Quetiapine hemifumarate

Quetiapine hemifumarate (systematic name: 1-[2-(2-hydroxy­ethoxy)eth­yl]-4-(dibenzo[b,f][1,4]thia­zepin-11-­yl)piperazinium hemifumarate), C₂₁H₂₆O₂N₃S⁺·0.5C₄H₂O₄²⁻, a new dibenzothia­zepine antipsychotic, has inter­national approvals for the treatment of schizophrenia. In the tricyclic framework, the central thia­zepine ring has a boat conformation and the dihedral angle between the planar benzene rings is 108.6 (1)°. The protonated piperazine ring exhibits a chair conformation with its ethoxy­ethanol side chain oriented equatorially. The fumarate anion possesses a centre of symmetry. The quetiapin­ium and fumarate ions are connected by O—H...O and N—H...O hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 273 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.055
• wR factor = 0.136
• Data-to-parameter ratio = 18.2

checkCIF/PLATON results

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Alert level C
PLAT029_ALERT_3_C _diffrn_measured_fraction_theta_full Low .......       0.97
PLAT042_ALERT_1_C Calc. and Rep. MoietyFormula Strings Differ ....          ?

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
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   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
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   0 ALERT type 4 Improvement, methodology, query or suggestion

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S1. Comment

Quetiapine, marketed by AstraZeneca under the brand name Seroquel, is a new atypical antipsychotic licensed for the treatment of schizophrenia (Lieberman, 1996). The Seroquel formulation is a fumarate salt. Quetiapine is a novel dibenzothiazepine derivative with its chemical structure reminiscent of that of other antipsychotics, e.g. clozapine and olanzapine. It is a dopamine, specifically D1 and D2 dopamine, inhibitor. Compared to conventional antipsychotics, such as chlorpromazine and haloperidol, quetiapine and other atypical antipsychotics provide superior efficacy or, less side effects, particularly extrapyramidal symptoms (EPS) (Peuskens & Link, 1997; Arvanitis & Miller, 1997). Quetiapine has a well tolerated side effect profile and in long term open label extension studies is found to be popular with patients with high levels of patient acceptability and satisfaction (Casey, 1996). Our interest in the crystal structure of (I) is in continuation of our on-going programmes on the structural elucidation of drug molecules and to gain further insight into structure–activity relationships.

The asymmetric unit of (I) consists of one singly charged quetiapine cation and one-half of a doubly charged fumarate anion; the latter is completed by inversion symmetry (Fig. 1). Bond lengths and angles in quetiapine do not differ significantly from the expected values (Table 1). The C—S bonds are symmetrical. The protonation site of the cation is established as N3. The N—C bonds at N3 are lengthened [mean value 1.494 (2) Å compared to 1.430 (2) Å for N2], as would be expected for a protonated system. Consequently, N3 shows quaternary character and bears a positive charge in a tetrahedral configuration, with bond angles ranging from 110.7 (1) to 114.5 (1)°. The positive charge of the cation is balanced by the negative charge of the fumarate anion which is connected to the cation via N—H···O and O—H···O hydrogen bonding (Table 2).

The conformation of the central thiazepine ring in the (6,7,6)-tricyclic ring system can be described as a boat, with the atoms common to the benzene rings (C1, C2, C9 and C4) as the basal plane, the S atom as the bow and the N1═ C3 bridge as the stern [puckering parameters (Cremer & Pople, 1975) are q2 = 1.009 (2), q3 = 0.291 (2) Å, Q_T = 1.051 (1), ϕ1 = 50.6 (1)°, ϕ2 = −107.4 (3)° and θ = 73.9 (1)°]. The bow angle is 130.5 (1)° and the stern angle is 138.5 (1)°. This facilitates the dibenzothiazepine ring skeleton to form a flattened V-shaped conformation. A similar conformation is observed in the crystal structures of the related antipsychotic agents amoxapine, clozapine, loxapine, loxapine succinate monohydrate, clothiapine-modified, clothiapine, olanzapine, olanzipinium nicotinate, oxyprothepine, and metitepine maleate. Least-squares plane calculations through the aromatic rings flanking the thiazepine ring show that benzene ring B is more planar [Σ(Δ/σ)² = 23.7] than benzene ring A [Σ(Δ/σ)² = 438.9]. The dihedral angle (χ) between the aromatic rings flanking the thiazepine ring planes is 108.6 (1)° and falls in the range 104–127.2° observed for related antipsychotic agents (Table 3). Incidentally, molecular modeling of quetiapine using HYPERCHEM (Hypercube, 1995) predicts this angle to be 145° (Lien et al., 1996). A superimposed fit of related antipsychotic drugs with the central thiazepine ring atoms of (I) shows significant structural similarity (Fig. 2).

