Perindoprilat monohydrate

The title compound [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carb­oxy­octa­hydro-1H-indol-1-yl]-1-oxo­propan-2-­yl}aza­nium­yl)pentan­oate monohydrate], C₁₇H₂₈N₂O₅·H₂O, (I)·H₂O, the active metabolite of the anti­hypertensive and cardiovascular drug perindopril, was obtained during polymorphism screening of perindoprilat. It crystallizes in the chiral ortho­rhom­bic space group P2₁2₁2₁, the same as the previously reported ethanol disolvate [Pascard, Guilhem, Vincent, Remond, Portevin & Laubie (1991). J. Med. Chem. 34, 663–669] and dimethyl sulfoxide hemisolvate [Bojarska, Maniukiewicz, Sieroń, Fruziński, Kopczacki, Walczyński & Remko (2012). Acta Cryst. C68, o341–o343]. The asymmetric unit of (I)·H₂O contains one independent perindoprilat zwitterion and one water mol­ecule. These inter­act via strong hydrogen bonds to give a cyclic R²₂(7) synthon, which provides a rigid mol­ecular conformation. The geometric parameters of all three forms are similar. The conformations of the perhydro­indole group are almost identical, but the n-alkyl chain has conformational freedom. A three-dimensional hydrogen-bonding network of O—H...O and N—H...O inter­actions is observed in the crystal structure of (I)·H₂O, similar to the other two solvates, but because of the presence of different solvents the three crystal structures have diverse packing motifs. All three solvatomorphs are additionally stabilized by nonclassical weak C—H...O contacts.

S1. Comment

Perindopril is an angiotensin-converting-enzyme (ACE) inhibitor and has an established position in the main clinical treatment guidelines (Brugts et al., 2009). As an active pharmaceutical ingredient, perindopril is contained in numerous drugs, for example coversyl (L-arginine salt) and aceon (perindopril erbumine) (Telejko, 2007; Remko, 2009). There is an official standard for perindopril salts in the European Pharmacopoeia (European Directorate for the Quality of Medicines and HealthCare, 2011; Malenović et al., 2011). Perindopril is a non-sulfhydryl acid–ester prodrug, which after oral administration undergoes hydrolysis, promoted by the esterases in the liver and plasma, to active dicarboxylic acid perindoprilat (Laubie et al., 1984; Lecocq et al., 1990). It has wide-ranging pharmacodynamic properties which include, inter alia, vasodilation, restriction of cardiovascular remodelling, anti-atherogenic, anti-ischaemic and anti-thrombotic activity, enhanced endothelial function and improved fibrinolytic balance. With high tissue ACE affinity and a long duration of action, it has a positive safety and tolerability profile (Ferrari, 2005; Opie, 2011). Moreover, perindopril, and also ramipril, have been associated with lower mortality than other ACE inhibitors (Pilote et al., 2004). More than 20 years ago, Pascard et al. (1991) characterized a preferential solid-state conformation of perindoprilat ethanol disolvate [denoted (I).2EtOH] [Cambridge Structural Database (CSD; Allen, 2002) refcode SIWBUV], but in that structure, determined at room temperature, the ethanol molecules and the alkyl chain of perindoprilat were disordered (0.8:0.2), with some imprecisely refined and some missing H atoms. Thus, hydrogen-bonding interactions could not be reliably defined.

Very recently, we reported a more precise molecular structure of perindoprilat DMSO hemisolvate, (I).0.5DMSO (Bojarska et al., 2012). We have now investigated a new crystal form of perindoprilat, which crystallizes as a monohydrate, with one perindoprilat entity and one water molecule in the asymmetric unit, (I).H₂O. From a pharmaceutical point of view a hydrate is considerably better. Thus, perindoprilat monohydrate, (I).H₂O, is the subject of this article as a continuation of our studies.

