C12—H12B109.5O23—C24—H24B109.8
H12A—C12—H12B109.5C25—C24—H24B109.8
C4—C12—H12C109.5H24A—C24—H24B108.2
H12A—C12—H12C109.5C24—C25—H25A109.5
H12B—C12—H12C109.5C24—C25—H25B109.5
O15—C13—O14123.9 (2)H25A—C25—H25B109.5
O15—C13—C5123.5 (2)C24—C25—H25C109.5
O14—C13—C5112.7 (2)H25A—C25—H25C109.5
C13—O14—H14113 (3)H25B—C25—H25C109.5
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O23—H23···N3i0.83 (2)2.07 (2)2.878 (3)162 (4)
O14—H14···O23ii0.84 (2)1.80 (2)2.631 (3)170 (4)
Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) x−1, y, z.
Conformation of febuxostat molecules in polymorphs and multi-component structures, indicated by the torsion angle τ top
FormCSDτ (°)Ref.
Polymorph QHIQQAB-174.1Maddileti et al. (2013)
Polymorph H1HIQQAB02177.9Yadav et al. (2017)
-1.2
MeOH solvate (173 K)CCDC 19811845.6Gelbrich et al. (2020a)
MeOH solvate (296 K)UREQOY5.0Jiang et al. (2011)
EtOH solvate (I)–4.5This study
Acetic acid solvate (173 K)CCDC 1981185-2.8Gelbrich et al. (2020b)
Acetic acid solvate (296 K)XULRUT-3.2Wu et al. (2015)
Pyridine solvatePUHGUV2.7Zhu et al. (2009)
Acetamide co-crystalHIQQEF-6.9Maddileti et al. (2013)
Nicotinamide co-crystalHIQQIJ0.7Maddileti et al. (2013)
4-Aminobenzoic acid co-crystalHIQQOP-176.9Maddileti et al. (2013)
Urea co-crystalHIQQUV4.4Maddileti et al. (2013)
Isonicotinamide co-crystalOYADAV-3.8Kang et al. (2017)
2-Methyl-1H-imidazole saltFAMQIW-19.4Zhang & Zhang (2017)
13.4
Imidazole salt monohydrateKIPMAA-5.7Gao et al. (2019)
2-(Pyridin-2-ylamino)pyridinium saltFAMQOC-174.5Zhang & Zhang (2017)
 

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ISSN: 2056-9890
Volume 76| Part 6| June 2020| Pages 816-819
https://doi.org/10.1107/S2056989020006076
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