Crystallographic study of PET radiotracers in clinical evaluation for early diagnosis of Alzheimers

Abstract

The title compound, C
24
H
25
NO
3
·2CH
3
OH, which crystallized as a methanol disolvate, has applications as a PET radiotracer in the early diagnosis of Alzheimer's disease. The dihedral angle between the biphenyl rings is 8.2 (2)° and the heterocyclic ring adopts a half-chair conformation with the N atom adopting a pyramidal geometry (bond-angle sum = 327.6°). The C atoms of both methoxy groups lie close to the plane of their attached ring [deviations = 0.107 (6) and 0.031 (6) Å]. In the crystal, the components are linked by O—H...O and O—H...N hydrogen bonds, generating [010] chains. C—H...O interactions are also observed.

Full text

Crystallographic study of PET radio-
tracers in clinical evaluation for early
diagnosis of Alzheimers
1
Angela Altomare,
a
Elena Capparelli,
b
Antonio Carrieri,
b
Nicola A. Colabufo,
c
Anna Moliterni,
a
Rosanna Rizzi
a
*
and Dritan Siliqi
a
a
Istituto di Cristallografia, Via G. Amendola, 122/o, 7016, Bari, Italy,
b
Dip. di
Farmacia-Scienze del Farmaco, Universita’ degli studi di Bari, Via Orabona, 4,
70125, Bari, Italy, and
c
Dip. di Farmacia-Scienze del Farmaco, Biofordrug, srl,
Universita’ degli studi di Bari, Via Orabona, 4, 70125, Bari, Italy. *Correspondence
e-mail: rosanna.rizzi@ic.cnr.it
Received 3 August 2014; accepted 26 September 2014
Edited by W. T. A. Harrison, University of Aberdeen, Scotland
The title compound, C
24
H
25
NO
3
2CH
3
OH, which crystallized
as a methanol disolvate, has applications as a PET radiotracer
in the early diagnosis of Alzheimer’s disease. The dihedral
angle between the biphenyl rings is 8.2 (2)and the
heterocyclic ring adopts a half-chair conformation with the
N atom adopting a pyramidal geometry (bond-angle sum =
327.6). The C atoms of both methoxy groups lie close to the
plane of their attached ring [deviations = 0.107 (6) and
0.031 (6) A
˚]. In the crystal, the components are linked by O—
HO and O—HN hydrogen bonds, generating [010]
chains. C—HO interactions are also observed.
Keywords: crystal structure; ligands; P-glycoprotein inhibitor; PET radio-
tracer; hydrogen bonds.
CCDC reference:915609
1. Related literature
For pharmacological and biological studies of the title
compound, see Colabufo et al. (2008, 2009).
2. Experimental
2.1. Crystal data
C
24
H
25
NO
3
2CH
4
O
M
r
= 439.53
Monoclinic, P21
a= 8.894 (2) A
˚
b= 13.7187 (16) A
˚
c= 10.680 (2) A
˚
= 111.575 (17)
V= 1211.8 (4) A
˚
3
Z=2
Mo Kradiation
= 0.08 mm
1
T= 293 K
0.30 0.30 0.15 mm
2.2. Data collection
Bruker–Nonius KappaCCD
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2008a)
T
min
= 0.921, T
max
= 0.988
14813 measured reflections
5436 independent reflections
2610 reflections with I>2(I)
R
int
= 0.116
2.3. Refinement
R[F
2
>2(F
2
)] = 0.061
wR(F
2
) = 0.115
S= 0.96
5436 reflections
305 parameters
1 restraint
H atoms treated by a mixture of
independent and constrained
refinement

