Exploring a solvated dimer of Gefitinib: a qu­anti­tative analysis

Gefitinib or Iressa is an orally administered anilinoquinazoline used in cancer chemotherapy for the treatment of lung and breast cancer. It is reported to exist in two polymorphic forms, a stable form I and a metastable form II. Both of the forms belong to the triclinic P space group. In this work, we report the crystallization of Gefitinib to form a methanol solvate [systematic name: N-(3-chloro-4-fluoro­phen­yl)-7-meth­oxy-6-[3-(morpholin-4-yl)prop­oxy]quinazolin-4-amine methanol hemisolvate, C₂₂H₂₄ClFN₄O₃·0.5CH₃OH] that was theoretically and experimentally investigated. The unit cell is composed of two independent Gefitinib mol­ecules (A and B) that form a stable mol­ecular complex with methanol in the crystal lattice. To understand the crystal lattice stabilization, a combination of techniques, namely X-ray diffraction, IR spectroscopy, thermogravimetric/differential scanning calorimetry (TG-DSC), Hirshfeld surface analysis and CLP-PIXEL methods were used. The analysis of the crystal structure of this dimer revealed a three-dimensional isostructurality with the already reported form II. The A and B mol­ecules are connected via trifurcated C—H...O and N—H...O hydrogen bonding. In addition, the presence of the methanol mol­ecule stabilizes the crystal structure via C—H...O, N—H...O and C—H...Cl inter­actions between the two monomers. The IR analysis of the dimer has shown characteristic fingerprint values when compared to the commercial form. The TG-DSC analysis of the solvated dimer is in good agreement with the patent reporting cocrystals of Gefitinib. Finally, theoretical calculations by the CLP-PIXEL method and Hirshfeld surface and two-dimensional (2D) fingerprint plot analysis were carried out in order to qu­antify the different inter­molecular inter­actions and their energies in the crystal packing.

Computing details

Data collection: APEX2 (Bruker, 2012); cell refinement: APEX2 (Bruker, 2012); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELX86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015) in WinGX (Farrugia, 2012) and olex2.refine (Bourhis et al., 2015); molecular graphics: ORTEP-3 (Farrugia, 2012), CAMERON (Watkin et al., 1996) and Mercury (Macrae et al., 2008); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine methanol hemisolvate

Crystal data

C22H24ClFN4O3·0.5CH4O	Z = 4
Mr = 463.28	F(000) = 973.9225
Triclinic, P1	Dx = 1.425 Mg m^−3
a = 7.337 (2) Å	Mo Kα radiation, λ = 0.71073 Å
b = 10.991 (3) Å	Cell parameters from 9417 reflections
c = 27.078 (8) Å	θ = 2.6–30.3°
α = 98.241 (9)°	µ = 0.22 mm^−1
β = 91.151 (10)°	T = 100 K
γ = 91.244 (9)°	Plate, white
V = 2159.9 (10) Å^3	0.4 × 0.2 × 0.2 mm

Data collection

Bruker APEXII CCD diffractometer	9815 reflections with I ≥ 2u(I)