A piperazine ring attached to the tricyclic system and its orientation with respect to the tricyclic system is essential for activity (Chakrabarti et al., 1982). The piperazine ring is in a normal chair conformation. The thiazepine nucleus can be viewed as being in equatorial orientation to the piperazine ring. Interestingly, in related antipsychotics, the corresponding torsion angles are observed as similar (Table 3). The ethoxyethanol side chain at the cationic N-atom site of the piperazine ring occupies an equatorial orientation and is in a folded conformation. The torsion angles about C19, O1, C20 and C21 indicate that these atoms do not have fully extended bonds, suggesting possible accommodative aspects of the receptor site of dopamine. However, the solid-state conformation need not reflect the conformational preference at the receptor (or in solution).

It has been shown that these drugs are capable of competing with dopamine in synaptosinal preparations (Seeman et al., 1975; Burt et al., 1975). The relationship of the protonated piperazine ring system to the aromatic ring system may be important for neuroleptic activity (Horn & Snyder, 1971). Some more parameters were compiled in Table 3. These data show a remarkable similarity in the disposition of the molecular fragments for the analyzed compounds and may be useful for postulating receptor interactions towards structure–activity relationship.

The molecular topography of this class of drugs studied by X-ray crystallography features some important structural and conformational determinants (Fig. 3): (a) two benzene rings (A and B) linked by a seven-membered ring are drawn towards each other to form a semi-rigid V-shaped conformation; (b) the central seven-membered ring consisting of one or two heteroatoms, similar or dissimilar, exists in a boat conformation; (c) the conformation of the piperazine ring is in a chair form.

The unit-cell packing (Fig. 2) shows the hydrogen bond which binds the quetiapine cationic species to the anionic fumarate. The protonated distal atom N3 of the piperazine ring and O2 of the ethoxyethanol side chain hydrogen bonds to the half fumarate dianion through atom O4.

S2. Experimental

To obtain crystals suitable for X-ray studies, quetiapine fumarate (procured from Ind-Swift Laboratories Ltd, Punjab, India) was dissolved in a methanol–water solution (95:5) and the solution was allowed to evaporate slowly.

S3. Refinement

The H atom on N3 was located in a difference density map and refined freely. All other H atoms were positioned geometrically and treated as riding, with C—H distances in the range 0.93–0.98 Å and with U_iso(H) = 1.2U_eq(CH).

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 (Bruno et al., 2002); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. A view of the title compound in the crystal structure, including the symmetry-generated half of the fumarate anion. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as small spheres of arbitrary radii and the hydrogen bond as a dashed line. Unlabelled atoms are generated by the symmetry code −x, 1 − y, 1 − z.
	Fig. 2. The superposition of the title compound (I) (red) with clozapine (magenta), amoxapine (green) and olanzapine (orange), revealing the structural similarities. Substituents at the piperazine ring and H atoms have been omitted for clarity.
	Fig. 3. Part of unit cell, showing the fumarate bridge between the quetiapinium molecules, through O—H···O and N—H···O hydrogen bonds. For clarity, H atoms bonded to C atoms have been omitted.

