Donepezilium oxalate trihydrate, a therapeutic agent for Alzheimer's disease

Donepezil, a cholinesterase inhibitor with good central nervous system penetration, has been crystallized as a tertiary amine salt with a disordered oxalate anion to give the title compound, (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidinium hydrogen oxalate trihydrate, C₂₄H₃₀NO₃⁺·C₂HO₄⁻·3H₂O. The indanone and piperidine ring planes are inclined at an angle of 33.4 (1)°. A comparison is made with the piperidinium cation bound in acetyl­cholinesterase in the solid state. The methyl­ene units bridging the indanone–piperidine–benzyl groups determine the mol­ecular shape and conformational features. The structure is stabilized mainly by O—H...O and N—H...O hydrogen bonds, with water mol­ecules mediating inter­actions between oxalate anions and donepezilium cations.

S1. Comment

Alzheimer's disease (AD) is a progressive degenerative disorder that ultimately produces the symptoms of senile dementia. A hallmark of AD is the decrease in number and function of basal forebrain cholinergic neurons (BFCN) (Davies & Maloney, 1976). Studies of AD in animal models also suggest impairment of functional neuronal interactions of BFCN (Villa et al., 2000). This evidence sustains the hypothesis that changes in the cholinergic system are the main cause of AD (Perry, 1986). One promising therapeutic strategy for activating central cholinergic functions has been the use of inhibitors of acetylcholinesterase (AChE).

Donepezil is a potent specific piperidine-based non-competitive and reversible inhibitor of AChE. It acts to inhibit the enzymes which break down unused acetylcholine, thus prolonging the existing acetylcholine and making it more effective. The Eisai Company Limited, Japan, developed the compound as donepezil hydrochloride, and widespread clinical testing began in 1990 for its potential role in AD therapeutics (Kawakami et al., 1996). It is also referred to as E2020 in pharmacological literature. Amongst the class of AChE inhibitors, donepezil has a long half-life, few clinically problematic drug interactions and generally good safety and tolerance. It was approved in 1996 by the US Food and Drug Administration for treatment of mild to moderate AD under the brand name Aricept, with subsequent registrations in Europe and Asia. The enantiomers of donepezil exhibit near identical pharmacological profiles, including inhibitory effects, and consequently it is being developed as a racemic mixture. In continuation of our ongoing programmes on structure elucidation of drug molecules, and to gain further insight into structure–activity relationships, the crystal structure of donepezilim oxalate trihydrate, (I), has been determined and is reported here (Fig. 1 and Table 1).

From an overall perspective, the bond lengths and angles in (I) are comparable with those in similar closely related structures. The composite framework of the molecule in terms of structural features may be viewed in four parts, viz. an indanone moiety, a linking group (methylene), a piperidine moiety and a benzyl moiety. The donepezil cation is in an extended conformation, with the two benzene rings separated by a centroid-to-centroid distance of 12.018 Å. In the oxalate anion, atoms C26, O6 and O7 are disordered over two interpenetrating? [Original text was not clear] sites, with occupancies of 0.604 (4) and 0.396 (4).

The crystal structure of E2020 (Cardozo et al., 1995) has no coordinates availablein the Cambridge Structural Database (CSD, Version?; Allen, 2002) for comparison. However, the crystal structure of the complex E2020–AChE is available [Kryger et al., 1999; Protein Data Bank (Berman et al., 2000) entry 1EVE] and the extracted ligand structure is used here for comparison. It has been reported that the methoxy groups at the C1 and C2 positions of the indanone moiety show dramatically increased activity compared with those substituted elsewhere in the indanone moiety (Sugimoto et al., 1995). Both these methoxy groups in (I) are coplanar with the indanone moiety, as also seen in the E2020–AChE complex structure, and we believe this contributes to the extension in the planar hydrophobic area at the binding site. Interestingly, both methoxy groups are cis-oriented in the title compound [C6—C1—O2—C23 = −0.3 (3)° and C3—C2—O3—C24 = −0.0 (2)°], while they are cis- and trans-oriented (torsion angles 3.3 and 179.3°, respectively) in E2020–AChE (Fig. 2).

