Comparison of the crystal structures of the potent anti­cancer and anti-angiogenic agent regorafenib and its monohydrate

Regorafenib {systematic name: 4-[4-({[4-chloro-3-(tri­fluoro­methy)phen­yl]car­bam­o­yl}amino)-3-fluoro­phen­oxy]-1-methyl­pyridine-2-carboxamide}, C₂₁H₁₅ClF₄N₄O₃, is a potent anti­cancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling mol­ecules. The compound has been crystallized as polymorphic form I and as the mono­hydrate, C₂₁H₁₅ClF₄N₄O₃·H₂O. The regorafenib mol­ecule consists of bi­aryl­urea and pyridine-2-carboxamide units linked by an ether group. A comparison of both forms shows that they differ in the relative orientation of the bi­aryl­urea and pyridine-2-carboxamide units, due to different rotations around the ether group, as measured by the C—O—C bond angles [119.5 (3)° in regorafenib and 116.10 (15)° in the monohydrate]. Meanwhile, the conformational differences are reflected in different hydrogen-bond networks. Polymorphic form I contains two inter­molecular N—H...O hydrogen bonds, which link the regorafenib mol­ecules into an infinite mol­ecular chain along the b axis. In the monohydrate, the presence of the solvent water mol­ecule results in more abundant hydrogen bonds. The water mol­ecules act as donors and acceptors, forming N—H...O and O—H...O hydrogen-bond inter­actions. Thus, R₄²(28) ring motifs are formed, which are fused to form continuous spiral ring motifs along the a axis. The (tri­fluoro­meth­yl)phenyl rings protrude on the outside of these motifs and inter­digitate with those of adjacent ring motifs, thereby forming columns populated by halogen atoms.

Computing details

For both compounds, data collection: PROCESS-AUTO (Rigaku, 2006); cell refinement: PROCESS-AUTO (Rigaku, 2006); data reduction: CrystalStructure (Rigaku, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and DIAMOND (Brandenburg & Putz, 2005); software used to prepare material for publication: WinGX (Farrugia, 2012).

(I) 4-[4-({[4-Chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide

Crystal data

C21H15ClF4N4O3	F(000) = 984
Mr = 482.82	Dx = 1.508 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 10707 reflections
a = 7.6972 (4) Å	θ = 3.0–27.5°
b = 24.3703 (12) Å	µ = 0.25 mm^−1
c = 11.3580 (7) Å	T = 296 K
β = 93.545 (2)°	Platelet, colorless
V = 2126.5 (2) Å^3	0.49 × 0.39 × 0.13 mm
Z = 4

Data collection

Rigaku R-AXIS RAPID/ZJUG diffractometer	3738 independent reflections
Radiation source: rotating anode	2311 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.051
Detector resolution: 10.00 pixels mm^-1	θmax = 25.0°, θmin = 3.1°
ω scans	h = −9→9
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)	k = −28→28
Tmin = 0.879, Tmax = 0.969	l = −13→13
16556 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.048	H-atom parameters constrained
wR(F^2) = 0.148	w = 1/[σ^2(Fo^2) + (0.0537P)^2 + 2.3081P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max < 0.001
3738 reflections	Δρmax = 0.29 e Å^−3
300 parameters	Δρmin = −0.35 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0149 (12)