A view of the molecular structure of (I).H₂O is shown in Fig. 1. Like the two structures reported previously, (I).H₂O crystallizes in an orthorhombic setting. The Sohnke space group P2₁2₁2₁, which is the most common for solvates with a chiral main component (Cruz Cabeza et al., 2007), was unambiguously determined. The stereochemical configuration of the main molecule was established to be S at its five chiral centres (C atoms C1, C3, C8, C10 and C11) (Eliel & Wilen, 1994) and was confirmed by the Flack (1983) and Hooft (Hooft et al., 2008) parameters of 0.04 (14) and 0.05 (3), respectively, which is important for its pharmacological activity (Vincent & Schiavi, 1991).

Intramolecular proton transfer from atom O3 of the carboxy group to alanine atom N2 leads to the zwitterionic form of perindoprilat (see scheme and Fig. 1). The bond lengths C17—O3 and C17—O2 are equal, at 1.2580 (16) and 1.2451 (16) Å, respectively, indicating that electron delocalization has increased in this group. All the bond lengths and angles are in the usual ranges (Orpen et al., 1994).

The molecular structure of (I).H₂O is largely comparable with the previously reported analogues. There is a fairly close resemblance between the perhydroindole group conformations, unlike the case of the n-alkyl chain, which is significantly different. The six-membered ring (C3–C8) adopts a slightly deformed chair conformation, as confirmed by the puckering parameters Q = 0.5445 (16) Å, θ = 165.17 (16)° and ϕ = 3.4 (6)° (Cremer & Pople, 1975; Spek, 2009). The proline ring (N1/C1–C3/C8) is in an envelope conformation [puckering parameters Q = 0.3973 (14) Å and ϕ = 284.50 (19)°]. The torsion angle between the alanine methyl group and the amide plane (O1/C9/C10/C16) is 74.70 (15)°. The terminal alkyl chain conformation of (I).H₂O is synclinal [the N2—C11—C12—C13 dihedral [torsion?] angle is -60.04 (15)°]. The conformational difference between the perindoprilat molecules in all three known solvates involves only the orientation of the n-alkyl chain, which in (I).0.5DMSO and (I).2EtOH has a syn-clinal or anti-periplanar orientation. In Fig. 2, all the solvates are superimposed to emphasize the different n-alkyl chain orientations. It is worth mentioning that the geometric parameters of perindoprilat hydrate are in good agreement with those of two perindopril erbumine structures (Remko et al., 2011; CSD refcodes IVEGIA and IVEGOG).

In the crystal structure of (I).H₂O, the perindoprilat molecules are connected to each other via intermolecular hydrogen bonding. Additional hydrogen bonds to the water molecules are also formed (Fig. 3, Table 1). Classical strong intermolecular interactions of O—H···O and N—H···O types create a three-dimensional network. The N—H···O hydrogen bonds are rather stronger and the O—H···O ones rather weaker in (I).H₂O than in (I).0.5DMSO. Among the hydrogen bonds listed, O5—H5O···O3ⁱⁱⁱ is the shortest [2.5929 (14) Å; symmetry code given in Table 1] and O1W—H2W···O1 is the longest [2.8307 (15) Å].

At the first level of graph-set theory (Etter et al., 1990) there are two chains perpendicular to each other: a five-membered chain with a C(5) graph-set motif which runs along the a axis, and a C(11) chain along the b axis, formed through N2—H2NB···O2(x + 1/2, -y + 3/2, -z + 2) and O5–H5O···O3(-x + 2, y + 1/2, -z + 3/2) interactions, respectively (Fig. 3). At the second level of graph-set theory (Bernstein et al., 1995), ten-membered helical and seven-membered extended chains are present, namely a C²₂(10) chain formed through O1W—H1W···O3(x + 1, y, z) and O1W—H2W···O1 interactions, and a C²₂(7) chain formed via N2—H2NA···O1W and O1W—H1W···O3(x + 1, y, z) interactions, forming a sheet along the a axis in which an R²₂ (7) motif can be identified (Fig. 3).

