Sorafenib and its tosyl­ate salt: a multikinase inhibitor for treating cancer

Sorafenib, a drug that targets malignant cancer cells and cuts off the blood supply feeding the tumour, has been crystallized as the free base, 4-(4-{3-[4-chloro-3-(trifluoro­meth­yl)phen­yl]ureido}phen­oxy)-N-methyl­pyridine-2-carboxamide, C₂₁H₁₆ClF₃N₄O₃, (I), and as a tosyl­ate salt, 4-(4-{3-[4-chloro-3-(trifluoro­meth­yl)phen­yl]ureido}phen­oxy)-2-(N-methylcarbamoyl)pyridinium 4-methyl­benzene­sulfonate, C₂₁H₁₇ClF₃N₄O₃⁺·C₇H₇O₃S⁻, (II). In both structures, the sorafenib mol­ecule is in an extended conformation. The pyridine-2-carboxamide group exhibits a syn conformation of the N atoms in (I), whereas an almost anti orientation is present in (II). In both crystal structures, the two terminal groups, viz. pyridine-2-carboxamide and the trifluoro­phenyl ring, are oriented differently to the conformations found in enzyme-bound sorafenib. The sorafenib mol­ecules in (I) are linked into zigzag chains by N—H...O hydrogen bonds, whereas in (II) the presence of the additional tosyl­ate anion results in the formation of chains of fused hydrogen-bonded rings. This study reveals the variations in the solid-state conformation of the sorafenib mol­ecule in different crystalline environments.

S1. Comment

Angiogenesis, the formation of new blood vessels from existing vasculature, is required for tumour growth and metastasis, and the concept of inhibiting tumour angiogenesis has become a compelling approach in the development of anticancer agents (Ferrara & Kerbal, 2005). Vascular endothelial growth factor (VEGF) is a known promoter of angiogenesis, and the increased expression of VEGF has been implicated in tumour growth and metastasis (Yancopoulos et al., 2000). VEGF signalling through its three tyrosine kinase receptors (RTK), VEGFR-1, VEGFR-2 and VEGFR-3, promotes several events required for the formation of new blood vessels, such as endothelial cell survival, proliferation and migration, and vascular permeability (Holmes et al., 2007). Therefore, the blockage of VEGF signalling by small-molecule inhibitors, particularly at the VEGFR-2 kinase domain, has been shown to be an attractive strategy in the treatment of cancers (Ferrara et al., 2004).

Sorafenib is an oral multikinase inhibitor acting on tumour cells and cells of the tumour vasculature. It also inhibits tumour cell proliferation by targeting the mitogen-activated protein kinase pathway at the level of RAF kinase (Wilhelm et al., 2004). Sorafenib is approved for use in advanced renal cell carcinoma (primary kidney cancer) when anticancer treatment with interferon-α or interleukin-2 has failed or cannot be used (Escudier et al., 2007). In 2007, the US Food and Drug Administration (FDA) approved sorafenib tosylate (BAY43–9006, Nexavar, 200 mg tablets; Bayer Pharmaceuticals Corporation, Montville, New Jersey, USA, and Onyx Pharmaceuticals Corporation, Emeryville, California, USA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (Kane et al., 2009). As part of our ongoing structural studies of pharmaceutical compounds (Ravikumar et al., 2008; Ravikumar & Sridhar, 2009, 2010), the crystal structures of sorafenib, (I), and its tosylate salt, (II), have been determined and are reported here.

The sorafenib molecule consists of a derivative of a bi-aryl urea joined to a pyridine carboxamide group. In both structures (I) and (II), the compounds crystallize in space group P2₁/c. Views of the asymmetric units of (I) and (II), with atom labelling, are presented in Figs. 1 and 2, respectively. The urea linkage plays an active role in the solid-state conformation and governs the overall shape of the sorafenib molecule, which is in an extended conformation in both structures. Atom N3 of the pyridine ring is protonated to form the pyridinum cation in (II); the sum of the angles at this atom is 356.4 (1)°. There are significant variations in the bond lengths and angles displayed by the pyridine carboxamide group of (I) compared with those of (II), as a consequence of the protonation in the latter (Table 1). The intra-ring angle at atom N3 is about 6° larger in (II) than in (I), while the intra-ring angles at atoms C16 and C17 decrease by about 4 and 5°, respectively. The pyridine ring bonds, except C15—C14, and the bonds involving atom C19 are significantly shorter in (II) than in the free base, (I). Other differences in the bond angles at atoms C17 and C19 (Table 1) suggest there may be some repulsion between atoms H4N and H18 in (II), while this interaction is not present in (I), as well as a stronger interaction involving N3—H···O1 in (II) compared with N4—H···N3 in (I).

The pyridine carboxamide group exhibits a syn conformation of the N atoms in (I), while an almost anti orientation is present in (II). These orientations are likely to be favoured because they facilitate the formation of an intramolecular hydrogen bond, N4—H···N3 in (I) and N3—H···O1 in (II), whereas the reverse conformation in each structure would obviate any intramolecular hydrogen bonds.

Fig. 3 shows an overlay of the sorafenib molecules of (I) and (II) with sorafenib ligands extracted from the crystal structures of complexes of sorafenib bound to the human P38 MAP kinase [Simard et al. (2009), Protein Data Bank (PDB; Berman et al., 2000) entry 3GCS; Namboodiri et al. (2010), PDB entry 3HEG] and B-RAF kinase [Wan et al. (2004), PDB entry 1UWH]. The conformational flexibility provided by the urea and ether linkages in the sorafenib molecule allows the terminal groups in the free and enzyme-bound molecules to adopt different orientations (Table 2). It is interesting to note that, in the enzyme-bound sorafenib molecules, the binding mode requires the pyridine carboxamide group to adopt a syn orientation. It can be seen that the lipophilic trifluorophenyl ring in the enzyme-bound sorafenib molecules always has roughly the same conformation, whereas quite different orientations are found in (I) and (II). As observed by Wan et al. (2004), the conformation in the enyme-bound molecule may be necessary to provide favourable hydrophobic interactions at the active site. On the other hand, the conformation of the pyridine carboxamide group seems to be quite variable, which suggests that different hydrogen-bonding interactions in the bound and unbound forms may influence the conformation of the hydrophilic end of the molecule.

The least-squares plane of the trifluorophenyl ring is more inclined to the pyridyl plane in (II) [69.5 (1)°] than (I) [40.1 (1)°], perhaps to accommodate the tosylate anion by allowing both the urea N atoms to be involved in hydrogen bonds with the anion. The phenyl ring in the tosylate anion makes almost equal dihedral angles of 51.7 (1) and 59.0 (1)° with the planes of the trifluorophenyl and pyridyl rings, respectively.

