Crystal structure of idelalisib tert-butanol monosolvate dihydrate

Nerdinger, S.; Stefinovic, M.; Richter, F.; Olma, J.; Brysz, M.; Walker, T.; Kahlenberg, V.; Gelbrich, T.

doi:10.1107/S2056989019002743

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ISSN: 2056-9890

Volume 75| Part 3| March 2019| Pages 414-417

https://doi.org/10.1107/S2056989019002743

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Crystal structure of idelalisib tert-butanol monosolvate dihydrate

Sven Nerdinger,^a Marijan Stefinovic,^a Frank Richter,^a Jacek Olma,^b Michal Brysz,^b Tracy Walker,^c Volker Kahlenberg ^d and Thomas Gelbrich ^e ^*

^aSandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria, ^bSelvita S.A., Park Life Science, Bobrzynskiego 14, 30-348 Kraków, Poland, ^cAlmac Group, Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom, ^dUniversity of Innsbruck, Institute of Mineralogy and Petrography, Innrain 52, 6020 Innsbruck, Austria, and ^eUniversity of Innsbruck, Institute of Pharmacy, Innrain 52, 6020 Innsbruck, Austria
^*Correspondence e-mail: thomas.gelbrich@uibk.ac.at

Edited by M. Weil, Vienna University of Technology, Austria (Received 11 February 2019; accepted 22 February 2019; online 28 February 2019)

In the title structure, 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one (= idelalisib) tert-butanol monosolvate dihydrate, C₂₂H₁₈FN₇O·C₄H₁₀O·2H₂O, the idelalisib molecule displays planar quinazoline and purine systems which are nearly perpendicular to one another. Seven distinct hydrogen-bonding interactions link the idelalisib, t-BuOH and water molecules into a complex chain structure with the topology of a 2,3,4,5-connected 4-nodal net having the point symbol (3.4.5².6²)(3.4.5².6⁴.7²)(3.5.6)(5).

Keywords: crystal structure; hydrogen bonding; hydrate; solvate; pharmaceuticals.

CCDC reference: 1898812

1. Chemical context

Idelalisib is a novel, orally available small-molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta). This compound was developed for the oral treatment of chronic lymphocytic leukemia and is currently marketed under the trade name Zydelig by Gilead Sciences, Inc. Carra et al. (2013 ) reported the existence of seven solid forms of idelalisib and unit-cell parameters for five of these, namely for two polymorphs, an i-PrOH solvate hydrate, a DMF and a DMSO solvate. The current study is part of an investigation of a modified synthetic route for idelalisib, which ultimately resulted in improved yields compared to the original synthesis by Kesicki & Zhichkin (2005 ).

2. Structural commentary

The asymmetric unit of the title compound, (I), contains one formula unit, i.e. a molecule each of idelalisib and of t-BuOH as well as two water molecules, denoted as w1 (O37) and w2 (O38) (Fig. 1). The conformation of the idelalisib molecule can be described in terms of the relative orientations adopted by the three planar fragments of the quinazoline group N1>C10, the phenyl ring C11>C16, and the purine group C20 >C28. The mean planes of the phenyl and purine units both lie approximately perpendicular to the quinazoline mean plane and form dihedral angles of 88.10 (8) and 86.97 (6)°, respectively, with the latter. The dihedral angle between the phenyl and purine mean planes is 73.75 (7)°. The torsion angles around the C30—C18 bond are C31—C30—C18—C6 = 165.5 (2)° (propyl group) and C31—C30—C18—N19 = −71.6 (3)°.

Figure 1
Asymmetric unit of (I)

with displacement ellipsoids drawn at the 50% probability level and hydrogen atoms as spheres of arbitrary size.