The water molecule acts as both a donor, donating its H atoms to the O atoms of the COO^- and CO groups [O1W—H1W···O3(x + 1, y, z) and O1W–H2W···O1, respectively], and an acceptor [N2—H2NA···O1W], linking perindoprilat molecules. In the case of carbonyl group O1, atom H2W participates in O—H···O hydrogen bonds with quite an acute angle. N2—H2NB···O2(x + 1/2, -y + 3/2, -z + 2), O1W—H1W···O3(x + 1, y, z) and N2—H2NA···O1W interactions form other R⁴₄(13) edge-fused rings connecting three perindoprilat molecules and one water molecule together. In addition, at the third level of graph-set theory, a large ring motif with graph-set notation R⁵₆(29) formed through O1W—H2W···O1, O1W—H1W···O3(x + 1, y, z), O5—H5O···O3(-x + 2, y + 1/2, -z + 3/2) and N2—H2NA···O1W contacts can be identified.

There are also short weak C—H···O intermolecular contacts present. The contact C1—H1···O4^iv, between the proline ring and the COOH group, has a length of 3.2777 (16) Å and an angle of 140° [symmetry code: (iv) -x + 2, y - 1/2, -z + 3/2], while the other hydrogen bond C4—H4A···O1^v, between the six-membered ring and the carbonyl group, has a length of 3.3926 (17) Å and an angle of 142° [symmetry code: (v) x - 1, y, z]. All hydrogen-bonding interactions are listed in Table 1.

In conclusion, the crystal structure of (I).H₂O has been resolved, revealing interesting conformational resemblances but also certain differences, especially different crystal packing motifs, compared with the (I).0.5DMSO and (I).2EtOH solvates published previously. The solvent water molecule appears to play a crucial role in the crystal packing and is a significant building element in the formation of a three-dimensional hydrogen-bond network.

Related literature

For related literature, see: Allen (2002); Bernstein et al. (1995); Bojarska et al. (2012); Brugts et al. (2009); Cremer & Pople (1975); Cruz Cabeza, Pidcock, Day, Motherwell & Jones (2007); Eliel & Wilen (1994); Etter et al. (1990); European & HealthCare (2011); Ferrari (2005); Flack (1983); Hooft et al. (2008); Laubie et al. (1984); Lecocq et al. (1990); Malenović et al. (2011); Opie (2011); Orpen et al. (1994); Pascard et al. (1991); Pilote et al. (2004); Remko (2009); Remko et al. (2011); Robert et al. (1984); Spek (2009); Telejko (2007); Vincent & Schiavi (1991); Vincent et al. (1982).

S2. Experimental

The title compound was obtained according to the synthesis described by Vincent et al. (1982) and Robert et al. (1984). Recrystallization from a solution in a water–ethanol mixture (1:1 v/v) at room temperature over one month afforded colourless prismatic crystals of (I).H₂O.

S3. Refinement

H atoms were located in difference Fourier maps and subsequently geometrically optimized and allowed for as riding atoms, with C—H = 1.00 for methine, 0.99 for methylene and 0.98 Å for methyl groups, and with U_iso(H) = 1.2U_eq(C) for methine and methylene H atoms or 1.5U_eq(C) for methyl H atoms. H atoms bonded to N or O atoms (including water molecules) were refined freely.

Computing details

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT-Plus (Bruker, 2008); data reduction: SAINT-Plus (Bruker, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009) and Mercury (Macrae et al., 2008); software used to prepare material for publication: PLATON (Spek, 2009).