φ and ω scans	Rint = 0.074
Absorption correction: multi-scan (SADABS; Bruker, 2012)	θmax = 30.6°, θmin = 2.2°
Tmin = 0.710, Tmax = 0.746	h = −10→10
113623 measured reflections	k = −15→15
13149 independent reflections	l = −38→38

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	93 constraints
R[F^2 > 2σ(F^2)] = 0.054	H-atom parameters constrained
wR(F^2) = 0.140	w = 1/[σ^2(Fo^2) + (0.0554P)^2 + 1.8243P] where P = (Fo^2 + 2Fc^2)/3
S = 1.07	(Δ/σ)max = 0.001
13149 reflections	Δρmax = 1.02 e Å^−3
600 parameters	Δρmin = −0.90 e Å^−3

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
F1	0.00820 (16)	−0.08595 (9)	0.14554 (4)	0.0263 (2)
O23	0.26683 (19)	0.87810 (13)	0.33762 (5)	0.0251 (3)
Cl1	−0.03025 (6)	0.13866 (4)	0.218034 (17)	0.02324 (11)
C8	0.2842 (2)	0.64891 (16)	−0.03667 (6)	0.0160 (3)
O7	0.39595 (17)	0.85505 (11)	−0.00454 (4)	0.0177 (2)
O33	0.41677 (17)	1.36956 (12)	0.51108 (5)	0.0219 (3)
O32	0.42764 (18)	1.24973 (12)	0.42247 (5)	0.0243 (3)
Cl2	−0.12679 (8)	0.49541 (5)	0.30277 (2)	0.03903 (15)
O6	0.44766 (17)	0.80275 (10)	0.08320 (4)	0.0168 (2)
C19	0.6030 (2)	0.90093 (17)	0.21532 (6)	0.0201 (3)
N20	0.4697 (2)	0.85006 (13)	0.24709 (5)	0.0181 (3)
C34	0.3040 (2)	1.19247 (16)	0.54607 (6)	0.0174 (3)
C35	0.2493 (2)	1.06703 (16)	0.53803 (6)	0.0168 (3)
C37	0.1174 (2)	0.68562 (16)	0.42415 (6)	0.0175 (3)
C38	0.0345 (2)	0.65485 (17)	0.37700 (7)	0.0198 (3)
F2	−0.01696 (18)	0.32409 (10)	0.37007 (5)	0.0324 (3)
O49	0.4390 (2)	1.45323 (14)	0.17040 (5)	0.0322 (3)
C14	0.0547 (2)	0.01869 (15)	0.12693 (7)	0.0190 (3)
C15	0.1155 (2)	0.01143 (16)	0.07897 (7)	0.0213 (4)
C16	0.1681 (2)	0.11788 (16)	0.06021 (7)	0.0197 (3)
C11	0.1553 (2)	0.23224 (15)	0.09020 (6)	0.0165 (3)
N4	0.2149 (2)	0.34502 (13)	0.07585 (5)	0.0188 (3)
C4	0.2097 (2)	0.37785 (15)	0.02922 (6)	0.0153 (3)
C10	0.2652 (2)	0.50030 (15)	0.02215 (6)	0.0136 (3)
C5	0.3367 (2)	0.59159 (15)	0.06052 (6)	0.0144 (3)
C6	0.3789 (2)	0.70719 (15)	0.04995 (6)	0.0136 (3)
C17	0.4710 (2)	0.78383 (15)	0.13429 (6)	0.0167 (3)
C18	0.5362 (2)	0.90692 (16)	0.16211 (6)	0.0183 (3)
C21	0.5558 (3)	0.8455 (2)	0.29608 (7)	0.0273 (4)
C22	0.4216 (3)	0.8011 (2)	0.33158 (8)	0.0343 (5)
C13	0.0417 (2)	0.13101 (16)	0.15705 (6)	0.0169 (3)
C12	0.0899 (2)	0.23827 (15)	0.13854 (6)	0.0169 (3)
C9	0.2413 (2)	0.52938 (15)	−0.02639 (6)	0.0146 (3)
C7	0.3514 (2)	0.73703 (15)	0.00057 (6)	0.0145 (3)
C26	0.3644 (3)	0.89215 (16)	−0.05258 (6)	0.0202 (3)
C25	0.3081 (2)	0.92556 (18)	0.25360 (7)	0.0217 (4)
C24	0.1790 (3)	0.8794 (2)	0.29029 (7)	0.0263 (4)
N1	0.1747 (2)	0.44361 (14)	−0.06517 (5)	0.0180 (3)
C2	0.1375 (2)	0.33378 (16)	−0.05356 (7)	0.0193 (3)
N3	0.1509 (2)	0.29505 (13)	−0.00881 (5)	0.0177 (3)
C52	0.4043 (3)	1.44220 (17)	0.55910 (7)	0.0242 (4)
C33	0.3619 (2)	1.24975 (16)	0.50709 (7)	0.0178 (3)
C36	0.2509 (2)	1.00135 (16)	0.48948 (6)	0.0163 (3)