The crystal packing in (I) and (II) is influenced by the N—H···O hydrogen bonds (Tables 3 and 4). Both atoms N1 and N2 of the urea group in (I) form hydrogen bonds with atom O1 of the carboxamide group of a neighbouring molecule to form zigzag chains of molceules which run along the b axis (Fig. 4). It is interesting to see that, in (II), each tosylate anion, as acceptor, links three sorafenib molecules by participating in all the N—H···O hydrogen bonds (Fig. 5). Combination with the interaction involving protonated atom N3 [N3—H···O5(-x + 2, y + 1/2, -z + 3/2)] of the pyridine ring facilitates the formation of an R₄³(29) ring pattern [Etter, 1990; Etter et al., 1990; Bernstein et al., 1995]. These rings are fused to form continuous chains along the b axis. The trifluorophenyl rings protrude on the outside of these chains and interdigitate with those from adjacent chains, thereby forming columns populated by halogen atoms.

In conclusion, this structural analysis highlights the variations in the solid-state conformations of the drug and its hydrogen-bonding interactions in different environments.

Related literature

For related literature, see: Berman et al. (2000); Bernstein et al. (1995); Escudier (2007); Etter (1990); Etter, MacDonald & Bernstein (1990); Ferrara & Kerbal (2005); Ferrara et al. (2004); Holmes et al. (2007); Kane et al. (2009); Namboodiri et al. (2010); Ravikumar & Sridhar (2009, 2010); Ravikumar et al. (2008); Simard et al. (2009); Wan et al. (2004); Wilhelm (2004); Yancopoulos et al. (2000).

S2. Experimental

Sorafenib, (I) (Natco Research Centre, Hyderabad) (50 mg), was dissolved in methanol (5 ml). After 2 d, crystals were obtained by slow evaporation. Sorafenib tosylate, (II) (Natco Research Centre, Hyderabad) (50 mg), was dissolved in a mixture of methanol (5 ml) and water (1 ml), and the solution allowed to evaporate slowly. After 3 d, crystals were obtained.

S3. Refinement

All N-bound H atoms were located in a difference Fourier map and their positions and isotropic displacement parameters were refined. All other H atoms were located in a difference density map, but were positioned geometrically and included as riding atoms, with C—H = 0.93–0.96 Å, and with U_iso(H) = 1.5U_eq(C) for the methyl groups or 1.2U_eq(c) for the other H atoms. Distance restraints were applied to N1—H1N, N2—H2N and N4—H4N of (II), with a set value of 0.87 (2) Å. The methyl groups were allowed to rotate but not to tip.

Computing details

For both compounds, data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2005) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The asymmetric unit of (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. The dashed line indicates the intramolecular hydrogen bond.
	Fig. 2. The asymmetric unit of (II), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. Hydrogen bond are shown as dashed lines.
	Fig. 3. A superposition of the molecular conformations of the sorafenib molecules. The overlay was made by making a least-squares fit of the central planar six-membered ring atoms with those of (I). The labels are as follows: (II) is sorafenib tosylate; 3 is PDB code 3GCS; 4 is 3HEG; 5 is 1UWH (molecule 1); 6 is 1UWH (molecule 2).
	Fig. 4. Part of the crystal packing of (I), showing the zigzag hydrogen-bonded chain. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity. Selected atoms of the molecules present in the asymmetric unit are labelled, primarily to provide a key for the coding of the atoms. [Symmetry code: (i) -x + 1, y - 1/2, -z + 3/2.]
	Fig. 5. Part of the crystal packing of (II), showing the hydrogen-bonded R4^3(29) rings, fused together to form chains. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity. Selected atoms of the molecules present in the asymmetric unit are labelled, primarily to provide a key for the coding of the atoms. [Symmetry codes: (i) -x + 2, y + 1/2, -z + 3/2; (ii) -x + 2, y - 1/2, -z + 3/2.]

(I) 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)- N-methylpyridine-2-carboxamide

Crystal data

C21H16ClF3N4O3	F(000) = 952
Mr = 464.83	Dx = 1.394 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 7634 reflections
a = 8.1587 (16) Å	θ = 2.2–26.9°
b = 9.8055 (19) Å	µ = 0.23 mm^−1
c = 27.758 (5) Å	T = 294 K
β = 94.358 (3)°	Needle, colourless
V = 2214.2 (7) Å^3	0.17 × 0.11 × 0.06 mm
Z = 4

Data collection

Bruker SMART APEX CCD area-detector diffractometer	3241 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.024
Graphite monochromator	θmax = 25.0°, θmin = 1.5°
ω scans	h = −9→9
20023 measured reflections	k = −11→11
3896 independent reflections	l = −32→32

