(3aS,7aS)-5-[(S)-3,3,3-Trifluoro-2-meth­oxy-2-phenyl­propano­yl]-2,3,4,5,6,7-hexa­hydro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one monohydrate

Abstract

rac-Benzyl 3-oxohexa­hydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxyl­ate was separated by chiral chromatography, and one of the enanti­omers ([α]²² _D = +10°) was hydrogenated in the presence of Pd/C in methanol, producing octa­hydro-3H-pyrrolo[3,4-c]pyridin-3-one. The latter was reacted with (2R)-3,3,3-trifluoro-2-meth­oxy-2-phenyl­propanoyl chloride [(R)-(−)-Mosher acid chloride], giving rise to the title compound, C₁₇H₁₉F₃N₂O₃·H₂O. The present structure established the absolute configuration of the pyrrolopiperidine fragment based on the known configuration of the (R)-Mosher acid chloride. The piperidine ring has a somewhat distorted chair conformation and is cis-fused with the five-membered envelope-shaped ring; the plane of the exocyclic amide bond is approximately orthogonal to the plane of the phenyl ring, making a dihedral angle of 82.31 (3)°. The water mol­ecule acts as an acceptor to the proton of the amino group in an N—H⋯O inter­action, and as a double proton donor in O—H⋯O hydrogen bonds, generating infinite bands along the a axis.

Related literature

For the structures of compounds with a similar bicyclic fragment, see: Kim et al. (2007 ▶); Arnott et al. (2006 ▶); Altomare et al. (1995 ▶). For the general synthesis method, see: von Dob­eneck & Hansen (1972 ▶).

Experimental

Crystal data

• C₁₇H₁₉F₃N₂O₃·H₂O

• M _r = 374.36

• Orthorhombic,

• a = 8.4870 (4) Å

• b = 13.7152 (7) Å

• c = 14.9113 (7) Å

• V = 1735.69 (15) ų

• Z = 4

• Mo Kα radiation

• μ = 0.12 mm⁻¹

• T = 150 K

• 0.36 × 0.25 × 0.13 mm

Data collection

• Bruker APEXII CCD diffractometer

• Absorption correction: multi-scan (SADABS; Bruker, 2001 ▶) T _min = 0.957, T _max = 0.984

• 23008 measured reflections

• 4020 independent reflections

• 3738 reflections with I > 2σ(I)

• R _int = 0.034

Refinement

• R[F ² > 2σ(F ²)] = 0.030

• wR(F ²) = 0.070

• S = 1.02

• 4020 reflections

• 248 parameters

• H atoms treated by a mixture of independent and constrained refinement

• Δρ_max = 0.22 e Å⁻³

• Δρ_min = −0.19 e Å⁻³

• Absolute structure: Flack (1983 ▶), 1537 Friedel pairs

• Flack parameter: 0.0 (5)

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1W—H1O⋯O1	0.88 (2)	1.96 (3)	2.8164 (16)	165 (2)
N1—H1N⋯O1Wi	0.933 (19)	2.037 (19)	2.8687 (17)	147.7 (16)
O1W—H2O⋯O2i	0.88 (2)	2.06 (2)	2.9111 (15)	162.8 (19)

Symmetry code: (i) .

supplementary crystallographic information

Comment

Catalytic hydrogenation of 1H-pyrrolo[3,4-c]pyridin-3(2H)-one (von Dobeneck & Hansen, 1972) with platinum gave rac-(3aR*,7aR*)-octahydro-3H-pyrrolo[3,4-c]-pyridin-3-one which was converted to rac-benzyl(3aR*,7aR*)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate, and separated into enantiomers by supercritical fluid chiral chromatography on Chiralpak column with 50% methanol-modified CO₂ as the eluent. The late eluting enantiomer ([α]²²_D = 10°) was hydrogenated in the presence of Pd/C in methanol producing octahydro-3H-pyrrolo[3,4-c]pyridin-3-one. The latter was reacted with (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride [(R)-(-)-Mosher acid chloride] giving rise to the title compound. The present structure (Fig. 1) established the absolute configuration of the pyrrolopiperidine fragment based on the known configuration at the C9 atom coming from the (R)-(-)-Mosher acid chloride (due to a change of the substituent priority of the product, the S-configuration is assigned).

