Alogliptin and its benzoate salt

The crystal structure of the free base of the anti­diabetic drug alogliptin [systematic name: 2-({6-[(3R)-3-amino­piperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetra­hydro­pyrimidin-1-yl}methyl)benzo­nitrile], C₁₈H₂₁N₅O₂, displays a two-dimensional N—H...O hydrogen-bonded network. It contains two independent mol­ecules, which have the same conformation but differ in their hydrogen-bond connectivity. In the crystal structure of the benzoate salt (systematic name: (3R)-1-{3-[(2-cyano­phenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetra­hydropyrimidin-4-yl}piperidin-3-aminium benzoate), C₁₈H₂₂N₅O₂⁺·C₇H₅O₂⁻, the NH₃⁺ group of the cation is engaged in three inter­molecular N—H...O hydrogen bonds to yield a hydrogen-bonded layer structure. The benzoate salt and the free base differ fundamentally in the conformations of their alogliptin moieties.

S1. Comment

Alogliptin, (I), is an antidiabetic drug for the treatment of type-2 diabetes mellitus which has been developed by Takeda Pharmaceutical Company (Osaka, Japan). The efficacy of (I) as a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor has been demonstrated (Feng et al., 2007). DPP-4 inhibitors (McIntosh et al., 2005) metabolize the insulin-increasing hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). By maintaining the blood levels of GLP-1 and GIP, secretion of glucagon is inhibited and the release of insulin from the pancreas is stimulated (Weber, 2004). The present work is part of a study undertaken to establish the characteristics of solid-state forms of alogliptin.

The crystal structure of (I) contains two independent molecules, denoted A and B, which possess the same conformation, and the overlay of A and B gives a low overall r.m.s. deviation of 0.067 Å (Figs. 1 and 2). In molecule A, the bridging atom C9 is significantly out of the mean plane of the pyrimidine ring (N1/C2/N3/C4–C6) by 0.468 (5) Å, and the corresponding distance in molecule B is 0.520 (4) Å. The benzonitrile group and the pyrimidine ring are oriented almost perpendicular to one another, their planes forming angles of 82.60 (10)° in molecule A and 87.68 (10)° in molecule B. The piperidine ring (N16/C17–C21) adopts a chair conformation, with an equatorial N16—C4 bond to the pyrimidine ring and an equatorial C18—N25 bond to the amino group.

The amino group of each independent molecule of (I) donates two N—H···O hydrogen bonds, but molecules A and B differ fundamentally from one another in their hydrogen-bond connectivity. In molecule A, the O atoms of the carbonyl groups on the pyrimidine ring in the ortho (O8) and para (O22) positions relative to the methylbenzonitrile substituent both serve as hydrogen-bond acceptors (Fig. 3a). By contrast, only the O atom of the para-carbonyl group (O22') accepts two hydrogen bonds in molecule B. Molecules A are linked to one another by N25—H25A···O22(x, y + 1, z) hydrogen bonds, generating an infinite chain parallel to the b axis. The equivalent N25'—H25D···O22'(x + 1, y, z) interaction between molecules B results in an N—H···O hydrogen-bonded chain along the a axis. The hydrogen-bonded A and B chains are at an angle of 87.4° (corresponding with the γ angle of the unit cell) and they are interlinked by a pair of N25—H25B···O22' and N25'—H25C···O8 interactions so that an R₂²(18) ring (Etter et al., 1990; Bernstein et al., 1995) is formed. Overall, a two-dimensional extended hydrogen-bonded net is generated parallel to the ab plane (Fig. 3b). Translation-related hydrogen-bonded layers are stacked along the c axis in such a way that the methylbenzonitrile fragments from neighbouring layers interdigitate with each other. The benzonitrile group of each molecule type forms two intermolecular C—H···N≡C contacts to two molecules of the other type, with C···N distances ranging between 3.470 (5) and 3.501 (5) Å, and C—H···N angles between 146.4 and 158.1°.

In recent years, several authors have commented on the occurrence of crystal structures with more than one (Z' > 1) independent molecule (Steiner, 2000; Steed, 2003; Desiraju, 2007; Anderson & Steed, 2007; Bernstein, 2011). A better understanding of a given Z' > 1 structure may be gained from comparing the geometries of the crystallographically distinct molecular environments of each unique molecule [see, for example, Gelbrich & Hursthouse (2006); Gelbrich et al. (2008, 2013); Gelbrich et al. (2012)]. In (I), the first environment of molecule A contains 14 molecules, and we have compared the cluster of (1+14) molecules centred by A with the corresponding (1+14) cluster around molecule B, using the program XPac (Gelbrich & Hursthouse, 2005). This analysis shows that the A and B clusters agree fundamentally in the geometry of a (1+10) subunit containing ten surrounding molecules, albeit with small deviations, as indicated by the corresponding dissimilarity index x of 4.6 (for the definition of x and reference examples, see Gelbrich et al., 2012a,b). This result is consistent with the presence of two geometrically similar layers parallel to the ab plane, both built up exclusively from one molecule type. Together they form a double-layer unit (Fig. 4) with an approximate local twofold symmetry axis along [110]. Within this double-layer unit, molecules A and B have equivalent molecular environments. However, stacking of the double-layer units along the c axis creates fundamentally different interlayer environments and hydrogen-bond characteristics for molecules A and B. The twofold rotation about [110] is a local symmetry operation as well as the twin law for the crystals of (I) investigated by us.

In a patent application concerning the benzoate salt of alogliptin, (II) (Andres & Lorimer, 2007), descriptions of an amorphous and a crystalline form were given. The crystalline phase (`Form A') was produced from solutions of (II) in 20 different solvents or solvent combinations and also by transition from the amorphous form. Limited crystallographic information [orthorhombic, Z = 4, a = 8.0869 (2), b = 9.9030 (3) and c = 28.5471 (10) Å at 150 K] was disclosed, which did not include the space-group symmetry or fractional atomic coordinates.

The asymmetric unit of (II) contains one alogliptin cation and one benzoate anion (Fig. 4). Crystallographic parameters, and characteristics revealed by IR spectroscopy, thermomicroscopy, differential thermal analysis and powder X-ray diffraction, of the crystals investigated by us match the patent information (Andres & Lorimer, 2007) for Form A. The overlay in Fig. 2 and comparison of relevant torsion angles (Table 3) illustrate that the alogliptin conformation in (II) differs from that in the free base, (I), most notably in the inversion of the piperidine ring and its rotation by approximately 180° about the C4—C16 bond. Thus, the C18—N25 bond to the ammonium (NH₃⁺) group is axial in (II), whereas the N25 amino substituent of (I) is in an equatorial position. Similar conformational flexibility is displayed by the 3-methylaminopiperidinyl fragment of the fluoroquinolone Q-35. The methylamino substituent of the piperidine ring is equatorial in two hydrates of this compound (Nawata, Sato et al., 1993), whereas it is axial and equatorial, respectively, in two symmetry-independent molecules of the corresponding hydrobromide salt (Nawata, Fukushima & Nagano, 1993).