max
= 0.17 e A
˚
3

min
=0.15 e A
˚
3
Table 1
Hydrogen-bond geometry (A
˚,).
D—HAD—H HADAD—HA
O2—H2ON1 0.94 (5) 1.87 (5) 2.812 (5) 178 (4)
O4—H4OO5
i
0.95 (6) 1.71 (6) 2.636 (6) 165 (5)
O5—H5OO2 0.71 (8) 2.00 (8) 2.684 (6) 162 (9)
C15—H15AO1
ii
0.97 2.50 3.445 (6) 164
C23—H23AO2
iii
0.96 2.56 3.437 (6) 152
Symmetry codes: (i) x;yþ1;z; (ii) xþ1;yþ1
2;z; (iii) x;y1
2;z.
Data collection: COLLECT (Nonius, 2002); cell determination and
refinement: DIRAX (Duisenberg,1992; Duisenberg et al., 2000); data
reduction: EVAL (Nonius, 2002; Duisenberg et al., 2003); program(s)
used to solve structure: SIR2011 (Burla et al., 2012); program(s) used
to refine structure: SHELXL2013 (Sheldrick, 2008b); molecular
graphics: ORTEP-3 for Windows (Farrugia, 2012) and EXPO2013
(Altomare et al., 2013); software used to prepare material for publi-
cation: WinGX (Farrugia, 2012) and publCIF (Westrip, 2010).
Acknowledgements
This work was supported by the Fondazione Cassa di
Risparmio di Puglia (FCRP) of Bari (research project: Studio
cristallografico di radiotraccianti PET in valutazione clinica
per la diagnosi precoce dell’ Alzheimer). The authors thank
Mr Giuseppe Chita (Institute of Crystallography CNR, Bari,
Italy) for his contribution to the X-ray powder diffraction data
collection and Dr Caterina Chiarella (Institute of Crystal-
lography CNR, Bari, Italy) for the technical support to project
management.
data reports
Acta Cryst. (2014). E70, o1149–o1150 doi:10.1107/S1600536814021400 Altomare et al. o1149
ISSN 1600-5368
1
Crystal structure of 40-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-
methyl]biphenyl-4-ol methanol disolvate.

Supporting information for this paper is available from the IUCr
electronic archives (Reference: HB7266).
References
Altomare, A., Cuocci, C., Giacovazzo, C., Moliterni, A., Rizzi, R., Corriero, N.
& Falcicchio, A. (2013). J. Appl. Cryst. 46, 1231–1235.
Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L.,
Giacovazzo, C., Mallamo, M., Mazzone, A., Polidori, G. & Spagna, R.
(2012). J. Appl. Cryst. 45, 357–361.
Colabufo, N. A., Berardi, F., Cantore, M., Perrone, M. G., Contino, M., Inglese,
C., Niso, M., Perrone, R., Azzariti, A., Simone, G. M. & Paradiso, A. (2008).
Bioorg. Med. Chem.16, 3732–3743.
Colabufo, N. A., Berardi, F., Perrone, M. G., Cantore, M., Contino, M., Inglese,
C., Niso, M. & Perrone, R. (2009). ChemMedChem,4, 188–195.
Duisenberg, A. J. M. (1992). J. Appl. Cryst. 25, 92–96.
Duisenberg, A. J. M., Hooft, R. W. W., Schreurs, A. M. M. & Kroon, J. (2000).
J. Appl. Cryst. 33, 893–898.
Duisenberg, A. J. M., Kroon-Batenburg, L. M. J. & Schreurs, A. M. M. (2003).
J. Appl. Cryst. 36, 220–229.
Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.
Nonius (2002). COLLECT and EVAL. Nonius BV, Delft, The Netherlands.
Sheldrick, G. M. (2008a). SADABS. University of Go
¨ttingen, Germany.
Sheldrick, G. M. (2008b). Acta Cryst. A64, 112–122.
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.
data reports
o1150 Altomare et al. C
24
H
25
NO
3
2CH
4
OActa Cryst. (2014). E70, o1149–o1150