The piperidine ring N2/C5/C2/C3/C7/C6 has a somewhat distorted chair conformation with torsion angles of alternating signs and absolute values in the range from 40.5 (2)° to 63.0 (1)°. The cis-fused 5-membered ring C1/C2/C3/C4/N1 adopts an envelope shape with the C3 atom displaced by 0.540 (2) Å from the C1/N1/C4/C2 plane which holds to within 0.01 Å. The overall conformation of pyrrolopiperidine fragment is similar to that observed in some of the previously studied compounds with analogous groups (Kim et al., 2007), however the conformation of the rings, especially of the piperidine part, in other related molecules (Arnott et al., 2006; Altomare et al., 1995) is varying broadly depending on the nature of the substituents in the cycle. The amide bond plane (passing through C5/C6/C8/N2/O2/C9 atoms and planar within 0.03 Å) is approximately orthogonal to the plane of the phenyl ring, corresponding dihedral angle being 82.31 (3)°. Water molecule acts as an acceptor of the HN1 group and as a double acceptor in O-H···O interactions generating hydrogen bond network (Table 1, Fig. 2).

Experimental

rac-(3aR*,7aR*)-Octahydro-3H-pyrrolo[3,4-c]-pyridin-3-one hydrochloride. A 1.0 L Parr shaker bottle was charged with 1,2-dihydropyrrolo[3,4-c]pyridin-3-one (68.0 g, 507.5 mmol), acetic acid (400 ml) and PtO₂ (6.8 g, 10% dry) catalyst (von Dobeneck & Hansen, 1972). A hydrogenation was performed 4 h at 40 psi. The reaction mixture was filtered through celite, and the solvent removed in vacuo to furnish an oil. HCl in 1,4-dioxane (4.0 M, 126.9 ml) was introduced into the flask at 0°C through an addition funnel. The solvent was then evaporated to dryness, ether (1 L) was added, and the mixture was stirred and filtered to yield 65.1 g (73%) of pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.50 (m, 1H), 1.82 (m, 1H). 2.45–2.55 (3H), 2.64 (m, 1H), 2.82 (m, 2H), 3.06 (m, 2H), 7.88 (s, 1H), 8.33 (brs, 1H), 9.42 (brs, 1H). LC—MS m/z: 141.2 (M+H)⁺.

rac-Benzyl (3aR*,7aR*)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5- carboxylate. To rac-(3aR*, 7aR*)-octahydro-3H-pyrrolo[3,4-c]-pyridin-3-one hydrochloride (45.0 g, 0.25 mol) in THF (300 ml) was added K₂CO₃ (95.4 g, 0.69 mol), benzyl chloroformate (47.8 g, 0.28 mol), and water (300 ml). The resulting mixture was stirred for 18 h at room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 300 ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was recrystallized from heptane to give 68.6 g (99%) white crystals. LC—MS (APCI) m/z: 275.1 (M+H)+. ¹H NMR (300 MHz, MeOD) δ 1.37 - 1.56 (m, 1H), 1.75 - 1.93 (m, 1H), 2.45 - 2.73 (m, 2H), 2.86 - 3.08 (m, 2H), 3.24 (d, J = 4.90 Hz, 1H), 3.48 (dd, J = 9.98, 6.22 Hz, 1H), 3.76 - 3.95 (m, 1H), 4.17 - 4.44 (m, 1H), 4.99 - 5.21 (m, 2H), 7.15 - 7.51 (m, 5H). LC—MS (APCI) m/z: 275.1 (M+H)⁺. The racemate (26 g) was separated into enantiomers using supercritical fluid chromatography on a Chiralpak(R) AS—H, 250 x 21 mm, 5µ column at 308 K at 100 bar isobaric pressure using 50% methanol-modified CO₂ and a flow rate of 50 ml/min.