The NH₃⁺ group in the cation of (II) donates an N25—H25C···O22(x - 1, y, z) hydrogen bond to the para-oriented carbonyl group (relative to the methylbenzonitrile substituent) on the pyrimidine ring of a second cation. This interaction generates a chain of linked cations parallel to the a axis. Another two N—H···O hydrogen bonds connect the NH₃⁺ unit to the carboxylate O atoms of two different benzoate anions, giving a chain of alternating anions and cations that displays 2₁ symmetry and propagates parallel to [010]. Altogether, a two-dimensional hydrogen-bonded sheet structure is generated, which lies parallel to (001) (Fig. 6). In the crystal structure, these sheets are stacked along the c axis via a 2₁ operation. From Tables 1 and 2 it can be seen that the geometries of the N—H···O interactions are, on the whole, considerably stronger in the benzoate salt, (II), than in the free base, (I).

Related literature

For related literature, see: Anderson & Steed (2007); Andres & Lorimer (2007); Bernstein (2011); Bernstein et al. (1995); Desiraju (2007); Etter et al. (1990); Feng et al. (2007); Flack (1983); Gelbrich & Hursthouse (2005, 2006); Gelbrich et al. (2008, 2012, 2012a, 2012b, 2013); Hooft et al. (2008); McIntosh et al. (2005); Nawata, Fukushima & Nagano (1993); Nawata, Sato, Fukushima & Nagano (1993); Spek (2009); Steed (2003); Steiner (2000); Weber (2004).

S2. Experimental

Samples of (I) and (II) were kindly provided by Sandoz, Kundl (Austria). Suitable single crystals of (I) were obtained by slow evaporation from an acetonitrile solution. Slow cooling of a hot saturated solution of (II) in acetonitrile yielded crystals of (II) after 2 d. Their identity with Form A described by Andres & Lorimer (2007) was confirmed by IR spectroscopy, thermomicroscopy, differential thermal analysis and powder X-ray diffraction.

S3. Refinement

All H atoms were identified in a difference map. Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip, with C—H = 0.98 Å, and refined with U_iso(H) = 1.5U_eq(C). H atoms bonded to secondary (CH₂; C—H = 0.99 Å), tertiary (C—H = 1.00 Å) and aromatic (CH; C—H = 0.95 Å) C atoms were positioned geometrically and refined with U_iso(H) = 1.2 U_eq(C). The NH₂ H atoms of (I) were refined with restrained distances of N—H = 0.86 (2) Å and their U_iso(H) parameters were refined freely. The NH₃⁺ H atoms of (II) were refined with restrained distances of N—H = 0.89 (2) Å and H···H = 1.49 (2) Å, and free U_iso(H) parameters.

The intensity data for (I) (R_int = 0.0259) were affected by nonmerohedral twinning. A modified reflection file was prepared using the twin matrix (0.010, 0.985, 0.010/1.010, -0.015, 0.010/0.505, 0.493, -0.995) indicated by the TwinRotMat routine within PLATON (Spek, 2009). This treatment reduced the wR(F²) value from 0.143 to 0.102, and the fraction of the minor twin component was refined to 0.121 (3).

The highest anomalous contribution to the intensity data of (I) and (II) comes from O atoms. In the case of (I), the data collection was carried out with Mo radiation. The Flack x parameter (Flack, 1983) and Hooft y parameter (Hooft et al., 2008) were both indeterminate due to a lack of significant resonant scattering. Accordingly, Friedel opposites were merged prior to the final refinement. The data collection for (II) was carried out with Cu radiation and refinement of the absolute structure parameter x (Flack, 1983) gave a value of -0.01 (15) for 1657 Friedel pairs (96% Friedel coverage). Additionally, a Bayesian statistics analysis on Bijvoet differences was performed using PLATON. The obtained Hooft parameter y was 0.03 (6) and the probability levels of having a false attribution, P2 (racemic twin) and P3 (false), were both essentially zero. These results indicate that the correct enantiomer has been determined. Moreover, the assignment of the chiral centre C18 (R) is consistent with the synthetic procedure.

Computing details

For both compounds, data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO (Agilent, 2011); data reduction: CrysAlis PRO (Agilent, 2011); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures

	Fig. 1. The molecular structures of the symmetry-independent molecules, A and B, of (I), with the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level. The arrangement of the two molecules does not reflect their relative position in the asymmetric unit.
	Fig. 2. A superposition of the alogliptin molecules present in (I) and (II), generated by least-squares fitting of their pyrimidine rings. Relevant torsion angles are collected in Table 3.
	Fig. 3. The two-dimensional hydrogen-bonded network of (I), formed by molecules A and B (orange and green, respectively, in the electronic version of the paper). Carbonyl O atoms and NH2 groups are highlighted and all other H atoms have been omitted for clarity. N—H···O interactions of types A···A and B···B are drawn as dotted lines, and A···B and B···A interactions as dashed lines. (a) N—H···O hydrogen-bonded A and B molecules, forming an R2^2(18) ring (molecules A and B are not equivalent with respect to their hydrogen-bond connectivity). (b) A portion of a single N—H···O hydrogen-bonded layer.
	Fig. 4. The approximate local twofold symmetry, indicated by a dashed line, in an (A+B) double-layer unit extending parallel to (001) in the structure of (I). H atoms have been omitted for clarity.
	Fig. 5. The molecular structure of (II), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. The arrangement of the two molecules does not reflect their relative position in the asymmetric unit.
	Fig. 6. The two-dimensional hydrogen-bonded network of (II), formed by alogliptin cations (capped sticks) and benzoate anions (balls and sticks; orange in the electronic version of the paper). H atoms have been omitted for clarity, except for those in NH3^+ groups. Cation–cation and cation–anion interactions are drawn as dashed and dotted lines, respectively.

(I) 2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile

Crystal data

C18H21N5O2	Z = 2
Mr = 339.4	F(000) = 360
Triclinic, P1	Dx = 1.315 Mg m^−3
Hall symbol: P 1	Mo Kα radiation, λ = 0.71073 Å
a = 8.4528 (5) Å	Cell parameters from 4121 reflections
b = 8.5689 (5) Å	θ = 3.4–28.4°
c = 12.4424 (7) Å	µ = 0.09 mm^−1
α = 87.840 (5)°	T = 173 K
β = 72.284 (5)°	Block, colourless
γ = 87.368 (8)°	0.15 × 0.10 × 0.10 mm
V = 857.31 (9) Å^3

Data collection

Agilent Xcalibur (Ruby, Gemini ultra) diffractometer	3634 independent reflections
Graphite monochromator	3260 reflections with I > 2σ(I)
Detector resolution: 10.3822 pixels mm^-1	Rint = 0.000
ω scans	θmax = 28.5°, θmin = 3.4°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011)	h = −9→10
Tmin = 0.987, Tmax = 0.991	k = −10→11
3634 measured reflections	l = −15→16