Special details

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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2sigma(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
C1	0.1725 (4)	0.72715 (13)	0.5281 (3)	0.0464 (8)
C2	0.1757 (4)	0.77854 (12)	0.5813 (3)	0.0478 (8)
H2	0.2250	0.7821	0.6577	0.057*
C3	0.1076 (4)	0.82442 (13)	0.5236 (3)	0.0479 (8)
C4	0.0367 (4)	0.81959 (13)	0.4082 (3)	0.0500 (8)
C5	0.0327 (5)	0.76842 (14)	0.3559 (3)	0.0559 (9)
H5	−0.0146	0.7650	0.2789	0.067*
C6	0.0965 (4)	0.72215 (13)	0.4142 (3)	0.0526 (9)
H6	0.0888	0.6880	0.3776	0.063*
C7	0.1012 (5)	0.87705 (15)	0.5909 (4)	0.0621 (10)
C8	0.2354 (4)	0.62834 (13)	0.5659 (3)	0.0502 (8)
C9	0.3390 (4)	0.53934 (12)	0.6434 (3)	0.0480 (8)
C10	0.4959 (4)	0.51292 (13)	0.6646 (3)	0.0535 (9)
C11	0.5121 (5)	0.45734 (14)	0.6781 (3)	0.0568 (9)
H11	0.6205	0.4409	0.6917	0.068*
C12	0.3624 (5)	0.42683 (13)	0.6707 (3)	0.0557 (10)
C13	0.2018 (5)	0.45053 (14)	0.6465 (3)	0.0626 (10)
H13	0.1019	0.4290	0.6394	0.075*
C14	0.1916 (5)	0.50704 (13)	0.6328 (3)	0.0583 (9)
H14	0.0837	0.5234	0.6163	0.070*
C15	0.3663 (5)	0.33260 (12)	0.6101 (3)	0.0494 (8)
C16	0.3099 (5)	0.34309 (13)	0.4950 (3)	0.0532 (9)
H16	0.2773	0.3783	0.4707	0.064*
C17	0.3033 (5)	0.29997 (14)	0.4174 (3)	0.0577 (9)
H17	0.2639	0.3072	0.3399	0.069*
C18	0.4042 (4)	0.23938 (12)	0.5568 (3)	0.0437 (8)
C19	0.4145 (4)	0.27964 (13)	0.6419 (3)	0.0478 (8)
H19	0.4530	0.2715	0.7191	0.057*
C20	0.4530 (4)	0.18162 (13)	0.5882 (3)	0.0488 (8)
C21	0.4420 (6)	0.08557 (14)	0.5253 (4)	0.0761 (12)
H21A	0.5504	0.0791	0.5697	0.114*
H21B	0.4430	0.0672	0.4506	0.114*
H21C	0.3480	0.0717	0.5684	0.114*
Cl1	−0.04400 (14)	0.87514 (4)	0.32732 (9)	0.0708 (4)
F1	0.1663 (4)	0.91993 (9)	0.5372 (3)	0.1068 (10)
F2	0.1880 (4)	0.87469 (9)	0.6945 (2)	0.1096 (11)
F3	−0.0588 (4)	0.89191 (12)	0.6106 (3)	0.1110 (11)
F4	0.6431 (3)	0.54431 (9)	0.6759 (2)	0.0844 (8)
N1	0.2461 (4)	0.68325 (10)	0.5930 (2)	0.0534 (8)
H1	0.3048	0.6916	0.6574	0.064*
N2	0.3362 (4)	0.59694 (10)	0.6409 (3)	0.0569 (8)
H2A	0.4046	0.6138	0.6915	0.068*
N3	0.3490 (4)	0.24839 (11)	0.4441 (2)	0.0535 (7)
N4	0.4190 (4)	0.14425 (11)	0.5061 (3)	0.0573 (8)
H4	0.3811	0.1552	0.4372	0.069*
O1	0.1457 (4)	0.60980 (9)	0.4827 (2)	0.0730 (8)
O2	0.3784 (4)	0.37076 (9)	0.6987 (2)	0.0700 (8)
O3	0.5190 (4)	0.17076 (9)	0.6882 (2)	0.0654 (7)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0463 (18)	0.0434 (18)	0.048 (2)	−0.0009 (14)	−0.0054 (15)	0.0005 (15)