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.102	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0506P)^2 + 0.5662P] where P = (Fo^2 + 2Fc^2)/3
3896 reflections	(Δ/σ)max = 0.001
302 parameters	Δρmax = 0.23 e Å^−3
0 restraints	Δρmin = −0.17 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	1.0026 (2)	0.7566 (2)	1.13693 (6)	0.0555 (4)
C2	0.95529 (19)	0.62000 (18)	1.12557 (5)	0.0485 (4)
C3	0.8941 (2)	0.58869 (17)	1.07760 (6)	0.0489 (4)
H3	0.8626	0.4997	1.0699	0.059*
C4	0.8799 (2)	0.69043 (17)	1.04100 (6)	0.0486 (4)
C5	0.9362 (2)	0.82454 (18)	1.05254 (6)	0.0597 (5)
H5	0.9335	0.8914	1.0287	0.072*
C6	0.9963 (3)	0.85606 (19)	1.10040 (7)	0.0645 (5)
H6	1.0324	0.9441	1.1078	0.077*
C7	0.7692 (2)	0.73446 (18)	0.95428 (6)	0.0539 (4)
C8	0.6343 (2)	0.71823 (16)	0.86926 (5)	0.0480 (4)
C9	0.4903 (2)	0.66724 (17)	0.84432 (6)	0.0526 (4)
H9	0.4235	0.6069	0.8597	0.063*
C10	0.4464 (2)	0.70712 (18)	0.79592 (6)	0.0566 (4)
H10	0.3518	0.6726	0.7795	0.068*
C11	0.5472 (2)	0.79926 (17)	0.77315 (5)	0.0523 (4)
C12	0.6892 (2)	0.85257 (18)	0.79774 (6)	0.0596 (5)
H12	0.7543	0.9144	0.7824	0.071*
C13	0.7334 (2)	0.81215 (19)	0.84593 (6)	0.0579 (5)
H13	0.8278	0.8474	0.8623	0.070*
C14	0.5178 (2)	0.75891 (16)	0.68634 (6)	0.0470 (4)
C15	0.6009 (2)	0.63316 (18)	0.68937 (6)	0.0547 (4)
H15	0.6504	0.6018	0.7186	0.066*
C16	0.6066 (2)	0.55589 (19)	0.64638 (7)	0.0622 (5)
H16	0.6607	0.4724	0.6485	0.075*
C17	0.4612 (2)	0.71866 (16)	0.60018 (5)	0.0447 (4)
C18	0.4464 (2)	0.80324 (16)	0.64079 (5)	0.0472 (4)
H18	0.3912	0.8861	0.6378	0.057*
C19	0.3855 (2)	0.76440 (17)	0.55022 (6)	0.0484 (4)
C20	0.2898 (3)	0.6881 (2)	0.46694 (6)	0.0711 (6)
H20A	0.1735	0.7023	0.4674	0.107*
H20B	0.3097	0.6102	0.4473	0.107*
H20C	0.3393	0.7673	0.4538	0.107*
C21	0.9677 (2)	0.5069 (2)	1.16348 (6)	0.0603 (5)
N1	0.8102 (2)	0.64977 (16)	0.99427 (5)	0.0599 (4)
H1N	0.774 (2)	0.567 (2)	0.9915 (7)	0.067 (6)*
N2	0.6806 (2)	0.66506 (16)	0.91699 (5)	0.0560 (4)
H2N	0.652 (2)	0.583 (2)	0.9235 (7)	0.060 (5)*
N3	0.53854 (19)	0.59478 (15)	0.60211 (5)	0.0562 (4)
N4	0.3622 (2)	0.66439 (17)	0.51688 (5)	0.0600 (4)
H3N	0.387 (3)	0.581 (3)	0.5272 (8)	0.086 (7)*
O1	0.34845 (19)	0.88759 (13)	0.54173 (4)	0.0697 (4)
O2	0.49976 (18)	0.84699 (12)	0.72516 (4)	0.0629 (4)
O3	0.8075 (2)	0.85716 (13)	0.95244 (5)	0.0815 (5)
F1	0.92783 (15)	0.38124 (12)	1.14415 (4)	0.0777 (3)
F2	1.12158 (15)	0.49440 (13)	1.18595 (4)	0.0818 (4)
F3	0.86219 (16)	0.52690 (15)	1.19909 (4)	0.0887 (4)
Cl1	1.06648 (7)	0.80683 (6)	1.196991 (17)	0.0823 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0571 (10)	0.0691 (12)	0.0390 (8)	−0.0011 (9)	−0.0045 (7)	−0.0119 (8)
C2	0.0448 (8)	0.0633 (11)	0.0371 (8)	−0.0001 (8)	0.0013 (7)	−0.0011 (7)
C3	0.0559 (9)	0.0500 (9)	0.0404 (9)	−0.0052 (8)	0.0006 (7)	−0.0020 (7)
C4	0.0578 (10)	0.0509 (9)	0.0363 (8)	−0.0030 (7)	−0.0017 (7)	−0.0030 (7)
C5	0.0826 (13)	0.0495 (10)	0.0453 (9)	−0.0070 (9)	−0.0061 (9)	−0.0008 (8)
C6	0.0826 (13)	0.0516 (10)	0.0567 (11)	−0.0081 (9)	−0.0110 (9)	−0.0112 (9)
C7	0.0724 (11)	0.0486 (10)	0.0394 (9)	−0.0078 (8)	−0.0051 (8)	0.0011 (7)
C8	0.0629 (10)	0.0443 (9)	0.0359 (8)	−0.0023 (7)	−0.0020 (7)	0.0000 (7)
C9	0.0635 (10)	0.0515 (9)	0.0422 (9)	−0.0108 (8)	−0.0006 (8)	0.0050 (7)
C10	0.0668 (11)	0.0552 (10)	0.0455 (9)	−0.0091 (8)	−0.0115 (8)	0.0022 (8)
C11	0.0775 (12)	0.0452 (9)	0.0331 (8)	0.0018 (8)	−0.0024 (8)	0.0017 (7)
C12	0.0795 (12)	0.0555 (10)	0.0435 (9)	−0.0157 (9)	0.0031 (9)	0.0062 (8)
C13	0.0673 (11)	0.0600 (11)	0.0447 (9)	−0.0163 (9)	−0.0071 (8)	0.0030 (8)
C14	0.0584 (10)	0.0446 (9)	0.0378 (8)	−0.0070 (7)	0.0023 (7)	0.0022 (7)
C15	0.0633 (10)	0.0560 (10)	0.0438 (9)	0.0042 (8)	−0.0020 (8)	0.0092 (8)
C16	0.0787 (13)	0.0548 (10)	0.0532 (10)	0.0206 (9)	0.0052 (9)	0.0068 (8)
C17	0.0519 (9)	0.0435 (9)	0.0392 (8)	−0.0005 (7)	0.0054 (7)	0.0029 (7)
C18	0.0624 (10)	0.0395 (8)	0.0396 (8)	0.0026 (7)	0.0025 (7)	0.0035 (7)
C19	0.0609 (10)	0.0462 (9)	0.0384 (8)	0.0039 (8)	0.0063 (7)	−0.0003 (7)
C20	0.0998 (16)	0.0707 (13)	0.0412 (10)	0.0126 (11)	−0.0043 (10)	−0.0074 (9)
C21	0.0584 (10)	0.0779 (13)	0.0440 (9)	−0.0018 (9)	0.0001 (8)	0.0043 (9)
N1	0.0928 (12)	0.0455 (8)	0.0386 (8)	−0.0122 (8)	−0.0126 (7)	−0.0001 (6)
N2	0.0800 (10)	0.0469 (8)	0.0389 (7)	−0.0127 (8)	−0.0101 (7)	0.0053 (6)
N3	0.0712 (9)	0.0514 (8)	0.0463 (8)	0.0108 (7)	0.0058 (7)	0.0015 (7)
N4	0.0886 (11)	0.0500 (9)	0.0403 (8)	0.0116 (8)	−0.0023 (7)	−0.0034 (7)
O1	0.1163 (11)	0.0474 (7)	0.0434 (7)	0.0133 (7)	−0.0078 (7)	0.0010 (5)
O2	0.1034 (10)	0.0480 (7)	0.0355 (6)	0.0039 (6)	−0.0053 (6)	0.0018 (5)
O3	0.1322 (13)	0.0539 (8)	0.0536 (8)	−0.0262 (8)	−0.0247 (8)	0.0080 (6)
F1	0.0974 (9)	0.0698 (7)	0.0639 (7)	−0.0089 (6)	−0.0065 (6)	0.0139 (6)
F2	0.0731 (7)	0.0979 (9)	0.0704 (7)	0.0032 (6)	−0.0198 (6)	0.0181 (7)
F3	0.0953 (9)	0.1190 (11)	0.0551 (7)	−0.0042 (7)	0.0275 (6)	0.0122 (7)
Cl1	0.0972 (4)	0.0991 (4)	0.0472 (3)	−0.0052 (3)	−0.0163 (3)	−0.0219 (3)