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Acta Cryst. (2014). E70, o1149–o1150
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Acta Cryst. (2014). E70, o1149–o1150 [doi:10.1107/S1600536814021400]
Crystallographic study of PET radiotracers in clinical evaluation for early
diagnosis of Alzheimers
Angela Altomare, Elena Capparelli, Antonio Carrieri, Nicola A. Colabufo, Anna Moliterni,
Rosanna Rizzi and Dritan Siliqi
S1. Comment
The single-crystal X-ray structure solution of 4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-methyl)-biphenyl-4-ol
(named MC70) radiotracer, previously pharmacologically characterized and biologically evaluated (compound 4e in
Colabufo et al., 2008, 2009), has been reported. At nanomolar concentrations MC70 is a potent inhibitor of P-
glycoprotein (P-gp), a membrane protein playing a protective role of the central nervous system and whose numerical and
functional alteration is responsible for the onset of the Alzheimer disease. The crystallographic characterization of MC70
represents the first necessary step for a further evaluation of its pharmacological properties and to obtain, f. e. through
docking techniques and homology modelling, a tridimensional interpretation of the main molecular determinants
responsible for most of MC70 features such as to be an inhibitor of the P-gp. The study of this behaviour will allow the
design of new ligands, more effective and selective in the monitoring the role of P-glycoprotein for the recognition and
early treatment of the Alzheimer disease. In addition, up to now none of the studies on interactions of this pump with
known inhibitors, report crystallographic data of P-gp inhibitors complexes. Therefore speculating the binding
conformation and pose for MC70 might be an added value to a better understanding of the mechanism of action of efflux
pumps involved in the Alzheimer's disease.
A view of the refined crystal structure is shown in Figure 1. The packing of the obtained crystal structure is represented
in Figure 2; it is interesting observing that the network of the structure features three hydrogen bonds (Table 1): the first
between the 2 molecules of methanol, the second between one methanol molecule and the phenolic residue of the
molecule and the last between the other methanol molecule and the isoquinoline nucleus. In the crystal weak C—H···O
hydrogen bonds also occur. In addition, the pendant biphenyl has an equatorial configuration as proved by a dihedral
angle among atoms C8—N1—C7—C18 of -175°.
S2. Experimental
MC70, [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-methyl)-biphenyl-4-ol] (C24H25NO3) has been obtained after
crystallization as yellow needles. The solvent/non-solvent diffusion has been used as crystallization technique: after
solubilizing MC70 (5 mg) in methanol (solvent, 1 ml), an equal volume of CH2Cl2 (non-solvent, 1 ml) has been
deposited. The vial has been covered with a perforated cap and left at room temperature. After a couple of days, yellow
needles of MC70 2CH3OH have grown on the interphase solvent/non-solvent.
S3. Refinement
The hydrogen atoms of the hydroxyl groups were located by difference Fourier synthesis and freely isotropically refined.
The C-bonded H atoms were positioned geometrically with C—H = 0.96, 0.97 and 0.93 Å for methyl, methylene and

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Acta Cryst. (2014). E70, o1149–o1150
aromatic H atoms, respectively, and constrained to ride on their parent atoms. The constraint Uiso(H) = kUeq(C), where k =
1.5 for methyl and k = 1.2 for aromatic and methylene H atoms, was applied. The highest residual electron density was
found 1.59 Å from C16 and the deepest hole 1.04 Å from H12A.
Figure 1
The molecular structure of the MC70 compound with displacement ellipsoids drawn at the 50% probability level.

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Acta Cryst. (2014). E70, o1149–o1150
Figure 2
Crystal packing of the MC70 compound. The light blue dashed lines show the hydrogen bonds (see Table 1 for details).
4′-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl-methyl)-biphenyl-4-ol methanol disolvate
Crystal data
C24H25NO3·2CH4O
Mr = 439.53
Monoclinic, P21
a = 8.894 (2) Å
b = 13.7187 (16) Å
c = 10.680 (2) Å
β = 111.575 (17)°
V = 1211.8 (4) Å3
Z = 2
F(000) = 472
Dx = 1.205 Mg m−3
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 130 reflections
θ = 2.9–26.6°
µ = 0.08 mm−1
T = 293 K
Needle, yellow
0.30 × 0.30 × 0.15 mm
Data collection
Bruker–Nonius KappaCCD
diffractometer
Radiation source: fine-focus sealed tube
Detector resolution: 9.091 pixels mm-1
φ scans and ω scans
Absorption correction: multi-scan
(SADABS; Sheldrick, 2008a)
Tmin = 0.921, Tmax = 0.988
14813 measured reflections
5436 independent reflections
2610 reflections with I > 2σ(I)
Rint = 0.116
θmax = 27.5°, θmin = 5.1°
h = −11→11
k = −16→17
l = −13→13
Refinement
Refinement on F2
Least-squares matrix: full
R[F2 > 2σ(F2)] = 0.061
wR(F2) = 0.115
S = 0.96
5436 reflections
305 parameters
1 restraint
Primary atom site location: structure-invariant
direct methods
Secondary atom site location: difference Fourier
map
Hydrogen site location: mixed
H atoms treated by a mixture of independent
and constrained refinement