3. Supramolecular features

The endocyclic NH group of the purine unit donates a hydrogen bond to the t-BuOH molecule, via N25—H25⋯O36(−x + 1, y + 1, −z + 2). Additionally, the secondary amino function attached to the pyrimidine ring of the purine fragment donates a hydrogen bond to a w2 water molecule, via N19—H19⋯O38. In turn, the idelalisib molecule accepts three hydrogen bonds. Its quinazoline group is linked to the w1 water molecule via an O37—H37A⋯N5 bond, and additionally each of N23 and N27 of the purine group is hydrogen-bonded to a water molecule of type w2 [O38—H38A⋯N23(x, y − 1, z)] or w1 [O37—H37B⋯N27(−x + 1, y, −z + 2)]. Moreover, the water molecule w1 is an acceptor for two H-bonds, O36—H36⋯O37 from a t-BuOH molecule and O38—H38B⋯O37 from a w2-type water molecule. There are no hydrogen bonds between neighbouring idelalisib molecules. Overall, the seven classical hydrogen-bonding interactions listed in Table 1 result in a chain that possesses a central twofold rotational axis and propagates parallel to the b axis (Fig. 2). Each idelalisib molecule represents a five-connected node within this hydrogen-bonded chain structure and is linked to one t-BuOH, two w1 and two w2 molecules. The t-BuOH molecule is a two-connected node and serves as a bridge between an idelalisib and a w1 molecule. The water molecule w1 is four-connected (2 × idelalisib, 1 × t-BuOH, 1 × w2), whilst w2 serves as a three-connected node (2 × idelalisib, 1 × w1). The hydrogen-bonded chain of (I) has the topology of the 2,3,4,5-connected 4-nodal 1D net depicted in Fig. 3, which has the point symbol (3.4.5².6²)(3.4.5².6⁴.7²)(3.5.6)(5). The topology of the hydrogen-bonded structure was determined and classified with the programs ADS and IsoTest of the TOPOS package (Blatov, 2006 ) in the manner described by Baburin & Blatov (2007 ).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N19—H19⋯O38	0.88 (2)	2.09 (2)	2.963 (3)	170 (3)
N25—H25⋯O36ⁱ	0.87 (2)	1.88 (2)	2.750 (3)	173 (4)
O36—H36⋯O37	0.82 (3)	1.92 (3)	2.741 (3)	174 (5)
O37—H37A⋯N5	0.86 (2)	2.09 (2)	2.939 (3)	172 (3)
O37—H37B⋯N27ⁱⁱ	0.90 (2)	2.06 (3)	2.888 (3)	153 (4)
O38—H38A⋯N23ⁱⁱⁱ	0.87 (2)	2.04 (2)	2.905 (3)	172 (3)
O38—H38B⋯O37	0.88 (2)	2.09 (3)	2.921 (4)	158 (4)
Symmetry codes: (i) -x+1, y+1, -z+2; (ii) -x+1, y, -z+2; (iii) x, y-1, z.

Figure 2
Hydrogen-bonded chain structure of (I)

, viewed along the a axis. H, N and O atoms directly engaged in hydrogen bonding are drawn as spheres. All other H atoms are omitted for clarity.

Figure 3
2,3,4,5-Connected 4-nodal topological net representing the hydrogen-bonded chain structure of (I)

which is based on the seven intermolecular interactions listed in Table 1

4. Database survey

The most recent version 5.40 (November 2018) of the Cambridge Structural Database (Groom et al., 2016 ) does not contain any data for solid forms of idelalisib.

The bond parameters of the quinazoline system are in agreement with the relevant features in two polymorphs of 3-phenylquinazolin-4(3H)-one (Zhou et al., 2008 ; Yu et al., 2018 ), in 2-[2-(4-nitrophenyl)vinyl]-3-phenylquinazolin-4(3H)-one (Nosova et al., 2012 ) and 2-diethylamino-3-phenylquinazolin-4(3H)-one (Xie & Li, 2006 ). Likewise, the structural parameters of the purine skeleton are consistent with the relevant reference structures such as 1- and 7-(β-D-ribofuranosyl)adenine (Framski et al., 2006 ).

5. Synthesis and crystallization

The preparation of idelalisib was carried out according to the scheme displayed in Fig. 4, which represents a modification of the original synthesis by Kesicki & Zhichkin (2005), and yielded the polymorphic form I described by Carra et al. (2013). To amorphous idelalisib (180 mg), which was obtained by lyophilization of form I in dioxane, were added 500 µL of t-BuOH/water 95:5 (v/v) at 296 K. The amorphous material was dissolved. Precipitation of solid material was observed after 5 min of stirring of the solution. The suspension was then stirred at 296 K for five days, which was followed by centrifugation and separation of the precipitate. Subsequent drying of the solid material yielded the title compound (I) as a crystalline, free-flowing white powder (120 mg, 55%).