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)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.102	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0586P)^2 + 0.1048P] where P = (Fo^2 + 2Fc^2)/3
3634 reflections	(Δ/σ)max < 0.001
466 parameters	Δρmax = 0.22 e Å^−3
7 restraints	Δρmin = −0.19 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 > σ(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 (Ų)

	x	y	z	Uiso*/Ueq
N1	0.5818 (3)	0.0494 (3)	0.0768 (2)	0.0254 (6)
C2	0.6281 (4)	0.2013 (4)	0.0568 (2)	0.0239 (7)
N3	0.5244 (3)	0.3033 (3)	0.0172 (2)	0.0227 (5)
C4	0.3792 (4)	0.2525 (4)	0.0004 (2)	0.0213 (6)
C5	0.3379 (4)	0.1035 (4)	0.0217 (3)	0.0241 (7)
H5	0.2394	0.0706	0.0089	0.029*
C6	0.4379 (4)	−0.0084 (4)	0.0632 (3)	0.0244 (7)
C7	0.6934 (5)	−0.0592 (5)	0.1139 (3)	0.0373 (8)
H7A	0.8076	−0.0462	0.0652	0.056*
H7B	0.6610	−0.1665	0.1095	0.056*
H7C	0.6867	−0.0378	0.1920	0.056*
O8	0.7543 (3)	0.2452 (3)	0.0710 (2)	0.0356 (6)
C9	0.6015 (4)	0.4446 (4)	−0.0415 (3)	0.0237 (6)
H9A	0.6893	0.4741	−0.0094	0.028*
H9B	0.5166	0.5312	−0.0283	0.028*
C10	0.6769 (4)	0.4236 (4)	−0.1674 (3)	0.0250 (7)
C11	0.7208 (4)	0.5550 (4)	−0.2380 (3)	0.0264 (7)
C12	0.7915 (4)	0.5405 (4)	−0.3546 (3)	0.0338 (8)
H12	0.8208	0.6312	−0.4016	0.041*
C13	0.8185 (5)	0.3954 (5)	−0.4009 (3)	0.0372 (8)
H13	0.8644	0.3849	−0.4802	0.045*
C14	0.7782 (5)	0.2649 (4)	−0.3312 (3)	0.0364 (8)
H14	0.7990	0.1641	−0.3629	0.044*
C15	0.7083 (4)	0.2782 (4)	−0.2162 (3)	0.0318 (8)
H15	0.6813	0.1867	−0.1698	0.038*
N16	0.2905 (3)	0.3668 (3)	−0.0411 (2)	0.0250 (6)
C17	0.2101 (4)	0.4942 (4)	0.0362 (3)	0.0257 (7)
H17A	0.2869	0.5269	0.0767	0.031*
H17B	0.1087	0.4559	0.0928	0.031*
C18	0.1648 (4)	0.6321 (4)	−0.0290 (3)	0.0264 (7)
H18	0.2686	0.6668	−0.0868	0.032*
C19	0.0473 (5)	0.5791 (4)	−0.0908 (3)	0.0359 (8)
H19A	−0.0579	0.5466	−0.0353	0.043*
H19B	0.0212	0.6671	−0.1372	0.043*
C20	0.1262 (5)	0.4433 (4)	−0.1661 (3)	0.0380 (9)
H20A	0.0461	0.4062	−0.2024	0.046*
H20B	0.2251	0.4790	−0.2264	0.046*
C21	0.1771 (5)	0.3098 (4)	−0.0988 (3)	0.0343 (8)
H21A	0.0774	0.2677	−0.0425	0.041*
H21B	0.2332	0.2247	−0.1498	0.041*
O22	0.4023 (3)	−0.1440 (3)	0.0891 (2)	0.0337 (5)
C23	0.6943 (4)	0.7080 (4)	−0.1925 (3)	0.0289 (7)
N24	0.6749 (4)	0.8330 (4)	−0.1579 (3)	0.0362 (7)
N25	0.0912 (4)	0.7642 (3)	0.0405 (3)	0.0306 (6)
H25A	0.166 (4)	0.796 (4)	0.070 (3)	0.037*
H25B	−0.003 (3)	0.742 (5)	0.089 (3)	0.037*
N1'	0.0699 (3)	0.9453 (3)	0.3052 (2)	0.0219 (5)
C2'	0.2171 (4)	0.9754 (4)	0.3245 (2)	0.0220 (6)
N3'	0.3006 (3)	0.8497 (3)	0.3589 (2)	0.0193 (5)
C4'	0.2445 (4)	0.6982 (3)	0.3665 (2)	0.0192 (6)
C5'	0.1000 (4)	0.6725 (4)	0.3460 (3)	0.0231 (6)
H5A	0.0617	0.5690	0.3524	0.028*
C6'	0.0030 (4)	0.7980 (3)	0.3148 (2)	0.0218 (7)
C7'	−0.0262 (4)	1.0779 (4)	0.2768 (3)	0.0312 (8)
H7D	−0.1435	1.0696	0.3208	0.047*
H7E	−0.0154	1.0776	0.1961	0.047*
H7F	0.0157	1.1754	0.2944	0.047*
O8'	0.2693 (3)	1.1059 (2)	0.3164 (2)	0.0322 (6)
C9'	0.4165 (4)	0.8898 (3)	0.4198 (2)	0.0211 (6)
H9C	0.4696	0.9888	0.3878	0.025*
H9D	0.5050	0.8068	0.4090	0.025*
C10'	0.3304 (4)	0.9076 (3)	0.5442 (3)	0.0203 (6)
C11'	0.4266 (4)	0.9212 (3)	0.6179 (3)	0.0233 (6)
C12'	0.3502 (4)	0.9391 (4)	0.7330 (3)	0.0304 (8)
H12B	0.4159	0.9472	0.7822	0.036*
C13'	0.1798 (5)	0.9450 (4)	0.7756 (3)	0.0334 (8)
H13B	0.1276	0.9571	0.8542	0.040*
C14'	0.0852 (4)	0.9332 (4)	0.7041 (3)	0.0303 (7)
H14B	−0.0325	0.9373	0.7338	0.036*
C15'	0.1590 (4)	0.9156 (4)	0.5896 (3)	0.0269 (7)
H15B	0.0914	0.9088	0.5415	0.032*
N16'	0.3450 (3)	0.5855 (3)	0.3976 (2)	0.0215 (5)
C17'	0.5076 (4)	0.5544 (4)	0.3122 (3)	0.0224 (6)
H17C	0.5556	0.6545	0.2782	0.027*
H17D	0.4919	0.4914	0.2513	0.027*
C18'	0.6266 (4)	0.4670 (3)	0.3656 (3)	0.0250 (7)
H18B	0.6401	0.5324	0.4269	0.030*
C19'	0.5504 (4)	0.3155 (4)	0.4186 (3)	0.0327 (8)
H19C	0.6232	0.2614	0.4584	0.039*
H19D	0.5414	0.2465	0.3589	0.039*
C20'	0.3782 (5)	0.3463 (4)	0.5020 (3)	0.0371 (8)
H20C	0.3274	0.2454	0.5313	0.044*
H20D	0.3890	0.4042	0.5666	0.044*
C21'	0.2658 (4)	0.4402 (4)	0.4467 (3)	0.0326 (8)
H21C	0.2453	0.3784	0.3869	0.039*
H21D	0.1576	0.4644	0.5035	0.039*
O22'	−0.1269 (3)	0.7820 (3)	0.2935 (2)	0.0305 (5)
C23'	0.6035 (4)	0.9179 (4)	0.5746 (3)	0.0259 (7)
