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Crystal structure of idelalisib tert-butanol monosolvate dihydrate

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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).

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[Carra, E., Gerber, M., Shi, B., Sujino, K., Tran, D. & Wang, F. (2013). Gilead Calistoga LLC, USA. Patent WO2013134288A1.]) 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[Kesicki, E. A. & Zhichkin, P. (2005). Gilead Calistoga LLC, USA. Patent WO2005113554A1.]).

[Scheme 1]

2. Structural commentary

The asymmetric unit of the title compound, (I)[link], 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[link]). 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]
Figure 1
Asymmetric unit of (I)[link] 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[link] result in a chain that possesses a central twofold rotational axis and propagates parallel to the b axis (Fig. 2[link]). 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)[link] has the topology of the 2,3,4,5-connected 4-nodal 1D net depicted in Fig. 3[link], 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[Blatov, V. A. (2006). IUCr Compcomm Newsl. 7, 4-38.]) in the manner described by Baburin & Blatov (2007[Baburin, I. A. & Blatov, V. A. (2007). Acta Cryst. B63, 791-802.]).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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]
Figure 2
Hydrogen-bonded chain structure of (I)[link], 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]
Figure 3
2,3,4,5-Connected 4-nodal topological net representing the hydrogen-bonded chain structure of (I)[link] which is based on the seven inter­molecular inter­actions listed in Table 1[link].

4. Database survey

The most recent version 5.40 (November 2018) of the Cambridge Structural Database (Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) 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[Zhou, J., Fu, L., Lv, M., Liu, J., Pei, D. & Ding, K. (2008). Synthesis, pp. 3974-3980.]; Yu et al., 2018[Yu, W., Zhang, X., Qin, B., Wang, Q., Ren, X. & He, X. (2018). Green Chem. 20, 2449-2454.]), in 2-[2-(4-nitro­phen­yl)vin­yl]-3-phenyl­quinazolin-4(3H)-one (Nosova et al., 2012[Nosova, E. V., Stupina, T. V., Lipunova, G. N., Valova, M. S., Slepukhin, P. A. & Charushin, V. N. (2012). Int. J. Org. Chem. 2, 56-63.]) and 2-di­ethyl­amino-3-phenyl­quinazolin-4(3H)-one (Xie & Li, 2006[Xie, C. & Li, H.-X. (2006). Acta Cryst. E62, o5632-o5633.]). 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[Framski, G., Gdaniec, Z., Gdaniec, M. & Boryski, J. (2006). Tetrahedron, 62, 10123-10129.]).

5. Synthesis and crystallization

The preparation of idelalisib was carried out according to the scheme displayed in Fig. 4[link], which represents a modification of the original synthesis by Kesicki & Zhichkin (2005[Kesicki, E. A. & Zhichkin, P. (2005). Gilead Calistoga LLC, USA. Patent WO2005113554A1.]), and yielded the polymorphic form I described by Carra et al. (2013[Carra, E., Gerber, M., Shi, B., Sujino, K., Tran, D. & Wang, F. (2013). Gilead Calistoga LLC, USA. Patent WO2013134288A1.]). 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)[link] as a crystalline, free-flowing white powder (120 mg, 55%).

[Figure 4]
Figure 4
Synthetic scheme for the preparation of idelalisib.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. 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 Uiso(H) = 1.5Ueq(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 Uiso(H) = 1.5Ueq(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 Uiso parameters were refined freely. The absolute structure was established by anomalous-dispersion effects (Table 2[link]).

Table 2
Experimental details

Crystal data
Chemical formula C22H18FN7O·C4H10O·2H2O
Mr 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)
V3) 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.])
Tmin, Tmax 0.835, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 8990, 5111, 4751
Rint 0.020
(sin θ/λ)max−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
Δρmax, Δρmin (e Å−3) 0.27, −0.18
Absolute structure Flack x determined using 1997 quotients [(I+)−(I)]/[(I+)+(I)] (Parsons et al., 2013[Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249-259.])
Absolute structure parameter −0.1 (4)
Computer programs: CrysAlis PRO (Rigaku OD, 2015[Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]), SIR2002 (Burla et al., 2003[Burla, M. C., Camalli, M., Carrozzini, B., Cascarano, G. L., Giacovazzo, C., Polidori, G. & Spagna, R. (2003). J. Appl. Cryst. 36, 1103.]), SHELXL2014 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]), XP (Bruker, 1998[Bruker (1998). XP. Bruker AXS Inc., Madison, Wisconsin, USA.]), Mercury (Macrae et al., 2006[Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39, 453-457.]), TOPOS (Blatov, 2006[Blatov, V. A. (2006). IUCr Compcomm Newsl. 7, 4-38.]), PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