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Acta Cryst. (2014). E70, o1149–o1150
w = 1/[σ2(Fo2) + (0.0345P)2]
where P = (Fo2 + 2Fc2)/3
(Δ/σ)max < 0.001
Δρmax = 0.17 e Å−3
Δρmin = −0.15 e Å−3
Special details
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full
covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and
torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry.
An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
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 > 2σ(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 (Å2)
xyzU
iso*/Ueq
O1 0.4571 (4) 0.0371 (2) 0.1278 (3) 0.0510 (9)
O2 0.2161 (4) 0.4009 (3) 0.3492 (4) 0.0591 (10)
H2O 0.284 (6) 0.426 (4) 0.307 (5) 0.061 (15)*
O3 0.1944 (4) 0.0677 (2) −0.0770 (4) 0.0660 (10)
O4 −0.0551 (4) 1.1537 (3) 0.4038 (4) 0.0686 (11)
H4O −0.058 (7) 1.200 (4) 0.337 (6) 0.09 (2)*
N1 0.4249 (4) 0.4745 (3) 0.2281 (4) 0.0448 (10)
C1 0.2616 (5) 0.8125 (3) 0.3304 (4) 0.0390 (10)
C2 0.1761 (5) 0.9019 (3) 0.3470 (4) 0.0409 (11)
C3 0.4907 (6) 0.2102 (4) 0.1807 (5) 0.0464 (12)
H3 0.5871 0.1998 0.2530 0.056*
C4 0.4297 (5) 0.3056 (4) 0.1500 (5) 0.0450 (12)
C5 0.4095 (6) 0.1326 (3) 0.1054 (5) 0.0450 (12)
C6 0.3543 (6) 0.6482 (3) 0.3954 (5) 0.0540 (13)
H6 0.3556 0.5936 0.4475 0.065*
C7 0.5309 (5) 0.5553 (3) 0.3000 (5) 0.0532 (14)
H7A 0.6029 0.5719 0.2535 0.064*
H7B 0.5969 0.5339 0.3900 0.064*
O5 −0.0663 (6) 0.3050 (3) 0.2485 (5) 0.0724 (12)
H5O 0.007 (9) 0.331 (6) 0.259 (8) 0.12 (4)*
C8 0.5275 (5) 0.3884 (3) 0.2354 (5) 0.0519 (13)
H8A 0.5766 0.3671 0.3283 0.062*
H8B 0.6136 0.4061 0.2045 0.062*
C9 0.2058 (6) 0.2421 (3) −0.0333 (5) 0.0510 (13)
H9 0.1102 0.2529 −0.1063 0.061*
C10 0.0835 (6) 0.9047 (4) 0.4265 (5) 0.0532 (13)
H10 0.0709 0.8477 0.4688 0.064*
C11 0.2866 (5) 0.3213 (3) 0.0452 (5) 0.0456 (12)
C12 0.2151 (6) 0.4222 (3) 0.0158 (5) 0.0514 (13)
H12A 0.1242 0.4268 0.0452 0.062*
H12B 0.1750 0.4335 −0.0806 0.062*
C13 0.3421 (6) 0.8087 (3) 0.2410 (4) 0.0491 (12)