Figures

	Fig. 1. The molecular structure of (I).H2O, showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and dashed lines indicate hydrogen bonds.
	Fig. 2. Overlay plot of all currently known perindoprilat crystal structures, (I).H2O, (I).0.5DMSO and (I).2EtOH, superimposed on their common amide plane.
	Fig. 3. A partial packing diagram for (I).H2O. Intermolecular hydrogen bonds are indicated by dashed lines. H atoms not involved in the hydrogen bonds have been omitted for clarity. [Symmetry codes: (i) x + 1/2, -y + 3/2, -z + 2; (ii) x + 1, y, z; (iii) -x + 2, y + 1/2, -z + 3/2].

(1S)-2-((S)-{1-[2S,3aS,7aS)-2- carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2yl}azaniumyl)pentanoate monohydrate

Crystal data

C17H28N2O5·H2O	F(000) = 776
Mr = 358.43	Dx = 1.253 Mg m^−3
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 9990 reflections
a = 8.1645 (2) Å	θ = 3.8–67.7°
b = 10.0136 (2) Å	µ = 0.78 mm^−1
c = 23.2429 (5) Å	T = 100 K
V = 1900.25 (7) Å^3	Prism, colourless
Z = 4	0.30 × 0.25 × 0.20 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	3321 independent reflections
Radiation source: 30W microsource with MonoCap capillary	3304 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.026
ω scans	θmax = 66.0°, θmin = 3.8°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −9→9
Tmin = 0.799, Tmax = 0.859	k = −11→10
19011 measured reflections	l = −27→27

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.027	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.069	w = 1/[σ^2(Fo^2) + (0.0354P)^2 + 0.4207P] where P = (Fo^2 + 2Fc^2)/3
S = 1.08	(Δ/σ)max = 0.001
3321 reflections	Δρmax = 0.17 e Å^−3
248 parameters	Δρmin = −0.15 e Å^−3
0 restraints	Absolute structure: Flack (1983), with 1396 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.04 (14)

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement on F² for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The observed criterion of F² > σ(F²) is used only for calculating -R-factor-obs 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 (Ų)