C30	0.1871 (2)	0.87587 (16)	0.48452 (6)	0.0168 (3)
N30	0.1722 (2)	0.80939 (14)	0.43765 (6)	0.0196 (3)
C39	−0.0115 (2)	0.53346 (17)	0.35924 (7)	0.0219 (4)
C40	0.0256 (2)	0.44298 (17)	0.38835 (7)	0.0223 (4)
N27	0.1958 (2)	1.01325 (14)	0.57856 (6)	0.0206 (3)
C28	0.1482 (3)	0.89654 (17)	0.56841 (7)	0.0221 (4)
N29	0.1403 (2)	0.82333 (14)	0.52372 (6)	0.0199 (3)
C31	0.3121 (2)	1.06152 (16)	0.44938 (6)	0.0179 (3)
C32	0.3671 (2)	1.18284 (16)	0.45802 (6)	0.0181 (3)
C43	0.4366 (3)	1.1861 (3)	0.37299 (7)	0.0420 (6)
C41	0.1018 (2)	0.47173 (17)	0.43530 (7)	0.0222 (4)
C42	0.1482 (2)	0.59304 (17)	0.45378 (7)	0.0209 (4)
C48	0.4109 (3)	1.52809 (18)	0.21642 (8)	0.0306 (4)
C47	0.3465 (4)	1.4524 (2)	0.25513 (8)	0.0410 (6)
N46	0.4821 (3)	1.3626 (2)	0.26267 (10)	0.0599 (8)
C51	0.5089 (3)	1.2860 (2)	0.21527 (16)	0.0659 (11)
C50	0.5675 (3)	1.3630 (2)	0.17738 (12)	0.0520 (7)
O54	0.0025 (2)	0.52498 (13)	0.15325 (5)	0.0307 (3)
C53	−0.0498 (3)	0.62857 (18)	0.18579 (8)	0.0302 (4)
C45B	0.3903 (5)	1.3219 (3)	0.31175 (12)	0.0180 (6)	0.504020
C45A	0.4592 (5)	1.2556 (3)	0.28887 (13)	0.0195 (7)	0.495980
C44B	0.4717 (6)	1.3051 (4)	0.34389 (13)	0.0255 (7)	0.553460
C44A	0.5329 (5)	1.2450 (4)	0.33508 (14)	0.0190 (7)	0.488990
H44a	0.4628 (6)	1.3791 (4)	0.36921 (13)	0.0306 (9)*	0.553460
H44b	0.6001 (6)	1.3020 (4)	0.33330 (13)	0.0306 (9)*	0.553460
H45a	0.3029 (5)	1.3862 (3)	0.32386 (12)	0.0215 (8)*	0.504020
H45b	0.3174 (5)	1.2458 (3)	0.30055 (12)	0.0215 (8)*	0.504020
H43a	0.5391 (3)	1.1286 (3)	0.36921 (7)	0.0504 (8)*	0.553460
H43b	0.3211 (3)	1.1413 (3)	0.36193 (7)	0.0504 (8)*	0.553460
H43c	0.4947 (3)	1.1064 (3)	0.37499 (7)	0.0504 (8)*	0.488990
H43d	0.3100 (3)	1.1673 (3)	0.36048 (7)	0.0504 (8)*	0.488990
H18a	0.4350 (2)	0.96526 (16)	0.16309 (6)	0.0219 (4)*
H18b	0.6366 (2)	0.93950 (16)	0.14349 (6)	0.0219 (4)*
H19a	0.6394 (2)	0.98502 (17)	0.23114 (6)	0.0241 (4)*
H19b	0.7132 (2)	0.85029 (17)	0.21397 (6)	0.0241 (4)*
H17a	0.3542 (2)	0.75760 (15)	0.14766 (6)	0.0200 (4)*
H17b	0.5624 (2)	0.72015 (15)	0.13731 (6)	0.0200 (4)*
H51a	0.6029 (3)	1.2246 (2)	0.21937 (16)	0.0790 (13)*
H51b	0.3937 (3)	1.2411 (2)	0.20388 (16)	0.0790 (13)*
H50a	0.5848 (3)	1.3096 (2)	0.14522 (12)	0.0624 (9)*
H50b	0.6862 (3)	1.4039 (2)	0.18809 (12)	0.0624 (9)*
H48a	0.5264 (3)	1.57203 (18)	0.22824 (8)	0.0368 (5)*
H48b	0.3191 (3)	1.59031 (18)	0.21165 (8)	0.0368 (5)*
H47a	0.3266 (4)	1.5066 (2)	0.28695 (8)	0.0492 (7)*
H47b	0.2293 (4)	1.4100 (2)	0.24391 (8)	0.0492 (7)*
H25a	0.3457 (2)	1.01179 (18)	0.26592 (7)	0.0261 (4)*
H25b	0.2441 (2)	0.92391 (18)	0.22096 (7)	0.0261 (4)*
H24a	0.1347 (3)	0.7952 (2)	0.27685 (7)	0.0315 (5)*
H24b	0.0722 (3)	0.9331 (2)	0.29441 (7)	0.0315 (5)*
H21a	0.6601 (3)	0.7895 (2)	0.29224 (7)	0.0328 (5)*
H21b	0.6033 (3)	0.9286 (2)	0.31014 (7)	0.0328 (5)*
H22a	0.4827 (3)	0.8003 (2)	0.36446 (8)	0.0412 (6)*