N24'	0.7456 (4)	0.9166 (4)	0.5427 (2)	0.0350 (7)
N25'	0.7895 (4)	0.4363 (3)	0.2865 (3)	0.0322 (7)
H25C	0.787 (5)	0.389 (4)	0.225 (2)	0.039*
H25D	0.840 (5)	0.522 (3)	0.262 (3)	0.039*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0215 (14)	0.0310 (15)	0.0260 (13)	−0.0008 (11)	−0.0110 (11)	0.0026 (11)
C2	0.0229 (17)	0.0275 (17)	0.0219 (15)	−0.0006 (13)	−0.0075 (13)	−0.0030 (12)
N3	0.0191 (14)	0.0235 (13)	0.0272 (14)	−0.0044 (10)	−0.0089 (11)	0.0003 (10)
C4	0.0158 (15)	0.0297 (17)	0.0183 (14)	−0.0012 (12)	−0.0045 (11)	−0.0034 (12)
C5	0.0142 (15)	0.0328 (18)	0.0262 (16)	−0.0064 (13)	−0.0067 (12)	−0.0009 (13)
C6	0.0215 (17)	0.0294 (18)	0.0202 (15)	−0.0039 (13)	−0.0028 (12)	−0.0003 (13)
C7	0.033 (2)	0.038 (2)	0.046 (2)	−0.0038 (16)	−0.0206 (17)	0.0117 (16)
O8	0.0259 (13)	0.0385 (14)	0.0502 (15)	−0.0060 (10)	−0.0227 (11)	0.0020 (11)
C9	0.0214 (16)	0.0230 (15)	0.0286 (16)	−0.0060 (12)	−0.0097 (13)	−0.0003 (12)
C10	0.0161 (16)	0.0278 (17)	0.0330 (17)	−0.0015 (13)	−0.0099 (13)	−0.0011 (13)
C11	0.0192 (16)	0.0272 (17)	0.0333 (17)	−0.0024 (13)	−0.0084 (13)	−0.0010 (13)
C12	0.030 (2)	0.0341 (19)	0.0347 (19)	−0.0039 (15)	−0.0062 (15)	0.0059 (15)
C13	0.030 (2)	0.048 (2)	0.0305 (18)	−0.0022 (16)	−0.0043 (15)	−0.0041 (16)
C14	0.033 (2)	0.0308 (19)	0.045 (2)	−0.0022 (15)	−0.0107 (17)	−0.0098 (16)
C15	0.0267 (19)	0.0290 (18)	0.0388 (19)	−0.0055 (14)	−0.0084 (15)	0.0020 (14)
N16	0.0208 (14)	0.0278 (14)	0.0302 (14)	0.0003 (11)	−0.0130 (11)	−0.0048 (11)
C17	0.0217 (17)	0.0304 (17)	0.0268 (16)	−0.0020 (13)	−0.0098 (13)	−0.0006 (13)
C18	0.0205 (17)	0.0273 (17)	0.0318 (17)	−0.0014 (13)	−0.0083 (13)	−0.0004 (13)
C19	0.0284 (19)	0.0311 (19)	0.057 (2)	0.0000 (15)	−0.0264 (17)	0.0055 (16)
C20	0.039 (2)	0.042 (2)	0.045 (2)	−0.0010 (17)	−0.0308 (18)	−0.0026 (17)
C21	0.0315 (19)	0.0326 (19)	0.047 (2)	−0.0016 (15)	−0.0235 (17)	−0.0043 (16)
O22	0.0321 (14)	0.0297 (13)	0.0396 (14)	−0.0078 (10)	−0.0113 (11)	0.0085 (10)
C23	0.0223 (17)	0.0328 (19)	0.0298 (17)	−0.0025 (14)	−0.0058 (13)	0.0068 (14)
N24	0.0356 (18)	0.0305 (17)	0.0370 (16)	−0.0033 (13)	−0.0026 (13)	0.0006 (13)
N25	0.0234 (16)	0.0304 (15)	0.0360 (16)	0.0045 (13)	−0.0070 (12)	−0.0013 (12)
N1'	0.0225 (14)	0.0199 (13)	0.0253 (13)	0.0006 (10)	−0.0106 (11)	−0.0007 (10)
C2'	0.0248 (17)	0.0196 (16)	0.0227 (16)	0.0012 (12)	−0.0087 (13)	−0.0039 (12)
N3'	0.0221 (13)	0.0163 (12)	0.0225 (12)	−0.0016 (10)	−0.0108 (10)	−0.0021 (10)
C4'	0.0203 (15)	0.0177 (15)	0.0182 (14)	−0.0024 (12)	−0.0031 (11)	−0.0008 (11)
C5'	0.0231 (16)	0.0163 (14)	0.0299 (16)	−0.0039 (12)	−0.0076 (13)	−0.0022 (12)
C6'	0.0193 (16)	0.0246 (16)	0.0220 (15)	−0.0020 (12)	−0.0066 (12)	−0.0045 (12)
C7'	0.0271 (18)	0.0261 (17)	0.0418 (19)	0.0041 (14)	−0.0138 (15)	0.0039 (14)
O8'	0.0396 (15)	0.0164 (11)	0.0466 (15)	−0.0034 (10)	−0.0219 (12)	0.0024 (10)
C9'	0.0195 (15)	0.0214 (15)	0.0247 (15)	−0.0037 (12)	−0.0092 (12)	−0.0024 (12)
C10'	0.0222 (16)	0.0117 (13)	0.0275 (15)	−0.0017 (11)	−0.0086 (12)	0.0023 (11)
C11'	0.0250 (17)	0.0200 (15)	0.0271 (16)	−0.0017 (12)	−0.0108 (13)	−0.0013 (12)
C12'	0.036 (2)	0.0317 (19)	0.0281 (17)	−0.0027 (15)	−0.0158 (15)	−0.0034 (14)
C13'	0.042 (2)	0.0318 (19)	0.0251 (16)	−0.0075 (16)	−0.0062 (15)	−0.0017 (14)
C14'	0.0265 (18)	0.0278 (17)	0.0334 (18)	−0.0056 (14)	−0.0036 (14)	−0.0037 (14)
C15'	0.0266 (18)	0.0249 (17)	0.0304 (17)	−0.0022 (13)	−0.0104 (14)	0.0006 (13)
N16'	0.0195 (13)	0.0165 (12)	0.0275 (13)	−0.0029 (10)	−0.0055 (11)	0.0006 (10)
C17'	0.0229 (16)	0.0204 (15)	0.0234 (15)	−0.0002 (12)	−0.0062 (12)	−0.0022 (12)
C18'	0.0259 (17)	0.0154 (14)	0.0375 (18)	−0.0008 (12)	−0.0149 (14)	−0.0035 (12)
C19'	0.0291 (19)	0.0236 (17)	0.047 (2)	0.0015 (14)	−0.0155 (15)	0.0048 (14)
C20'	0.039 (2)	0.0215 (17)	0.050 (2)	−0.0036 (15)	−0.0139 (17)	0.0122 (15)
C21'	0.0258 (18)	0.0223 (16)	0.047 (2)	−0.0030 (13)	−0.0072 (15)	0.0072 (14)
O22'	0.0237 (12)	0.0346 (13)	0.0369 (13)	−0.0004 (10)	−0.0147 (10)	−0.0034 (10)
C23'	0.032 (2)	0.0255 (16)	0.0259 (15)	−0.0007 (14)	−0.0173 (14)	−0.0036 (12)
N24'	0.0276 (18)	0.0430 (17)	0.0375 (17)	0.0009 (13)	−0.0143 (13)	−0.0054 (14)
N25'	0.0209 (15)	0.0239 (15)	0.0514 (19)	−0.0001 (11)	−0.0102 (13)	−0.0043 (13)