A significant difference between the structures of (I) and E2020–AChE is in the orientation of the benzylpiperidine fragment. The orientation differs principally by a rotation of the benzylpiperidine ring about the C10–C11 bond (Fig 2.), defined by the torsion angles C8—C10—C11—C12 and C8—C10—C11—C15 (Table 1). The corresponding angles observed in E2020–AChE are −71.4 and 56.8°, respectively. The position of the N atom on the benzylpiperidine moiety and its distance from the carbonyl group are critical for anti-AChE activity (Sugimoto et al., 2002). This N1···O1 distance is 7.211 (2) Å in (I), with the corresponding distance in the E2020–AChE structure being 6.713 Å. Similarly, the distance between the N atom and the centroid of the benzyl ring (C17–C22) is 3.746 Å in (I) and 3.751 Å in E2020–AChE. The displacement of the piperidine ring (the only H-atom donating site towards binding at the receptor) with respect to the indanone and benzyl ring moieties is illustrated in Fig. 3. The piperidine ring hangs outside these planes; atom N1 is displaced by −1.327 (1) and 1.631 (1) Å from the benzyl and indanone planes, respectively (1.602 and 0.652 Å, respectively, in E2020–AChE). The dihedral angle between the benzyl and indanone planes is 67.6 (1)° (87.2° in E2020–AChE).

Different modes of hydrogen-bonding interactions, viz. cation–anion, water–anion, water–cation and water–water, stabilize the crystal structure of (I) (Fig. 4). Water molecules play an important role in the cohesion and stability of the crystal structure; two of them (O1W and O2W) are involved in seven hydrogen bonds connecting one oxalate anion and two donepezilium cations as donor, with the third water molecule (O3W) as acceptor (Table 2). In addition, the third molecule (O3W) links the other two water molecules as donor and an oxalate anion as acceptor. The centrosymmetrically related indanone ring systems tend to stack and facilitate a significant C8—H8···π interaction (Cg1 is the centroid of the C1–C6 ring in Table 2; interaction not shown in Fig. 4).

In the E2020–AChE structure, donepezil makes no direct hydrogen bonds to the amino acid residues of the binding pocket and only water-bridged hydrogen bonds have been detected. Interestingly, compound (I) also crystallized with three water molecules that similarly mediate the hydrogen bonding.

S2. Experimental

To obtain crystals suitable for X-ray studies, donepezil oxalate (USV Ltd., Mumbai) was dissolved in methanol–water solution (60:40 v/v) and the solvents were allowed to evaporate slowly.

S3. Refinement

The site-occupation factors of the disordered oxalate molecule were refined to 0.604 (4) and 0.396 (4). The H atoms of the water molecule and all N– and O-bound H atoms of the donepezil were located in a difference density map and refined isotropically. All other H atoms were positioned geometrically and treated as riding on their parent C atoms, with C—H distances of 0.93–0.98 Å and an O—H distance of 0.82 Å, with U_iso(H) = 1.2U_eq(C) or 1.5U_eq(methyl C, O). The methyl groups were allowed to rotate but not to tip.

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 1990) and Mercury (Macrae et al., 2006); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. A view of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. The hydrogen bond is shown as a dashed line. The disordered atoms of the minor component (C261, O61 and O71) have been omitted for clarity.
	Fig. 2. An overlay of E2020–AChE (labelled 1) with the title compound (labelled 2) (r.m.s deviation 0.053 Å), superimposing the indanone moieties. H atoms have been omitted for clarity.
	Fig. 3. Orthogonal orientations of the two aromatic ring planes. H atoms have been omitted for clarity. Selected atoms are labelled for ring identification.
	Fig. 4. Part of the crystal structure of (I), viewed down the a axis, showing the networks of hydrogen bonding (dashed lines). A representative set of O atoms are labelled as in Table 2. The minor disordered oxalate component (C261, O61 and O71) and other H atoms attached to C atoms have been omitted for clarity. [Symmetry codes: (i) x, y, z − 1; (ii) 2 − x, 1 − y, 1 − z; (iii) 1 − x, 1/2 + y, 1/2 − z; (iv) x, 3/2 − y, 1/2 + z.]