H22b	0.3806 (3)	0.7159 (2)	0.31860 (8)	0.0412 (6)*
H31	0.3147 (2)	1.01745 (16)	0.41656 (6)	0.0215 (4)*
H34	0.3007 (2)	1.23759 (16)	0.57869 (6)	0.0209 (4)*
H28	0.1145 (3)	0.85808 (17)	0.59625 (7)	0.0265 (4)*
H42	0.2007 (2)	0.61328 (17)	0.48637 (7)	0.0251 (4)*
H38	0.0096 (2)	0.71731 (17)	0.35710 (7)	0.0238 (4)*
H41	0.1229 (2)	0.40868 (17)	0.45519 (7)	0.0266 (4)*
H12	0.0784 (2)	0.31574 (15)	0.15873 (6)	0.0202 (4)*
H15	0.1216 (2)	−0.06627 (16)	0.05863 (7)	0.0255 (4)*
H16	0.2124 (2)	0.11309 (16)	0.02728 (7)	0.0236 (4)*
H5	0.3552 (2)	0.57269 (15)	0.09337 (6)	0.0172 (4)*
H2	0.0956 (2)	0.27380 (16)	−0.08041 (7)	0.0231 (4)*
H8	0.2664 (2)	0.66830 (16)	−0.06948 (6)	0.0192 (4)*
H26a	0.4405 (14)	0.8443 (9)	−0.07720 (12)	0.0303 (5)*
H26b	0.2356 (5)	0.8777 (12)	−0.0624 (2)	0.0303 (5)*
H26c	0.3955 (18)	0.9798 (3)	−0.05094 (14)	0.0303 (5)*
H52a	0.4465 (19)	1.5266 (4)	0.55722 (15)	0.0363 (6)*
H52b	0.2773 (4)	1.4427 (11)	0.5696 (3)	0.0363 (6)*
H52c	0.4806 (16)	1.4071 (8)	0.58334 (14)	0.0363 (6)*
H53a	0.0088 (17)	0.7024 (2)	0.1762 (4)	0.0453 (7)*
H53b	−0.1826 (4)	0.6358 (8)	0.1839 (4)	0.0453 (7)*
H53c	−0.0121 (19)	0.6199 (7)	0.22002 (11)	0.0453 (7)*
H45c	0.3260 (5)	1.2424 (3)	0.29144 (13)	0.0234 (8)*	0.495980
H45d	0.5027 (5)	1.1844 (3)	0.26593 (13)	0.0234 (8)*	0.495980
H44c	0.5667 (5)	1.3295 (4)	0.35098 (14)	0.0228 (8)*	0.488990
H44d	0.6485 (5)	1.2010 (4)	0.32908 (14)	0.0228 (8)*	0.488990
H4	0.2606 (2)	0.40043 (13)	0.09983 (5)	0.0226 (4)*
H30	0.2007 (2)	0.84941 (14)	0.41285 (6)	0.0235 (4)*
H54	−0.055 (3)	0.5217 (14)	0.1260 (4)	0.0461 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0323 (6)	0.0132 (5)	0.0347 (6)	−0.0052 (4)	−0.0028 (5)	0.0094 (4)
O23	0.0310 (7)	0.0295 (7)	0.0149 (6)	−0.0037 (6)	0.0012 (5)	0.0034 (5)
Cl1	0.0246 (2)	0.0237 (2)	0.0233 (2)	−0.00247 (16)	0.00430 (16)	0.00959 (17)
C8	0.0158 (7)	0.0197 (8)	0.0130 (7)	−0.0017 (6)	0.0002 (6)	0.0041 (6)
O7	0.0254 (6)	0.0143 (6)	0.0139 (6)	−0.0032 (5)	−0.0020 (5)	0.0043 (4)
O33	0.0237 (6)	0.0179 (6)	0.0250 (7)	−0.0052 (5)	0.0006 (5)	0.0071 (5)
O32	0.0254 (7)	0.0274 (7)	0.0232 (7)	−0.0034 (5)	0.0033 (5)	0.0142 (5)
Cl2	0.0556 (3)	0.0333 (3)	0.0275 (3)	−0.0212 (2)	−0.0161 (2)	0.0079 (2)
O6	0.0247 (6)	0.0137 (5)	0.0114 (5)	−0.0046 (5)	−0.0012 (4)	0.0008 (4)
C19	0.0210 (8)	0.0215 (9)	0.0165 (8)	−0.0026 (7)	−0.0017 (6)	−0.0010 (6)
N20	0.0241 (7)	0.0171 (7)	0.0129 (6)	−0.0010 (6)	−0.0024 (5)	0.0017 (5)
C34	0.0158 (7)	0.0200 (8)	0.0168 (8)	−0.0008 (6)	−0.0007 (6)	0.0042 (6)
C35	0.0154 (7)	0.0197 (8)	0.0162 (8)	0.0001 (6)	−0.0011 (6)	0.0062 (6)
C37	0.0150 (7)	0.0187 (8)	0.0189 (8)	−0.0003 (6)	0.0026 (6)	0.0033 (6)
C38	0.0193 (8)	0.0230 (9)	0.0184 (8)	−0.0037 (7)	0.0023 (6)	0.0078 (7)
F2	0.0433 (7)	0.0194 (6)	0.0338 (7)	−0.0096 (5)	0.0005 (5)	0.0035 (5)
O49	0.0431 (9)	0.0376 (8)	0.0159 (6)	−0.0074 (7)	0.0007 (6)	0.0052 (6)