	x	y	z	Uiso*/Ueq
O1	1.19141 (11)	0.77807 (9)	0.81604 (4)	0.0234 (3)
O2	0.81043 (12)	0.73189 (10)	0.96914 (4)	0.0267 (3)
O3	0.74520 (11)	0.57632 (10)	0.90423 (4)	0.0271 (3)
O4	1.14302 (11)	1.05823 (9)	0.73988 (4)	0.0258 (3)
O5	1.12231 (12)	0.91004 (10)	0.66751 (4)	0.0256 (3)
N1	0.95001 (13)	0.88641 (11)	0.80975 (4)	0.0188 (3)
N2	1.13397 (14)	0.73600 (11)	0.93327 (5)	0.0202 (3)
C1	0.95227 (16)	0.87467 (13)	0.74669 (5)	0.0203 (4)
C2	0.78361 (16)	0.92720 (15)	0.72808 (5)	0.0243 (4)
C3	0.67608 (16)	0.90273 (14)	0.78116 (6)	0.0226 (4)
C4	0.51274 (16)	0.97735 (16)	0.78149 (6)	0.0298 (4)
C5	0.52798 (18)	1.12478 (16)	0.79661 (7)	0.0351 (5)
C6	0.62553 (18)	1.14382 (14)	0.85218 (7)	0.0319 (4)
C7	0.79826 (17)	1.08739 (13)	0.84432 (6)	0.0259 (4)
C8	0.79096 (15)	0.93817 (13)	0.83136 (5)	0.0194 (3)
C9	1.07581 (15)	0.83683 (12)	0.83935 (5)	0.0190 (3)
C10	1.07867 (15)	0.86178 (13)	0.90427 (5)	0.0206 (3)
C11	1.02815 (16)	0.61545 (13)	0.92251 (5)	0.0203 (3)
C12	1.08206 (18)	0.50005 (14)	0.96119 (6)	0.0275 (4)
C13	1.2594 (2)	0.45466 (17)	0.95242 (7)	0.0361 (5)
C14	1.2974 (2)	0.32644 (17)	0.98464 (8)	0.0450 (6)
C15	1.08629 (15)	0.95782 (13)	0.71945 (6)	0.0205 (3)
C16	1.19887 (18)	0.97438 (14)	0.91845 (6)	0.0276 (4)
C17	0.84528 (16)	0.64538 (13)	0.93266 (5)	0.0202 (3)
O1W	1.45303 (14)	0.71407 (13)	0.89105 (5)	0.0389 (3)
H1	0.96460	0.77890	0.73520	0.0240*
H2NB	1.145 (2)	0.7501 (16)	0.9706 (8)	0.029 (4)*
H2NA	1.243 (2)	0.7151 (17)	0.9209 (7)	0.030 (4)*
H2A	0.78860	1.02350	0.71850	0.0290*
H2B	0.74180	0.87740	0.69430	0.0290*
H3	0.65210	0.80490	0.78330	0.0270*
H4A	0.43870	0.93410	0.80960	0.0360*
H4B	0.46180	0.96930	0.74300	0.0360*
H5A	0.41730	1.16370	0.80130	0.0420*
H5B	0.58340	1.17250	0.76480	0.0420*
H5O	1.180 (2)	0.971 (2)	0.6484 (9)	0.044 (5)*
H6A	0.56990	1.09720	0.88430	0.0380*
H6B	0.63180	1.24000	0.86180	0.0380*
H7A	0.86280	1.10250	0.87980	0.0310*
H7B	0.85360	1.13440	0.81230	0.0310*
H8	0.75760	0.88800	0.86670	0.0230*
H10	0.96640	0.88620	0.91790	0.0250*
H11	1.04260	0.58750	0.88150	0.0240*
H12A	1.00870	0.42300	0.95420	0.0330*
H12B	1.06800	0.52740	1.00180	0.0330*
H13A	1.27940	0.44070	0.91080	0.0430*
H13B	1.33430	0.52590	0.96580	0.0430*