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


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·2H2OF(000) = 1112
Mr = 525.58Dx = 1.291 Mg m3
Monoclinic, C2Mo Kα radiation, λ = 0.71073 Å
a = 21.3758 (6) ÅCell parameters from 5110 reflections
b = 9.2781 (3) Åθ = 2.7–28.3°
c = 13.9722 (5) ŵ = 0.09 mm1
β = 102.654 (3)°T = 173 K
V = 2703.75 (15) Å3Irregular fragment, colourless
Z = 40.34 × 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 Source4751 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.020
Detector resolution: 10.3575 pixels mm-1θmax = 26.0°, θmin = 2.2°
ω scansh = 2026
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku OD, 2015)
k = 1011
Tmin = 0.835, Tmax = 1.000l = 1612
8990 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.039H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.098 w = 1/[σ2(Fo2) + (0.0448P)2 + 1.4882P]
where P = (Fo2 + 2Fc2)/3
S = 1.07(Δ/σ)max < 0.001
5111 reflectionsΔρmax = 0.27 e Å3
375 parametersΔρmin = 0.18 e Å3
10 restraintsAbsolute structure: Flack x determined using 1997 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methodsAbsolute 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
xyzUiso*/Ueq
N10.31764 (11)0.8629 (3)0.59496 (16)0.0225 (5)
C20.25203 (13)0.8986 (3)0.5816 (2)0.0269 (6)
C30.22506 (13)0.8657 (3)0.6664 (2)0.0238 (6)
C40.26486 (13)0.8111 (3)0.7519 (2)0.0220 (6)
N50.32934 (10)0.7807 (2)0.75732 (16)0.0205 (5)
C60.35268 (13)0.8049 (3)0.68133 (18)0.0190 (5)
C70.16088 (14)0.8885 (3)0.6679 (2)0.0301 (7)
C80.13634 (14)0.8634 (4)0.7481 (3)0.0357 (7)
H80.09220.87960.74610.043*
C90.17702 (16)0.8135 (4)0.8331 (2)0.0350 (7)
H90.16090.79830.89050.042*
C100.24025 (14)0.7861 (3)0.8347 (2)0.0266 (6)
H100.26740.74980.89280.032*
C110.34784 (13)0.8965 (4)0.5149 (2)0.0281 (7)
C120.35269 (15)0.7897 (4)0.4473 (2)0.0367 (8)
H120.33430.69730.45140.044*
C130.38504 (18)0.8210 (5)0.3736 (3)0.0519 (11)
H130.38910.74920.32690.062*
C140.4111 (2)0.9557 (6)0.3681 (3)0.0635 (14)
H140.43350.97600.31790.076*
C150.40512 (18)1.0609 (5)0.4347 (3)0.0559 (12)
H150.42291.15380.42970.067*
C160.37325 (15)1.0323 (4)0.5091 (2)0.0395 (8)
H160.36901.10480.55530.047*
O170.22461 (10)0.9541 (3)0.50590 (16)0.0443 (6)
C180.42053 (13)0.7557 (3)0.68211 (19)0.0206 (6)
H180.43640.80910.63000.025*
N190.46407 (11)0.7818 (3)0.77607 (17)0.0210 (5)
H190.4813 (14)0.709 (3)0.813 (2)0.021 (8)*