Benzyl (3aR,7aR)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate: 12.1 g (46%), R_f = 0.87, ee: 100%, LC–MS (APCI) m/z: 275.3 (M+H)⁺. [α]²²_D = -13.5° (C=0.006 g/ml, MeOH).

Benzyl (3aS,7aS)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate: 12.1 g (46%), R_f = 1.88, ee: 100%. LC—MS (APCI) m/z: 275.3. [α]²²_D = +10.1° (c 0.007 g/ml, MeOH).

(3aS,7aS)-Octahydro-3H-pyrrolo[3,4-c]pyridin-3-one. To a solution of benzyl (3aR,7aR)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (500 mg, 1.82 mmol) in MeOH (5 ml) was added Pd/C (25 mg, 10 wt. % on activated carbon). The mixture was stirred for 18 h at room-temperature with a hydrogen balloon. The Pd/C was filtered off, and the filtrate was concentrated. Yield: 240 mg (95%). [α]²²_D = -25.9° (c 0.004 g/ml, MeOH).

(3aS,7aS)-5-((S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)hexahydro-1H- pyrrolo[3,4-c]pyridin-3(2H)-one. To a solution of (3aS,7aS)-octahydro-3H-pyrrolo[3,4-c]pyridin-3-one (180 mg, 1.28 mmol) in DMF (2 ml) was added DIEA (498 mg, 1.28 mmol). The mixture was stirred at 0°C for 5 min. (2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl chloride (Mosher acid chloride, 324 mg, 1.28 mmol) was added at 273 K. The reaction mixture was slowly warmed up to room-temperature and stirred for 10 min at room temperature. The product was purified by flash chromatography (ISCO, 10% MeOH in DCM, UV collect all) to afford 347 mg (76%) of white solid. ¹H NMR (300 MHz, MeOD) δ 0.18 - 0.37 (m, 1H), 1.09 - 1.23 (m, 1H), 2.47 (dq, J = 11.56, 5.94 Hz, 1H), 2.55 - 2.72 (m, 2H), 2.85 - 3.12 (m, 2H), 3.37 - 3.54 (m, 1H), 3.59 - 3.79 (m, 3H), 3.84 - 3.99 (m, 1H), 4.94 - 5.06 (m, 1H), 7.38 - 7.44 (m, 2H), 7.44 - 7.57 (m, 3H). LC—MS (APCI) m/z: 357.2 (M+H)⁺. [α]²²_D = -57.9° (c 0.007 g/ml, MeOH). Crystals of the subject compound were grown by heating the sample in a 353 K sand bath for one hour and then allowing it to cool and sit at room temperature for several days.

Refinement

All H atoms, bonded to C, were placed geometrically (C—H 0.95, 0.98, 0.99 and 1.00 Å for aromatic, methyl, methylene and methine groups respectively) and included in the refinement in riding motion approximation with U_iso(H) set to 1.2U_eq(C) [1.5U_eq(C) for methyl H atoms]. The H atoms at the N and O atoms were located in the difference map and refined isotropically [N—H 0.93 (2) Å; both O—H 0.88 (2) Å]. Even though there are no atoms with Z>Si, taking into account the chirality of the molecule, we chose not to merge the Friedel pairs. The Flack parameter, as one would expect, is inconclusive, and the absolute configuration was assigned on the basis of the known chirality of the starting material [(R)-(-)-Mosher acid chloride].

Figures

Fig. 1.

Asymmetric unit of the title compound showing 50% probability displacement ellipsoids and atom numbering scheme. H atoms are drawn as circles of arbitrary small radius.

Fig. 2.