H14A	1.22450	0.25530	0.97120	0.0680*
H14B	1.28070	0.34050	1.02600	0.0680*
H14C	1.41150	0.30080	0.97760	0.0680*
H16A	1.31020	0.94670	0.90810	0.0410*
H16B	1.19410	0.99410	0.95970	0.0410*
H16C	1.16930	1.05450	0.89660	0.0410*
H1W	1.538 (3)	0.658 (2)	0.8949 (9)	0.052 (6)*
H2W	1.436 (3)	0.717 (2)	0.8567 (10)	0.059 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0188 (4)	0.0282 (5)	0.0232 (4)	0.0040 (4)	0.0021 (4)	0.0033 (4)
O2	0.0275 (5)	0.0316 (5)	0.0211 (4)	−0.0010 (4)	0.0060 (4)	−0.0047 (4)
O3	0.0187 (4)	0.0330 (5)	0.0296 (5)	−0.0006 (4)	0.0012 (4)	−0.0080 (4)
O4	0.0210 (5)	0.0241 (5)	0.0324 (5)	−0.0029 (4)	0.0002 (4)	0.0002 (4)
O5	0.0268 (5)	0.0268 (5)	0.0232 (4)	−0.0001 (4)	0.0049 (4)	0.0048 (4)
N1	0.0162 (5)	0.0222 (5)	0.0179 (5)	0.0001 (4)	0.0005 (4)	0.0018 (4)
N2	0.0201 (5)	0.0246 (6)	0.0159 (5)	0.0011 (5)	−0.0028 (4)	0.0003 (4)
C1	0.0210 (7)	0.0220 (6)	0.0179 (6)	−0.0001 (5)	−0.0004 (5)	0.0016 (5)
C2	0.0191 (6)	0.0332 (7)	0.0207 (6)	−0.0035 (6)	−0.0029 (5)	0.0045 (5)
C3	0.0174 (6)	0.0278 (7)	0.0226 (6)	−0.0036 (5)	−0.0015 (5)	0.0058 (5)
C4	0.0150 (6)	0.0440 (8)	0.0304 (7)	−0.0024 (6)	−0.0020 (6)	0.0111 (6)
C5	0.0193 (7)	0.0397 (8)	0.0462 (9)	0.0087 (6)	0.0046 (6)	0.0167 (7)
C6	0.0246 (7)	0.0262 (7)	0.0450 (8)	0.0049 (6)	0.0082 (6)	0.0025 (6)
C7	0.0183 (6)	0.0255 (7)	0.0339 (7)	0.0002 (5)	0.0020 (6)	−0.0010 (6)
C8	0.0134 (6)	0.0244 (6)	0.0203 (6)	0.0001 (5)	0.0003 (5)	0.0029 (5)
C9	0.0165 (6)	0.0178 (6)	0.0228 (6)	−0.0029 (5)	0.0003 (5)	0.0032 (5)
C10	0.0189 (6)	0.0222 (6)	0.0206 (6)	0.0008 (5)	−0.0024 (5)	0.0012 (5)
C11	0.0205 (6)	0.0235 (6)	0.0168 (6)	−0.0016 (5)	−0.0015 (5)	−0.0003 (5)
C12	0.0299 (7)	0.0254 (7)	0.0271 (7)	0.0010 (6)	−0.0027 (6)	0.0034 (5)
C13	0.0359 (8)	0.0372 (8)	0.0353 (8)	0.0080 (7)	−0.0039 (7)	0.0040 (6)
C14	0.0489 (10)	0.0361 (9)	0.0501 (10)	0.0098 (8)	−0.0089 (8)	0.0028 (7)
C15	0.0168 (6)	0.0226 (6)	0.0222 (6)	0.0043 (5)	−0.0005 (5)	0.0046 (5)
C16	0.0281 (7)	0.0256 (7)	0.0291 (7)	−0.0034 (6)	−0.0052 (6)	−0.0001 (5)
C17	0.0238 (6)	0.0220 (6)	0.0148 (5)	0.0002 (5)	0.0037 (5)	0.0033 (5)
O1W	0.0250 (5)	0.0593 (7)	0.0324 (6)	0.0102 (5)	0.0022 (5)	0.0117 (5)