C2	0.0523 (19)	0.0450 (18)	0.045 (2)	−0.0004 (15)	−0.0089 (15)	0.0016 (15)
C3	0.0467 (18)	0.0421 (17)	0.054 (2)	−0.0015 (15)	−0.0018 (16)	−0.0048 (15)
C4	0.0525 (19)	0.0489 (19)	0.048 (2)	0.0047 (16)	−0.0021 (16)	0.0044 (15)
C5	0.065 (2)	0.059 (2)	0.042 (2)	0.0091 (18)	−0.0067 (17)	0.0008 (16)
C6	0.062 (2)	0.0441 (18)	0.050 (2)	0.0019 (16)	−0.0061 (17)	−0.0060 (15)
C7	0.064 (2)	0.051 (2)	0.070 (3)	−0.0005 (19)	−0.013 (2)	−0.0019 (19)
C8	0.057 (2)	0.0422 (18)	0.050 (2)	−0.0022 (16)	−0.0080 (17)	−0.0020 (15)
C9	0.058 (2)	0.0349 (16)	0.050 (2)	−0.0021 (15)	−0.0058 (16)	−0.0022 (14)
C10	0.056 (2)	0.0426 (18)	0.061 (2)	−0.0097 (16)	−0.0058 (17)	0.0040 (16)
C11	0.067 (2)	0.0442 (19)	0.058 (2)	0.0053 (18)	−0.0082 (18)	0.0027 (16)
C12	0.089 (3)	0.0343 (17)	0.042 (2)	−0.0062 (18)	−0.0103 (19)	−0.0006 (14)
C13	0.072 (2)	0.047 (2)	0.067 (3)	−0.0154 (18)	−0.012 (2)	0.0034 (18)
C14	0.060 (2)	0.0459 (19)	0.067 (2)	−0.0056 (17)	−0.0086 (18)	−0.0002 (17)
C15	0.065 (2)	0.0387 (17)	0.043 (2)	−0.0048 (15)	−0.0068 (16)	0.0010 (14)
C16	0.071 (2)	0.0412 (18)	0.047 (2)	−0.0009 (16)	−0.0062 (17)	0.0096 (15)
C17	0.077 (2)	0.055 (2)	0.039 (2)	0.0018 (19)	−0.0080 (17)	0.0047 (16)
C18	0.0469 (18)	0.0447 (17)	0.0389 (19)	−0.0029 (14)	−0.0035 (14)	0.0050 (14)
C19	0.060 (2)	0.0451 (18)	0.0373 (18)	−0.0079 (16)	−0.0063 (15)	0.0041 (14)
C20	0.0516 (19)	0.0445 (18)	0.049 (2)	0.0039 (15)	−0.0046 (16)	0.0033 (16)
C21	0.092 (3)	0.046 (2)	0.090 (3)	0.011 (2)	0.005 (2)	−0.007 (2)
Cl1	0.0917 (8)	0.0579 (6)	0.0616 (6)	0.0171 (5)	−0.0061 (5)	0.0108 (5)
F1	0.149 (3)	0.0457 (13)	0.126 (2)	−0.0188 (15)	0.0107 (19)	0.0017 (14)
F2	0.167 (3)	0.0591 (14)	0.094 (2)	0.0092 (15)	−0.0652 (19)	−0.0231 (13)
F3	0.0850 (19)	0.112 (2)	0.136 (3)	0.0117 (16)	0.0082 (17)	−0.0691 (19)
F4	0.0649 (14)	0.0612 (13)	0.124 (2)	−0.0101 (11)	−0.0187 (13)	0.0195 (13)
N1	0.0669 (19)	0.0383 (15)	0.0521 (18)	0.0016 (13)	−0.0197 (14)	−0.0006 (12)
N2	0.0671 (19)	0.0347 (14)	0.065 (2)	−0.0002 (13)	−0.0241 (16)	−0.0005 (13)
N3	0.0684 (19)	0.0492 (16)	0.0417 (17)	0.0026 (14)	−0.0081 (14)	0.0012 (13)
N4	0.077 (2)	0.0413 (15)	0.0520 (19)	0.0021 (14)	−0.0058 (15)	−0.0033 (13)
O1	0.093 (2)	0.0476 (14)	0.0733 (19)	−0.0051 (13)	−0.0369 (16)	−0.0029 (13)
O2	0.126 (2)	0.0345 (12)	0.0469 (15)	−0.0066 (13)	−0.0187 (15)	0.0024 (10)
O3	0.0899 (19)	0.0463 (13)	0.0568 (17)	0.0035 (13)	−0.0216 (14)	0.0036 (12)