Geometric parameters (Å, º)

C1—C6	1.405 (3)	C12—H12	0.9300
C1—C2	1.423 (3)	C13—H13	0.9300
C1—Cl1	1.7782 (17)	C14—O2	1.397 (2)
C2—C3	1.420 (2)	C14—C15	1.407 (2)
C2—C21	1.527 (2)	C14—C18	1.419 (2)
C3—C4	1.422 (2)	C15—C16	1.417 (3)
C3—H3	0.9300	C15—H15	0.9300
C4—C5	1.422 (2)	C16—N3	1.364 (2)
C4—N1	1.433 (2)	C16—H16	0.9300
C5—C6	1.415 (2)	C17—N3	1.368 (2)
C5—H5	0.9300	C17—C18	1.412 (2)
C6—H6	0.9300	C17—C19	1.541 (2)
C7—O3	1.245 (2)	C18—H18	0.9300
C7—N2	1.394 (2)	C19—O1	1.263 (2)
C7—N1	1.406 (2)	C19—N4	1.352 (2)
C8—C9	1.409 (2)	C20—N4	1.483 (2)
C8—C13	1.415 (2)	C20—H20A	0.9600
C8—N2	1.447 (2)	C20—H20B	0.9600
C9—C10	1.419 (2)	C20—H20C	0.9600
C9—H9	0.9300	C21—F2	1.365 (2)
C10—C11	1.404 (2)	C21—F1	1.373 (2)
C10—H10	0.9300	C21—F3	1.373 (2)
C11—C12	1.400 (3)	N1—H1N	0.86 (2)
C11—O2	1.4368 (18)	N2—H2N	0.86 (2)
C12—C13	1.415 (2)	N4—H3N	0.88 (2)
C6—C1—C2	119.94 (15)	O2—C14—C18	115.96 (14)
C6—C1—Cl1	118.45 (14)	C15—C14—C18	119.01 (15)
C2—C1—Cl1	121.59 (14)	C14—C15—C16	117.68 (15)
C3—C2—C1	118.79 (15)	C14—C15—H15	121.2
C3—C2—C21	119.31 (16)	C16—C15—H15	121.2
C1—C2—C21	121.90 (15)	N3—C16—C15	124.90 (16)
C2—C3—C4	121.48 (15)	N3—C16—H16	117.5
C2—C3—H3	119.3	C15—C16—H16	117.5
C4—C3—H3	119.3	N3—C17—C18	123.86 (14)
C5—C4—C3	118.71 (15)	N3—C17—C19	116.47 (13)
C5—C4—N1	124.10 (15)	C18—C17—C19	119.66 (14)
C3—C4—N1	117.18 (15)	C17—C18—C14	118.51 (15)
C6—C5—C4	119.79 (16)	C17—C18—H18	120.7
C6—C5—H5	120.1	C14—C18—H18	120.7
C4—C5—H5	120.1	O1—C19—N4	123.14 (15)
C1—C6—C5	121.13 (17)	O1—C19—C17	121.34 (14)
C1—C6—H6	119.4	N4—C19—C17	115.52 (14)
C5—C6—H6	119.4	N4—C20—H20A	109.5
O3—C7—N2	123.99 (15)	N4—C20—H20B	109.5
O3—C7—N1	123.90 (15)	H20A—C20—H20B	109.5
N2—C7—N1	112.12 (15)	N4—C20—H20C	109.5
C9—C8—C13	119.35 (15)	H20A—C20—H20C	109.5
C9—C8—N2	118.14 (15)	H20B—C20—H20C	109.5
C13—C8—N2	122.38 (15)	F2—C21—F1	106.28 (16)
C8—C9—C10	120.57 (16)	F2—C21—F3	106.81 (14)
C8—C9—H9	119.7	F1—C21—F3	105.49 (15)
C10—C9—H9	119.7	F2—C21—C2	112.98 (15)
C11—C10—C9	119.28 (16)	F1—C21—C2	112.40 (14)
C11—C10—H10	120.4	F3—C21—C2	112.34 (16)
C9—C10—H10	120.4	C7—N1—C4	127.19 (15)
C12—C11—C10	120.80 (15)	C7—N1—H1N	115.0 (13)
C12—C11—O2	118.99 (15)	C4—N1—H1N	116.9 (13)
C10—C11—O2	120.08 (15)	C7—N2—C8	126.04 (15)
C11—C12—C13	119.89 (16)	C7—N2—H2N	115.7 (12)
C11—C12—H12	120.1	C8—N2—H2N	118.3 (13)
C13—C12—H12	120.1	C16—N3—C17	116.01 (14)
C8—C13—C12	120.10 (16)	C19—N4—C20	123.45 (16)
C8—C13—H13	120.0	C19—N4—H3N	115.4 (15)
C12—C13—H13	120.0	C20—N4—H3N	121.0 (15)
O2—C14—C15	125.04 (14)	C14—O2—C11	118.48 (13)
C6—C1—C2—C3	−3.3 (3)	C15—C14—C18—C17	0.3 (2)
Cl1—C1—C2—C3	175.43 (13)	N3—C17—C19—O1	−162.16 (16)
C6—C1—C2—C21	177.05 (17)	C18—C17—C19—O1	18.5 (2)
Cl1—C1—C2—C21	−4.2 (2)	N3—C17—C19—N4	17.9 (2)
C1—C2—C3—C4	0.2 (2)	C18—C17—C19—N4	−161.45 (16)
C21—C2—C3—C4	179.87 (15)	C3—C2—C21—F2	125.30 (17)
C2—C3—C4—C5	3.2 (3)	C1—C2—C21—F2	−55.0 (2)
C2—C3—C4—N1	−177.41 (15)	C3—C2—C21—F1	5.0 (2)
C3—C4—C5—C6	−3.5 (3)	C1—C2—C21—F1	−175.30 (16)
N1—C4—C5—C6	177.16 (18)	C3—C2—C21—F3	−113.77 (18)
C2—C1—C6—C5	3.0 (3)	C1—C2—C21—F3	65.9 (2)
Cl1—C1—C6—C5	−175.75 (16)	O3—C7—N1—C4	9.3 (3)
C4—C5—C6—C1	0.4 (3)	N2—C7—N1—C4	−170.62 (17)
C13—C8—C9—C10	1.3 (3)	C5—C4—N1—C7	−7.4 (3)
N2—C8—C9—C10	−174.71 (16)	C3—C4—N1—C7	173.19 (17)
C8—C9—C10—C11	−0.6 (3)	O3—C7—N2—C8	6.8 (3)
C9—C10—C11—C12	−0.4 (3)	N1—C7—N2—C8	−173.28 (16)
C9—C10—C11—O2	−176.37 (15)	C9—C8—N2—C7	−151.49 (18)
C10—C11—C12—C13	0.8 (3)	C13—C8—N2—C7	32.6 (3)
O2—C11—C12—C13	176.77 (16)	C15—C16—N3—C17	0.6 (3)
C9—C8—C13—C12	−1.0 (3)	C18—C17—N3—C16	−1.4 (2)
N2—C8—C13—C12	174.90 (17)	C19—C17—N3—C16	179.34 (15)
C11—C12—C13—C8	−0.1 (3)	O1—C19—N4—C20	−0.4 (3)
O2—C14—C15—C16	179.57 (16)	C17—C19—N4—C20	179.51 (16)
C18—C14—C15—C16	−1.0 (2)	C15—C14—O2—C11	−9.8 (2)
C14—C15—C16—N3	0.6 (3)	C18—C14—O2—C11	170.80 (15)
N3—C17—C18—C14	0.9 (3)	C12—C11—O2—C14	108.49 (19)
C19—C17—C18—C14	−179.78 (14)	C10—C11—O2—C14	−75.5 (2)
O2—C14—C18—C17	179.79 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O1^i	0.86 (2)	2.19 (2)	3.014 (2)	159.0 (18)
N2—H2N···O1^i	0.86 (2)	2.15 (2)	2.969 (2)	159.8 (17)
N4—H3N···N3	0.88 (2)	2.34 (2)	2.760 (2)	109.4 (18)