(R,S)-1-benzyl-4[(5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl] piperidinium hydrogen oxalate trihydrate

Crystal data

C24H30NO3^+·C2HO4^−·3H2O	F(000) = 1120
Mr = 523.57	Dx = 1.286 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 9309 reflections
a = 8.5002 (5) Å	θ = 2.3–27.2°
b = 17.6318 (10) Å	µ = 0.10 mm^−1
c = 18.2158 (10) Å	T = 294 K
β = 97.744 (1)°	Block, colourless
V = 2705.2 (3) Å^3	0.23 × 0.12 × 0.09 mm
Z = 4

Data collection

Bruker SMART APEX CCD area-detector diffractometer	4003 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.023
Graphite monochromator	θmax = 25.0°, θmin = 1.6°
ω scans	h = −10→10
25718 measured reflections	k = −20→20
4754 independent reflections	l = −21→21

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.122	H atoms treated by a mixture of independent and constrained refinement
S = 1.01	w = 1/[σ^2(Fo^2) + (0.0612P)^2 + 0.8458P] where P = (Fo^2 + 2Fc^2)/3
4754 reflections	(Δ/σ)max < 0.001
394 parameters	Δρmax = 0.40 e Å^−3
0 restraints	Δρmin = −0.20 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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
C1	0.8911 (2)	0.44992 (10)	0.59049 (9)	0.0454 (4)
C2	0.90724 (19)	0.53028 (10)	0.58928 (9)	0.0457 (4)
C3	0.8241 (2)	0.57287 (10)	0.53377 (9)	0.0462 (4)
H3	0.8339	0.6254	0.5335	0.055*
C4	0.72559 (19)	0.53591 (9)	0.47822 (9)	0.0439 (4)
C5	0.71080 (18)	0.45798 (9)	0.47910 (9)	0.0431 (4)
C6	0.79357 (19)	0.41371 (10)	0.53567 (9)	0.0451 (4)
H6	0.7824	0.3612	0.5358	0.054*
C7	0.6044 (2)	0.43317 (10)	0.41435 (9)	0.0472 (4)
C8	0.5430 (2)	0.50277 (9)	0.37002 (9)	0.0479 (4)
H8	0.4291	0.5074	0.3727	0.058*
C9	0.6277 (2)	0.57040 (10)	0.41146 (10)	0.0508 (4)
H9A	0.6949	0.5964	0.3805	0.061*
H9B	0.5512	0.6062	0.4263	0.061*
C10	0.5654 (2)	0.49422 (10)	0.28910 (10)	0.0524 (4)
H10A	0.5544	0.4410	0.2759	0.063*
H10B	0.6729	0.5093	0.2836	0.063*
C11	0.4496 (2)	0.54024 (9)	0.23408 (9)	0.0476 (4)
H11	0.3414	0.5243	0.2398	0.057*
C12	0.4766 (2)	0.52315 (10)	0.15519 (9)	0.0530 (4)
H12A	0.5859	0.5348	0.1497	0.064*
H12B	0.4601	0.4694	0.1457	0.064*
C13	0.3676 (2)	0.56782 (9)	0.09831 (9)	0.0481 (4)
H13A	0.3927	0.5564	0.0491	0.058*
H13B	0.2584	0.5530	0.1004	0.058*
C14	0.3533 (2)	0.67000 (10)	0.18939 (8)	0.0449 (4)
H14A	0.2434	0.6585	0.1938	0.054*
H14B	0.3696	0.7239	0.1983	0.054*
C15	0.4609 (2)	0.62547 (9)	0.24723 (9)	0.0461 (4)
H15A	0.4324	0.6367	0.2959	0.055*
H15B	0.5698	0.6416	0.2466	0.055*
C16	0.28026 (19)	0.69832 (10)	0.05737 (9)	0.0441 (4)
H16A	0.1708	0.6830	0.0580	0.053*