1-[2-(2-hydroxyethoxy)ethyl]-4-(dibenzo[b,f][1,4]thiazepin-11- yl)piperazinium hemifumarate

Crystal data

C21H26O2N3S^+·0.5C4H2O4^2^−	F(000) = 936
Mr = 441.54	Dx = 1.332 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 5025 reflections
a = 11.9479 (8) Å	θ = 2.3–27.6°
b = 13.2197 (9) Å	µ = 0.18 mm^−1
c = 13.9479 (9) Å	T = 273 K
β = 92.327 (1)°	Needle, colorless
V = 2201.2 (3) Å^3	0.22 × 0.13 × 0.08 mm
Z = 4

Data collection

CCD Area Detector diffractometer	4655 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.024
Graphite monochromator	θmax = 28.0°, θmin = 1.7°
ω scans	h = −15→15
24936 measured reflections	k = −17→17
5179 independent reflections	l = −18→18

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)] = 0.055	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.136	H atoms treated by a mixture of independent and constrained refinement
S = 1.12	w = 1/[σ^2(Fo^2) + (0.0578P)^2 + 0.9667P] where P = (Fo^2 + 2Fc^2)/3
5179 reflections	(Δ/σ)max < 0.001
285 parameters	Δρmax = 0.33 e Å^−3
0 restraints	Δρmin = −0.25 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
S1	0.67917 (5)	0.23918 (4)	1.21306 (4)	0.04982 (16)
O1	0.02234 (11)	0.41896 (10)	0.83165 (9)	0.0455 (3)
O2	−0.16062 (13)	0.56205 (15)	0.78615 (12)	0.0703 (5)
H2	−0.1591	0.5660	0.7275	0.106*
N1	0.46811 (12)	0.36975 (12)	1.16361 (10)	0.0372 (3)
H1N	0.2176 (16)	0.2380 (16)	0.8787 (14)	0.037 (5)*
N2	0.41724 (11)	0.31784 (12)	1.01269 (10)	0.0371 (3)
N3	0.24826 (11)	0.29750 (11)	0.86343 (9)	0.0307 (3)
C1	0.70266 (14)	0.29197 (14)	1.09893 (12)	0.0378 (4)
C2	0.61584 (14)	0.34007 (12)	1.04670 (11)	0.0333 (3)
C3	0.49932 (13)	0.34088 (12)	1.08108 (11)	0.0320 (3)
C4	0.54110 (14)	0.40333 (14)	1.23794 (11)	0.0364 (4)
C5	0.50722 (18)	0.48747 (16)	1.28965 (13)	0.0496 (5)
H5	0.4427	0.5221	1.2696	0.060*
C6	0.5678 (2)	0.52017 (19)	1.37005 (15)	0.0619 (6)
H6	0.5441	0.5767	1.4033	0.074*
C7	0.6632 (2)	0.4697 (2)	1.40139 (15)	0.0637 (6)
H7	0.7037	0.4918	1.4558	0.076*
C8	0.69821 (18)	0.38651 (18)	1.35184 (14)	0.0538 (5)