Figure 4
Synthetic scheme for the preparation of idelalisib.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were identified in Fourier-difference maps. Methyl H atoms were idealized (C—H = 0.98 Å) and included as rigid groups allowed to rotate but not to tip and were refined with U_iso(H) = 1.5U_eq(C) of the parent carbon atom. All other hydrogen atoms bonded to carbon atoms were positioned geometrically (C—H = 0.95 Å) and refined with U_iso(H) = 1.5U_eq(C) of the parent carbon atom. Hydrogen atoms of OH and NH groups were refined with restrained distances [O—H = 0.84 (1) Å; N—H = 0.88 (1) Å] and their U_iso parameters were refined freely. The absolute structure was established by anomalous-dispersion effects (Table 2).

Table 2
Experimental details

Crystal data
Chemical formula	C₂₂H₁₈FN₇O·C₄H₁₀O·2H₂O
M_r	525.58
Crystal system, space group	Monoclinic, C2
Temperature (K)	173
a, b, c (Å)	21.3758 (6), 9.2781 (3), 13.9722 (5)
β (°)	102.654 (3)
V (Å³)	2703.75 (15)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.09
Crystal size (mm)	0.34 × 0.26 × 0.18

Data collection
Diffractometer	Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini ultra
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2015 $[Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.835, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	8990, 5111, 4751
R_int	0.020
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.039, 0.098, 1.07
No. of reflections	5111
No. of parameters	375
No. of restraints	10
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.27, −0.18
Absolute structure	Flack x determined using 1997 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−0.1 (4)
Computer programs: CrysAlis PRO (Rigaku OD, 2015 $[Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SIR2002 (Burla et al., 2003 ), SHELXL2014 (Sheldrick, 2015 ), XP (Bruker, 1998 ), Mercury (Macrae et al., 2006 ), TOPOS (Blatov, 2006), PLATON (Spek, 2009 ) and publCIF (Westrip, 2010 ).

The largest residual peak of 0.73 e Å⁻³ is located 1.00 Å from C30. An alternative refinement of a disorder model with a split C30 position was attempted but resulted in a few unreasonably short intramolecular H⋯H distances for the minor disorder fragment. This feature could not be eliminated even with the application of an anti-bumping restraint.

Supporting information

CCDC reference: 1898812

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989019002743/wm5487sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989019002743/wm5487Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989019002743/wm5487Isup3.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: SIR2002 (Burla et al., 2003); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: XP (Bruker, 1998), Mercury (Macrae et al., 2006) and TOPOS (Blatov, 2006); software used to prepare material for publication: PLATON (Spek, 2009), publCIF (Westrip, 2010) and TOPOS (Blatov, 2006).

5-Fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one tert-butanol monosolvate dihydrate top

Crystal data top

C₂₂H₁₈FN₇O·C₄H₁₀O·2H₂O	F(000) = 1112
M_r = 525.58	D_x = 1.291 Mg m⁻³
Monoclinic, C2	Mo Kα radiation, λ = 0.71073 Å
a = 21.3758 (6) Å	Cell parameters from 5110 reflections
b = 9.2781 (3) Å	θ = 2.7–28.3°
c = 13.9722 (5) Å	µ = 0.09 mm⁻¹
β = 102.654 (3)°	T = 173 K
V = 2703.75 (15) Å³	Irregular fragment, colourless
Z = 4	0.34 × 0.26 × 0.18 mm

Data collection top

Rigaku Oxford Diffraction Xcalibur, Ruby, Gemini ultra diffractometer	5111 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	4751 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.020
Detector resolution: 10.3575 pixels mm^-1	θ_max = 26.0°, θ_min = 2.2°
ω scans	h = −20→26
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2015)	k = −10→11
T_min = 0.835, T_max = 1.000	l = −16→12
8990 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.039	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.098	w = 1/[σ²(F_o²) + (0.0448P)² + 1.4882P] where P = (F_o² + 2F_c²)/3
S = 1.07	(Δ/σ)_max < 0.001
5111 reflections	Δρ_max = 0.27 e Å⁻³
375 parameters	Δρ_min = −0.18 e Å⁻³
10 restraints	Absolute structure: Flack x determined using 1997 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.1 (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