H16B	0.2894	0.7512	0.0722	0.053*
C17	0.32028 (18)	0.69091 (9)	−0.02005 (8)	0.0401 (4)
C18	0.2275 (2)	0.64753 (11)	−0.07228 (10)	0.0536 (4)
H18	0.1395	0.6220	−0.0593	0.064*
C19	0.2644 (3)	0.64186 (12)	−0.14359 (10)	0.0631 (5)
H19	0.2016	0.6126	−0.1785	0.076*
C20	0.3943 (3)	0.67958 (11)	−0.16275 (10)	0.0600 (5)
H20	0.4188	0.6761	−0.2109	0.072*
C21	0.4879 (2)	0.72234 (10)	−0.11144 (10)	0.0548 (5)
H21	0.5765	0.7471	−0.1246	0.066*
C22	0.4508 (2)	0.72867 (9)	−0.04025 (9)	0.0462 (4)
H22	0.5136	0.7584	−0.0057	0.055*
C23	0.9683 (3)	0.33462 (12)	0.65410 (12)	0.0709 (6)
H23A	0.8595	0.3203	0.6547	0.106*
H23B	1.0310	0.3175	0.6988	0.106*
H23C	1.0071	0.3119	0.6121	0.106*
C24	1.0328 (3)	0.63899 (11)	0.64834 (11)	0.0635 (5)
H24A	1.0675	0.6556	0.6030	0.095*
H24B	1.1119	0.6516	0.6892	0.095*
H24C	0.9347	0.6637	0.6544	0.095*
N1	0.38583 (16)	0.65127 (7)	0.11266 (7)	0.0377 (3)
H1N	0.489 (2)	0.6633 (10)	0.1105 (9)	0.047 (5)*
O1	0.56777 (17)	0.36806 (7)	0.39698 (8)	0.0662 (4)
O2	0.97918 (16)	0.41530 (7)	0.64921 (7)	0.0595 (3)
O3	1.00949 (15)	0.55892 (7)	0.64598 (7)	0.0583 (3)
C25	0.8246 (2)	0.66591 (10)	0.10047 (10)	0.0493 (4)
O4	0.70269 (15)	0.68997 (9)	0.12309 (7)	0.0649 (4)
O5	0.95164 (16)	0.64930 (10)	0.13661 (8)	0.0750 (4)
C26	0.8335 (4)	0.6778 (3)	0.0168 (3)	0.0472 (9)	0.604 (4)
O6	0.8012 (5)	0.61519 (18)	−0.0208 (2)	0.0711 (9)	0.604 (4)
H6A	0.8082	0.6229	−0.0646	0.107*	0.604 (4)
O7	0.8669 (3)	0.73696 (15)	−0.00972 (14)	0.0685 (9)	0.604 (4)
C261	0.7870 (7)	0.6287 (5)	0.0247 (5)	0.0574 (15)	0.396 (4)
O61	0.8572 (6)	0.6683 (5)	−0.0229 (4)	0.080 (2)	0.396 (4)
H61	0.8379	0.6492	−0.0642	0.120*	0.396 (4)
O71	0.7009 (7)	0.5755 (3)	0.0084 (3)	0.105 (2)	0.396 (4)
O1W	0.9973 (3)	0.50532 (11)	0.20202 (11)	0.0860 (5)
H1W	0.982 (4)	0.5495 (19)	0.1808 (17)	0.110 (11)*
H2W	1.002 (4)	0.5139 (18)	0.2439 (19)	0.111 (11)*
O2W	0.6710 (2)	0.81085 (12)	0.21527 (9)	0.0762 (4)
H3W	0.696 (3)	0.7712 (16)	0.1938 (15)	0.088 (9)*
H4W	0.601 (4)	0.8355 (18)	0.1797 (18)	0.122 (11)*
O3W	1.1696 (2)	0.38293 (14)	0.16047 (9)	0.0910 (6)
H5W	1.123 (3)	0.4201 (15)	0.1737 (14)	0.086 (9)*
H6W	1.225 (4)	0.3627 (17)	0.2011 (18)	0.112 (10)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0472 (9)	0.0492 (9)	0.0397 (9)	0.0035 (7)	0.0052 (7)	0.0040 (7)
C2	0.0450 (9)	0.0518 (10)	0.0404 (9)	−0.0036 (7)	0.0059 (7)	−0.0019 (7)
C3	0.0512 (9)	0.0407 (9)	0.0467 (9)	−0.0039 (7)	0.0062 (7)	0.0003 (7)
C4	0.0453 (9)	0.0439 (9)	0.0430 (9)	0.0010 (7)	0.0069 (7)	0.0031 (7)
C5	0.0426 (9)	0.0434 (9)	0.0433 (9)	0.0001 (7)	0.0054 (7)	0.0020 (7)