H8	0.7631	0.3528	1.3726	0.065*
C9	0.63751 (15)	0.35192 (14)	1.27059 (12)	0.0401 (4)
C10	0.80920 (16)	0.28831 (17)	1.06292 (16)	0.0509 (5)
H10	0.8661	0.2537	1.0965	0.061*
C11	0.83106 (17)	0.33554 (19)	0.97797 (16)	0.0573 (6)
H11	0.9024	0.3319	0.9538	0.069*
C12	0.74784 (19)	0.38824 (16)	0.92836 (14)	0.0526 (5)
H12	0.7638	0.4228	0.8725	0.063*
C13	0.64046 (16)	0.38960 (14)	0.96192 (12)	0.0413 (4)
H13	0.5841	0.4240	0.9275	0.050*
C14	0.43095 (14)	0.24429 (13)	0.93601 (12)	0.0360 (4)
H14A	0.4021	0.1791	0.9553	0.043*
H14B	0.5099	0.2365	0.9240	0.043*
C15	0.36893 (14)	0.27925 (13)	0.84560 (11)	0.0348 (4)
H15A	0.4026	0.3412	0.8230	0.042*
H15B	0.3752	0.2283	0.7960	0.042*
C16	0.23632 (14)	0.36913 (14)	0.94511 (12)	0.0366 (4)
H16A	0.1577	0.3764	0.9585	0.044*
H16B	0.2647	0.4351	0.9276	0.044*
C17	0.29978 (14)	0.33152 (15)	1.03376 (12)	0.0387 (4)
H17A	0.2933	0.3800	1.0854	0.046*
H17B	0.2684	0.2678	1.0541	0.046*
C18	0.18940 (15)	0.33216 (15)	0.77255 (12)	0.0406 (4)
H18A	0.2076	0.2861	0.7213	0.049*
H18B	0.2178	0.3984	0.7561	0.049*
C19	0.06342 (16)	0.33834 (15)	0.77731 (15)	0.0468 (4)
H19A	0.0317	0.3438	0.7124	0.056*
H19B	0.0367	0.2755	0.8040	0.056*
C20	0.03659 (17)	0.51652 (16)	0.79182 (15)	0.0496 (5)
H20A	0.0323	0.5128	0.7223	0.060*
H20B	0.1093	0.5436	0.8118	0.060*
C21	−0.0544 (2)	0.58319 (17)	0.82660 (18)	0.0617 (6)
H21A	−0.0569	0.5765	0.8957	0.074*
H21B	−0.0359	0.6530	0.8126	0.074*
O3	−0.06674 (14)	0.68278 (12)	0.48024 (13)	0.0689 (5)
O4	−0.16634 (12)	0.62037 (11)	0.59699 (10)	0.0521 (4)
C22	−0.09474 (15)	0.61342 (14)	0.53231 (14)	0.0420 (4)
C23	−0.04473 (16)	0.50922 (15)	0.52307 (13)	0.0438 (4)
H23	−0.0802	0.4553	0.5521	0.053*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0578 (3)	0.0458 (3)	0.0453 (3)	0.0060 (2)	−0.0041 (2)	0.0118 (2)
O1	0.0474 (7)	0.0426 (7)	0.0466 (7)	0.0092 (6)	0.0048 (6)	0.0041 (6)
O2	0.0576 (10)	0.0902 (13)	0.0641 (10)	0.0193 (9)	0.0135 (8)	0.0275 (9)
N1	0.0348 (7)	0.0478 (8)	0.0290 (7)	−0.0036 (6)	0.0001 (5)	−0.0012 (6)