Geometric parameters (Å, º)

C1—C2	1.390 (4)	C12—C13	1.377 (5)
C1—C6	1.391 (4)	C12—O2	1.407 (4)
C1—N1	1.399 (4)	C13—C14	1.387 (5)
C2—C3	1.383 (4)	C13—H13	0.9300
C2—H2	0.9300	C14—H14	0.9300
C3—C4	1.393 (5)	C15—O2	1.370 (4)
C3—C7	1.496 (5)	C15—C16	1.376 (4)
C4—C5	1.381 (5)	C15—C19	1.384 (4)
C4—Cl1	1.730 (3)	C16—C17	1.371 (5)
C5—C6	1.382 (5)	C16—H16	0.9300
C5—H5	0.9300	C17—N3	1.335 (4)
C6—H6	0.9300	C17—H17	0.9300
C7—F3	1.316 (4)	C18—N3	1.341 (4)
C7—F2	1.317 (4)	C18—C19	1.376 (4)
C7—F1	1.324 (4)	C18—C20	1.495 (4)
C8—O1	1.222 (4)	C19—H19	0.9300
C8—N2	1.353 (4)	C20—O3	1.244 (4)
C8—N1	1.375 (4)	C20—N4	1.318 (4)
C9—C10	1.377 (5)	C21—N4	1.456 (4)
C9—C14	1.380 (5)	C21—H21A	0.9600
C9—N2	1.404 (4)	C21—H21B	0.9600
C10—F4	1.366 (4)	C21—H21C	0.9600
C10—C11	1.368 (5)	N1—H1	0.8600
C11—C12	1.370 (5)	N2—H2A	0.8600
C11—H11	0.9300	N4—H4	0.8600
C2—C1—C6	118.6 (3)	C12—C13—H13	120.6
C2—C1—N1	117.6 (3)	C14—C13—H13	120.6
C6—C1—N1	123.8 (3)	C9—C14—C13	121.0 (3)
C3—C2—C1	121.8 (3)	C9—C14—H14	119.5
C3—C2—H2	119.1	C13—C14—H14	119.5
C1—C2—H2	119.1	O2—C15—C16	125.1 (3)
C2—C3—C4	119.5 (3)	O2—C15—C19	115.9 (3)
C2—C3—C7	118.3 (3)	C16—C15—C19	119.0 (3)
C4—C3—C7	122.0 (3)	C17—C16—C15	117.7 (3)
C5—C4—C3	118.6 (3)	C17—C16—H16	121.1
C5—C4—Cl1	118.7 (3)	C15—C16—H16	121.1
C3—C4—Cl1	122.7 (3)	N3—C17—C16	125.2 (3)
C4—C5—C6	122.2 (3)	N3—C17—H17	117.4
C4—C5—H5	118.9	C16—C17—H17	117.4
C6—C5—H5	118.9	N3—C18—C19	123.7 (3)
C5—C6—C1	119.4 (3)	N3—C18—C20	116.2 (3)
C5—C6—H6	120.3	C19—C18—C20	120.1 (3)
C1—C6—H6	120.3	C18—C19—C15	118.6 (3)
F3—C7—F2	106.8 (4)	C18—C19—H19	120.7
F3—C7—F1	104.2 (3)	C15—C19—H19	120.7
F2—C7—F1	105.1 (3)	O3—C20—N4	123.5 (3)
F3—C7—C3	112.5 (3)	O3—C20—C18	120.1 (3)
F2—C7—C3	112.9 (3)	N4—C20—C18	116.5 (3)
F1—C7—C3	114.6 (3)	N4—C21—H21A	109.5
O1—C8—N2	123.5 (3)	N4—C21—H21B	109.5
O1—C8—N1	123.8 (3)	H21A—C21—H21B	109.5
N2—C8—N1	112.7 (3)	N4—C21—H21C	109.5
C10—C9—C14	117.1 (3)	H21A—C21—H21C	109.5
C10—C9—N2	118.9 (3)	H21B—C21—H21C	109.5
C14—C9—N2	123.8 (3)	C8—N1—C1	127.6 (3)
F4—C10—C11	118.3 (3)	C8—N1—H1	116.2
F4—C10—C9	117.9 (3)	C1—N1—H1	116.2
C11—C10—C9	123.7 (3)	C8—N2—C9	125.9 (3)
C10—C11—C12	117.4 (3)	C8—N2—H2A	117.1
C10—C11—H11	121.3	C9—N2—H2A	117.1
C12—C11—H11	121.3	C17—N3—C18	115.8 (3)
C11—C12—C13	121.7 (3)	C20—N4—C21	123.7 (3)
C11—C12—O2	116.9 (3)	C20—N4—H4	118.1
C13—C12—O2	121.2 (3)	C21—N4—H4	118.1
C12—C13—C14	118.9 (3)	C15—O2—C12	119.5 (3)
C6—C1—C2—C3	−0.8 (5)	N2—C9—C14—C13	−174.2 (3)
N1—C1—C2—C3	179.4 (3)	C12—C13—C14—C9	−0.2 (6)
C1—C2—C3—C4	−1.3 (5)	O2—C15—C16—C17	−179.1 (4)
C1—C2—C3—C7	174.4 (3)	C19—C15—C16—C17	0.4 (5)
C2—C3—C4—C5	1.7 (5)	C15—C16—C17—N3	−0.7 (6)
C7—C3—C4—C5	−173.8 (3)	N3—C18—C19—C15	−0.4 (5)
C2—C3—C4—Cl1	−177.6 (3)	C20—C18—C19—C15	−179.2 (3)
C7—C3—C4—Cl1	6.9 (5)	O2—C15—C19—C18	179.6 (3)
C3—C4—C5—C6	−0.1 (5)	C16—C15—C19—C18	0.1 (5)
Cl1—C4—C5—C6	179.2 (3)	N3—C18—C20—O3	174.0 (3)
C4—C5—C6—C1	−2.0 (6)	C19—C18—C20—O3	−7.0 (5)
C2—C1—C6—C5	2.4 (5)	N3—C18—C20—N4	−7.3 (4)
N1—C1—C6—C5	−177.8 (3)	C19—C18—C20—N4	171.7 (3)
C2—C3—C7—F3	−111.0 (4)	O1—C8—N1—C1	−6.0 (6)
C4—C3—C7—F3	64.6 (5)	N2—C8—N1—C1	173.6 (3)
C2—C3—C7—F2	9.9 (5)	C2—C1—N1—C8	169.7 (3)
C4—C3—C7—F2	−174.5 (3)	C6—C1—N1—C8	−10.1 (6)
C2—C3—C7—F1	130.2 (4)	O1—C8—N2—C9	−7.5 (6)
C4—C3—C7—F1	−54.3 (5)	N1—C8—N2—C9	173.0 (3)
C14—C9—C10—F4	−179.7 (3)	C10—C9—N2—C8	141.3 (4)
N2—C9—C10—F4	−3.4 (5)	C14—C9—N2—C8	−42.7 (6)
C14—C9—C10—C11	−1.6 (6)	C16—C17—N3—C18	0.4 (5)
N2—C9—C10—C11	174.7 (3)	C19—C18—N3—C17	0.1 (5)
F4—C10—C11—C12	177.6 (3)	C20—C18—N3—C17	179.1 (3)
C9—C10—C11—C12	−0.5 (6)	O3—C20—N4—C21	4.9 (6)
C10—C11—C12—C13	2.3 (5)	C18—C20—N4—C21	−173.8 (3)
C10—C11—C12—O2	−172.5 (3)	C16—C15—O2—C12	−11.8 (5)
C11—C12—C13—C14	−2.0 (6)	C19—C15—O2—C12	168.7 (3)
O2—C12—C13—C14	172.6 (3)	C11—C12—O2—C15	−105.6 (4)
C10—C9—C14—C13	1.9 (6)	C13—C12—O2—C15	79.5 (5)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O3^i	0.86	2.21	2.997 (4)	152
N2—H2A···O3^i	0.86	2.01	2.825 (4)	158