Geometric parameters (Å, º)

O1—C9	1.2372 (15)	C12—C13	1.531 (2)
O2—C17	1.2451 (16)	C13—C14	1.518 (2)
O3—C17	1.2580 (16)	C1—H1	1.0000
O4—C15	1.2046 (16)	C2—H2B	0.9900
O5—C15	1.3315 (17)	C2—H2A	0.9900
O5—H5O	0.890 (19)	C3—H3	1.0000
O1W—H2W	0.81 (2)	C4—H4B	0.9900
O1W—H1W	0.90 (2)	C4—H4A	0.9900
N1—C8	1.4857 (16)	C5—H5A	0.9900
N1—C1	1.4705 (15)	C5—H5B	0.9900
N1—C9	1.3322 (16)	C6—H6B	0.9900
N2—C11	1.5054 (17)	C6—H6A	0.9900
N2—C10	1.4982 (17)	C7—H7B	0.9900
N2—H2NB	0.884 (19)	C7—H7A	0.9900
N2—H2NA	0.959 (16)	C8—H8	1.0000
C1—C15	1.5137 (18)	C10—H10	1.0000
C1—C2	1.5362 (18)	C11—H11	1.0000
C2—C3	1.5339 (18)	C12—H12A	0.9900
C3—C8	1.5385 (18)	C12—H12B	0.9900
C3—C4	1.5287 (19)	C13—H13A	0.9900
C4—C5	1.523 (2)	C13—H13B	0.9900
C5—C6	1.529 (2)	C14—H14B	0.9800
C6—C7	1.530 (2)	C14—H14C	0.9800
C7—C8	1.5255 (18)	C14—H14A	0.9800
C9—C10	1.5297 (16)	C16—H16C	0.9800
C10—C16	1.5307 (19)	C16—H16A	0.9800
C11—C12	1.5288 (19)	C16—H16B	0.9800
C11—C17	1.5410 (18)
C15—O5—H5O	108.8 (13)	C4—C3—H3	108.00
H1W—O1W—H2W	105 (2)	C3—C4—H4A	109.00
C1—N1—C8	112.08 (9)	C3—C4—H4B	109.00
C8—N1—C9	129.00 (10)	C5—C4—H4B	109.00
C1—N1—C9	118.38 (10)	H4A—C4—H4B	108.00
C10—N2—C11	115.24 (10)	C5—C4—H4A	109.00
C10—N2—H2NB	109.8 (10)	C4—C5—H5B	109.00
C11—N2—H2NB	110.5 (11)	C6—C5—H5A	109.00
C11—N2—H2NA	107.9 (10)	C6—C5—H5B	109.00
C10—N2—H2NA	109.2 (10)	H5A—C5—H5B	108.00
H2NB—N2—H2NA	103.6 (14)	C4—C5—H5A	109.00
N1—C1—C15	112.46 (10)	C5—C6—H6B	110.00
C2—C1—C15	109.99 (10)	C7—C6—H6A	110.00
N1—C1—C2	104.01 (10)	C5—C6—H6A	110.00
C1—C2—C3	103.41 (10)	H6A—C6—H6B	108.00
C4—C3—C8	114.54 (11)	C7—C6—H6B	110.00
C2—C3—C8	102.96 (10)	C6—C7—H7A	110.00
C2—C3—C4	115.17 (11)	C6—C7—H7B	110.00
C3—C4—C5	113.82 (11)	C8—C7—H7B	110.00
C4—C5—C6	111.00 (12)	H7A—C7—H7B	108.00
C5—C6—C7	109.46 (12)	C8—C7—H7A	110.00
C6—C7—C8	110.44 (11)	C3—C8—H8	110.00
N1—C8—C3	101.30 (9)	C7—C8—H8	110.00
N1—C8—C7	111.98 (10)	N1—C8—H8	110.00
C3—C8—C7	113.55 (11)	C9—C10—H10	110.00
O1—C9—N1	122.63 (11)	C16—C10—H10	110.00
O1—C9—C10	119.87 (11)	N2—C10—H10	110.00
N1—C9—C10	117.41 (10)	C12—C11—H11	108.00
N2—C10—C16	109.22 (10)	C17—C11—H11	108.00
N2—C10—C9	108.13 (10)	N2—C11—H11	108.00
C9—C10—C16	110.03 (10)	C11—C12—H12B	109.00
C12—C11—C17	109.63 (10)	C13—C12—H12A	109.00
N2—C11—C12	110.07 (10)	C13—C12—H12B	109.00
N2—C11—C17	112.00 (10)	H12A—C12—H12B	108.00
C11—C12—C13	114.73 (12)	C11—C12—H12A	109.00
C12—C13—C14	112.24 (13)	C12—C13—H13A	109.00