Symmetry code: (i) −x+1, y−1/2, −z+3/2.

(II) 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-2-(N- methylcarbamoyl)pyridinium 4-methylbenzenesulfonate

Crystal data

C21H17ClF3N4O3^+·C7H7O3S^−	F(000) = 1312
Mr = 637.02	Dx = 1.428 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 5897 reflections
a = 21.276 (4) Å	θ = 2.5–22.5°
b = 9.1160 (17) Å	µ = 0.27 mm^−1
c = 16.077 (3) Å	T = 294 K
β = 108.143 (3)°	Block, colourless
V = 2963.2 (10) Å^3	0.14 × 0.11 × 0.07 mm
Z = 4

Data collection

Bruker SMART APEX CCD area-detector diffractometer	3604 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.045
Graphite monochromator	θmax = 25.0°, θmin = 2.0°
ω scans	h = −25→25
25287 measured reflections	k = −10→10
5198 independent reflections	l = −19→19

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.050	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.142	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0687P)^2 + 0.772P] where P = (Fo^2 + 2Fc^2)/3
5198 reflections	(Δ/σ)max = 0.001
406 parameters	Δρmax = 0.67 e Å^−3
3 restraints	Δρmin = −0.53 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.51073 (15)	0.7718 (4)	0.3696 (3)	0.0786 (10)
C2	0.55028 (15)	0.7874 (3)	0.3167 (2)	0.0638 (8)
C3	0.61352 (13)	0.8434 (3)	0.35387 (19)	0.0576 (7)
H3	0.6409	0.8537	0.3190	0.069*
C4	0.63728 (13)	0.8846 (3)	0.44087 (19)	0.0562 (7)
C5	0.59663 (15)	0.8725 (4)	0.4924 (2)	0.0809 (11)
H5	0.6111	0.9030	0.5505	0.097*
C6	0.53317 (16)	0.8136 (5)	0.4560 (3)	0.0941 (13)
H6	0.5058	0.8026	0.4908	0.113*
C7	0.74502 (14)	0.9122 (3)	0.55559 (19)	0.0535 (7)
C8	0.86510 (13)	0.9296 (3)	0.63840 (16)	0.0444 (6)
C9	0.92318 (13)	0.9999 (3)	0.63931 (18)	0.0504 (7)
H9	0.9231	1.0621	0.5934	0.060*
C10	0.98135 (14)	0.9789 (3)	0.70771 (19)	0.0560 (7)
H10	1.0203	1.0245	0.7073	0.067*
C11	0.98020 (13)	0.8891 (3)	0.77628 (17)	0.0504 (7)
C12	0.92379 (14)	0.8172 (3)	0.77633 (18)	0.0529 (7)
H12	0.9243	0.7552	0.8225	0.064*
C13	0.86586 (14)	0.8364 (3)	0.70763 (18)	0.0541 (7)
H13	0.8276	0.7873	0.7077	0.065*
C14	1.05976 (13)	0.9779 (3)	0.90513 (17)	0.0457 (6)
C15	1.02296 (13)	1.1043 (3)	0.90419 (17)	0.0470 (6)
H15	0.9812	1.1158	0.8637	0.056*
C16	1.04991 (13)	1.2110 (3)	0.96449 (17)	0.0477 (6)
H16	1.0260	1.2961	0.9653	0.057*
C17	1.14623 (12)	1.0711 (3)	1.02715 (16)	0.0437 (6)
C18	1.12134 (13)	0.9605 (3)	0.96861 (17)	0.0497 (7)
H18	1.1453	0.8743	0.9711	0.060*
C19	1.21185 (13)	1.0762 (3)	1.09940 (17)	0.0488 (7)
C20	1.30126 (15)	0.9396 (4)	1.2013 (2)	0.0763 (10)
H20A	1.3358	0.9894	1.1857	0.114*
H20B	1.3132	0.8385	1.2136	0.114*
H20C	1.2953	0.9849	1.2522	0.114*
C21	0.5282 (2)	0.7430 (5)	0.2219 (3)	0.0948 (12)
N1	0.70262 (12)	0.9394 (3)	0.47353 (17)	0.0656 (7)
H1N	0.7196 (13)	0.966 (3)	0.4354 (15)	0.057 (9)*
N2	0.80881 (11)	0.9516 (3)	0.56508 (15)	0.0534 (6)
H2N	0.8149 (14)	0.999 (3)	0.5240 (15)	0.055 (9)*
N3	1.11009 (11)	1.1950 (2)	1.02220 (15)	0.0466 (6)
H3N	1.1281 (14)	1.262 (3)	1.0562 (19)	0.056 (9)*
N4	1.23951 (12)	0.9488 (3)	1.12850 (17)	0.0606 (7)
H4N	1.2211 (14)	0.866 (2)	1.1151 (19)	0.069 (10)*
O1	1.23485 (10)	1.1967 (2)	1.12619 (14)	0.0674 (6)
O2	1.03907 (9)	0.86635 (19)	0.84726 (12)	0.0616 (6)
O3	0.72679 (10)	0.8638 (3)	0.61514 (15)	0.0850 (7)
F1	0.57259 (13)	0.7741 (4)	0.18275 (16)	0.1407 (11)
F2	0.51541 (18)	0.6034 (3)	0.2097 (2)	0.1714 (14)
F3	0.47348 (13)	0.8151 (4)	0.17657 (16)	0.1439 (11)
Cl1	0.43132 (5)	0.69613 (16)	0.33071 (8)	0.1303 (5)
C22	0.6514 (2)	1.0798 (6)	0.0037 (2)	0.1105 (15)
H22A	0.6085	1.0702	0.0111	0.166*
H22B	0.6594	0.9978	−0.0291	0.166*
H22C	0.6531	1.1691	−0.0272	0.166*
C23	0.70397 (16)	1.0838 (4)	0.0931 (2)	0.0697 (9)
C24	0.7495 (2)	1.1948 (4)	0.1163 (2)	0.0810 (10)
H24	0.7488	1.2680	0.0758	0.097*
C25	0.79710 (17)	1.2016 (3)	0.1990 (2)	0.0677 (9)