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

(II) 4-[4-({[4-Chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide monohydrate

Crystal data

C21H15ClF4N4O3·H2O	F(000) = 1024
Mr = 500.84	Dx = 1.544 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 13751 reflections
a = 4.7783 (2) Å	θ = 3.1–27.4°
b = 21.9538 (9) Å	µ = 0.25 mm^−1
c = 20.5581 (8) Å	T = 296 K
β = 92.341 (1)°	Platelet, colorless
V = 2154.78 (15) Å^3	0.48 × 0.38 × 0.16 mm
Z = 4

Data collection

Rigaku R-AXIS RAPID/ZJUG diffractometer	4903 independent reflections
Radiation source: rotating anode	3197 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.045
Detector resolution: 10.00 pixels mm^-1	θmax = 27.5°, θmin = 3.1°
ω scans	h = −5→6
Absorption correction: multi-scan (ABSCOR; Higashi, 1995)	k = −28→28
Tmin = 0.890, Tmax = 0.961	l = −26→26
20501 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.042	H-atom parameters constrained
wR(F^2) = 0.120	w = 1/[σ^2(Fo^2) + (0.0538P)^2 + 0.7939P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max < 0.001
4903 reflections	Δρmax = 0.23 e Å^−3
309 parameters	Δρmin = −0.31 e Å^−3
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0203 (14)