N2	0.0308 (7)	0.0495 (8)	0.0308 (7)	0.0036 (6)	0.0003 (5)	−0.0089 (6)
N3	0.0314 (7)	0.0335 (7)	0.0272 (6)	−0.0012 (5)	0.0023 (5)	−0.0032 (5)
C1	0.0356 (9)	0.0396 (9)	0.0382 (9)	−0.0016 (7)	0.0005 (7)	−0.0014 (7)
C2	0.0344 (8)	0.0349 (8)	0.0307 (8)	−0.0047 (6)	0.0023 (6)	−0.0010 (6)
C3	0.0333 (8)	0.0323 (8)	0.0304 (8)	−0.0007 (6)	0.0000 (6)	0.0030 (6)
C4	0.0390 (9)	0.0440 (9)	0.0263 (7)	−0.0092 (7)	0.0019 (6)	0.0032 (7)
C5	0.0565 (12)	0.0544 (12)	0.0378 (9)	−0.0013 (9)	0.0001 (8)	−0.0054 (8)
C6	0.0779 (16)	0.0630 (14)	0.0445 (11)	−0.0100 (12)	−0.0015 (11)	−0.0162 (10)
C7	0.0713 (15)	0.0776 (16)	0.0408 (11)	−0.0226 (12)	−0.0141 (10)	−0.0078 (11)
C8	0.0492 (11)	0.0708 (14)	0.0404 (10)	−0.0120 (10)	−0.0108 (8)	0.0101 (10)
C9	0.0427 (9)	0.0457 (10)	0.0318 (8)	−0.0085 (8)	0.0004 (7)	0.0071 (7)
C10	0.0359 (10)	0.0600 (12)	0.0567 (12)	0.0011 (8)	−0.0010 (8)	−0.0134 (10)
C11	0.0388 (10)	0.0746 (15)	0.0595 (13)	−0.0142 (10)	0.0152 (9)	−0.0212 (11)
C12	0.0643 (13)	0.0554 (12)	0.0394 (10)	−0.0255 (10)	0.0183 (9)	−0.0103 (9)
C13	0.0502 (10)	0.0416 (9)	0.0324 (8)	−0.0091 (8)	0.0031 (7)	−0.0007 (7)
C14	0.0336 (8)	0.0391 (9)	0.0351 (8)	0.0035 (7)	0.0003 (6)	−0.0071 (7)
C15	0.0344 (8)	0.0400 (9)	0.0304 (8)	0.0018 (7)	0.0067 (6)	−0.0062 (6)
C16	0.0337 (8)	0.0434 (9)	0.0326 (8)	0.0040 (7)	0.0016 (6)	−0.0111 (7)
C17	0.0313 (8)	0.0566 (11)	0.0283 (8)	0.0014 (7)	0.0027 (6)	−0.0085 (7)
C18	0.0469 (10)	0.0469 (10)	0.0279 (8)	0.0076 (8)	−0.0007 (7)	−0.0031 (7)
C19	0.0440 (10)	0.0445 (10)	0.0510 (11)	0.0038 (8)	−0.0088 (8)	−0.0051 (8)
C20	0.0491 (11)	0.0499 (11)	0.0498 (11)	0.0003 (9)	0.0017 (9)	0.0053 (9)
C21	0.0732 (16)	0.0485 (12)	0.0634 (14)	0.0170 (11)	0.0034 (11)	0.0054 (10)
O3	0.0691 (10)	0.0533 (9)	0.0867 (12)	0.0146 (8)	0.0316 (9)	0.0097 (8)
O4	0.0599 (9)	0.0479 (8)	0.0492 (8)	0.0172 (6)	0.0107 (7)	0.0016 (6)
C22	0.0396 (9)	0.0405 (9)	0.0454 (10)	0.0077 (7)	−0.0031 (8)	−0.0050 (8)
C23	0.0449 (10)	0.0424 (10)	0.0441 (10)	0.0056 (8)	−0.0006 (8)	−0.0028 (8)