C14	0.0169 (8)	0.0120 (7)	0.0293 (9)	−0.0016 (6)	−0.0026 (7)	0.0077 (7)
C15	0.0227 (8)	0.0127 (8)	0.0277 (9)	0.0014 (6)	−0.0016 (7)	0.0006 (7)
C16	0.0212 (8)	0.0164 (8)	0.0213 (8)	0.0014 (6)	0.0027 (7)	0.0017 (6)
C11	0.0158 (7)	0.0144 (7)	0.0196 (8)	−0.0024 (6)	−0.0007 (6)	0.0041 (6)
N4	0.0268 (8)	0.0132 (7)	0.0159 (7)	−0.0068 (6)	0.0003 (6)	0.0015 (5)
C4	0.0144 (7)	0.0151 (7)	0.0162 (8)	−0.0008 (6)	0.0026 (6)	0.0014 (6)
C10	0.0122 (7)	0.0136 (7)	0.0146 (7)	−0.0011 (5)	0.0019 (6)	0.0013 (6)
C5	0.0165 (7)	0.0149 (7)	0.0115 (7)	−0.0005 (6)	0.0006 (6)	0.0013 (6)
C6	0.0142 (7)	0.0147 (7)	0.0113 (7)	−0.0011 (6)	0.0009 (5)	0.0000 (6)
C17	0.0224 (8)	0.0159 (8)	0.0117 (7)	−0.0021 (6)	−0.0008 (6)	0.0023 (6)
C18	0.0230 (8)	0.0176 (8)	0.0137 (7)	−0.0035 (6)	0.0004 (6)	0.0007 (6)
C21	0.0295 (10)	0.0364 (11)	0.0165 (8)	0.0066 (8)	−0.0037 (7)	0.0050 (8)
C22	0.0452 (13)	0.0400 (12)	0.0209 (10)	0.0088 (10)	0.0018 (9)	0.0134 (9)
C13	0.0138 (7)	0.0182 (8)	0.0196 (8)	−0.0004 (6)	−0.0003 (6)	0.0060 (6)
C12	0.0176 (8)	0.0134 (7)	0.0196 (8)	−0.0017 (6)	−0.0009 (6)	0.0026 (6)
C9	0.0130 (7)	0.0160 (7)	0.0141 (7)	−0.0010 (6)	0.0003 (6)	−0.0001 (6)
C7	0.0137 (7)	0.0144 (7)	0.0157 (7)	−0.0005 (6)	0.0018 (6)	0.0034 (6)
C26	0.0254 (9)	0.0198 (8)	0.0168 (8)	−0.0039 (7)	−0.0025 (7)	0.0083 (6)
C25	0.0229 (9)	0.0261 (9)	0.0174 (8)	0.0013 (7)	0.0006 (7)	0.0069 (7)
C24	0.0260 (9)	0.0353 (11)	0.0174 (9)	−0.0058 (8)	−0.0012 (7)	0.0044 (8)
N1	0.0188 (7)	0.0197 (7)	0.0143 (7)	−0.0035 (5)	−0.0014 (5)	−0.0003 (5)
C2	0.0195 (8)	0.0188 (8)	0.0179 (8)	−0.0034 (6)	−0.0013 (6)	−0.0020 (6)
N3	0.0188 (7)	0.0169 (7)	0.0169 (7)	−0.0031 (5)	0.0010 (5)	0.0006 (5)
C52	0.0250 (9)	0.0183 (8)	0.0287 (10)	−0.0040 (7)	0.0050 (7)	0.0012 (7)
C33	0.0137 (7)	0.0176 (8)	0.0233 (9)	−0.0003 (6)	−0.0011 (6)	0.0072 (6)
C36	0.0151 (7)	0.0185 (8)	0.0160 (8)	0.0000 (6)	−0.0005 (6)	0.0054 (6)
C30	0.0149 (7)	0.0184 (8)	0.0177 (8)	0.0005 (6)	−0.0002 (6)	0.0046 (6)
N30	0.0241 (7)	0.0185 (7)	0.0166 (7)	−0.0025 (6)	0.0000 (6)	0.0044 (6)
C39	0.0214 (8)	0.0261 (9)	0.0181 (8)	−0.0076 (7)	0.0017 (7)	0.0041 (7)
C40	0.0217 (9)	0.0188 (8)	0.0263 (9)	−0.0038 (7)	0.0055 (7)	0.0030 (7)
N27	0.0244 (8)	0.0219 (7)	0.0166 (7)	−0.0033 (6)	0.0001 (6)	0.0071 (6)
C28	0.0270 (9)	0.0225 (9)	0.0183 (8)	−0.0035 (7)	0.0015 (7)	0.0087 (7)
N29	0.0224 (7)	0.0195 (7)	0.0186 (7)	−0.0015 (6)	0.0006 (6)	0.0061 (6)
C31	0.0179 (8)	0.0216 (8)	0.0152 (8)	0.0007 (6)	0.0003 (6)	0.0061 (6)
C32	0.0152 (7)	0.0221 (8)	0.0192 (8)	−0.0003 (6)	0.0012 (6)	0.0104 (7)
C43	0.0392 (12)	0.0720 (17)	0.0157 (9)	−0.0338 (12)	−0.0060 (8)	0.0159 (10)
C41	0.0221 (9)	0.0202 (9)	0.0259 (9)	0.0052 (7)	0.0035 (7)	0.0081 (7)
C42	0.0203 (8)	0.0219 (9)	0.0212 (9)	0.0031 (7)	−0.0006 (7)	0.0049 (7)
C48	0.0461 (12)	0.0188 (9)	0.0274 (10)	−0.0002 (8)	0.0010 (9)	0.0049 (8)