Geometric parameters (Å, º)

N1—C2	1.369 (4)	N1'—C2'	1.374 (4)
N1—C6	1.393 (4)	N1'—C6'	1.392 (4)
N1—C7	1.456 (4)	N1'—C7'	1.462 (4)
C2—O8	1.211 (4)	C2'—O8'	1.211 (4)
C2—N3	1.391 (4)	C2'—N3'	1.385 (4)
N3—C4	1.398 (4)	N3'—C4'	1.393 (4)
N3—C9	1.463 (4)	N3'—C9'	1.467 (4)
C4—C5	1.335 (4)	C4'—C5'	1.350 (4)
C4—N16	1.385 (4)	C4'—N16'	1.378 (4)
C5—C6	1.434 (5)	C5'—C6'	1.436 (4)
C5—H5	0.9500	C5'—H5A	0.9500
C6—O22	1.221 (4)	C6'—O22'	1.221 (4)
C7—H7A	0.9800	C7'—H7D	0.9800
C7—H7B	0.9800	C7'—H7E	0.9800
C7—H7C	0.9800	C7'—H7F	0.9800
C9—C10	1.515 (4)	C9'—C10'	1.508 (4)
C9—H9A	0.9900	C9'—H9C	0.9900
C9—H9B	0.9900	C9'—H9D	0.9900
C10—C15	1.386 (5)	C10'—C15'	1.385 (4)
C10—C11	1.393 (5)	C10'—C11'	1.410 (4)
C11—C12	1.399 (5)	C11'—C12'	1.391 (4)
C11—C23	1.429 (5)	C11'—C23'	1.427 (5)
C12—C13	1.371 (5)	C12'—C13'	1.375 (5)
C12—H12	0.9500	C12'—H12B	0.9500
C13—C14	1.379 (6)	C13'—C14'	1.373 (5)
C13—H13	0.9500	C13'—H13B	0.9500
C14—C15	1.379 (5)	C14'—C15'	1.381 (5)
C14—H14	0.9500	C14'—H14B	0.9500
C15—H15	0.9500	C15'—H15B	0.9500
N16—C21	1.470 (4)	N16'—C21'	1.463 (4)
N16—C17	1.480 (4)	N16'—C17'	1.479 (4)
C17—C18	1.509 (4)	C17'—C18'	1.521 (4)
C17—H17A	0.9900	C17'—H17C	0.9900
C17—H17B	0.9900	C17'—H17D	0.9900
C18—N25	1.448 (4)	C18'—N25'	1.447 (4)
C18—C19	1.522 (4)	C18'—C19'	1.513 (5)
C18—H18	1.0000	C18'—H18B	1.0000
C19—C20	1.519 (5)	C19'—C20'	1.526 (5)
C19—H19A	0.9900	C19'—H19C	0.9900
C19—H19B	0.9900	C19'—H19D	0.9900
C20—C21	1.516 (5)	C20'—C21'	1.520 (5)
C20—H20A	0.9900	C20'—H20C	0.9900
C20—H20B	0.9900	C20'—H20D	0.9900
C21—H21A	0.9900	C21'—H21C	0.9900
C21—H21B	0.9900	C21'—H21D	0.9900
C23—N24	1.155 (4)	C23'—N24'	1.144 (4)
N25—H25A	0.877 (19)	N25'—H25C	0.886 (19)
N25—H25B	0.863 (19)	N25'—H25D	0.865 (19)
C2—N1—C6	125.0 (3)	C2'—N1'—C6'	124.6 (2)
C2—N1—C7	116.9 (3)	C2'—N1'—C7'	117.7 (3)
C6—N1—C7	118.1 (3)	C6'—N1'—C7'	117.7 (3)
O8—C2—N1	122.0 (3)	O8'—C2'—N1'	122.2 (3)
O8—C2—N3	121.2 (3)	O8'—C2'—N3'	121.0 (3)
N1—C2—N3	116.7 (3)	N1'—C2'—N3'	116.8 (3)
C2—N3—C4	121.3 (3)	C2'—N3'—C4'	121.9 (2)
C2—N3—C9	115.5 (3)	C2'—N3'—C9'	115.5 (2)
C4—N3—C9	120.0 (2)	C4'—N3'—C9'	120.0 (2)
C5—C4—N16	125.3 (3)	C5'—C4'—N16'	125.5 (3)
C5—C4—N3	120.1 (3)	C5'—C4'—N3'	119.7 (3)
N16—C4—N3	114.5 (3)	N16'—C4'—N3'	114.8 (2)
C4—C5—C6	121.9 (3)	C4'—C5'—C6'	121.4 (3)
C4—C5—H5	119.1	C4'—C5'—H5A	119.3
C6—C5—H5	119.1	C6'—C5'—H5A	119.3
O22—C6—N1	120.3 (3)	O22'—C6'—N1'	119.9 (3)
O22—C6—C5	124.6 (3)	O22'—C6'—C5'	124.6 (3)
N1—C6—C5	115.1 (3)	N1'—C6'—C5'	115.5 (3)
N1—C7—H7A	109.5	N1'—C7'—H7D	109.5
N1—C7—H7B	109.5	N1'—C7'—H7E	109.5
H7A—C7—H7B	109.5	H7D—C7'—H7E	109.5
N1—C7—H7C	109.5	N1'—C7'—H7F	109.5
H7A—C7—H7C	109.5	H7D—C7'—H7F	109.5
H7B—C7—H7C	109.5	H7E—C7'—H7F	109.5
N3—C9—C10	112.6 (2)	N3'—C9'—C10'	111.9 (2)
N3—C9—H9A	109.1	N3'—C9'—H9C	109.2
C10—C9—H9A	109.1	C10'—C9'—H9C	109.2
N3—C9—H9B	109.1	N3'—C9'—H9D	109.2
C10—C9—H9B	109.1	C10'—C9'—H9D	109.2
H9A—C9—H9B	107.8	H9C—C9'—H9D	107.9
C15—C10—C11	117.8 (3)	C15'—C10'—C11'	118.0 (3)
C15—C10—C9	122.8 (3)	C15'—C10'—C9'	122.7 (3)
C11—C10—C9	119.3 (3)	C11'—C10'—C9'	119.3 (3)
C10—C11—C12	121.1 (3)	C12'—C11'—C10'	120.5 (3)
C10—C11—C23	120.5 (3)	C12'—C11'—C23'	119.5 (3)
C12—C11—C23	118.5 (3)	C10'—C11'—C23'	120.0 (3)
C13—C12—C11	119.9 (3)	C13'—C12'—C11'	120.1 (3)
C13—C12—H12	120.0	C13'—C12'—H12B	120.0
C11—C12—H12	120.0	C11'—C12'—H12B	120.0
C12—C13—C14	119.2 (3)	C14'—C13'—C12'	119.8 (3)
C12—C13—H13	120.4	C14'—C13'—H13B	120.1
C14—C13—H13	120.4	C12'—C13'—H13B	120.1
C15—C14—C13	121.1 (3)	C13'—C14'—C15'	120.9 (3)
C15—C14—H14	119.4	C13'—C14'—H14B	119.6
C13—C14—H14	119.4	C15'—C14'—H14B	119.6
C14—C15—C10	120.8 (3)	C14'—C15'—C10'	120.8 (3)
C14—C15—H15	119.6	C14'—C15'—H15B	119.6
C10—C15—H15	119.6	C10'—C15'—H15B	119.6
C4—N16—C21	115.6 (3)	C4'—N16'—C21'	116.2 (3)
C4—N16—C17	116.5 (2)	C4'—N16'—C17'	115.1 (2)
C21—N16—C17	111.1 (2)	C21'—N16'—C17'	111.4 (2)
N16—C17—C18	110.4 (2)	N16'—C17'—C18'	110.6 (2)
N16—C17—H17A	109.6	N16'—C17'—H17C	109.5
C18—C17—H17A	109.6	C18'—C17'—H17C	109.5
N16—C17—H17B	109.6	N16'—C17'—H17D	109.5
C18—C17—H17B	109.6	C18'—C17'—H17D	109.5
H17A—C17—H17B	108.1	H17C—C17'—H17D	108.1
N25—C18—C17	113.7 (3)	N25'—C18'—C19'	110.3 (3)
N25—C18—C19	110.3 (3)	N25'—C18'—C17'	113.2 (3)
C17—C18—C19	108.7 (3)	C19'—C18'—C17'	108.9 (3)
N25—C18—H18	108.0	N25'—C18'—H18B	108.1
C17—C18—H18	108.0	C19'—C18'—H18B	108.1
C19—C18—H18	108.0	C17'—C18'—H18B	108.1
C20—C19—C18	110.3 (3)	C18'—C19'—C20'	110.8 (3)
C20—C19—H19A	109.6	C18'—C19'—H19C	109.5
C18—C19—H19A	109.6	C20'—C19'—H19C	109.5
C20—C19—H19B	109.6	C18'—C19'—H19D	109.5
C18—C19—H19B	109.6	C20'—C19'—H19D	109.5
H19A—C19—H19B	108.1	H19C—C19'—H19D	108.1
C21—C20—C19	111.0 (3)	C21'—C20'—C19'	111.3 (3)
C21—C20—H20A	109.4	C21'—C20'—H20C	109.4
C19—C20—H20A	109.4	C19'—C20'—H20C	109.4
C21—C20—H20B	109.4	C21'—C20'—H20D	109.4
C19—C20—H20B	109.4	C19'—C20'—H20D	109.4
H20A—C20—H20B	108.0	H20C—C20'—H20D	108.0
N16—C21—C20	109.3 (3)	N16'—C21'—C20'	109.5 (3)
N16—C21—H21A	109.8	N16'—C21'—H21C	109.8
C20—C21—H21A	109.8	C20'—C21'—H21C	109.8
N16—C21—H21B	109.8	N16'—C21'—H21D	109.8
C20—C21—H21B	109.8	C20'—C21'—H21D	109.8
H21A—C21—H21B	108.3	H21C—C21'—H21D	108.2
N24—C23—C11	178.6 (4)	N24'—C23'—C11'	178.0 (3)
C18—N25—H25A	108 (3)	C18'—N25'—H25C	113 (3)
C18—N25—H25B	112 (3)	C18'—N25'—H25D	111 (3)
H25A—N25—H25B	115 (4)	H25C—N25'—H25D	105 (4)
C11—C10—C9—N3	165.5 (3)	C11'—C10'—C9'—N3'	169.9 (3)
C10—C9—N3—C4	−69.3 (4)	C10'—C9'—N3'—C4'	−76.1 (3)
N3—C4—N16—C17	−68.6 (3)	N3'—C4'—N16'—C17'	−69.1 (3)
C4—N16—C17—C18	162.7 (3)	C4'—N16'—C17'—C18'	163.3 (2)
N16—C17—C18—N25	−177.7 (3)	N16'—C17'—C18'—N25'	−178.6 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N25—H25A···O22^i	0.88 (2)	2.17 (2)	3.015 (4)	161 (4)
N25—H25B···O22′	0.86 (2)	2.47 (3)	3.132 (4)	134 (3)
N25′—H25C···O8	0.89 (2)	2.41 (2)	3.290 (4)	174 (4)
N25′—H25D···O22′^ii	0.87 (2)	2.32 (3)	3.087 (4)	148 (4)