	x	y	z	U_iso*/U_eq
N1	0.31764 (11)	0.8629 (3)	0.59496 (16)	0.0225 (5)
C2	0.25203 (13)	0.8986 (3)	0.5816 (2)	0.0269 (6)
C3	0.22506 (13)	0.8657 (3)	0.6664 (2)	0.0238 (6)
C4	0.26486 (13)	0.8111 (3)	0.7519 (2)	0.0220 (6)
N5	0.32934 (10)	0.7807 (2)	0.75732 (16)	0.0205 (5)
C6	0.35268 (13)	0.8049 (3)	0.68133 (18)	0.0190 (5)
C7	0.16088 (14)	0.8885 (3)	0.6679 (2)	0.0301 (7)
C8	0.13634 (14)	0.8634 (4)	0.7481 (3)	0.0357 (7)
H8	0.0922	0.8796	0.7461	0.043*
C9	0.17702 (16)	0.8135 (4)	0.8331 (2)	0.0350 (7)
H9	0.1609	0.7983	0.8905	0.042*
C10	0.24025 (14)	0.7861 (3)	0.8347 (2)	0.0266 (6)
H10	0.2674	0.7498	0.8928	0.032*
C11	0.34784 (13)	0.8965 (4)	0.5149 (2)	0.0281 (7)
C12	0.35269 (15)	0.7897 (4)	0.4473 (2)	0.0367 (8)
H12	0.3343	0.6973	0.4514	0.044*
C13	0.38504 (18)	0.8210 (5)	0.3736 (3)	0.0519 (11)
H13	0.3891	0.7492	0.3269	0.062*
C14	0.4111 (2)	0.9557 (6)	0.3681 (3)	0.0635 (14)
H14	0.4335	0.9760	0.3179	0.076*
C15	0.40512 (18)	1.0609 (5)	0.4347 (3)	0.0559 (12)
H15	0.4229	1.1538	0.4297	0.067*
C16	0.37325 (15)	1.0323 (4)	0.5091 (2)	0.0395 (8)
H16	0.3690	1.1048	0.5553	0.047*
O17	0.22461 (10)	0.9541 (3)	0.50590 (16)	0.0443 (6)
C18	0.42053 (13)	0.7557 (3)	0.68211 (19)	0.0206 (6)
H18	0.4364	0.8091	0.6300	0.025*
N19	0.46407 (11)	0.7818 (3)	0.77607 (17)	0.0210 (5)
H19	0.4813 (14)	0.709 (3)	0.813 (2)	0.021 (8)*
C20	0.48111 (12)	0.9170 (3)	0.8058 (2)	0.0200 (6)
N21	0.45009 (11)	1.0276 (3)	0.75290 (17)	0.0249 (5)
C22	0.46761 (14)	1.1613 (3)	0.7819 (2)	0.0275 (7)
H22	0.4447	1.2358	0.7424	0.033*
N23	0.51255 (12)	1.2060 (3)	0.85799 (19)	0.0278 (6)
C24	0.54192 (13)	1.0929 (3)	0.9097 (2)	0.0216 (6)
N25	0.58955 (11)	1.0964 (3)	0.99228 (18)	0.0242 (5)
H25	0.6096 (17)	1.174 (3)	1.017 (3)	0.043 (11)*
C26	0.60377 (13)	0.9565 (3)	1.0169 (2)	0.0251 (6)
H26	0.6358	0.9289	1.0724	0.030*
N27	0.56911 (11)	0.8628 (3)	0.95710 (17)	0.0227 (5)
C28	0.52953 (12)	0.9492 (3)	0.88899 (19)	0.0193 (6)
F29	0.12046 (8)	0.9365 (2)	0.58583 (14)	0.0450 (5)
C30	0.41885 (13)	0.5942 (3)	0.6584 (2)	0.0233 (6)
H30A	0.4119	0.5392	0.7159	0.028*
H30B	0.3824	0.5742	0.6028	0.028*
C31	0.48062 (15)	0.5434 (4)	0.6322 (2)	0.0379 (8)
H31A	0.5164	0.5557	0.6889	0.057*
H31B	0.4887	0.6004	0.5771	0.057*
H31C	0.4766	0.4414	0.6136	0.057*
C32	0.28332 (15)	0.3199 (3)	0.8427 (2)	0.0338 (7)
C33	0.2706 (2)	0.1621 (5)	0.8256 (4)	0.0719 (15)
H33A	0.2641	0.1171	0.8862	0.108*
H33B	0.3073	0.1170	0.8060	0.108*
H33C	0.2320	0.1490	0.7736	0.108*
C34	0.23156 (19)	0.3891 (5)	0.8861 (3)	0.0569 (11)
H34A	0.2445	0.4875	0.9073	0.085*
H34B	0.2254	0.3326	0.9426	0.085*
H34C	0.1913	0.3920	0.8365	0.085*
C35	0.28984 (18)	0.3982 (5)	0.7512 (3)	0.0461 (9)
H35A	0.3226	0.3509	0.7230	0.069*
H35B	0.3024	0.4983	0.7674	0.069*
H35C	0.2487	0.3964	0.7035	0.069*
O36	0.34320 (12)	0.3280 (2)	0.91451 (19)	0.0419 (6)
H36	0.353 (2)	0.414 (3)	0.920 (3)	0.063 (14)*
O37	0.38596 (12)	0.6073 (2)	0.93073 (17)	0.0386 (6)
H37A	0.3696 (17)	0.665 (4)	0.884 (2)	0.044 (11)*
H37B	0.402 (2)	0.665 (4)	0.982 (2)	0.068 (14)*
O38	0.50757 (12)	0.5153 (2)	0.88771 (17)	0.0361 (5)