C47	0.0528 (14)	0.0506 (14)	0.0179 (10)	−0.0215 (11)	0.0058 (9)	0.0019 (9)
N46	0.0540 (13)	0.0650 (15)	0.0710 (16)	−0.0449 (12)	−0.0445 (12)	0.0580 (14)
C51	0.0270 (12)	0.0227 (11)	0.150 (3)	−0.0041 (9)	−0.0333 (16)	0.0259 (16)
C50	0.0279 (11)	0.0394 (14)	0.080 (2)	−0.0029 (10)	0.0129 (12)	−0.0222 (13)
O54	0.0440 (9)	0.0219 (7)	0.0251 (7)	0.0080 (6)	−0.0126 (6)	0.0000 (5)
C53	0.0449 (12)	0.0226 (10)	0.0224 (9)	−0.0004 (8)	−0.0025 (8)	0.0015 (7)
C45B	0.0201 (16)	0.0206 (17)	0.0140 (15)	−0.0001 (13)	0.0036 (13)	0.0049 (13)
C45A	0.0278 (18)	0.0173 (16)	0.0136 (15)	−0.0029 (14)	0.0018 (14)	0.0034 (13)
C44B	0.033 (2)	0.0254 (19)	0.0179 (17)	−0.0136 (16)	0.0013 (15)	0.0048 (14)
C44A	0.0211 (18)	0.0182 (19)	0.0186 (18)	−0.0033 (15)	0.0024 (14)	0.0056 (15)

Geometric parameters (Å, º)

F1—C14	1.3596 (19)	C26—H26a	0.9800
O23—C22	1.429 (3)	C26—H26b	0.9800
O23—C24	1.425 (2)	C26—H26c	0.9800
Cl1—C13	1.7348 (18)	C25—C24	1.517 (3)
C8—C9	1.412 (2)	C25—H25a	0.9900
C8—C7	1.370 (2)	C25—H25b	0.9900
C8—H8	0.9500	C24—H24a	0.9900
O7—C7	1.358 (2)	C24—H24b	0.9900
O7—C26	1.434 (2)	N1—C2	1.315 (2)
O33—C52	1.431 (2)	C2—N3	1.343 (2)
O33—C33	1.357 (2)	C2—H2	0.9500
O32—C32	1.368 (2)	C52—H52a	0.9800
O32—C43	1.423 (3)	C52—H52b	0.9800
Cl2—C39	1.7258 (19)	C52—H52c	0.9800
O6—C6	1.3623 (19)	C33—C32	1.425 (3)
O6—C17	1.436 (2)	C36—C30	1.434 (2)
C19—N20	1.469 (2)	C36—C31	1.425 (2)
C19—C18	1.523 (2)	C30—N30	1.372 (2)
C19—H19a	0.9900	C30—N29	1.327 (2)
C19—H19b	0.9900	N30—H30	0.8800
N20—C21	1.466 (2)	C39—C40	1.383 (3)
N20—C25	1.461 (2)	C40—C41	1.370 (3)
C34—C35	1.413 (2)	N27—C28	1.311 (2)
C34—C33	1.374 (2)	C28—N29	1.353 (2)
C34—H34	0.9500	C28—H28	0.9500
C35—C36	1.407 (2)	C31—C32	1.371 (2)
C35—N27	1.379 (2)	C31—H31	0.9500
C37—C38	1.397 (2)	C43—C44B	1.640 (4)
C37—N30	1.405 (2)	C43—C44A	1.474 (4)
C37—C42	1.403 (2)	C43—H43a	0.9900
C38—C39	1.384 (3)	C43—H43b	0.9900
C38—H38	0.9500	C43—H43c	0.9900
F2—C40	1.357 (2)	C43—H43d	0.9900
O49—C48	1.413 (3)	C41—C42	1.388 (3)
O49—C50	1.413 (3)	C41—H41	0.9500
C14—C15	1.374 (3)	C42—H42	0.9500
C14—C13	1.385 (2)	C48—C47	1.506 (3)
C15—C16	1.391 (2)	C48—H48a	0.9900
C15—H15	0.9500	C48—H48b	0.9900
C16—C11	1.401 (2)	C47—N46	1.449 (4)
C16—H16	0.9500	C47—H47a	0.9900
C11—N4	1.414 (2)	C47—H47b	0.9900
C11—C12	1.396 (2)	N46—C51	1.450 (5)
N4—C4	1.362 (2)	N46—C45B	1.616 (4)
N4—H4	0.8800	N46—C45A	1.466 (4)
C4—C10	1.438 (2)	C51—C50	1.485 (5)
C4—N3	1.331 (2)	C51—H51a	0.9900
C10—C5	1.420 (2)	C51—H51b	0.9900
C10—C9	1.405 (2)	C50—H50a	0.9900
C5—C6	1.372 (2)	C50—H50b	0.9900
C5—H5	0.9500	O54—C53	1.402 (2)
C6—C7	1.433 (2)	O54—H54	0.8400
C17—C18	1.514 (2)	C53—H53a	0.9800
C17—H17a	0.9900	C53—H53b	0.9800
C17—H17b	0.9900	C53—H53c	0.9800
C18—H18a	0.9900	C45B—C44B	1.085 (5)
C18—H18b	0.9900	C45B—H45a	0.9900
C21—C22	1.511 (3)	C45B—H45b	0.9900
C21—H21a	0.9900	C45A—C44A	1.374 (5)
C21—H21b	0.9900	C45A—H45c	0.9900