Geometric parameters (Å, º)

S1—C1	1.7710 (18)	C11—C12	1.377 (3)
S1—C9	1.773 (2)	C11—H11	0.9300
O1—C19	1.408 (2)	C12—C13	1.384 (3)
O1—C20	1.417 (2)	C12—H12	0.9300
O2—C21	1.396 (3)	C13—H13	0.9300
O2—H2	0.8200	C14—C15	1.509 (2)
N1—C3	1.282 (2)	C14—H14A	0.9700
N1—C4	1.400 (2)	C14—H14B	0.9700
N2—C3	1.374 (2)	C15—H15A	0.9700
N2—C17	1.457 (2)	C15—H15B	0.9700
N2—C14	1.460 (2)	C16—C17	1.508 (2)
N3—C15	1.493 (2)	C16—H16A	0.9700
N3—C16	1.493 (2)	C16—H16B	0.9700
N3—C18	1.496 (2)	C17—H17A	0.9700
N3—H1N	0.90 (2)	C17—H17B	0.9700
C1—C10	1.388 (3)	C18—C19	1.511 (3)
C1—C2	1.396 (2)	C18—H18A	0.9700
C2—C13	1.393 (2)	C18—H18B	0.9700
C2—C3	1.491 (2)	C19—H19A	0.9700
C4—C5	1.395 (3)	C19—H19B	0.9700
C4—C9	1.398 (3)	C20—C21	1.496 (3)
C5—C6	1.379 (3)	C20—H20A	0.9700
C5—H5	0.9300	C20—H20B	0.9700
C6—C7	1.376 (4)	C21—H21A	0.9700
C6—H6	0.9300	C21—H21B	0.9700
C7—C8	1.373 (3)	O3—C22	1.225 (2)
C7—H7	0.9300	O4—C22	1.272 (2)
C8—C9	1.397 (3)	C22—C23	1.509 (3)
C8—H8	0.9300	C23—C23^i	1.293 (4)
C10—C11	1.374 (3)	C23—H23	0.9300
C10—H10	0.9300
C1—S1—C9	97.66 (8)	N2—C14—H14A	109.7
C19—O1—C20	115.34 (15)	C15—C14—H14A	109.7
C21—O2—H2	109.5	N2—C14—H14B	109.7
C3—N1—C4	124.35 (15)	C15—C14—H14B	109.7
C3—N2—C17	119.91 (13)	H14A—C14—H14B	108.2
C3—N2—C14	123.93 (14)	N3—C15—C14	110.80 (13)
C17—N2—C14	111.61 (13)	N3—C15—H15A	109.5
C15—N3—C16	110.65 (12)	C14—C15—H15A	109.5
C15—N3—C18	109.41 (12)	N3—C15—H15B	109.5
C16—N3—C18	113.33 (13)	C14—C15—H15B	109.5
C15—N3—H1N	107.7 (13)	H15A—C15—H15B	108.1
C16—N3—H1N	108.8 (12)	N3—C16—C17	110.86 (14)
C18—N3—H1N	106.7 (13)	N3—C16—H16A	109.5
C10—C1—C2	119.99 (17)	C17—C16—H16A	109.5
C10—C1—S1	119.51 (15)	N3—C16—H16B	109.5
C2—C1—S1	120.46 (13)	C17—C16—H16B	109.5
C13—C2—C1	118.60 (16)	H16A—C16—H16B	108.1
C13—C2—C3	120.11 (15)	N2—C17—C16	109.38 (13)
C1—C2—C3	121.28 (14)	N2—C17—H17A	109.8
N1—C3—N2	117.63 (14)	C16—C17—H17A	109.8
N1—C3—C2	126.89 (15)	N2—C17—H17B	109.8
N2—C3—C2	115.12 (13)	C16—C17—H17B	109.8
C5—C4—C9	118.16 (16)	H17A—C17—H17B	108.2
C5—C4—N1	116.81 (17)	N3—C18—C19	114.46 (15)
C9—C4—N1	124.58 (17)	N3—C18—H18A	108.6
C6—C5—C4	121.1 (2)	C19—C18—H18A	108.6
C6—C5—H5	119.4	N3—C18—H18B	108.6
C4—C5—H5	119.4	C19—C18—H18B	108.6
C7—C6—C5	120.5 (2)	H18A—C18—H18B	107.6
C7—C6—H6	119.8	O1—C19—C18	115.73 (16)
C5—C6—H6	119.8	O1—C19—H19A	108.3
C8—C7—C6	119.56 (19)	C18—C19—H19A	108.3
C8—C7—H7	120.2	O1—C19—H19B	108.3