C200.48111 (12)0.9170 (3)0.8058 (2)0.0200 (6)
N210.45009 (11)1.0276 (3)0.75290 (17)0.0249 (5)
C220.46761 (14)1.1613 (3)0.7819 (2)0.0275 (7)
H220.44471.23580.74240.033*
N230.51255 (12)1.2060 (3)0.85799 (19)0.0278 (6)
C240.54192 (13)1.0929 (3)0.9097 (2)0.0216 (6)
N250.58955 (11)1.0964 (3)0.99228 (18)0.0242 (5)
H250.6096 (17)1.174 (3)1.017 (3)0.043 (11)*
C260.60377 (13)0.9565 (3)1.0169 (2)0.0251 (6)
H260.63580.92891.07240.030*
N270.56911 (11)0.8628 (3)0.95710 (17)0.0227 (5)
C280.52953 (12)0.9492 (3)0.88899 (19)0.0193 (6)
F290.12046 (8)0.9365 (2)0.58583 (14)0.0450 (5)
C300.41885 (13)0.5942 (3)0.6584 (2)0.0233 (6)
H30A0.41190.53920.71590.028*
H30B0.38240.57420.60280.028*
C310.48062 (15)0.5434 (4)0.6322 (2)0.0379 (8)
H31A0.51640.55570.68890.057*
H31B0.48870.60040.57710.057*
H31C0.47660.44140.61360.057*
C320.28332 (15)0.3199 (3)0.8427 (2)0.0338 (7)
C330.2706 (2)0.1621 (5)0.8256 (4)0.0719 (15)
H33A0.26410.11710.88620.108*
H33B0.30730.11700.80600.108*
H33C0.23200.14900.77360.108*
C340.23156 (19)0.3891 (5)0.8861 (3)0.0569 (11)
H34A0.24450.48750.90730.085*
H34B0.22540.33260.94260.085*
H34C0.19130.39200.83650.085*
C350.28984 (18)0.3982 (5)0.7512 (3)0.0461 (9)
H35A0.32260.35090.72300.069*
H35B0.30240.49830.76740.069*
H35C0.24870.39640.70350.069*
O360.34320 (12)0.3280 (2)0.91451 (19)0.0419 (6)
H360.353 (2)0.414 (3)0.920 (3)0.063 (14)*
O370.38596 (12)0.6073 (2)0.93073 (17)0.0386 (6)
H37A0.3696 (17)0.665 (4)0.884 (2)0.044 (11)*
H37B0.402 (2)0.665 (4)0.982 (2)0.068 (14)*
O380.50757 (12)0.5153 (2)0.88771 (17)0.0361 (5)
H38A0.5126 (16)0.424 (3)0.877 (3)0.040 (10)*
H38B0.4728 (15)0.523 (4)0.911 (3)0.064 (14)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0200 (11)0.0277 (12)0.0181 (11)0.0050 (10)0.0007 (9)0.0021 (9)
C20.0222 (13)0.0359 (17)0.0212 (14)0.0069 (13)0.0014 (11)0.0031 (12)
C30.0207 (13)0.0223 (14)0.0277 (15)0.0022 (12)0.0036 (11)0.0008 (12)
C40.0228 (13)0.0172 (13)0.0246 (14)0.0006 (11)0.0023 (11)0.0004 (11)
N50.0192 (11)0.0211 (12)0.0193 (12)0.0023 (9)0.0005 (9)0.0003 (9)
C60.0203 (13)0.0168 (12)0.0179 (13)0.0009 (11)0.0000 (10)0.0006 (10)
C70.0206 (14)0.0323 (18)0.0351 (17)0.0040 (13)0.0009 (12)0.0059 (13)
C80.0213 (14)0.0426 (18)0.0464 (19)0.0062 (14)0.0142 (14)0.0094 (15)
C90.0323 (16)0.0390 (18)0.0376 (18)0.0005 (14)0.0160 (14)0.0070 (15)
C100.0253 (15)0.0266 (16)0.0278 (15)0.0023 (12)0.0051 (12)0.0046 (12)