C22—H22a	0.9900	C45A—H45d	0.9900
C22—H22b	0.9900	C44B—H44a	0.9900
C13—C12	1.387 (2)	C44B—H44b	0.9900
C12—H12	0.9500	C44A—H44c	0.9900
C9—N1	1.380 (2)	C44A—H44d	0.9900
C24—O23—C22	109.32 (15)	H25b—C25—H25a	108.0
C7—C8—C9	120.14 (15)	C25—C24—O23	111.26 (15)
H8—C8—C9	119.93 (9)	H24a—C24—O23	109.38 (10)
H8—C8—C7	119.93 (9)	H24a—C24—C25	109.38 (11)
C26—O7—C7	117.38 (13)	H24b—C24—O23	109.38 (10)
C33—O33—C52	117.03 (14)	H24b—C24—C25	109.38 (11)
C43—O32—C32	116.50 (15)	H24b—C24—H24a	108.0
C17—O6—C6	117.85 (12)	C2—N1—C9	115.49 (14)
C18—C19—N20	114.98 (14)	N3—C2—N1	128.65 (16)
H19a—C19—N20	108.52 (9)	H2—C2—N1	115.67 (10)
H19a—C19—C18	108.52 (9)	H2—C2—N3	115.67 (10)
H19b—C19—N20	108.52 (9)	C2—N3—C4	116.47 (15)
H19b—C19—C18	108.52 (10)	H52a—C52—O33	109.5
H19b—C19—H19a	107.5	H52b—C52—O33	109.5
C21—N20—C19	108.57 (14)	H52b—C52—H52a	109.5
C25—N20—C19	111.49 (14)	H52c—C52—O33	109.5
C25—N20—C21	108.98 (14)	H52c—C52—H52a	109.5
C33—C34—C35	120.53 (16)	H52c—C52—H52b	109.5
H34—C34—C35	119.73 (10)	C34—C33—O33	124.84 (16)
H34—C34—C33	119.73 (11)	C32—C33—O33	115.04 (15)
C36—C35—C34	119.47 (15)	C32—C33—C34	120.12 (16)
N27—C35—C34	118.26 (16)	C30—C36—C35	115.65 (15)
N27—C35—C36	122.27 (15)	C31—C36—C35	119.50 (15)
N30—C37—C38	116.29 (15)	C31—C36—C30	124.85 (16)
C42—C37—C38	119.39 (16)	N30—C30—C36	118.59 (15)
C42—C37—N30	124.25 (16)	N29—C30—C36	121.95 (16)
C39—C38—C37	120.06 (16)	N29—C30—N30	119.45 (15)
H38—C38—C37	119.97 (10)	C30—N30—C37	128.34 (15)
H38—C38—C39	119.97 (10)	H30—N30—C37	115.83 (9)
C50—O49—C48	109.44 (18)	H30—N30—C30	115.83 (9)
C15—C14—F1	119.71 (16)	C38—C39—Cl2	120.47 (14)
C13—C14—F1	119.18 (16)	C40—C39—Cl2	119.75 (14)
C13—C14—C15	121.10 (16)	C40—C39—C38	119.67 (17)
C16—C15—C14	119.97 (17)	C39—C40—F2	119.03 (17)
H15—C15—C14	120.01 (10)	C41—C40—F2	119.83 (16)
H15—C15—C16	120.01 (11)	C41—C40—C39	121.13 (17)
C11—C16—C15	119.56 (17)	C28—N27—C35	114.94 (16)
H16—C16—C15	120.22 (11)	N29—C28—N27	128.91 (16)
H16—C16—C11	120.22 (10)	H28—C28—N27	115.54 (10)
N4—C11—C16	124.06 (16)	H28—C28—N29	115.54 (10)
C12—C11—C16	119.76 (15)	C28—N29—C30	116.16 (15)
C12—C11—N4	116.08 (15)	C32—C31—C36	120.18 (16)
C4—N4—C11	127.56 (15)	H31—C31—C36	119.91 (10)
H4—N4—C11	116.22 (9)	H31—C31—C32	119.91 (10)
H4—N4—C4	116.22 (9)	C33—C32—O32	114.66 (15)
C10—C4—N4	119.81 (15)	C31—C32—O32	125.17 (16)
N3—C4—N4	118.59 (15)	C31—C32—C33	120.17 (15)
N3—C4—C10	121.59 (15)	H43a—C43—C44B	112.09 (19)
C5—C10—C4	124.66 (15)	H43b—C43—C44B	112.09 (15)
C9—C10—C4	115.99 (14)	H43b—C43—H43a	109.7
C9—C10—C5	119.33 (14)	H43c—C43—C44A	107.5 (2)
C6—C5—C10	119.75 (14)	H43d—C43—C44A	107.54 (17)
H5—C5—C10	120.13 (9)	H43d—C43—H43c	107.0
H5—C5—C6	120.13 (9)	C42—C41—C40	119.96 (17)
C5—C6—O6	125.61 (14)	H41—C41—C40	120.02 (11)
C7—C6—O6	113.67 (14)	H41—C41—C42	120.02 (11)
C7—C6—C5	120.72 (14)	C41—C42—C37	119.72 (17)