Symmetry codes: (i) x, y+1, z; (ii) x+1, y, z.

(II) (3R)-1-{3-[(2-Cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl}piperidin-3-aminium benzoate

Crystal data

C18H22N5O2^+·C7H5O2^−	F(000) = 976
Mr = 461.52	Dx = 1.353 Mg m^−3
Orthorhombic, P212121	Cu Kα radiation, λ = 1.5418 Å
Hall symbol: P 2ac 2ab	Cell parameters from 8409 reflections
a = 8.0666 (2) Å	θ = 4.7–67.3°
b = 9.8727 (2) Å	µ = 0.77 mm^−1
c = 28.4593 (6) Å	T = 173 K
V = 2266.47 (9) Å^3	Prism, colourless
Z = 4	0.2 × 0.12 × 0.02 mm

Data collection

Agilent Xcalibur (Ruby, Gemini Ultra) diffractometer	3997 independent reflections
Graphite monochromator	3800 reflections with I > 2σ(I)
Detector resolution: 10.3822 pixels mm^-1	Rint = 0.025
ω scans	θmax = 67.4°, θmin = 4.7°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011)	h = −9→9
Tmin = 0.862, Tmax = 0.985	k = −11→11
12561 measured reflections	l = −27→33

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)] = 0.030	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.076	w = 1/[σ^2(Fo^2) + (0.0553P)^2 + 0.1001P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.001
3997 reflections	Δρmax = 0.12 e Å^−3
321 parameters	Δρmin = −0.21 e Å^−3
6 restraints	Absolute structure: Flack (1983), with 1657 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.01 (15)

Special details

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.

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 > 2sigma(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 (Ų)