C6	0.0494 (9)	0.0407 (9)	0.0450 (9)	0.0014 (7)	0.0060 (7)	0.0036 (7)
C7	0.0490 (9)	0.0437 (10)	0.0476 (9)	−0.0033 (7)	0.0021 (7)	0.0036 (7)
C8	0.0498 (9)	0.0472 (10)	0.0452 (9)	0.0019 (7)	0.0005 (7)	0.0037 (7)
C9	0.0578 (10)	0.0441 (9)	0.0488 (10)	0.0009 (8)	0.0008 (8)	0.0042 (7)
C10	0.0601 (11)	0.0489 (10)	0.0485 (10)	0.0062 (8)	0.0092 (8)	0.0029 (8)
C11	0.0570 (10)	0.0454 (9)	0.0394 (9)	−0.0042 (8)	0.0029 (7)	0.0013 (7)
C12	0.0757 (12)	0.0397 (9)	0.0420 (9)	0.0048 (8)	0.0020 (8)	−0.0010 (7)
C13	0.0640 (11)	0.0417 (9)	0.0372 (8)	−0.0015 (8)	0.0016 (7)	−0.0032 (7)
C14	0.0506 (9)	0.0474 (9)	0.0365 (8)	0.0030 (7)	0.0056 (7)	−0.0050 (7)
C15	0.0553 (10)	0.0478 (9)	0.0341 (8)	−0.0008 (8)	0.0020 (7)	−0.0032 (7)
C16	0.0410 (8)	0.0492 (9)	0.0416 (9)	0.0086 (7)	0.0042 (7)	0.0040 (7)
C17	0.0417 (8)	0.0393 (8)	0.0384 (8)	0.0074 (7)	0.0021 (6)	0.0046 (6)
C18	0.0509 (10)	0.0610 (11)	0.0475 (10)	−0.0045 (8)	0.0016 (8)	0.0025 (8)
C19	0.0785 (14)	0.0644 (12)	0.0434 (10)	−0.0004 (10)	−0.0026 (9)	−0.0063 (9)
C20	0.0856 (14)	0.0550 (11)	0.0417 (10)	0.0166 (10)	0.0175 (9)	0.0070 (8)
C21	0.0608 (11)	0.0489 (10)	0.0577 (11)	0.0071 (8)	0.0188 (9)	0.0153 (9)
C22	0.0492 (9)	0.0419 (9)	0.0468 (9)	0.0018 (7)	0.0035 (7)	0.0052 (7)
C23	0.0909 (15)	0.0557 (12)	0.0609 (12)	0.0088 (11)	−0.0091 (11)	0.0124 (9)
C24	0.0702 (13)	0.0587 (12)	0.0590 (12)	−0.0132 (10)	−0.0009 (9)	−0.0091 (9)
N1	0.0373 (7)	0.0399 (7)	0.0354 (7)	0.0002 (6)	0.0037 (5)	−0.0002 (5)
O1	0.0824 (10)	0.0440 (7)	0.0648 (8)	−0.0076 (6)	−0.0173 (7)	0.0054 (6)
O2	0.0739 (8)	0.0529 (7)	0.0468 (7)	0.0035 (6)	−0.0094 (6)	0.0067 (6)
O3	0.0670 (8)	0.0560 (8)	0.0479 (7)	−0.0087 (6)	−0.0068 (6)	−0.0015 (6)
C25	0.0422 (9)	0.0551 (10)	0.0503 (10)	−0.0004 (8)	0.0050 (8)	−0.0012 (8)
O4	0.0454 (7)	0.0889 (10)	0.0616 (8)	−0.0036 (7)	0.0119 (6)	−0.0182 (7)
O5	0.0496 (8)	0.1077 (12)	0.0650 (9)	0.0047 (7)	−0.0025 (7)	0.0156 (8)
C26	0.0356 (16)	0.051 (3)	0.055 (3)	0.0047 (17)	0.0059 (15)	−0.001 (2)
O6	0.094 (2)	0.0599 (19)	0.060 (2)	−0.0031 (18)	0.0115 (18)	−0.0086 (16)
O7	0.0889 (18)	0.0596 (17)	0.0588 (14)	−0.0103 (13)	0.0167 (12)	0.0049 (13)
C261	0.053 (3)	0.057 (5)	0.063 (5)	0.007 (3)	0.012 (3)	−0.003 (3)
O61	0.063 (3)	0.123 (7)	0.055 (3)	−0.018 (3)	0.013 (2)	−0.014 (3)
O71	0.159 (5)	0.077 (3)	0.078 (3)	−0.039 (3)	0.009 (3)	−0.021 (2)
O1W	0.1223 (15)	0.0767 (12)	0.0575 (10)	0.0141 (10)	0.0067 (10)	−0.0002 (9)
O2W	0.0811 (11)	0.0847 (12)	0.0607 (9)	0.0070 (9)	0.0017 (8)	−0.0167 (9)
O3W	0.0996 (13)	0.1195 (16)	0.0510 (9)	0.0351 (12)	−0.0001 (9)	−0.0113 (10)