H38A	0.5126 (16)	0.424 (3)	0.877 (3)	0.040 (10)*
H38B	0.4728 (15)	0.523 (4)	0.911 (3)	0.064 (14)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0200 (11)	0.0277 (12)	0.0181 (11)	0.0050 (10)	0.0007 (9)	0.0021 (9)
C2	0.0222 (13)	0.0359 (17)	0.0212 (14)	0.0069 (13)	0.0014 (11)	0.0031 (12)
C3	0.0207 (13)	0.0223 (14)	0.0277 (15)	0.0022 (12)	0.0036 (11)	0.0008 (12)
C4	0.0228 (13)	0.0172 (13)	0.0246 (14)	−0.0006 (11)	0.0023 (11)	0.0004 (11)
N5	0.0192 (11)	0.0211 (12)	0.0193 (12)	0.0023 (9)	0.0005 (9)	0.0003 (9)
C6	0.0203 (13)	0.0168 (12)	0.0179 (13)	0.0009 (11)	0.0000 (10)	−0.0006 (10)
C7	0.0206 (14)	0.0323 (18)	0.0351 (17)	0.0040 (13)	0.0009 (12)	0.0059 (13)
C8	0.0213 (14)	0.0426 (18)	0.0464 (19)	0.0062 (14)	0.0142 (14)	0.0094 (15)
C9	0.0323 (16)	0.0390 (18)	0.0376 (18)	−0.0005 (14)	0.0160 (14)	0.0070 (15)
C10	0.0253 (15)	0.0266 (16)	0.0278 (15)	0.0023 (12)	0.0051 (12)	0.0046 (12)
C11	0.0218 (13)	0.0403 (18)	0.0208 (14)	0.0120 (13)	0.0015 (11)	0.0085 (12)
C12	0.0312 (16)	0.055 (2)	0.0221 (15)	0.0162 (16)	0.0016 (13)	0.0000 (15)
C13	0.041 (2)	0.088 (3)	0.0276 (18)	0.026 (2)	0.0085 (16)	0.0061 (19)
C14	0.041 (2)	0.116 (4)	0.039 (2)	0.022 (3)	0.0210 (17)	0.028 (3)
C15	0.043 (2)	0.073 (3)	0.052 (2)	0.002 (2)	0.0115 (18)	0.035 (2)
C16	0.0358 (17)	0.048 (2)	0.0333 (18)	0.0057 (16)	0.0041 (14)	0.0154 (16)
O17	0.0270 (11)	0.0747 (18)	0.0298 (12)	0.0214 (12)	0.0027 (9)	0.0201 (12)
C18	0.0182 (13)	0.0242 (14)	0.0175 (13)	0.0002 (11)	0.0001 (10)	0.0001 (11)
N19	0.0188 (11)	0.0201 (13)	0.0201 (12)	0.0018 (10)	−0.0045 (9)	0.0010 (9)
C20	0.0168 (12)	0.0222 (14)	0.0211 (13)	0.0005 (11)	0.0047 (10)	0.0001 (11)
N21	0.0238 (12)	0.0241 (13)	0.0250 (12)	0.0030 (11)	0.0016 (10)	0.0035 (10)
C22	0.0270 (15)	0.0233 (16)	0.0313 (16)	0.0024 (13)	0.0043 (13)	0.0059 (12)
N23	0.0283 (13)	0.0207 (13)	0.0342 (14)	−0.0003 (11)	0.0067 (11)	0.0022 (10)
C24	0.0189 (13)	0.0249 (14)	0.0217 (14)	−0.0024 (12)	0.0063 (11)	−0.0023 (12)
N25	0.0234 (12)	0.0220 (12)	0.0269 (13)	−0.0043 (11)	0.0048 (10)	−0.0050 (10)
C26	0.0212 (14)	0.0269 (16)	0.0250 (15)	−0.0026 (12)	0.0001 (11)	−0.0005 (12)
N27	0.0195 (11)	0.0233 (12)	0.0242 (12)	−0.0005 (10)	0.0024 (9)	0.0010 (9)
C28	0.0163 (12)	0.0218 (15)	0.0207 (13)	−0.0009 (11)	0.0056 (10)	0.0020 (11)
F29	0.0225 (9)	0.0661 (14)	0.0441 (11)	0.0116 (9)	0.0020 (8)	0.0223 (10)
C30	0.0204 (13)	0.0233 (14)	0.0233 (14)	0.0023 (12)	−0.0014 (11)	−0.0037 (12)
C31	0.0369 (17)	0.039 (2)	0.0394 (19)	0.0112 (15)	0.0117 (14)	−0.0049 (15)
C32	0.0291 (16)	0.0276 (17)	0.0388 (17)	0.0007 (13)	−0.0054 (13)	0.0049 (13)
C33	0.057 (3)	0.035 (2)	0.104 (4)	−0.009 (2)	−0.026 (3)	0.004 (2)
C34	0.050 (2)	0.071 (3)	0.051 (2)	0.003 (2)	0.0133 (18)	0.008 (2)
C35	0.0412 (19)	0.056 (2)	0.0387 (19)	−0.0058 (18)	0.0037 (15)	0.0013 (17)
O36	0.0383 (13)	0.0236 (13)	0.0525 (15)	−0.0013 (10)	−0.0151 (11)	0.0061 (11)
O37	0.0517 (15)	0.0267 (12)	0.0284 (12)	−0.0038 (11)	−0.0106 (11)	0.0012 (10)
O38	0.0453 (14)	0.0233 (12)	0.0370 (13)	0.0031 (11)	0.0032 (11)	0.0010 (10)