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Acta Cryst. (2014). E70, o1149–o1150
H13 0.3378 0.8621 0.1862 0.059*
C14 0.1866 (6) 0.9887 (3) 0.2849 (6) 0.0602 (15)
H14 0.2464 0.9906 0.2295 0.072*
C15 0.3377 (6) 0.5000 (3) 0.0859 (5) 0.0527 (14)
H15A 0.4142 0.5069 0.0411 0.063*
H15B 0.2831 0.5619 0.0803 0.063*
C16 0.2641 (6) 0.1490 (4) −0.0050 (5) 0.0469 (11)
C17 0.2690 (6) 0.7294 (3) 0.4065 (5) 0.0542 (14)
H17 0.2151 0.7285 0.4664 0.065*
C18 0.4376 (5) 0.6453 (3) 0.3097 (5) 0.0459 (12)
C19 0.0090 (6) 0.9887 (4) 0.4456 (5) 0.0578 (14)
H19 −0.0502 0.9877 0.5015 0.069*
C20 0.0220 (6) 1.0731 (4) 0.3825 (5) 0.0522 (13)
C21 0.4286 (6) 0.7268 (3) 0.2323 (5) 0.0538 (13)
H21 0.4823 0.7270 0.1723 0.065*
C22 0.1113 (7) 1.0729 (4) 0.3026 (6) 0.0646 (15)
H22 0.1216 1.1300 0.2594 0.078*
C23 0.0516 (7) 0.0832 (5) −0.1916 (6) 0.0864 (19)
H23A 0.0125 0.0219 −0.2346 0.130*
H23B 0.0750 0.1257 −0.2535 0.130*
H23C −0.0293 0.1126 −0.1641 0.130*
C24 0.3132 (7) 0.3394 (4) 0.4543 (6) 0.0847 (19)
H24A 0.2517 0.3176 0.5063 0.127*
H24B 0.4062 0.3749 0.5112 0.127*
H24C 0.3475 0.2841 0.4165 0.127*
C25 0.6072 (7) 0.0187 (4) 0.2328 (6) 0.0707 (17)
H25A 0.6324 −0.0494 0.2345 0.106*
H25B 0.6006 0.0371 0.3174 0.106*
H25C 0.6903 0.0561 0.2179 0.106*
C26 −0.1413 (7) 0.2993 (5) 0.1057 (6) 0.0846 (19)
H26A −0.1724 0.3634 0.0694 0.127*
H26B −0.2353 0.2585 0.0821 0.127*
H26C −0.0665 0.2721 0.0694 0.127*
Atomic displacement parameters (Å2)
U11 U22 U33 U12 U13 U23
O1 0.052 (2) 0.045 (2) 0.058 (2) 0.0013 (16) 0.0214 (19) −0.0015 (16)
O2 0.045 (2) 0.069 (2) 0.061 (2) 0.0081 (19) 0.0175 (19) 0.016 (2)
O3 0.060 (2) 0.054 (2) 0.067 (3) −0.0115 (19) 0.004 (2) −0.016 (2)
O4 0.079 (3) 0.058 (2) 0.085 (3) 0.008 (2) 0.049 (2) −0.005 (3)
N1 0.039 (2) 0.045 (2) 0.045 (3) −0.0019 (19) 0.0086 (18) −0.0088 (19)
C1 0.037 (3) 0.045 (3) 0.034 (3) −0.009 (2) 0.012 (2) −0.009 (2)
C2 0.039 (3) 0.047 (3) 0.035 (3) −0.006 (2) 0.012 (2) −0.004 (2)
C3 0.042 (3) 0.058 (3) 0.039 (3) 0.004 (3) 0.014 (2) −0.008 (3)
C4 0.039 (3) 0.051 (3) 0.047 (3) −0.002 (3) 0.019 (2) −0.013 (3)
C5 0.047 (3) 0.044 (3) 0.049 (3) −0.001 (2) 0.023 (3) −0.005 (2)
C6 0.067 (3) 0.040 (3) 0.055 (3) −0.004 (3) 0.023 (3) 0.003 (3)