Special details

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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2sigma(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
C1	0.3084 (4)	0.50642 (9)	0.78416 (9)	0.0365 (4)
C2	0.2383 (4)	0.56444 (9)	0.80461 (9)	0.0396 (4)
H2	0.3179	0.5980	0.7849	0.048*
C3	0.0523 (4)	0.57359 (9)	0.85373 (9)	0.0399 (5)
C4	−0.0680 (4)	0.52315 (10)	0.88298 (9)	0.0431 (5)
C5	−0.0057 (4)	0.46555 (10)	0.86138 (10)	0.0467 (5)
H5	−0.0906	0.4321	0.8800	0.056*
C6	0.1811 (4)	0.45644 (10)	0.81244 (10)	0.0449 (5)
H6	0.2211	0.4172	0.7986	0.054*
C7	−0.0075 (5)	0.63711 (11)	0.87514 (12)	0.0528 (6)
C8	0.6276 (4)	0.45096 (9)	0.71187 (9)	0.0384 (4)
C9	0.9572 (4)	0.42249 (9)	0.62695 (9)	0.0380 (4)
C10	1.1447 (5)	0.44482 (10)	0.58269 (10)	0.0464 (5)
C11	1.3031 (5)	0.40850 (11)	0.54408 (10)	0.0497 (5)
H11	1.4264	0.4253	0.5151	0.060*
C12	1.2726 (4)	0.34615 (10)	0.54983 (9)	0.0428 (5)
C13	1.0902 (5)	0.32204 (10)	0.59238 (11)	0.0490 (5)
H13	1.0718	0.2800	0.5957	0.059*
C14	0.9328 (5)	0.35968 (10)	0.63054 (10)	0.0480 (5)
H14	0.8086	0.3426	0.6590	0.058*
C15	1.3094 (4)	0.26889 (9)	0.47089 (9)	0.0384 (4)
C16	1.4089 (4)	0.21037 (10)	0.46580 (10)	0.0451 (5)
H16	1.5580	0.1968	0.4924	0.054*
C17	1.2815 (5)	0.17248 (10)	0.42016 (10)	0.0494 (5)
H17	1.3448	0.1325	0.4180	0.059*
C18	0.9847 (4)	0.24709 (9)	0.38363 (9)	0.0356 (4)
C19	1.0900 (4)	0.28804 (9)	0.42978 (9)	0.0384 (4)
H19	1.0158	0.3270	0.4330	0.046*
C20	0.7640 (4)	0.26877 (9)	0.33469 (9)	0.0379 (4)
C21	0.4359 (5)	0.24031 (11)	0.24568 (10)	0.0506 (5)
H21A	0.3351	0.2762	0.2576	0.076*
H21B	0.3088	0.2065	0.2415	0.076*
H21C	0.5218	0.2471	0.2049	0.076*
Cl1	−0.29708 (13)	0.53054 (3)	0.94589 (3)	0.0634 (2)
F1	−0.2793 (3)	0.65122 (7)	0.87287 (8)	0.0683 (4)
F2	0.1154 (4)	0.67905 (7)	0.83876 (9)	0.0874 (6)
F3	0.0824 (3)	0.64786 (8)	0.93637 (8)	0.0883 (6)
F4	1.1708 (3)	0.50629 (6)	0.57779 (7)	0.0740 (5)
N1	0.5009 (4)	0.50228 (8)	0.73467 (8)	0.0429 (4)
H1	0.5447	0.5360	0.7164	0.051*
N2	0.8044 (4)	0.46440 (8)	0.66270 (8)	0.0422 (4)
H2A	0.8229	0.5022	0.6529	0.051*
N3	1.0727 (4)	0.18938 (8)	0.37872 (8)	0.0435 (4)
N4	0.6509 (3)	0.22688 (8)	0.29560 (8)	0.0426 (4)
H4	0.7074	0.1899	0.3000	0.051*
O1	0.5883 (3)	0.39990 (7)	0.73256 (7)	0.0514 (4)
O2	1.4446 (3)	0.30739 (7)	0.51463 (7)	0.0533 (4)
O3	0.7020 (3)	0.32373 (6)	0.33169 (7)	0.0501 (4)
O4	0.7761 (4)	0.60161 (7)	0.67180 (9)	0.0682 (5)
H41	0.9210	0.6212	0.6771	0.102*
H42	0.6563	0.6250	0.6570	0.102*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0385 (10)	0.0353 (10)	0.0355 (9)	0.0003 (8)	−0.0005 (8)	−0.0002 (8)