	x	y	z	Uiso*/Ueq
N1	0.71185 (14)	0.38379 (12)	0.94160 (4)	0.0185 (3)
C2	0.55565 (17)	0.37518 (13)	0.96031 (5)	0.0180 (3)
N3	0.42973 (14)	0.33862 (11)	0.92965 (4)	0.0174 (2)
C4	0.46194 (17)	0.30293 (13)	0.88319 (5)	0.0165 (3)
C5	0.61640 (18)	0.31617 (14)	0.86543 (5)	0.0182 (3)
H5	0.6359	0.2967	0.8332	0.022*
C6	0.75069 (18)	0.35916 (13)	0.89455 (5)	0.0183 (3)
C7	0.84851 (18)	0.42369 (16)	0.97251 (5)	0.0235 (3)
H7A	0.8053	0.4424	1.0040	0.035*
H7B	0.9018	0.5053	0.9600	0.035*
H7C	0.9298	0.3501	0.9742	0.035*
O8	0.52572 (13)	0.40112 (11)	1.00152 (3)	0.0223 (2)
C9	0.26114 (17)	0.37158 (13)	0.94653 (5)	0.0181 (3)
H9A	0.2445	0.3320	0.9781	0.022*
H9B	0.1781	0.3313	0.9251	0.022*
C10	0.23578 (17)	0.52378 (14)	0.94884 (5)	0.0191 (3)
C11	0.19870 (18)	0.59036 (15)	0.99121 (5)	0.0216 (3)
C12	0.1621 (2)	0.72872 (15)	0.99163 (6)	0.0264 (3)
H12	0.1358	0.7726	1.0204	0.032*
C13	0.1642 (2)	0.80162 (16)	0.95017 (6)	0.0311 (4)
H13	0.1380	0.8954	0.9503	0.037*
C14	0.2046 (2)	0.73729 (16)	0.90845 (6)	0.0308 (4)
H14	0.2087	0.7878	0.8801	0.037*
C15	0.23908 (19)	0.59939 (15)	0.90780 (5)	0.0240 (3)
H15	0.2653	0.5564	0.8789	0.029*
N16	0.32400 (15)	0.25479 (11)	0.85862 (4)	0.0173 (2)
C17	0.34230 (18)	0.25624 (14)	0.80718 (5)	0.0185 (3)
H17A	0.4232	0.1862	0.7975	0.022*
H17B	0.3849	0.3455	0.7969	0.022*
C18	0.17591 (18)	0.22888 (14)	0.78397 (5)	0.0195 (3)
H18	0.1945	0.2210	0.7493	0.023*
C19	0.09874 (19)	0.09676 (14)	0.80110 (5)	0.0217 (3)
H19A	0.1630	0.0194	0.7885	0.026*
H19B	−0.0160	0.0897	0.7890	0.026*
C20	0.09586 (18)	0.08891 (15)	0.85491 (5)	0.0216 (3)
H20A	0.0137	0.1543	0.8673	0.026*
H20B	0.0612	−0.0031	0.8647	0.026*
C21	0.26532 (18)	0.12028 (13)	0.87560 (5)	0.0193 (3)
H21A	0.2583	0.1209	0.9103	0.023*
H21B	0.3453	0.0492	0.8662	0.023*
O22	0.89606 (12)	0.37338 (10)	0.88178 (3)	0.0214 (2)
C23	0.1880 (2)	0.51417 (15)	1.03420 (5)	0.0265 (3)
N24	0.1735 (2)	0.45223 (15)	1.06805 (5)	0.0418 (4)
N25	0.05861 (15)	0.34471 (12)	0.79237 (4)	0.0188 (3)
H25A	−0.036 (2)	0.3301 (19)	0.7757 (6)	0.039 (5)*
H25B	0.108 (2)	0.4232 (17)	0.7833 (6)	0.037 (5)*
H25C	0.026 (2)	0.3516 (18)	0.8240 (4)	0.030 (5)*
C26	0.46189 (18)	0.73998 (14)	0.79859 (5)	0.0192 (3)
C27	0.5572 (2)	0.64553 (16)	0.82237 (5)	0.0250 (3)
H27	0.5225	0.5536	0.8232	0.030*
C28	0.7025 (2)	0.68302 (17)	0.84504 (6)	0.0298 (4)
H28	0.7674	0.6168	0.8608	0.036*
C29	0.7526 (2)	0.81729 (16)	0.84457 (5)	0.0278 (3)
H29	0.8500	0.8439	0.8609	0.033*
C30	0.6604 (2)	0.91261 (15)	0.82025 (6)	0.0261 (3)
H30	0.6955	1.0044	0.8195	0.031*
C31	0.51688 (19)	0.87414 (14)	0.79701 (5)	0.0213 (3)
H31	0.4553	0.9396	0.7799	0.026*
C32	0.29937 (18)	0.69985 (14)	0.77516 (5)	0.0196 (3)
O33	0.23601 (14)	0.78671 (10)	0.74818 (4)	0.0267 (2)
O34	0.24313 (14)	0.58486 (10)	0.78434 (4)	0.0269 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0134 (6)	0.0221 (5)	0.0199 (6)	−0.0008 (4)	−0.0015 (4)	−0.0013 (5)
C2	0.0166 (7)	0.0168 (6)	0.0205 (7)	0.0000 (5)	−0.0017 (6)	0.0012 (5)
N3	0.0155 (6)	0.0183 (5)	0.0185 (6)	−0.0002 (4)	0.0007 (5)	−0.0006 (5)
C4	0.0188 (7)	0.0138 (6)	0.0169 (6)	0.0024 (5)	−0.0011 (6)	0.0016 (5)
C5	0.0196 (7)	0.0181 (6)	0.0168 (7)	0.0010 (5)	0.0002 (6)	0.0003 (5)
C6	0.0186 (7)	0.0162 (6)	0.0201 (7)	0.0026 (5)	−0.0002 (6)	0.0013 (5)
C7	0.0153 (7)	0.0332 (8)	0.0220 (8)	−0.0017 (6)	−0.0040 (6)	−0.0036 (6)
O8	0.0200 (5)	0.0288 (5)	0.0180 (5)	−0.0019 (4)	0.0003 (4)	−0.0032 (4)
C9	0.0139 (6)	0.0210 (6)	0.0194 (7)	−0.0016 (5)	0.0010 (6)	−0.0009 (5)
C10	0.0127 (6)	0.0225 (7)	0.0221 (7)	−0.0012 (5)	−0.0015 (6)	−0.0016 (6)
C11	0.0172 (7)	0.0251 (7)	0.0226 (7)	−0.0044 (6)	0.0013 (6)	−0.0027 (6)
C12	0.0256 (8)	0.0258 (7)	0.0277 (8)	−0.0009 (6)	0.0020 (7)	−0.0066 (6)
C13	0.0357 (9)	0.0211 (7)	0.0364 (9)	0.0046 (7)	0.0003 (8)	−0.0019 (7)
C14	0.0372 (10)	0.0263 (8)	0.0288 (8)	0.0052 (7)	0.0027 (7)	0.0049 (6)
C15	0.0249 (8)	0.0262 (7)	0.0211 (7)	0.0029 (6)	0.0018 (6)	−0.0011 (6)
N16	0.0175 (6)	0.0178 (5)	0.0167 (6)	−0.0023 (5)	−0.0005 (5)	−0.0002 (5)
C17	0.0166 (7)	0.0225 (6)	0.0164 (7)	−0.0006 (6)	0.0010 (5)	−0.0004 (6)
C18	0.0176 (7)	0.0223 (7)	0.0186 (7)	0.0011 (6)	−0.0006 (6)	−0.0032 (6)
C19	0.0179 (7)	0.0195 (7)	0.0276 (8)	−0.0003 (6)	−0.0035 (6)	−0.0035 (6)
C20	0.0196 (7)	0.0169 (6)	0.0284 (8)	−0.0022 (5)	−0.0024 (6)	0.0023 (6)
C21	0.0208 (7)	0.0164 (6)	0.0207 (7)	−0.0018 (6)	−0.0008 (6)	0.0013 (5)
O22	0.0142 (5)	0.0269 (5)	0.0232 (5)	−0.0002 (4)	0.0013 (4)	−0.0010 (4)
C23	0.0316 (8)	0.0246 (7)	0.0234 (8)	−0.0046 (6)	0.0033 (7)	−0.0071 (6)
N24	0.0691 (11)	0.0302 (7)	0.0261 (7)	−0.0062 (7)	0.0136 (8)	−0.0015 (6)
N25	0.0178 (6)	0.0201 (6)	0.0184 (6)	−0.0007 (5)	−0.0021 (5)	0.0011 (5)
C26	0.0189 (7)	0.0221 (7)	0.0164 (6)	−0.0003 (6)	0.0015 (6)	−0.0011 (6)
C27	0.0251 (8)	0.0238 (7)	0.0261 (7)	−0.0051 (6)	−0.0032 (6)	0.0051 (6)
C28	0.0264 (8)	0.0338 (8)	0.0293 (8)	−0.0028 (7)	−0.0069 (7)	0.0094 (7)
C29	0.0222 (7)	0.0351 (8)	0.0261 (8)	−0.0051 (7)	−0.0039 (7)	−0.0013 (6)
C30	0.0250 (8)	0.0224 (7)	0.0308 (8)	−0.0046 (6)	0.0020 (7)	−0.0037 (6)
C31	0.0219 (7)	0.0212 (7)	0.0207 (7)	0.0012 (6)	0.0012 (6)	−0.0019 (6)
C32	0.0204 (7)	0.0215 (7)	0.0170 (7)	0.0001 (6)	0.0024 (6)	−0.0027 (6)
O33	0.0213 (5)	0.0280 (5)	0.0308 (6)	0.0003 (4)	−0.0069 (5)	0.0041 (5)
O34	0.0260 (6)	0.0244 (5)	0.0303 (6)	−0.0064 (5)	−0.0048 (5)	0.0003 (4)