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Acta Cryst. (2014). E70, o1149–o1150
C7 0.049 (3) 0.048 (3) 0.062 (3) −0.004 (3) 0.020 (3) −0.015 (3)
O5 0.071 (3) 0.067 (3) 0.075 (3) −0.010 (3) 0.022 (2) 0.001 (2)
C8 0.042 (3) 0.047 (3) 0.065 (4) 0.003 (2) 0.017 (3) −0.013 (3)
C9 0.044 (3) 0.054 (3) 0.047 (3) −0.002 (3) 0.007 (2) −0.007 (3)
C10 0.061 (3) 0.056 (3) 0.051 (3) 0.002 (3) 0.030 (3) 0.011 (3)
C11 0.043 (3) 0.045 (3) 0.047 (3) 0.002 (2) 0.014 (3) −0.009 (2)
C12 0.047 (3) 0.050 (3) 0.049 (3) 0.004 (3) 0.009 (2) −0.003 (3)
C13 0.058 (3) 0.044 (3) 0.048 (3) −0.003 (3) 0.021 (3) −0.001 (2)
C14 0.070 (4) 0.049 (3) 0.081 (4) 0.005 (3) 0.052 (3) 0.004 (3)
C15 0.054 (3) 0.052 (3) 0.053 (4) −0.004 (3) 0.020 (3) −0.004 (3)
C16 0.047 (3) 0.048 (3) 0.047 (3) −0.007 (3) 0.018 (3) −0.010 (3)
C17 0.070 (3) 0.047 (3) 0.057 (4) −0.007 (3) 0.036 (3) −0.004 (3)
C18 0.043 (3) 0.045 (3) 0.046 (3) −0.004 (2) 0.012 (2) −0.009 (3)
C19 0.062 (3) 0.062 (4) 0.063 (4) 0.005 (3) 0.039 (3) 0.001 (3)
C20 0.049 (3) 0.049 (3) 0.063 (3) −0.003 (3) 0.026 (3) −0.007 (3)
C21 0.065 (3) 0.047 (3) 0.057 (4) −0.008 (3) 0.032 (3) −0.008 (3)
C22 0.074 (4) 0.052 (3) 0.089 (4) −0.002 (3) 0.055 (4) 0.007 (3)
C23 0.074 (4) 0.078 (4) 0.079 (4) −0.017 (3) −0.005 (4) −0.024 (4)
C24 0.074 (4) 0.100 (5) 0.067 (4) 0.020 (4) 0.010 (3) 0.028 (4)
C25 0.069 (4) 0.063 (4) 0.068 (4) 0.015 (3) 0.012 (3) 0.002 (3)
C26 0.078 (4) 0.106 (5) 0.073 (5) −0.022 (4) 0.031 (4) −0.018 (4)
Geometric parameters (Å, º)
O1—C5 1.371 (5) C9—C11 1.399 (6)
O1—C25 1.415 (6) C9—H9 0.9300
O2—C24 1.415 (6) C10—C19 1.380 (7)
O2—H2O 0.94 (5) C10—H10 0.9300
O3—C16 1.367 (6) C11—C12 1.508 (6)
O3—C23 1.419 (6) C12—C15 1.513 (6)
O4—C20 1.364 (5) C12—H12A 0.9700
O4—H4O 0.95 (6) C12—H12B 0.9700
N1—C15 1.471 (6) C13—C21 1.383 (6)
N1—C7 1.475 (5) C13—H13 0.9300
N1—C8 1.477 (5) C14—C22 1.382 (7)
C1—C17 1.388 (6) C14—H14 0.9300
C1—C13 1.389 (6) C15—H15A 0.9700
C1—C2 1.488 (6) C15—H15B 0.9700
C2—C14 1.383 (6) C17—H17 0.9300
C2—C10 1.384 (6) C18—C21 1.376 (6)
C3—C5 1.369 (6) C19—C20 1.366 (6)
C3—C4 1.409 (6) C19—H19 0.9300
C3—H3 0.9300 C20—C22 1.364 (6)
C4—C11 1.367 (6) C21—H21 0.9300
C4—C8 1.516 (6) C22—H22 0.9300
C5—C16 1.411 (6) C23—H23A 0.9600
C6—C18 1.373 (6) C23—H23B 0.9600
C6—C17 1.378 (6) C23—H23C 0.9600