Geometric parameters (Å, º) top

N1—C6	1.382 (3)	N21—C22	1.333 (4)
N1—C2	1.413 (3)	C22—N23	1.334 (4)
N1—C11	1.443 (4)	C22—H22	0.9500
C2—O17	1.207 (3)	N23—C24	1.348 (4)
C2—C3	1.459 (4)	C24—N25	1.362 (4)
C3—C7	1.393 (4)	C24—C28	1.378 (4)
C3—C4	1.401 (4)	N25—C26	1.360 (4)
C4—C10	1.392 (4)	N25—H25	0.87 (2)
C4—N5	1.392 (4)	C26—N27	1.316 (4)
N5—C6	1.288 (4)	C26—H26	0.9500
C6—C18	1.518 (4)	N27—C28	1.382 (4)
C7—F29	1.351 (3)	C30—C31	1.520 (4)
C7—C8	1.358 (4)	C30—H30A	0.9900
C8—C9	1.388 (5)	C30—H30B	0.9900
C8—H8	0.9500	C31—H31A	0.9800
C9—C10	1.371 (4)	C31—H31B	0.9800
C9—H9	0.9500	C31—H31C	0.9800
C10—H10	0.9500	C32—O36	1.445 (4)
C11—C16	1.381 (5)	C32—C33	1.498 (5)
C11—C12	1.388 (5)	C32—C35	1.504 (5)
C12—C13	1.392 (5)	C32—C34	1.516 (5)
C12—H12	0.9500	C33—H33A	0.9800
C13—C14	1.378 (7)	C33—H33B	0.9800
C13—H13	0.9500	C33—H33C	0.9800
C14—C15	1.374 (7)	C34—H34A	0.9800
C14—H14	0.9500	C34—H34B	0.9800
C15—C16	1.389 (5)	C34—H34C	0.9800
C15—H15	0.9500	C35—H35A	0.9800
C16—H16	0.9500	C35—H35B	0.9800
C18—N19	1.454 (3)	C35—H35C	0.9800
C18—C30	1.534 (4)	O36—H36	0.82 (3)
C18—H18	1.0000	O37—H37A	0.86 (2)
N19—C20	1.346 (4)	O37—H37B	0.90 (2)
N19—H19	0.88 (2)	O38—H38A	0.87 (2)
C20—N21	1.351 (4)	O38—H38B	0.88 (2)
C20—C28	1.409 (4)