C2	0.0391 (10)	0.0357 (10)	0.0440 (10)	−0.0038 (9)	0.0013 (9)	0.0018 (8)
C3	0.0347 (10)	0.0429 (11)	0.0419 (10)	0.0011 (9)	−0.0023 (8)	−0.0041 (9)
C4	0.0356 (10)	0.0556 (13)	0.0382 (10)	0.0042 (10)	0.0021 (8)	0.0074 (9)
C5	0.0474 (12)	0.0410 (12)	0.0522 (12)	−0.0008 (10)	0.0074 (10)	0.0100 (9)
C6	0.0499 (12)	0.0354 (11)	0.0495 (11)	0.0011 (9)	0.0044 (10)	0.0035 (9)
C7	0.0392 (11)	0.0526 (14)	0.0667 (14)	−0.0015 (10)	0.0048 (11)	−0.0134 (12)
C8	0.0434 (11)	0.0340 (10)	0.0375 (10)	−0.0003 (9)	−0.0008 (8)	−0.0032 (8)
C9	0.0410 (10)	0.0376 (11)	0.0351 (9)	0.0009 (9)	−0.0017 (8)	−0.0030 (8)
C10	0.0539 (12)	0.0394 (12)	0.0462 (11)	−0.0014 (10)	0.0055 (10)	0.0012 (9)
C11	0.0497 (13)	0.0540 (14)	0.0459 (11)	−0.0023 (11)	0.0098 (10)	−0.0019 (10)
C12	0.0385 (10)	0.0503 (13)	0.0390 (10)	0.0062 (9)	−0.0046 (9)	−0.0120 (9)
C13	0.0581 (13)	0.0369 (11)	0.0523 (12)	0.0003 (10)	0.0040 (11)	−0.0077 (9)
C14	0.0562 (13)	0.0395 (12)	0.0492 (12)	−0.0031 (10)	0.0115 (10)	−0.0033 (9)
C15	0.0340 (10)	0.0460 (12)	0.0355 (9)	−0.0024 (9)	0.0047 (8)	−0.0054 (8)
C16	0.0436 (11)	0.0482 (12)	0.0435 (11)	0.0085 (10)	−0.0001 (9)	0.0025 (9)
C17	0.0558 (13)	0.0375 (11)	0.0545 (12)	0.0083 (10)	−0.0019 (11)	0.0004 (10)
C18	0.0371 (10)	0.0329 (10)	0.0372 (9)	−0.0008 (8)	0.0061 (8)	0.0013 (8)
C19	0.0383 (10)	0.0361 (10)	0.0412 (10)	0.0020 (8)	0.0064 (8)	−0.0033 (8)
C20	0.0361 (10)	0.0371 (11)	0.0409 (10)	−0.0014 (9)	0.0047 (8)	−0.0002 (8)
C21	0.0482 (12)	0.0573 (14)	0.0456 (11)	−0.0010 (11)	−0.0077 (10)	−0.0001 (10)
Cl1	0.0567 (4)	0.0824 (5)	0.0525 (3)	0.0105 (3)	0.0181 (3)	0.0094 (3)
F1	0.0450 (7)	0.0585 (9)	0.1017 (11)	0.0110 (6)	0.0062 (7)	−0.0105 (8)
F2	0.0861 (11)	0.0408 (8)	0.1391 (15)	−0.0050 (8)	0.0526 (11)	−0.0124 (9)
F3	0.0791 (11)	0.0966 (13)	0.0876 (11)	0.0064 (9)	−0.0146 (9)	−0.0525 (10)
F4	0.0999 (12)	0.0393 (8)	0.0856 (10)	−0.0040 (7)	0.0408 (9)	0.0048 (7)
N1	0.0529 (10)	0.0309 (9)	0.0456 (9)	0.0005 (8)	0.0126 (8)	0.0010 (7)
N2	0.0516 (10)	0.0329 (9)	0.0427 (9)	0.0002 (8)	0.0080 (8)	−0.0004 (7)
N3	0.0495 (10)	0.0340 (9)	0.0468 (9)	0.0029 (8)	−0.0001 (8)	−0.0014 (7)
N4	0.0449 (9)	0.0378 (9)	0.0445 (9)	0.0007 (8)	−0.0047 (8)	−0.0006 (7)
O1	0.0670 (10)	0.0330 (8)	0.0553 (9)	−0.0003 (7)	0.0170 (8)	0.0012 (7)
O2	0.0392 (8)	0.0650 (10)	0.0553 (9)	0.0063 (7)	−0.0037 (7)	−0.0239 (8)
O3	0.0497 (8)	0.0360 (8)	0.0637 (9)	0.0048 (7)	−0.0087 (7)	−0.0023 (7)
O4	0.0555 (10)	0.0393 (9)	0.1097 (14)	0.0004 (8)	0.0043 (10)	0.0222 (9)