Geometric parameters (Å, º)

N1—C2	1.3705 (18)	C17—H17A	0.9900
N1—C6	1.3964 (19)	C17—H17B	0.9900
N1—C7	1.4643 (18)	C18—N25	1.5034 (18)
C2—O8	1.2246 (18)	C18—C19	1.525 (2)
C2—N3	1.3869 (19)	C18—H18	1.0000
N3—C4	1.3929 (18)	C19—C20	1.533 (2)
N3—C9	1.4786 (18)	C19—H19A	0.9900
C4—C5	1.351 (2)	C19—H19B	0.9900
C4—N16	1.3975 (18)	C20—C21	1.520 (2)
C5—C6	1.428 (2)	C20—H20A	0.9900
C5—H5	0.9500	C20—H20B	0.9900
C6—O22	1.2357 (18)	C21—H21A	0.9900
C7—H7A	0.9800	C21—H21B	0.9900
C7—H7B	0.9800	C23—N24	1.147 (2)
C7—H7C	0.9800	N25—H25A	0.908 (13)
C9—C10	1.5179 (18)	N25—H25B	0.908 (14)
C9—H9A	0.9900	N25—H25C	0.939 (13)
C9—H9B	0.9900	C26—C27	1.385 (2)
C10—C15	1.387 (2)	C26—C31	1.398 (2)
C10—C11	1.405 (2)	C26—C32	1.523 (2)
C11—C12	1.398 (2)	C27—C28	1.388 (2)
C11—C23	1.439 (2)	C27—H27	0.9500
C12—C13	1.382 (2)	C28—C29	1.386 (2)
C12—H12	0.9500	C28—H28	0.9500
C13—C14	1.385 (2)	C29—C30	1.385 (2)
C13—H13	0.9500	C29—H29	0.9500
C14—C15	1.390 (2)	C30—C31	1.386 (2)
C14—H14	0.9500	C30—H30	0.9500
C15—H15	0.9500	C31—H31	0.9500
N16—C17	1.4713 (17)	C32—O34	1.2501 (18)
N16—C21	1.4904 (17)	C32—O33	1.2595 (18)
C17—C18	1.520 (2)
C2—N1—C6	124.61 (12)	C18—C17—H17B	109.7
C2—N1—C7	118.38 (12)	H17A—C17—H17B	108.2
C6—N1—C7	117.00 (11)	N25—C18—C17	110.57 (11)
O8—C2—N1	122.71 (13)	N25—C18—C19	110.04 (11)
O8—C2—N3	120.84 (13)	C17—C18—C19	111.93 (12)
N1—C2—N3	116.42 (12)	N25—C18—H18	108.1
C2—N3—C4	121.77 (12)	C17—C18—H18	108.1
C2—N3—C9	114.33 (11)	C19—C18—H18	108.1
C4—N3—C9	122.39 (11)	C18—C19—C20	111.63 (12)
C5—C4—N3	120.18 (13)	C18—C19—H19A	109.3
C5—C4—N16	125.46 (13)	C20—C19—H19A	109.3
N3—C4—N16	114.36 (12)	C18—C19—H19B	109.3
C4—C5—C6	120.74 (13)	C20—C19—H19B	109.3
C4—C5—H5	119.6	H19A—C19—H19B	108.0
C6—C5—H5	119.6	C21—C20—C19	111.28 (12)
O22—C6—N1	118.37 (13)	C21—C20—H20A	109.4
O22—C6—C5	125.65 (13)	C19—C20—H20A	109.4
N1—C6—C5	115.97 (13)	C21—C20—H20B	109.4
N1—C7—H7A	109.5	C19—C20—H20B	109.4
N1—C7—H7B	109.5	H20A—C20—H20B	108.0
H7A—C7—H7B	109.5	N16—C21—C20	109.97 (11)
N1—C7—H7C	109.5	N16—C21—H21A	109.7
H7A—C7—H7C	109.5	C20—C21—H21A	109.7
H7B—C7—H7C	109.5	N16—C21—H21B	109.7
N3—C9—C10	110.85 (11)	C20—C21—H21B	109.7
N3—C9—H9A	109.5	H21A—C21—H21B	108.2
C10—C9—H9A	109.5	N24—C23—C11	177.43 (19)
N3—C9—H9B	109.5	C18—N25—H25A	108.9 (13)
C10—C9—H9B	109.5	C18—N25—H25B	109.2 (13)
H9A—C9—H9B	108.1	H25A—N25—H25B	110.6 (16)
C15—C10—C11	118.36 (13)	C18—N25—H25C	112.5 (11)
C15—C10—C9	119.59 (12)	H25A—N25—H25C	106.2 (15)
C11—C10—C9	121.93 (13)	H25B—N25—H25C	109.4 (14)
C12—C11—C10	120.64 (14)	C27—C26—C31	118.53 (14)
C12—C11—C23	119.40 (14)	C27—C26—C32	121.09 (13)
C10—C11—C23	119.85 (13)	C31—C26—C32	120.38 (13)
C13—C12—C11	119.93 (14)	C26—C27—C28	121.08 (14)
C13—C12—H12	120.0	C26—C27—H27	119.5
C11—C12—H12	120.0	C28—C27—H27	119.5
C12—C13—C14	119.72 (14)	C29—C28—C27	119.79 (15)
C12—C13—H13	120.1	C29—C28—H28	120.1
C14—C13—H13	120.1	C27—C28—H28	120.1
C13—C14—C15	120.51 (15)	C30—C29—C28	119.87 (15)
C13—C14—H14	119.7	C30—C29—H29	120.1
C15—C14—H14	119.7	C28—C29—H29	120.1
C10—C15—C14	120.81 (14)	C29—C30—C31	120.05 (14)
C10—C15—H15	119.6	C29—C30—H30	120.0
C14—C15—H15	119.6	C31—C30—H30	120.0
C4—N16—C17	114.49 (11)	C30—C31—C26	120.63 (14)
C4—N16—C21	113.19 (11)	C30—C31—H31	119.7
C17—N16—C21	111.29 (11)	C26—C31—H31	119.7
N16—C17—C18	110.00 (11)	O34—C32—O33	126.76 (14)
N16—C17—H17A	109.7	O34—C32—C26	117.20 (13)
C18—C17—H17A	109.7	O33—C32—C26	116.04 (12)
N16—C17—H17B	109.7
C11—C10—C9—N3	−119.39 (14)	C4—N16—C17—C18	−168.89 (11)
C10—C9—N3—C4	−99.19 (14)	N16—C17—C18—N25	67.67 (14)
N3—C4—N16—C17	162.30 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N25—H25A···O33^i	0.91 (1)	1.81 (1)	2.7033 (16)	170 (2)
N25—H25B···O34	0.91 (1)	1.93 (1)	2.8088 (16)	161 (2)
N25—H25C···O22^ii	0.94 (1)	1.96 (1)	2.8764 (16)	164 (2)

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