Geometric parameters (Å, º)

C1—O2	1.364 (2)	C16—H16A	0.9700
C1—C6	1.367 (2)	C16—H16B	0.9700
C1—C2	1.424 (2)	C17—C18	1.382 (2)
C2—O3	1.3548 (19)	C17—C22	1.385 (2)
C2—C3	1.376 (2)	C18—C19	1.381 (3)
C3—C4	1.386 (2)	C18—H18	0.9300
C3—H3	0.9300	C19—C20	1.374 (3)
C4—C5	1.380 (2)	C19—H19	0.9300
C4—C9	1.506 (2)	C20—C21	1.369 (3)
C5—C6	1.404 (2)	C20—H20	0.9300
C5—C7	1.454 (2)	C21—C22	1.380 (2)
C6—H6	0.9300	C21—H21	0.9300
C7—O1	1.220 (2)	C22—H22	0.9300
C7—C8	1.522 (2)	C23—O2	1.429 (2)
C8—C10	1.519 (2)	C23—H23A	0.9600
C8—C9	1.537 (2)	C23—H23B	0.9600
C8—H8	0.9800	C23—H23C	0.9600
C9—H9A	0.9700	C24—O3	1.425 (2)
C9—H9B	0.9700	C24—H24A	0.9600
C10—C11	1.538 (2)	C24—H24B	0.9600
C10—H10A	0.9700	C24—H24C	0.9600
C10—H10B	0.9700	N1—H1N	0.912 (18)
C11—C12	1.516 (2)	C25—O5	1.222 (2)
C11—C15	1.523 (2)	C25—O4	1.240 (2)
C11—H11	0.9800	C25—C261	1.522 (10)
C12—C13	1.514 (2)	C25—C26	1.550 (7)
C12—H12A	0.9700	C26—O7	1.200 (7)
C12—H12B	0.9700	C26—O6	1.308 (6)
C13—N1	1.499 (2)	O6—H6A	0.8200
C13—H13A	0.9700	C261—O71	1.202 (12)
C13—H13B	0.9700	C261—O61	1.318 (10)
C14—N1	1.4978 (19)	O61—H61	0.8200
C14—C15	1.518 (2)	O1W—H1W	0.87 (3)
C14—H14A	0.9700	O1W—H2W	0.77 (3)
C14—H14B	0.9700	O2W—H3W	0.84 (3)
C15—H15A	0.9700	O2W—H4W	0.92 (3)
C15—H15B	0.9700	O3W—H5W	0.82 (3)
C16—C17	1.500 (2)	O3W—H6W	0.90 (3)
C16—N1	1.5047 (19)
O2—C1—C6	125.33 (16)	C14—C15—H15A	109.1
O2—C1—C2	114.42 (14)	C11—C15—H15A	109.1
C6—C1—C2	120.25 (15)	C14—C15—H15B	109.1
O3—C2—C3	124.75 (16)	C11—C15—H15B	109.1
O3—C2—C1	114.36 (15)	H15A—C15—H15B	107.8
C3—C2—C1	120.89 (15)	C17—C16—N1	113.01 (12)
C2—C3—C4	118.67 (16)	C17—C16—H16A	109.0
C2—C3—H3	120.7	N1—C16—H16A	109.0
C4—C3—H3	120.7	C17—C16—H16B	109.0
C5—C4—C3	120.44 (15)	N1—C16—H16B	109.0
C5—C4—C9	111.72 (14)	H16A—C16—H16B	107.8
C3—C4—C9	127.83 (15)	C18—C17—C22	119.11 (15)
C4—C5—C6	121.65 (15)	C18—C17—C16	120.96 (15)
C4—C5—C7	109.74 (14)	C22—C17—C16	119.93 (14)
C6—C5—C7	128.59 (15)	C19—C18—C17	120.42 (17)
C1—C6—C5	118.10 (16)	C19—C18—H18	119.8
C1—C6—H6	120.9	C17—C18—H18	119.8
C5—C6—H6	120.9	C20—C19—C18	119.78 (18)
O1—C7—C5	127.06 (16)	C20—C19—H19	120.1