C110.0218 (13)0.0403 (18)0.0208 (14)0.0120 (13)0.0015 (11)0.0085 (12)
C120.0312 (16)0.055 (2)0.0221 (15)0.0162 (16)0.0016 (13)0.0000 (15)
C130.041 (2)0.088 (3)0.0276 (18)0.026 (2)0.0085 (16)0.0061 (19)
C140.041 (2)0.116 (4)0.039 (2)0.022 (3)0.0210 (17)0.028 (3)
C150.043 (2)0.073 (3)0.052 (2)0.002 (2)0.0115 (18)0.035 (2)
C160.0358 (17)0.048 (2)0.0333 (18)0.0057 (16)0.0041 (14)0.0154 (16)
O170.0270 (11)0.0747 (18)0.0298 (12)0.0214 (12)0.0027 (9)0.0201 (12)
C180.0182 (13)0.0242 (14)0.0175 (13)0.0002 (11)0.0001 (10)0.0001 (11)
N190.0188 (11)0.0201 (13)0.0201 (12)0.0018 (10)0.0045 (9)0.0010 (9)
C200.0168 (12)0.0222 (14)0.0211 (13)0.0005 (11)0.0047 (10)0.0001 (11)
N210.0238 (12)0.0241 (13)0.0250 (12)0.0030 (11)0.0016 (10)0.0035 (10)
C220.0270 (15)0.0233 (16)0.0313 (16)0.0024 (13)0.0043 (13)0.0059 (12)
N230.0283 (13)0.0207 (13)0.0342 (14)0.0003 (11)0.0067 (11)0.0022 (10)
C240.0189 (13)0.0249 (14)0.0217 (14)0.0024 (12)0.0063 (11)0.0023 (12)
N250.0234 (12)0.0220 (12)0.0269 (13)0.0043 (11)0.0048 (10)0.0050 (10)
C260.0212 (14)0.0269 (16)0.0250 (15)0.0026 (12)0.0001 (11)0.0005 (12)
N270.0195 (11)0.0233 (12)0.0242 (12)0.0005 (10)0.0024 (9)0.0010 (9)
C280.0163 (12)0.0218 (15)0.0207 (13)0.0009 (11)0.0056 (10)0.0020 (11)
F290.0225 (9)0.0661 (14)0.0441 (11)0.0116 (9)0.0020 (8)0.0223 (10)
C300.0204 (13)0.0233 (14)0.0233 (14)0.0023 (12)0.0014 (11)0.0037 (12)
C310.0369 (17)0.039 (2)0.0394 (19)0.0112 (15)0.0117 (14)0.0049 (15)
C320.0291 (16)0.0276 (17)0.0388 (17)0.0007 (13)0.0054 (13)0.0049 (13)
C330.057 (3)0.035 (2)0.104 (4)0.009 (2)0.026 (3)0.004 (2)
C340.050 (2)0.071 (3)0.051 (2)0.003 (2)0.0133 (18)0.008 (2)
C350.0412 (19)0.056 (2)0.0387 (19)0.0058 (18)0.0037 (15)0.0013 (17)
O360.0383 (13)0.0236 (13)0.0525 (15)0.0013 (10)0.0151 (11)0.0061 (11)
O370.0517 (15)0.0267 (12)0.0284 (12)0.0038 (11)0.0106 (11)0.0012 (10)
O380.0453 (14)0.0233 (12)0.0370 (13)0.0031 (11)0.0032 (11)0.0010 (10)
Geometric parameters (Å, º) top
N1—C61.382 (3)N21—C221.333 (4)
N1—C21.413 (3)C22—N231.334 (4)
N1—C111.443 (4)C22—H220.9500
C2—O171.207 (3)N23—C241.348 (4)
C2—C31.459 (4)C24—N251.362 (4)
C3—C71.393 (4)C24—C281.378 (4)
C3—C41.401 (4)N25—C261.360 (4)
C4—C101.392 (4)N25—H250.87 (2)
C4—N51.392 (4)C26—N271.316 (4)
N5—C61.288 (4)C26—H260.9500
C6—C181.518 (4)N27—C281.382 (4)
C7—F291.351 (3)C30—C311.520 (4)
C7—C81.358 (4)C30—H30A0.9900
C8—C91.388 (5)C30—H30B0.9900
C8—H80.9500C31—H31A0.9800
C9—C101.371 (4)C31—H31B0.9800