O4—C15—O5	124.92 (12)	C12—C13—H13B	109.00
O4—C15—C1	124.90 (12)	C14—C13—H13B	109.00
O5—C15—C1	109.95 (11)	H13A—C13—H13B	108.00
O2—C17—O3	126.28 (12)	C14—C13—H13A	109.00
O2—C17—C11	117.45 (11)	C13—C14—H14A	109.00
O3—C17—C11	116.23 (11)	C13—C14—H14B	109.00
C2—C1—H1	110.00	H14A—C14—H14B	109.00
C15—C1—H1	110.00	H14A—C14—H14C	110.00
N1—C1—H1	110.00	C13—C14—H14C	109.00
C1—C2—H2B	111.00	H14B—C14—H14C	109.00
C3—C2—H2A	111.00	C10—C16—H16B	109.00
C1—C2—H2A	111.00	C10—C16—H16C	109.00
H2A—C2—H2B	109.00	C10—C16—H16A	109.00
C3—C2—H2B	111.00	H16A—C16—H16C	109.00
C2—C3—H3	108.00	H16B—C16—H16C	109.00
C8—C3—H3	108.00	H16A—C16—H16B	110.00
C8—N1—C1—C2	1.77 (14)	C1—C2—C3—C4	164.73 (11)
C9—N1—C1—C2	174.04 (11)	C4—C3—C8—N1	−163.06 (11)
C8—N1—C1—C15	120.74 (11)	C8—C3—C4—C5	42.24 (16)
C9—N1—C1—C15	−66.99 (15)	C2—C3—C8—N1	−37.28 (12)
C9—N1—C8—C7	89.79 (15)	C2—C3—C4—C5	−76.90 (15)
C1—N1—C9—O1	−2.22 (18)	C4—C3—C8—C7	−42.83 (15)
C8—N1—C9—O1	168.55 (12)	C2—C3—C8—C7	82.95 (13)
C1—N1—C9—C10	174.37 (11)	C3—C4—C5—C6	−51.32 (16)
C1—N1—C8—C3	22.37 (13)	C4—C5—C6—C7	60.79 (15)
C9—N1—C8—C3	−148.87 (13)	C5—C6—C7—C8	−61.20 (15)
C1—N1—C8—C7	−98.97 (12)	C6—C7—C8—N1	166.25 (11)
C8—N1—C9—C10	−14.86 (19)	C6—C7—C8—C3	52.27 (15)
C11—N2—C10—C9	−59.50 (13)	O1—C9—C10—C16	74.70 (15)
C10—N2—C11—C12	−171.58 (10)	N1—C9—C10—N2	138.80 (11)
C10—N2—C11—C17	−49.34 (13)	N1—C9—C10—C16	−101.99 (13)
C11—N2—C10—C16	−179.22 (10)	O1—C9—C10—N2	−44.52 (15)
C2—C1—C15—O4	88.09 (15)	N2—C11—C12—C13	−60.04 (15)
C2—C1—C15—O5	−86.70 (13)	C17—C11—C12—C13	176.34 (11)
C15—C1—C2—C3	−146.10 (11)	N2—C11—C17—O2	−29.99 (15)
N1—C1—C15—O4	−27.32 (18)	N2—C11—C17—O3	152.14 (11)
N1—C1—C2—C3	−25.46 (13)	C12—C11—C17—O2	92.49 (14)
N1—C1—C15—O5	157.90 (11)	C12—C11—C17—O3	−85.38 (13)
C1—C2—C3—C8	39.36 (13)	C11—C12—C13—C14	−170.69 (13)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2NB···O2^i	0.884 (19)	1.954 (17)	2.7063 (15)	142.1 (15)
O1W—H1W···O3^ii	0.90 (2)	1.89 (2)	2.7725 (15)	167 (2)
N2—H2NA···O1W	0.959 (16)	1.850 (16)	2.7923 (16)	167.0 (15)
O1W—H2W···O1	0.81 (2)	2.29 (2)	2.8307 (15)	124 (2)
O5—H5O···O3^iii	0.890 (19)	1.73 (2)	2.5929 (14)	163.7 (19)
C1—H1···O4^iv	1.00	2.45	3.2777 (16)	140
C4—H4A···O1^v	0.99	2.56	3.3926 (17)	142
C10—H10···O2	1.00	2.33	2.9600 (16)	120
C11—H11···O5^iv	1.00	2.50	3.1808 (16)	125

Symmetry codes: (i) x+1/2, −y+3/2, −z+2; (ii) x+1, y, z; (iii) −x+2, y+1/2, −z+3/2; (iv) −x+2, y−1/2, −z+3/2; (v) x−1, y, z.