O1—C7—C8	124.33 (15)	C18—C19—H19	120.1
C5—C7—C8	108.61 (14)	C21—C20—C19	120.40 (17)
C10—C8—C7	110.86 (14)	C21—C20—H20	119.8
C10—C8—C9	116.24 (15)	C19—C20—H20	119.8
C7—C8—C9	105.12 (13)	C20—C21—C22	120.06 (17)
C10—C8—H8	108.1	C20—C21—H21	120.0
C7—C8—H8	108.1	C22—C21—H21	120.0
C9—C8—H8	108.1	C21—C22—C17	120.23 (16)
C4—C9—C8	104.74 (14)	C21—C22—H22	119.9
C4—C9—H9A	110.8	C17—C22—H22	119.9
C8—C9—H9A	110.8	O2—C23—H23A	109.5
C4—C9—H9B	110.8	O2—C23—H23B	109.5
C8—C9—H9B	110.8	H23A—C23—H23B	109.5
H9A—C9—H9B	108.9	O2—C23—H23C	109.5
C8—C10—C11	115.29 (14)	H23A—C23—H23C	109.5
C8—C10—H10A	108.5	H23B—C23—H23C	109.5
C11—C10—H10A	108.5	O3—C24—H24A	109.5
C8—C10—H10B	108.5	O3—C24—H24B	109.5
C11—C10—H10B	108.5	H24A—C24—H24B	109.5
H10A—C10—H10B	107.5	O3—C24—H24C	109.5
C12—C11—C15	109.32 (14)	H24A—C24—H24C	109.5
C12—C11—C10	110.33 (14)	H24B—C24—H24C	109.5
C15—C11—C10	113.38 (14)	C14—N1—C13	110.58 (12)
C12—C11—H11	107.9	C14—N1—C16	109.55 (12)
C15—C11—H11	107.9	C13—N1—C16	112.72 (12)
C10—C11—H11	107.9	C14—N1—H1N	106.9 (11)
C13—C12—C11	112.86 (15)	C13—N1—H1N	107.3 (11)
C13—C12—H12A	109.0	C16—N1—H1N	109.6 (11)
C11—C12—H12A	109.0	C1—O2—C23	117.46 (14)
C13—C12—H12B	109.0	C2—O3—C24	117.68 (14)
C11—C12—H12B	109.0	O5—C25—O4	128.32 (18)
H12A—C12—H12B	107.8	O5—C25—C261	116.6 (2)
N1—C13—C12	110.61 (13)	O4—C25—C261	111.5 (2)
N1—C13—H13A	109.5	O5—C25—C26	113.88 (19)
C12—C13—H13A	109.5	O4—C25—C26	115.75 (18)
N1—C13—H13B	109.5	O7—C26—O6	124.6 (7)
C12—C13—H13B	109.5	O7—C26—C25	123.9 (4)
H13A—C13—H13B	108.1	O6—C26—C25	111.5 (6)
N1—C14—C15	111.34 (13)	O71—C261—O61	124.3 (11)
N1—C14—H14A	109.4	O71—C261—C25	127.4 (6)
C15—C14—H14A	109.4	O61—C261—C25	108.1 (10)
N1—C14—H14B	109.4	C261—O61—H61	109.5
C15—C14—H14B	109.4	H1W—O1W—H2W	104 (3)
H14A—C14—H14B	108.0	H3W—O2W—H4W	104 (3)
C14—C15—C11	112.46 (13)	H5W—O3W—H6W	107 (3)
O2—C1—C2—O3	1.0 (2)	N1—C14—C15—C11	−55.49 (19)
C6—C1—C2—O3	−178.87 (15)	C12—C11—C15—C14	52.78 (19)
O2—C1—C2—C3	−179.30 (15)	C10—C11—C15—C14	176.32 (14)
C6—C1—C2—C3	0.8 (2)	N1—C16—C17—C18	103.79 (18)
O3—C2—C3—C4	178.75 (15)	N1—C16—C17—C22	−77.04 (18)
C1—C2—C3—C4	−0.9 (2)	C22—C17—C18—C19	0.1 (3)