C9—H90.9500C31—H31C0.9800
C10—H100.9500C32—O361.445 (4)
C11—C161.381 (5)C32—C331.498 (5)
C11—C121.388 (5)C32—C351.504 (5)
C12—C131.392 (5)C32—C341.516 (5)
C12—H120.9500C33—H33A0.9800
C13—C141.378 (7)C33—H33B0.9800
C13—H130.9500C33—H33C0.9800
C14—C151.374 (7)C34—H34A0.9800
C14—H140.9500C34—H34B0.9800
C15—C161.389 (5)C34—H34C0.9800
C15—H150.9500C35—H35A0.9800
C16—H160.9500C35—H35B0.9800
C18—N191.454 (3)C35—H35C0.9800
C18—C301.534 (4)O36—H360.82 (3)
C18—H181.0000O37—H37A0.86 (2)
N19—C201.346 (4)O37—H37B0.90 (2)
N19—H190.88 (2)O38—H38A0.87 (2)
C20—N211.351 (4)O38—H38B0.88 (2)
C20—C281.409 (4)
C6—N1—C2122.6 (2)C22—N21—C20118.0 (2)
C6—N1—C11120.8 (2)N21—C22—N23129.6 (3)
C2—N1—C11116.5 (2)N21—C22—H22115.2
O17—C2—N1119.6 (3)N23—C22—H22115.2
O17—C2—C3126.8 (3)C22—N23—C24110.8 (2)
N1—C2—C3113.6 (2)N23—C24—N25127.6 (3)
C7—C3—C4117.3 (3)N23—C24—C28126.5 (3)
C7—C3—C2123.1 (3)N25—C24—C28105.9 (2)
C4—C3—C2119.6 (2)C26—N25—C24106.0 (2)
C10—C4—N5118.1 (2)C26—N25—H25129 (2)
C10—C4—C3120.0 (3)C24—N25—H25125 (2)
N5—C4—C3121.9 (2)N27—C26—N25113.9 (3)
C6—N5—C4118.5 (2)N27—C26—H26123.0
N5—C6—N1123.6 (2)N25—C26—H26123.0
N5—C6—C18118.9 (2)C26—N27—C28103.2 (2)
N1—C6—C18117.2 (2)C24—C28—N27110.9 (2)
F29—C7—C8117.8 (3)C24—C28—C20116.8 (2)
F29—C7—C3119.1 (3)N27—C28—C20132.3 (3)
C8—C7—C3123.1 (3)C31—C30—C18112.0 (3)
C7—C8—C9118.7 (3)C31—C30—H30A109.2
C7—C8—H8120.7C18—C30—H30A109.2
C9—C8—H8120.7C31—C30—H30B109.2
C10—C9—C8120.5 (3)C18—C30—H30B109.2
C10—C9—H9119.8H30A—C30—H30B107.9
C8—C9—H9119.8C30—C31—H31A109.5
C9—C10—C4120.4 (3)C30—C31—H31B109.5
C9—C10—H10119.8H31A—C31—H31B109.5
C4—C10—H10119.8C30—C31—H31C109.5
C16—C11—C12121.5 (3)H31A—C31—H31C109.5
C16—C11—N1119.4 (3)H31B—C31—H31C109.5
C12—C11—N1119.1 (3)O36—C32—C33105.3 (3)
C11—C12—C13118.6 (4)O36—C32—C35109.4 (3)
C11—C12—H12120.7C33—C32—C35112.6 (4)
C13—C12—H12120.7O36—C32—C34108.3 (3)
C14—C13—C12120.2 (4)C33—C32—C34110.8 (4)
C14—C13—H13119.9C35—C32—C34110.3 (3)
C12—C13—H13119.9C32—C33—H33A109.5
C15—C14—C13120.5 (4)C32—C33—H33B109.5
C15—C14—H14119.7H33A—C33—H33B109.5
C13—C14—H14119.7C32—C33—H33C109.5
C14—C15—C16120.4 (4)H33A—C33—H33C109.5
C14—C15—H15119.8H33B—C33—H33C109.5
C16—C15—H15119.8C32—C34—H34A109.5
C11—C16—C15118.8 (4)C32—C34—H34B109.5
C11—C16—H16120.6H34A—C34—H34B109.5
C15—C16—H16120.6C32—C34—H34C109.5
N19—C18—C6112.2 (2)H34A—C34—H34C109.5
N19—C18—C30109.7 (2)H34B—C34—H34C109.5