supporting information
sup-7
Acta Cryst. (2014). E70, o1149–o1150
C6—H6 0.9300 C24—H24A 0.9600
C7—C18 1.511 (6) C24—H24B 0.9600
C7—H7A 0.9700 C24—H24C 0.9600
C7—H7B 0.9700 C25—H25A 0.9600
O5—C26 1.424 (7) C25—H25B 0.9600
O5—H5O 0.71 (8) C25—H25C 0.9600
C8—H8A 0.9700 C26—H26A 0.9600
C8—H8B 0.9700 C26—H26B 0.9600
C9—C16 1.370 (7) C26—H26C 0.9600
C5—O1—C25 116.7 (4) C1—C13—H13 119.4
C24—O2—H2O 107 (3) C22—C14—C2 122.1 (5)
C16—O3—C23 116.1 (4) C22—C14—H14 118.9
C20—O4—H4O 107 (3) C2—C14—H14 118.9
C15—N1—C7 110.6 (4) N1—C15—C12 110.7 (4)
C15—N1—C8 109.0 (4) N1—C15—H15A 109.5
C7—N1—C8 108.0 (3) C12—C15—H15A 109.5
C17—C1—C13 116.5 (4) N1—C15—H15B 109.5
C17—C1—C2 121.6 (4) C12—C15—H15B 109.5
C13—C1—C2 121.9 (4) H15A—C15—H15B 108.1
C14—C2—C10 115.5 (4) O3—C16—C9 125.5 (4)
C14—C2—C1 121.6 (4) O3—C16—C5 115.2 (5)
C10—C2—C1 122.8 (4) C9—C16—C5 119.3 (5)
C5—C3—C4 120.7 (4) C6—C17—C1 121.5 (5)
C5—C3—H3 119.6 C6—C17—H17 119.2
C4—C3—H3 119.6 C1—C17—H17 119.2
C11—C4—C3 120.0 (4) C6—C18—C21 116.7 (5)
C11—C4—C8 122.0 (4) C6—C18—C7 120.9 (5)
C3—C4—C8 118.0 (4) C21—C18—C7 122.3 (5)
C3—C5—O1 125.4 (5) C20—C19—C10 120.2 (5)
C3—C5—C16 119.3 (5) C20—C19—H19 119.9
O1—C5—C16 115.3 (4) C10—C19—H19 119.9
C18—C6—C17 122.0 (5) C22—C20—O4 123.4 (5)
C18—C6—H6 119.0 C22—C20—C19 118.8 (5)
C17—C6—H6 119.0 O4—C20—C19 117.8 (5)
N1—C7—C18 112.8 (4) C18—C21—C13 122.1 (5)
N1—C7—H7A 109.0 C18—C21—H21 119.0
C18—C7—H7A 109.0 C13—C21—H21 119.0
N1—C7—H7B 109.0 C20—C22—C14 120.7 (5)
C18—C7—H7B 109.0 C20—C22—H22 119.6
H7A—C7—H7B 107.8 C14—C22—H22 119.6
C26—O5—H5O 104 (7) O3—C23—H23A 109.5
N1—C8—C4 111.2 (4) O3—C23—H23B 109.5
N1—C8—H8A 109.4 H23A—C23—H23B 109.5
C4—C8—H8A 109.4 O3—C23—H23C 109.5
N1—C8—H8B 109.4 H23A—C23—H23C 109.5
C4—C8—H8B 109.4 H23B—C23—H23C 109.5
H8A—C8—H8B 108.0 O2—C24—H24A 109.5