C18—C17—O6	105.43 (13)	H42—C42—C37	120.14 (10)
H17a—C17—O6	110.66 (8)	H42—C42—C41	120.14 (11)
H17a—C17—C18	110.66 (9)	C47—C48—O49	111.08 (17)
H17b—C17—O6	110.66 (9)	H48a—C48—O49	109.42 (11)
H17b—C17—C18	110.66 (9)	H48a—C48—C47	109.42 (13)
H17b—C17—H17a	108.8	H48b—C48—O49	109.42 (11)
C17—C18—C19	113.60 (14)	H48b—C48—C47	109.42 (14)
H18a—C18—C19	108.84 (10)	H48b—C48—H48a	108.0
H18a—C18—C17	108.84 (9)	N46—C47—C48	109.4 (2)
H18b—C18—C19	108.84 (9)	H47a—C47—C48	109.79 (12)
H18b—C18—C17	108.84 (9)	H47a—C47—N46	109.79 (14)
H18b—C18—H18a	107.7	H47b—C47—C48	109.79 (13)
C22—C21—N20	111.07 (17)	H47b—C47—N46	109.79 (12)
H21a—C21—N20	109.42 (10)	H47b—C47—H47a	108.2
H21a—C21—C22	109.42 (11)	C51—N46—C47	108.17 (18)
H21b—C21—N20	109.42 (10)	C50—C51—N46	110.1 (2)
H21b—C21—C22	109.42 (12)	H51a—C51—N46	109.64 (13)
H21b—C21—H21a	108.0	H51a—C51—C50	109.64 (14)
C21—C22—O23	111.42 (16)	H51b—C51—N46	109.64 (13)
H22a—C22—O23	109.34 (10)	H51b—C51—C50	109.64 (15)
H22a—C22—C21	109.34 (11)	H51b—C51—H51a	108.2
H22b—C22—O23	109.34 (11)	C51—C50—O49	112.0 (2)
H22b—C22—C21	109.34 (12)	H50a—C50—O49	109.20 (14)
H22b—C22—H22a	108.0	H50a—C50—C51	109.20 (17)
C14—C13—Cl1	120.65 (13)	H50b—C50—O49	109.20 (12)
C12—C13—Cl1	119.70 (14)	H50b—C50—C51	109.20 (15)
C12—C13—C14	119.64 (16)	H50b—C50—H50a	107.9
C13—C12—C11	119.93 (16)	H54—O54—C53	109.5
H12—C12—C11	120.03 (10)	H53a—C53—O54	109.5
H12—C12—C13	120.03 (10)	H53b—C53—O54	109.5
C10—C9—C8	120.31 (15)	H53b—C53—H53a	109.5
N1—C9—C8	118.02 (14)	H53c—C53—O54	109.5
N1—C9—C10	121.67 (15)	H53c—C53—H53a	109.5
O7—C7—C8	125.62 (15)	H53c—C53—H53b	109.5
C6—C7—C8	119.73 (15)	H45a—C45B—C44B	106.9 (3)
C6—C7—O7	114.65 (14)	H45b—C45B—C44B	106.9 (3)
H26a—C26—O7	109.5	H45b—C45B—H45a	106.7
H26b—C26—O7	109.5	H45c—C45A—C44A	106.0 (2)
H26b—C26—H26a	109.5	H45d—C45A—C44A	106.0 (3)
H26c—C26—O7	109.5	H45d—C45A—H45c	106.3
H26c—C26—H26a	109.5	H44a—C44B—C45B	106.6 (3)
H26c—C26—H26b	109.5	H44b—C44B—C45B	106.6 (3)
C24—C25—N20	111.22 (15)	H44b—C44B—H44a	106.5
H25a—C25—N20	109.39 (9)	H44c—C44A—C45A	106.4 (2)
H25a—C25—C24	109.39 (11)	H44d—C44A—C45A	106.4 (2)
H25b—C25—N20	109.39 (9)	H44d—C44A—H44c	106.5
H25b—C25—C24	109.39 (10)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O54—H54···N1^i	0.84	1.94	2.7620 (8)	166
C16—H16···N3	0.95	2.40	2.8888 (9)	112
N4—H4···O49^ii	0.88	2.29	3.0898 (3)	151
C12—H12···O54	0.95	2.40	3.1998 (9)	141
C52—H52A···O33^iii	0.98	2.52	3.2749 (10)	165
C52—H52A···O32^iii	0.98	2.59	3.5418 (10)	134
N30—H30···O23	0.88	2.17	3.0046 (9)	159
C28—H28···F2^iv	0.95	2.42	3.2716 (10)	150
C31—H31···O23	0.95	2.46	3.3932 (10)	168
C42—H42···N29	0.95	2.44	2.9382 (9)	113
C38—H38···O23	0.95	2.67	3.272 (10)	122
C53—H53A···F1^v	0.98	2.59	3.484 (10)	152
C53—H53C···Cl2	0.98	2.92	3.723 (10)	140

Symmetry codes: (i) −x, −y+1, −z; (ii) x, y−1, z; (iii) −x+1, −y+3, −z+1; (iv) −x, −y+1, −z+1; (v) x, y+1, z.