H25	0.8274	1.2782	0.2130	0.081*
C26	0.79855 (13)	1.0927 (3)	0.25972 (17)	0.0463 (6)
C27	0.75373 (14)	0.9786 (3)	0.2358 (2)	0.0578 (8)
H27	0.7550	0.9034	0.2754	0.069*
C28	0.70697 (16)	0.9750 (4)	0.1536 (2)	0.0696 (9)
H28	0.6770	0.8976	0.1390	0.084*
O4	0.80990 (10)	1.1404 (2)	0.42143 (12)	0.0616 (5)
O5	0.88266 (10)	0.9593 (2)	0.39154 (13)	0.0638 (6)
O6	0.89983 (10)	1.2172 (2)	0.37058 (15)	0.0765 (7)
S1	0.85259 (3)	1.10295 (7)	0.36806 (5)	0.0480 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0416 (17)	0.100 (3)	0.080 (2)	−0.0034 (17)	−0.0012 (17)	0.030 (2)
C2	0.0490 (17)	0.0658 (19)	0.065 (2)	−0.0005 (15)	0.0016 (16)	0.0089 (16)
C3	0.0436 (16)	0.0672 (19)	0.0579 (19)	0.0026 (14)	0.0098 (14)	0.0018 (15)
C4	0.0384 (15)	0.0726 (19)	0.0537 (18)	0.0024 (14)	0.0086 (14)	0.0053 (15)
C5	0.0440 (18)	0.133 (3)	0.061 (2)	0.0031 (19)	0.0099 (16)	0.007 (2)
C6	0.047 (2)	0.152 (4)	0.084 (3)	0.002 (2)	0.0225 (19)	0.034 (3)
C7	0.0442 (16)	0.0629 (18)	0.0502 (17)	−0.0037 (13)	0.0102 (14)	0.0022 (14)
C8	0.0450 (15)	0.0449 (15)	0.0397 (15)	−0.0041 (12)	0.0080 (12)	−0.0031 (11)
C9	0.0501 (16)	0.0474 (15)	0.0475 (16)	−0.0078 (12)	0.0060 (14)	0.0030 (12)
C10	0.0485 (17)	0.0505 (16)	0.0627 (19)	−0.0126 (13)	0.0083 (15)	−0.0061 (14)
C11	0.0492 (16)	0.0441 (15)	0.0469 (16)	0.0035 (13)	−0.0013 (13)	−0.0112 (13)
C12	0.0612 (18)	0.0533 (16)	0.0425 (16)	0.0048 (14)	0.0136 (14)	0.0015 (12)
C13	0.0486 (16)	0.0604 (17)	0.0525 (17)	−0.0066 (13)	0.0147 (14)	0.0033 (14)
C14	0.0476 (15)	0.0392 (14)	0.0451 (15)	0.0013 (12)	0.0068 (13)	−0.0053 (11)
C15	0.0438 (15)	0.0438 (15)	0.0471 (15)	0.0047 (12)	0.0050 (12)	−0.0039 (12)
C16	0.0486 (16)	0.0401 (14)	0.0515 (16)	0.0050 (12)	0.0114 (14)	−0.0020 (12)
C17	0.0429 (14)	0.0421 (14)	0.0438 (15)	−0.0007 (11)	0.0102 (12)	−0.0004 (11)
C18	0.0467 (16)	0.0421 (15)	0.0527 (17)	0.0079 (12)	0.0045 (13)	−0.0041 (12)
C19	0.0435 (15)	0.0524 (17)	0.0474 (16)	−0.0052 (13)	0.0097 (13)	−0.0047 (13)
C20	0.0559 (19)	0.092 (2)	0.062 (2)	0.0036 (17)	−0.0087 (16)	0.0044 (18)
C21	0.075 (3)	0.116 (3)	0.076 (3)	−0.029 (2)	−0.002 (2)	−0.009 (2)
N1	0.0427 (14)	0.105 (2)	0.0458 (15)	−0.0112 (14)	0.0093 (12)	0.0035 (14)
N2	0.0448 (14)	0.0699 (16)	0.0417 (14)	−0.0095 (12)	0.0080 (11)	0.0082 (12)
N3	0.0491 (14)	0.0405 (13)	0.0474 (14)	−0.0052 (11)	0.0111 (11)	−0.0071 (11)
N4	0.0496 (14)	0.0554 (16)	0.0625 (16)	−0.0069 (13)	−0.0029 (12)	0.0012 (13)
O1	0.0596 (12)	0.0572 (13)	0.0730 (14)	−0.0100 (10)	0.0024 (11)	−0.0149 (10)
O2	0.0606 (12)	0.0448 (11)	0.0587 (12)	0.0112 (9)	−0.0113 (10)	−0.0151 (9)
O3	0.0513 (13)	0.131 (2)	0.0696 (15)	−0.0071 (13)	0.0141 (11)	0.0310 (15)
F1	0.115 (2)	0.225 (3)	0.0781 (16)	−0.051 (2)	0.0237 (15)	−0.0510 (18)
F2	0.215 (3)	0.118 (2)	0.154 (3)	−0.062 (2)	0.019 (2)	−0.054 (2)
F3	0.0958 (18)	0.216 (3)	0.0823 (16)	0.0093 (19)	−0.0271 (14)	0.0067 (17)
Cl1	0.0531 (6)	0.1863 (13)	0.1294 (10)	−0.0378 (7)	−0.0036 (6)	0.0463 (9)
C22	0.095 (3)	0.172 (4)	0.054 (2)	0.024 (3)	0.008 (2)	0.006 (2)
C23	0.064 (2)	0.091 (3)	0.0521 (19)	0.0181 (19)	0.0159 (16)	0.0011 (18)
C24	0.105 (3)	0.083 (3)	0.055 (2)	0.016 (2)	0.025 (2)	0.0279 (18)
C25	0.083 (2)	0.0588 (19)	0.061 (2)	−0.0078 (16)	0.0229 (18)	0.0140 (15)
C26	0.0452 (15)	0.0449 (15)	0.0524 (16)	0.0043 (12)	0.0205 (13)	0.0082 (12)
C27	0.0514 (17)	0.0560 (17)	0.0615 (19)	0.0003 (14)	0.0110 (15)	0.0123 (14)
C28	0.0573 (19)	0.075 (2)	0.069 (2)	−0.0044 (16)	0.0097 (17)	−0.0028 (18)
O4	0.0634 (12)	0.0690 (13)	0.0526 (12)	0.0064 (10)	0.0184 (10)	0.0054 (10)
O5	0.0626 (13)	0.0510 (11)	0.0699 (13)	0.0104 (10)	0.0090 (11)	0.0156 (10)
O6	0.0659 (14)	0.0670 (14)	0.0886 (16)	−0.0246 (11)	0.0124 (12)	0.0171 (12)
S1	0.0435 (4)	0.0418 (4)	0.0559 (4)	−0.0024 (3)	0.0116 (3)	0.0103 (3)