C6—C18—C30108.4 (2)C32—C35—H35A109.5
N19—C18—H18108.8C32—C35—H35B109.5
C6—C18—H18108.8H35A—C35—H35B109.5
C30—C18—H18108.8C32—C35—H35C109.5
C20—N19—C18120.7 (2)H35A—C35—H35C109.5
C20—N19—H19119 (2)H35B—C35—H35C109.5
C18—N19—H19120 (2)C32—O36—H36107 (3)
N19—C20—N21118.2 (2)H37A—O37—H37B105 (3)
N19—C20—C28123.5 (2)H38A—O38—H38B107 (3)
N21—C20—C28118.3 (2)
C6—N1—C2—O17177.1 (3)C11—C12—C13—C140.4 (5)
C11—N1—C2—O170.0 (4)C12—C13—C14—C150.5 (6)
C6—N1—C2—C31.2 (4)C13—C14—C15—C160.8 (6)
C11—N1—C2—C3178.3 (3)C12—C11—C16—C151.0 (5)
O17—C2—C3—C73.7 (5)N1—C11—C16—C15176.7 (3)
N1—C2—C3—C7178.2 (3)C14—C15—C16—C110.0 (5)
O17—C2—C3—C4175.0 (3)N5—C6—C18—N1941.0 (3)
N1—C2—C3—C43.1 (4)N1—C6—C18—N19144.2 (2)
C7—C3—C4—C101.9 (4)N5—C6—C18—C3080.3 (3)
C2—C3—C4—C10176.8 (3)N1—C6—C18—C3094.4 (3)
C7—C3—C4—N5178.2 (3)C6—C18—N19—C2069.6 (3)
C2—C3—C4—N53.0 (4)C30—C18—N19—C20169.8 (2)
C10—C4—N5—C6179.3 (3)C18—N19—C20—N219.1 (4)
C3—C4—N5—C60.5 (4)C18—N19—C20—C28171.0 (2)
C4—N5—C6—N11.6 (4)N19—C20—N21—C22179.2 (3)
C4—N5—C6—C18172.7 (2)C28—C20—N21—C220.8 (4)
C2—N1—C6—N51.3 (4)C20—N21—C22—N230.3 (5)
C11—N1—C6—N5175.7 (3)N21—C22—N23—C240.5 (4)
C2—N1—C6—C18173.2 (2)C22—N23—C24—N25179.3 (3)
C11—N1—C6—C189.8 (4)C22—N23—C24—C280.8 (4)
C4—C3—C7—F29177.8 (3)N23—C24—N25—C26179.6 (3)
C2—C3—C7—F293.4 (5)C28—C24—N25—C260.3 (3)
C4—C3—C7—C81.5 (5)C24—N25—C26—N270.1 (3)
C2—C3—C7—C8177.2 (3)N25—C26—N27—C280.2 (3)
F29—C7—C8—C9179.8 (3)N23—C24—C28—N27179.5 (3)
C3—C7—C8—C90.5 (5)N25—C24—C28—N270.5 (3)
C7—C8—C9—C102.0 (5)N23—C24—C28—C200.3 (4)
C8—C9—C10—C41.5 (5)N25—C24—C28—C20179.7 (2)
N5—C4—C10—C9179.7 (3)C26—N27—C28—C240.4 (3)
C3—C4—C10—C90.5 (4)C26—N27—C28—C20179.9 (3)
C6—N1—C11—C1690.8 (3)N19—C20—C28—C24179.5 (3)
C2—N1—C11—C1686.4 (3)N21—C20—C28—C240.5 (4)
C6—N1—C11—C1287.0 (3)N19—C20—C28—N270.2 (5)
C2—N1—C11—C1295.9 (3)N21—C20—C28—N27179.7 (3)
C16—C11—C12—C131.2 (4)N19—C18—C30—C3171.6 (3)
N1—C11—C12—C13176.5 (3)C6—C18—C30—C31165.5 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N19—H19···O380.88 (2)2.09 (2)2.963 (3)170 (3)
N25—H25···O36i0.87 (2)1.88 (2)2.750 (3)173 (4)
O36—H36···O370.82 (3)1.92 (3)2.741 (3)174 (5)
O37—H37A···N50.86 (2)2.09 (2)2.939 (3)172 (3)
O37—H37B···N27ii0.90 (2)2.06 (3)2.888 (3)153 (4)
O38—H38A···N23iii0.87 (2)2.04 (2)2.905 (3)172 (3)
O38—H38B···O370.88 (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, y1, z.
 

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