C6—N1—C2	122.6 (2)	C22—N21—C20	118.0 (2)
C6—N1—C11	120.8 (2)	N21—C22—N23	129.6 (3)
C2—N1—C11	116.5 (2)	N21—C22—H22	115.2
O17—C2—N1	119.6 (3)	N23—C22—H22	115.2
O17—C2—C3	126.8 (3)	C22—N23—C24	110.8 (2)
N1—C2—C3	113.6 (2)	N23—C24—N25	127.6 (3)
C7—C3—C4	117.3 (3)	N23—C24—C28	126.5 (3)
C7—C3—C2	123.1 (3)	N25—C24—C28	105.9 (2)
C4—C3—C2	119.6 (2)	C26—N25—C24	106.0 (2)
C10—C4—N5	118.1 (2)	C26—N25—H25	129 (2)
C10—C4—C3	120.0 (3)	C24—N25—H25	125 (2)
N5—C4—C3	121.9 (2)	N27—C26—N25	113.9 (3)
C6—N5—C4	118.5 (2)	N27—C26—H26	123.0
N5—C6—N1	123.6 (2)	N25—C26—H26	123.0
N5—C6—C18	118.9 (2)	C26—N27—C28	103.2 (2)
N1—C6—C18	117.2 (2)	C24—C28—N27	110.9 (2)
F29—C7—C8	117.8 (3)	C24—C28—C20	116.8 (2)
F29—C7—C3	119.1 (3)	N27—C28—C20	132.3 (3)
C8—C7—C3	123.1 (3)	C31—C30—C18	112.0 (3)
C7—C8—C9	118.7 (3)	C31—C30—H30A	109.2
C7—C8—H8	120.7	C18—C30—H30A	109.2
C9—C8—H8	120.7	C31—C30—H30B	109.2
C10—C9—C8	120.5 (3)	C18—C30—H30B	109.2
C10—C9—H9	119.8	H30A—C30—H30B	107.9
C8—C9—H9	119.8	C30—C31—H31A	109.5
C9—C10—C4	120.4 (3)	C30—C31—H31B	109.5
C9—C10—H10	119.8	H31A—C31—H31B	109.5
C4—C10—H10	119.8	C30—C31—H31C	109.5
C16—C11—C12	121.5 (3)	H31A—C31—H31C	109.5
C16—C11—N1	119.4 (3)	H31B—C31—H31C	109.5
C12—C11—N1	119.1 (3)	O36—C32—C33	105.3 (3)
C11—C12—C13	118.6 (4)	O36—C32—C35	109.4 (3)
C11—C12—H12	120.7	C33—C32—C35	112.6 (4)
C13—C12—H12	120.7	O36—C32—C34	108.3 (3)
C14—C13—C12	120.2 (4)	C33—C32—C34	110.8 (4)
C14—C13—H13	119.9	C35—C32—C34	110.3 (3)
C12—C13—H13	119.9	C32—C33—H33A	109.5
C15—C14—C13	120.5 (4)	C32—C33—H33B	109.5
C15—C14—H14	119.7	H33A—C33—H33B	109.5
C13—C14—H14	119.7	C32—C33—H33C	109.5
C14—C15—C16	120.4 (4)	H33A—C33—H33C	109.5
C14—C15—H15	119.8	H33B—C33—H33C	109.5
C16—C15—H15	119.8	C32—C34—H34A	109.5
C11—C16—C15	118.8 (4)	C32—C34—H34B	109.5
C11—C16—H16	120.6	H34A—C34—H34B	109.5
C15—C16—H16	120.6	C32—C34—H34C	109.5
N19—C18—C6	112.2 (2)	H34A—C34—H34C	109.5
N19—C18—C30	109.7 (2)	H34B—C34—H34C	109.5
C6—C18—C30	108.4 (2)	C32—C35—H35A	109.5
N19—C18—H18	108.8	C32—C35—H35B	109.5
C6—C18—H18	108.8	H35A—C35—H35B	109.5
C30—C18—H18	108.8	C32—C35—H35C	109.5
C20—N19—C18	120.7 (2)	H35A—C35—H35C	109.5
C20—N19—H19	119 (2)	H35B—C35—H35C	109.5
C18—N19—H19	120 (2)	C32—O36—H36	107 (3)
N19—C20—N21	118.2 (2)	H37A—O37—H37B	105 (3)
N19—C20—C28	123.5 (2)	H38A—O38—H38B	107 (3)
N21—C20—C28	118.3 (2)