Geometric parameters (Å, º)

C1—C6	1.375 (5)	C17—C18	1.369 (3)
C1—C2	1.377 (5)	C17—C19	1.513 (4)
C1—Cl1	1.750 (3)	C18—H18	0.9300
C2—C3	1.388 (4)	C19—O1	1.225 (3)
C2—C21	1.504 (5)	C19—N4	1.320 (4)
C3—C4	1.383 (4)	C20—N4	1.465 (4)
C3—H3	0.9300	C20—H20A	0.9600
C4—C5	1.376 (4)	C20—H20B	0.9600
C4—N1	1.416 (4)	C20—H20C	0.9600
C5—C6	1.400 (5)	C21—F2	1.304 (5)
C5—H5	0.9300	C21—F1	1.318 (4)
C6—H6	0.9300	C21—F3	1.338 (5)
C7—O3	1.222 (3)	N1—H1N	0.838 (17)
C7—N2	1.366 (4)	N2—H2N	0.834 (17)
C7—N1	1.369 (4)	N3—H3N	0.83 (3)
C8—C9	1.388 (4)	N4—H4N	0.845 (18)
C8—C13	1.396 (4)	C22—C23	1.521 (5)
C8—N2	1.409 (3)	C22—H22A	0.9600
C9—C10	1.389 (4)	C22—H22B	0.9600
C9—H9	0.9300	C22—H22C	0.9600
C10—C11	1.380 (4)	C23—C24	1.370 (5)
C10—H10	0.9300	C23—C28	1.377 (5)
C11—C12	1.368 (4)	C24—C25	1.399 (5)
C11—O2	1.423 (3)	C24—H24	0.9300
C12—C13	1.386 (4)	C25—C26	1.386 (4)
C12—H12	0.9300	C25—H25	0.9300
C13—H13	0.9300	C26—C27	1.382 (4)
C14—O2	1.356 (3)	C26—S1	1.766 (3)
C14—C15	1.390 (3)	C27—C28	1.385 (4)
C14—C18	1.397 (3)	C27—H27	0.9300
C15—C16	1.367 (3)	C28—H28	0.9300
C15—H15	0.9300	O4—S1	1.471 (2)
C16—N3	1.335 (3)	O5—S1	1.4551 (19)
C16—H16	0.9300	O6—S1	1.439 (2)
C17—N3	1.355 (3)
C6—C1—C2	120.6 (3)	N4—C19—C17	116.6 (2)
C6—C1—Cl1	117.6 (3)	N4—C20—H20A	109.5
C2—C1—Cl1	121.9 (3)	N4—C20—H20B	109.5
C1—C2—C3	118.0 (3)	H20A—C20—H20B	109.5
C1—C2—C21	122.7 (3)	N4—C20—H20C	109.5
C3—C2—C21	119.3 (3)	H20A—C20—H20C	109.5
C4—C3—C2	122.3 (3)	H20B—C20—H20C	109.5
C4—C3—H3	118.8	F2—C21—F1	106.6 (4)
C2—C3—H3	118.8	F2—C21—F3	107.0 (3)
C5—C4—C3	119.2 (3)	F1—C21—F3	105.4 (4)
C5—C4—N1	122.3 (3)	F2—C21—C2	113.5 (4)
C3—C4—N1	118.6 (3)	F1—C21—C2	112.5 (3)
C4—C5—C6	119.0 (3)	F3—C21—C2	111.3 (4)
C4—C5—H5	120.5	C7—N1—C4	124.7 (3)
C6—C5—H5	120.5	C7—N1—H1N	117 (2)
C1—C6—C5	121.0 (3)	C4—N1—H1N	115 (2)
C1—C6—H6	119.5	C7—N2—C8	127.8 (2)
C5—C6—H6	119.5	C7—N2—H2N	116 (2)
O3—C7—N2	123.7 (3)	C8—N2—H2N	116 (2)
O3—C7—N1	123.1 (3)	C16—N3—C17	122.4 (2)
N2—C7—N1	113.2 (3)	C16—N3—H3N	122 (2)
C9—C8—C13	118.9 (2)	C17—N3—H3N	116 (2)
C9—C8—N2	117.7 (2)	C19—N4—C20	121.6 (3)
C13—C8—N2	123.3 (2)	C19—N4—H4N	125 (2)
C8—C9—C10	121.0 (3)	C20—N4—H4N	112 (2)
C8—C9—H9	119.5	C14—O2—C11	117.23 (19)
C10—C9—H9	119.5	C23—C22—H22A	109.5
C11—C10—C9	118.8 (3)	C23—C22—H22B	109.5
C11—C10—H10	120.6	H22A—C22—H22B	109.5
C9—C10—H10	120.6	C23—C22—H22C	109.5
C12—C11—C10	121.3 (3)	H22A—C22—H22C	109.5
C12—C11—O2	118.9 (3)	H22B—C22—H22C	109.5
C10—C11—O2	119.8 (3)	C24—C23—C28	117.8 (3)
C11—C12—C13	120.1 (3)	C24—C23—C22	121.6 (3)
C11—C12—H12	120.0	C28—C23—C22	120.6 (4)
C13—C12—H12	120.0	C23—C24—C25	122.2 (3)
C12—C13—C8	119.9 (3)	C23—C24—H24	118.9
C12—C13—H13	120.0	C25—C24—H24	118.9
C8—C13—H13	120.0	C26—C25—C24	119.2 (3)
O2—C14—C15	123.6 (2)	C26—C25—H25	120.4