C6—C7—H7	120.2	C18—C19—H19B	108.3
C7—C8—C9	120.8 (2)	H19A—C19—H19B	107.4
C7—C8—H8	119.6	O1—C20—C21	107.97 (17)
C9—C8—H8	119.6	O1—C20—H20A	110.1
C8—C9—C4	119.92 (19)	C21—C20—H20A	110.1
C8—C9—S1	119.74 (16)	O1—C20—H20B	110.1
C4—C9—S1	120.26 (13)	C21—C20—H20B	110.1
C11—C10—C1	120.4 (2)	H20A—C20—H20B	108.4
C11—C10—H10	119.8	O2—C21—C20	114.3 (2)
C1—C10—H10	119.8	O2—C21—H21A	108.7
C10—C11—C12	120.30 (18)	C20—C21—H21A	108.7
C10—C11—H11	119.8	O2—C21—H21B	108.7
C12—C11—H11	119.8	C20—C21—H21B	108.7
C11—C12—C13	119.80 (19)	H21A—C21—H21B	107.6
C11—C12—H12	120.1	O3—C22—O4	125.06 (17)
C13—C12—H12	120.1	O3—C22—C23	120.94 (17)
C12—C13—C2	120.78 (19)	O4—C22—C23	114.00 (17)
C12—C13—H13	119.6	C23^i—C23—C22	123.6 (2)
C2—C13—H13	119.6	C23^i—C23—H23	118.2
N2—C14—C15	110.03 (13)	C22—C23—H23	118.2
C9—S1—C1—C10	118.05 (16)	N1—C4—C9—S1	3.5 (2)
C9—S1—C1—C2	−59.75 (16)	C1—S1—C9—C8	−120.59 (16)
C10—C1—C2—C13	−4.3 (3)	C1—S1—C9—C4	62.67 (15)
S1—C1—C2—C13	173.48 (13)	C2—C1—C10—C11	2.8 (3)
C10—C1—C2—C3	176.95 (17)	S1—C1—C10—C11	−175.02 (16)
S1—C1—C2—C3	−5.3 (2)	C1—C10—C11—C12	0.9 (3)
C4—N1—C3—N2	−174.76 (16)	C10—C11—C12—C13	−3.1 (3)
C4—N1—C3—C2	−2.1 (3)	C11—C12—C13—C2	1.5 (3)
C17—N2—C3—N1	3.1 (2)	C1—C2—C13—C12	2.2 (3)
C14—N2—C3—N1	−150.93 (16)	C3—C2—C13—C12	−179.03 (16)
C17—N2—C3—C2	−170.47 (15)	C3—N2—C14—C15	−144.34 (16)
C14—N2—C3—C2	35.5 (2)	C17—N2—C14—C15	59.76 (19)
C13—C2—C3—N1	−125.31 (19)	C16—N3—C15—C14	54.35 (18)
C1—C2—C3—N1	53.4 (2)	C18—N3—C15—C14	179.91 (14)
C13—C2—C3—N2	47.6 (2)	N2—C14—C15—N3	−56.15 (18)
C1—C2—C3—N2	−133.72 (17)	C15—N3—C16—C17	−55.19 (18)
C3—N1—C4—C5	138.06 (18)	C18—N3—C16—C17	−178.52 (14)
C3—N1—C4—C9	−49.9 (3)	C3—N2—C17—C16	142.80 (16)
C9—C4—C5—C6	0.9 (3)	C14—N2—C17—C16	−60.21 (19)
N1—C4—C5—C6	173.51 (19)	N3—C16—C17—N2	57.50 (19)
C4—C5—C6—C7	−0.4 (3)	C15—N3—C18—C19	171.36 (15)
C5—C6—C7—C8	0.2 (4)	C16—N3—C18—C19	−64.6 (2)
C6—C7—C8—C9	−0.6 (3)	C20—O1—C19—C18	69.2 (2)
C7—C8—C9—C4	1.2 (3)	N3—C18—C19—O1	72.8 (2)
C7—C8—C9—S1	−175.56 (17)	C19—O1—C20—C21	152.51 (17)
C5—C4—C9—C8	−1.3 (3)	O1—C20—C21—O2	−71.7 (2)
N1—C4—C9—C8	−173.27 (16)	O3—C22—C23—C23^i	15.3 (4)
C5—C4—C9—S1	175.44 (14)	O4—C22—C23—C23^i	−165.0 (2)

Symmetry code: (i) −x, −y+1, −z+1.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O4	0.82	1.96	2.747 (2)	162
N3—H1N···O4^ii	0.90 (2)	1.71 (2)	2.606 (2)	175.8 (19)

Symmetry code: (ii) −x, y−1/2, −z+3/2.