C2—C3—C4—C5	0.4 (2)	C16—C17—C18—C19	179.24 (16)
C2—C3—C4—C9	−178.19 (16)	C17—C18—C19—C20	0.0 (3)
C3—C4—C5—C6	0.2 (2)	C18—C19—C20—C21	0.4 (3)
C9—C4—C5—C6	178.99 (15)	C19—C20—C21—C22	−0.9 (3)
C3—C4—C5—C7	−178.61 (15)	C20—C21—C22—C17	1.0 (3)
C9—C4—C5—C7	0.20 (19)	C18—C17—C22—C21	−0.6 (2)
O2—C1—C6—C5	179.90 (15)	C16—C17—C22—C21	−179.75 (15)
C2—C1—C6—C5	−0.2 (2)	C15—C14—N1—C13	56.89 (17)
C4—C5—C6—C1	−0.3 (2)	C15—C14—N1—C16	−178.28 (13)
C7—C5—C6—C1	178.26 (16)	C12—C13—N1—C14	−57.20 (18)
C4—C5—C7—O1	178.27 (18)	C12—C13—N1—C16	179.80 (13)
C6—C5—C7—O1	−0.4 (3)	C17—C16—N1—C14	172.20 (13)
C4—C5—C7—C8	−1.87 (19)	C17—C16—N1—C13	−64.22 (17)
C6—C5—C7—C8	179.45 (16)	C6—C1—O2—C23	−0.3 (3)
O1—C7—C8—C10	−51.1 (2)	C2—C1—O2—C23	179.79 (16)
C5—C7—C8—C10	129.07 (15)	C3—C2—O3—C24	0.0 (2)
O1—C7—C8—C9	−177.44 (18)	C1—C2—O3—C24	179.62 (15)
C5—C7—C8—C9	2.70 (18)	O5—C25—C26—O7	−87.0 (3)
C5—C4—C9—C8	1.50 (19)	O4—C25—C26—O7	78.2 (4)
C3—C4—C9—C8	−179.80 (16)	C261—C25—C26—O7	170.1 (6)
C10—C8—C9—C4	−125.46 (16)	O5—C25—C26—O6	92.7 (4)
C7—C8—C9—C4	−2.48 (18)	O4—C25—C26—O6	−102.2 (3)
C7—C8—C10—C11	154.46 (15)	C261—C25—C26—O6	−10.3 (4)
C9—C8—C10—C11	−85.6 (2)	O5—C25—C261—O71	101.3 (6)
C8—C10—C11—C12	−176.34 (15)	O4—C25—C261—O71	−59.0 (7)
C8—C10—C11—C15	60.7 (2)	C26—C25—C261—O71	−163.7 (9)
C15—C11—C12—C13	−53.7 (2)	O5—C25—C261—O61	−83.1 (6)
C10—C11—C12—C13	−179.07 (15)	O4—C25—C261—O61	116.6 (4)
C11—C12—C13—N1	56.8 (2)	C26—C25—C261—O61	11.9 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···O4	0.912 (18)	1.857 (19)	2.7601 (18)	170.4 (16)
O6—H6A···O3W^i	0.82	1.78	2.590 (5)	167
O61—H61···O3W^i	0.82	1.84	2.644 (8)	168
O1W—H1W···O5	0.87 (3)	1.94 (3)	2.809 (3)	178 (3)
O1W—H2W···O2^ii	0.77 (3)	2.30 (3)	3.033 (2)	158 (3)
O1W—H2W···O3^ii	0.77 (3)	2.40 (3)	2.999 (2)	136 (3)
O2W—H3W···O4	0.84 (3)	1.93 (3)	2.749 (2)	163 (3)
O2W—H4W···O1^iii	0.92 (3)	1.95 (3)	2.864 (2)	168 (3)
O3W—H5W···O1W	0.82 (3)	1.95 (3)	2.770 (3)	176 (3)
O3W—H6W···O2W^iv	0.90 (3)	1.89 (3)	2.783 (3)	174 (3)
C8—H8···Cg1^v	0.98	2.81	3.657 (2)	146

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