supporting information
sup-8
Acta Cryst. (2014). E70, o1149–o1150
C16—C9—C11 121.5 (5) O2—C24—H24B 109.5
C16—C9—H9 119.3 H24A—C24—H24B 109.5
C11—C9—H9 119.3 O2—C24—H24C 109.5
C19—C10—C2 122.7 (5) H24A—C24—H24C 109.5
C19—C10—H10 118.7 H24B—C24—H24C 109.5
C2—C10—H10 118.7 O1—C25—H25A 109.5
C4—C11—C9 119.1 (4) O1—C25—H25B 109.5
C4—C11—C12 120.6 (4) H25A—C25—H25B 109.5
C9—C11—C12 120.2 (4) O1—C25—H25C 109.5
C11—C12—C15 111.8 (4) H25A—C25—H25C 109.5
C11—C12—H12A 109.2 H25B—C25—H25C 109.5
C15—C12—H12A 109.2 O5—C26—H26A 109.5
C11—C12—H12B 109.2 O5—C26—H26B 109.5
C15—C12—H12B 109.2 H26A—C26—H26B 109.5
H12A—C12—H12B 107.9 O5—C26—H26C 109.5
C21—C13—C1 121.1 (4) H26A—C26—H26C 109.5
C21—C13—H13 119.4 H26B—C26—H26C 109.5
C17—C1—C2—C14 171.2 (5) C1—C2—C14—C22 −178.2 (5)
C13—C1—C2—C14 −6.9 (6) C7—N1—C15—C12 −173.6 (4)
C17—C1—C2—C10 −7.7 (7) C8—N1—C15—C12 67.8 (5)
C13—C1—C2—C10 174.2 (5) C11—C12—C15—N1 −47.5 (5)
C5—C3—C4—C11 1.1 (6) C23—O3—C16—C9 1.4 (7)
C5—C3—C4—C8 −178.6 (4) C23—O3—C16—C5 −177.6 (4)
C4—C3—C5—O1 −179.1 (4) C11—C9—C16—O3 −179.2 (4)
C4—C3—C5—C16 0.7 (6) C11—C9—C16—C5 −0.3 (7)
C25—O1—C5—C3 −3.8 (6) C3—C5—C16—O3 177.9 (4)
C25—O1—C5—C16 176.4 (4) O1—C5—C16—O3 −2.3 (5)
C15—N1—C7—C18 65.8 (5) C3—C5—C16—C9 −1.1 (6)
C8—N1—C7—C18 −175.0 (4) O1—C5—C16—C9 178.7 (4)
C15—N1—C8—C4 −53.1 (5) C18—C6—C17—C1 0.6 (7)
C7—N1—C8—C4 −173.4 (4) C13—C1—C17—C6 1.1 (7)
C11—C4—C8—N1 22.3 (6) C2—C1—C17—C6 −177.0 (4)
C3—C4—C8—N1 −158.0 (4) C17—C6—C18—C21 −1.6 (7)
C14—C2—C10—C19 −1.4 (7) C17—C6—C18—C7 179.7 (4)
C1—C2—C10—C19 177.6 (5) N1—C7—C18—C6 73.2 (6)
C3—C4—C11—C9 −2.4 (6) N1—C7—C18—C21 −105.4 (5)
C8—C4—C11—C9 177.3 (4) C2—C10—C19—C20 1.5 (8)
C3—C4—C11—C12 176.6 (4) C10—C19—C20—C22 −0.9 (8)
C8—C4—C11—C12 −3.8 (6) C10—C19—C20—O4 179.4 (5)
C16—C9—C11—C4 2.0 (7) C6—C18—C21—C13 0.9 (7)
C16—C9—C11—C12 −176.9 (4) C7—C18—C21—C13 179.6 (4)
C4—C11—C12—C15 15.9 (6) C1—C13—C21—C18 0.8 (8)
C9—C11—C12—C15 −165.2 (4) O4—C20—C22—C14 180.0 (5)
C17—C1—C13—C21 −1.8 (7) C19—C20—C22—C14 0.4 (8)
C2—C1—C13—C21 176.3 (4) C2—C14—C22—C20 −0.3 (9)
C10—C2—C14—C22 0.8 (8)

supporting information
sup-9
Acta Cryst. (2014). E70, o1149–o1150
Hydrogen-bond geometry (Å, º)
D—H···AD—H H···AD···AD—H···A
O2—H2O···N1 0.94 (5) 1.87 (5) 2.812 (5) 178 (4)
O4—H4O···O5i0.95 (6) 1.71 (6) 2.636 (6) 165 (5)
O5—H5O···O2 0.71 (8) 2.00 (8) 2.684 (6) 162 (9)
C15—H15A···O1ii 0.97 2.50 3.445 (6) 164
C23—H23A···O2iii 0.96 2.56 3.437 (6) 152
Symmetry codes: (i) x, y+1, z; (ii) −x+1, y+1/2, −z; (iii) −x, y−1/2, −z.