O2—C14—C18	116.5 (2)	C24—C25—H25	120.4
C15—C14—C18	120.0 (2)	C27—C26—C25	118.7 (3)
C16—C15—C14	118.2 (2)	C27—C26—S1	119.7 (2)
C16—C15—H15	120.9	C25—C26—S1	121.5 (2)
C14—C15—H15	120.9	C26—C27—C28	120.7 (3)
N3—C16—C15	121.0 (2)	C26—C27—H27	119.6
N3—C16—H16	119.5	C28—C27—H27	119.6
C15—C16—H16	119.5	C23—C28—C27	121.2 (3)
N3—C17—C18	118.9 (2)	C23—C28—H28	119.4
N3—C17—C19	113.0 (2)	C27—C28—H28	119.4
C18—C17—C19	128.1 (2)	O6—S1—O5	113.41 (13)
C17—C18—C14	119.5 (2)	O6—S1—O4	111.63 (13)
C17—C18—H18	120.2	O5—S1—O4	111.04 (12)
C14—C18—H18	120.2	O6—S1—C26	107.49 (12)
O1—C19—N4	125.4 (3)	O5—S1—C26	107.88 (12)
O1—C19—C17	118.0 (2)	O4—S1—C26	104.89 (12)
C6—C1—C2—C3	1.3 (5)	C1—C2—C21—F1	176.9 (4)
Cl1—C1—C2—C3	−177.6 (2)	C3—C2—C21—F1	−4.6 (5)
C6—C1—C2—C21	179.8 (4)	C1—C2—C21—F3	58.9 (5)
Cl1—C1—C2—C21	0.9 (5)	C3—C2—C21—F3	−122.6 (4)
C1—C2—C3—C4	−0.6 (5)	O3—C7—N1—C4	−15.8 (5)
C21—C2—C3—C4	−179.1 (3)	N2—C7—N1—C4	167.3 (3)
C2—C3—C4—C5	−1.3 (5)	C5—C4—N1—C7	37.7 (5)
C2—C3—C4—N1	179.4 (3)	C3—C4—N1—C7	−143.0 (3)
C3—C4—C5—C6	2.4 (5)	O3—C7—N2—C8	7.8 (5)
N1—C4—C5—C6	−178.3 (3)	C9—C8—N2—C7	−169.5 (3)
C2—C1—C6—C5	−0.2 (6)	C13—C8—N2—C7	13.3 (4)
Cl1—C1—C6—C5	178.8 (3)	C15—C16—N3—C17	−3.2 (4)
C4—C5—C6—C1	−1.8 (6)	C18—C17—N3—C16	2.7 (4)
C13—C8—C9—C10	−0.1 (4)	C19—C17—N3—C16	−178.1 (2)
N2—C8—C9—C10	−177.4 (3)	O1—C19—N4—C20	3.0 (5)
C8—C9—C10—C11	−1.5 (4)	C17—C19—N4—C20	−176.8 (3)
C9—C10—C11—C12	2.4 (4)	C15—C14—O2—C11	7.6 (4)
C9—C10—C11—O2	−179.7 (2)	C18—C14—O2—C11	−173.0 (2)
C10—C11—C12—C13	−1.6 (4)	C12—C11—O2—C14	−107.6 (3)
O2—C11—C12—C13	−179.5 (2)	C10—C11—O2—C14	74.4 (3)
C11—C12—C13—C8	−0.1 (4)	C28—C23—C24—C25	−1.3 (5)
C9—C8—C13—C12	0.9 (4)	C22—C23—C24—C25	178.4 (3)
N2—C8—C13—C12	178.1 (2)	C23—C24—C25—C26	0.0 (5)
O2—C14—C15—C16	−178.2 (3)	C24—C25—C26—C27	1.5 (4)
C18—C14—C15—C16	2.4 (4)	C24—C25—C26—S1	−174.5 (2)
C14—C15—C16—N3	0.5 (4)	C25—C26—C27—C28	−1.8 (4)
N3—C17—C18—C14	0.3 (4)	S1—C26—C27—C28	174.3 (2)
C19—C17—C18—C14	−178.7 (3)	C24—C23—C28—C27	1.1 (5)
O2—C14—C18—C17	177.7 (2)	C22—C23—C28—C27	−178.7 (3)
C15—C14—C18—C17	−2.8 (4)	C26—C27—C28—C23	0.5 (5)
N3—C17—C19—O1	−22.1 (4)	C27—C26—S1—O6	171.2 (2)
C18—C17—C19—O1	157.0 (3)	C25—C26—S1—O6	−12.8 (3)
N3—C17—C19—N4	157.7 (2)	C27—C26—S1—O5	48.5 (2)
C18—C17—C19—N4	−23.1 (4)	C25—C26—S1—O5	−135.4 (2)
C1—C2—C21—F2	−61.9 (5)	C27—C26—S1—O4	−69.9 (2)
C3—C2—C21—F2	116.6 (4)	C25—C26—S1—O4	106.1 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O4	0.84 (2)	2.56 (2)	3.234 (3)	138 (2)
N2—H2N···O4	0.83 (2)	2.07 (2)	2.886 (3)	167 (3)
N3—H3N···O1	0.83 (3)	2.28 (3)	2.660 (3)	109 (2)
N3—H3N···O5^i	0.83 (3)	2.03 (3)	2.760 (3)	147 (3)
N4—H4N···O4^ii	0.85 (2)	2.19 (2)	3.021 (3)	170 (3)

Symmetry codes: (i) −x+2, y+1/2, −z+3/2; (ii) −x+2, y−1/2, −z+3/2.