Geometric parameters (Å, º)

C1—C2	1.387 (3)	C12—O2	1.404 (2)
C1—C6	1.393 (3)	C13—C14	1.383 (3)
C1—N1	1.402 (3)	C13—H13	0.9300
C2—C3	1.387 (3)	C14—H14	0.9300
C2—H2	0.9300	C15—C16	1.375 (3)
C3—C4	1.395 (3)	C15—O2	1.376 (2)
C3—C7	1.494 (3)	C15—C19	1.385 (3)
C4—C5	1.377 (3)	C16—C17	1.377 (3)
C4—Cl1	1.736 (2)	C16—H16	0.9300
C5—C6	1.386 (3)	C17—N3	1.338 (3)
C5—H5	0.9300	C17—H17	0.9300
C6—H6	0.9300	C18—N3	1.340 (2)
C7—F1	1.334 (2)	C18—C19	1.386 (3)
C7—F3	1.334 (3)	C18—C20	1.505 (3)
C7—F2	1.337 (3)	C19—H19	0.9300
C8—O1	1.216 (2)	C20—O3	1.243 (2)
C8—N1	1.371 (2)	C20—N4	1.322 (2)
C8—N2	1.375 (3)	C21—N4	1.452 (3)
C9—C14	1.386 (3)	C21—H21A	0.9600
C9—C10	1.392 (3)	C21—H21B	0.9600
C9—N2	1.401 (3)	C21—H21C	0.9600
C10—F4	1.359 (2)	N1—H1	0.8600
C10—C11	1.374 (3)	N2—H2A	0.8600
C11—C12	1.382 (3)	N4—H4	0.8600
C11—H11	0.9300	O4—H41	0.8191
C12—C13	1.366 (3)	O4—H42	0.8189
C2—C1—C6	118.80 (19)	C14—C13—H13	119.7
C2—C1—N1	116.96 (17)	C13—C14—C9	121.0 (2)
C6—C1—N1	124.23 (18)	C13—C14—H14	119.5
C3—C2—C1	121.58 (19)	C9—C14—H14	119.5
C3—C2—H2	119.2	C16—C15—O2	117.97 (17)
C1—C2—H2	119.2	C16—C15—C19	119.51 (18)
C2—C3—C4	119.11 (19)	O2—C15—C19	122.42 (18)
C2—C3—C7	119.06 (19)	C15—C16—C17	118.13 (19)
C4—C3—C7	121.81 (19)	C15—C16—H16	120.9
C5—C4—C3	119.45 (19)	C17—C16—H16	120.9
C5—C4—Cl1	118.51 (17)	N3—C17—C16	124.3 (2)
C3—C4—Cl1	122.03 (17)	N3—C17—H17	117.8
C4—C5—C6	121.4 (2)	C16—C17—H17	117.8
C4—C5—H5	119.3	N3—C18—C19	123.94 (18)
C6—C5—H5	119.3	N3—C18—C20	117.53 (16)
C5—C6—C1	119.6 (2)	C19—C18—C20	118.51 (17)
C5—C6—H6	120.2	C15—C19—C18	117.74 (18)
C1—C6—H6	120.2	C15—C19—H19	121.1
F1—C7—F3	105.52 (19)	C18—C19—H19	121.1
F1—C7—F2	105.6 (2)	O3—C20—N4	123.65 (18)
F3—C7—F2	105.91 (19)	O3—C20—C18	119.95 (17)
F1—C7—C3	113.84 (18)	N4—C20—C18	116.38 (17)
F3—C7—C3	112.6 (2)	N4—C21—H21A	109.5
F2—C7—C3	112.60 (19)	N4—C21—H21B	109.5
O1—C8—N1	124.14 (19)	H21A—C21—H21B	109.5
O1—C8—N2	124.27 (18)	N4—C21—H21C	109.5
N1—C8—N2	111.60 (17)	H21A—C21—H21C	109.5
C14—C9—C10	116.30 (19)	H21B—C21—H21C	109.5
C14—C9—N2	125.33 (19)	C8—N1—C1	127.84 (17)
C10—C9—N2	118.35 (18)	C8—N1—H1	116.1
F4—C10—C11	118.6 (2)	C1—N1—H1	116.1
F4—C10—C9	117.50 (19)	C8—N2—C9	126.40 (17)
C11—C10—C9	123.9 (2)	C8—N2—H2A	116.8
C10—C11—C12	117.6 (2)	C9—N2—H2A	116.8
C10—C11—H11	121.2	C17—N3—C18	116.26 (17)
C12—C11—H11	121.2	C20—N4—C21	123.23 (18)
C13—C12—C11	120.7 (2)	C20—N4—H4	118.4
C13—C12—O2	119.8 (2)	C21—N4—H4	118.4
C11—C12—O2	119.3 (2)	C15—O2—C12	116.10 (15)
C12—C13—C14	120.5 (2)	H41—O4—H42	107.0
C12—C13—H13	119.7
C6—C1—C2—C3	2.1 (3)	C10—C9—C14—C13	0.7 (3)
N1—C1—C2—C3	−179.30 (17)	N2—C9—C14—C13	178.94 (19)
C1—C2—C3—C4	−0.3 (3)	O2—C15—C16—C17	−177.33 (19)
C1—C2—C3—C7	177.96 (18)	C19—C15—C16—C17	−1.1 (3)
C2—C3—C4—C5	−1.7 (3)	C15—C16—C17—N3	2.4 (3)
C7—C3—C4—C5	−179.96 (19)	C16—C15—C19—C18	−1.7 (3)
C2—C3—C4—Cl1	178.65 (14)	O2—C15—C19—C18	174.42 (17)
C7—C3—C4—Cl1	0.4 (3)	N3—C18—C19—C15	3.6 (3)
C3—C4—C5—C6	2.0 (3)	C20—C18—C19—C15	−174.64 (17)
Cl1—C4—C5—C6	−178.36 (16)	N3—C18—C20—O3	−170.53 (18)
C4—C5—C6—C1	−0.2 (3)	C19—C18—C20—O3	7.8 (3)
C2—C1—C6—C5	−1.8 (3)	N3—C18—C20—N4	7.8 (3)
N1—C1—C6—C5	179.68 (18)	C19—C18—C20—N4	−173.84 (17)
C2—C3—C7—F1	125.5 (2)	O1—C8—N1—C1	−0.1 (3)
C4—C3—C7—F1	−56.3 (3)	N2—C8—N1—C1	179.85 (17)
C2—C3—C7—F3	−114.5 (2)	C2—C1—N1—C8	171.48 (19)
C4—C3—C7—F3	63.8 (3)	C6—C1—N1—C8	−10.0 (3)
C2—C3—C7—F2	5.2 (3)	O1—C8—N2—C9	2.7 (3)
C4—C3—C7—F2	−176.54 (19)	N1—C8—N2—C9	−177.20 (17)
C14—C9—C10—F4	179.43 (19)	C14—C9—N2—C8	7.3 (3)
N2—C9—C10—F4	1.1 (3)	C10—C9—N2—C8	−174.52 (18)
C14—C9—C10—C11	−0.6 (3)	C16—C17—N3—C18	−0.7 (3)
N2—C9—C10—C11	−178.92 (19)	C19—C18—N3—C17	−2.4 (3)
F4—C10—C11—C12	−179.89 (19)	C20—C18—N3—C17	175.85 (18)
C9—C10—C11—C12	0.1 (3)	O3—C20—N4—C21	−1.5 (3)
C10—C11—C12—C13	0.2 (3)	C18—C20—N4—C21	−179.85 (18)
C10—C11—C12—O2	−175.58 (18)	C16—C15—O2—C12	−140.3 (2)
C11—C12—C13—C14	0.0 (3)	C19—C15—O2—C12	43.5 (3)
O2—C12—C13—C14	175.73 (18)	C13—C12—O2—C15	64.7 (2)
C12—C13—C14—C9	−0.5 (3)	C11—C12—O2—C15	−119.5 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H42···O3^i	0.82	2.07	2.810 (2)	150
O4—H41···O3^ii	0.82	2.18	2.988 (2)	168
N4—H4···O1^iii	0.86	2.46	3.080 (2)	129
N1—H1···O4	0.86	2.05	2.880 (2)	161
N2—H2A···O4	0.86	2.23	3.021 (2)	153

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