C6—N1—C2—O17	177.1 (3)	C11—C12—C13—C14	−0.4 (5)
C11—N1—C2—O17	0.0 (4)	C12—C13—C14—C15	−0.5 (6)
C6—N1—C2—C3	−1.2 (4)	C13—C14—C15—C16	0.8 (6)
C11—N1—C2—C3	−178.3 (3)	C12—C11—C16—C15	−1.0 (5)
O17—C2—C3—C7	3.7 (5)	N1—C11—C16—C15	176.7 (3)
N1—C2—C3—C7	−178.2 (3)	C14—C15—C16—C11	0.0 (5)
O17—C2—C3—C4	−175.0 (3)	N5—C6—C18—N19	−41.0 (3)
N1—C2—C3—C4	3.1 (4)	N1—C6—C18—N19	144.2 (2)
C7—C3—C4—C10	−1.9 (4)	N5—C6—C18—C30	80.3 (3)
C2—C3—C4—C10	176.8 (3)	N1—C6—C18—C30	−94.4 (3)
C7—C3—C4—N5	178.2 (3)	C6—C18—N19—C20	−69.6 (3)
C2—C3—C4—N5	−3.0 (4)	C30—C18—N19—C20	169.8 (2)
C10—C4—N5—C6	−179.3 (3)	C18—N19—C20—N21	9.1 (4)
C3—C4—N5—C6	0.5 (4)	C18—N19—C20—C28	−171.0 (2)
C4—N5—C6—N1	1.6 (4)	N19—C20—N21—C22	−179.2 (3)
C4—N5—C6—C18	−172.7 (2)	C28—C20—N21—C22	0.8 (4)
C2—N1—C6—N5	−1.3 (4)	C20—N21—C22—N23	−0.3 (5)
C11—N1—C6—N5	175.7 (3)	N21—C22—N23—C24	−0.5 (4)
C2—N1—C6—C18	173.2 (2)	C22—N23—C24—N25	−179.3 (3)
C11—N1—C6—C18	−9.8 (4)	C22—N23—C24—C28	0.8 (4)
C4—C3—C7—F29	−177.8 (3)	N23—C24—N25—C26	−179.6 (3)
C2—C3—C7—F29	3.4 (5)	C28—C24—N25—C26	0.3 (3)
C4—C3—C7—C8	1.5 (5)	C24—N25—C26—N27	−0.1 (3)
C2—C3—C7—C8	−177.2 (3)	N25—C26—N27—C28	−0.2 (3)
F29—C7—C8—C9	179.8 (3)	N23—C24—C28—N27	179.5 (3)
C3—C7—C8—C9	0.5 (5)	N25—C24—C28—N27	−0.5 (3)
C7—C8—C9—C10	−2.0 (5)	N23—C24—C28—C20	−0.3 (4)
C8—C9—C10—C4	1.5 (5)	N25—C24—C28—C20	179.7 (2)
N5—C4—C10—C9	−179.7 (3)	C26—N27—C28—C24	0.4 (3)
C3—C4—C10—C9	0.5 (4)	C26—N27—C28—C20	−179.9 (3)
C6—N1—C11—C16	−90.8 (3)	N19—C20—C28—C24	179.5 (3)
C2—N1—C11—C16	86.4 (3)	N21—C20—C28—C24	−0.5 (4)
C6—N1—C11—C12	87.0 (3)	N19—C20—C28—N27	−0.2 (5)
C2—N1—C11—C12	−95.9 (3)	N21—C20—C28—N27	179.7 (3)
C16—C11—C12—C13	1.2 (4)	N19—C18—C30—C31	−71.6 (3)
N1—C11—C12—C13	−176.5 (3)	C6—C18—C30—C31	165.5 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N19—H19···O38	0.88 (2)	2.09 (2)	2.963 (3)	170 (3)
N25—H25···O36ⁱ	0.87 (2)	1.88 (2)	2.750 (3)	173 (4)
O36—H36···O37	0.82 (3)	1.92 (3)	2.741 (3)	174 (5)
O37—H37A···N5	0.86 (2)	2.09 (2)	2.939 (3)	172 (3)
O37—H37B···N27ⁱⁱ	0.90 (2)	2.06 (3)	2.888 (3)	153 (4)
O38—H38A···N23ⁱⁱⁱ	0.87 (2)	2.04 (2)	2.905 (3)	172 (3)
O38—H38B···O37	0.88 (2)	2.09 (3)	2.921 (4)	158 (4)

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

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