Packing diagram of the title compound viewed down the b axis; hydrogen bonds are shown as dashed lines. H-atoms which do not participate in the hydrogen bonds are omitted.

Crystal data

C17H19F3N2O3·H2O	F(000) = 784
Mr = 374.36	Dx = 1.433 Mg m−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 7669 reflections
a = 8.4870 (4) Å	θ = 2.7–27.4°
b = 13.7152 (7) Å	µ = 0.12 mm−1
c = 14.9113 (7) Å	T = 150 K
V = 1735.69 (15) Å3	Block, colourless
Z = 4	0.36 × 0.25 × 0.13 mm

Data collection

Bruker APEX CCD diffractometer	4020 independent reflections
Radiation source: fine-focus sealed tube	3738 reflections with I > 2σ(I)
graphite	Rint = 0.034
φ and ω scans	θmax = 28.4°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Bruker, 2001)	h = −11→10
Tmin = 0.957, Tmax = 0.984	k = −17→18
23008 measured reflections	l = −19→18

Refinement

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.030	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.070	w = 1/[σ2(Fo2) + (0.0343P)2 + 0.299P] where P = (Fo2 + 2Fc2)/3
S = 1.02	(Δ/σ)max = 0.001
4020 reflections	Δρmax = 0.22 e Å−3
248 parameters	Δρmin = −0.19 e Å−3
0 restraints	Absolute structure: Flack (1983), 1537 Friedel pairs
Primary atom site location: structure-invariant direct methods	Flack parameter: 0.0 (5)

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
C1	0.46490 (18)	0.72722 (9)	0.80771 (10)	0.0226 (3)
C2	0.43300 (15)	0.68038 (10)	0.71644 (9)	0.0201 (3)
H2	0.4493	0.7315	0.6695	0.024*
C3	0.56770 (15)	0.60584 (10)	0.70764 (10)	0.0216 (3)
H3	0.5959	0.5953	0.6433	0.026*
C4	0.70183 (16)	0.65726 (11)	0.75757 (10)	0.0255 (3)
H4A	0.7755	0.6096	0.7846	0.031*
H4B	0.7612	0.7012	0.7172	0.031*
C5	0.26691 (16)	0.64039 (10)	0.70513 (9)	0.0201 (3)
H5A	0.1896	0.6895	0.7259	0.024*
H5B	0.2466	0.6274	0.6409	0.024*
C6	0.36089 (16)	0.47410 (9)	0.73187 (9)	0.0202 (3)
H6A	0.3522	0.4596	0.6670	0.024*
H6B	0.3380	0.4136	0.7656	0.024*
C7	0.52719 (16)	0.50895 (9)	0.75338 (10)	0.0217 (3)
H7A	0.6036	0.4587	0.7339	0.026*
H7B	0.5378	0.5167	0.8191	0.026*
C8	0.13686 (15)	0.54710 (9)	0.82186 (9)	0.0164 (2)
C9	0.12702 (15)	0.45319 (9)	0.87997 (9)	0.0170 (3)
C10	0.27529 (15)	0.44736 (9)	0.93844 (9)	0.0180 (3)
C11	0.33668 (16)	0.53289 (10)	0.97544 (9)	0.0210 (3)
H11	0.2841	0.5932	0.9660	0.025*
C12	0.47440 (17)	0.53028 (10)	1.02599 (9)	0.0236 (3)
H12	0.5161	0.5887	1.0507	0.028*
C13	0.55050 (16)	0.44225 (10)	1.04025 (10)	0.0245 (3)
H13	0.6450	0.4404	1.0744	0.029*
C14	0.48909 (16)	0.35704 (10)	1.00488 (10)	0.0245 (3)
H14	0.5409	0.2967	1.0155	0.029*
C15	0.35139 (16)	0.35918 (9)	0.95366 (9)	0.0204 (3)
H15	0.3099	0.3006	0.9293	0.025*
C16	−0.01874 (16)	0.45986 (9)	0.94228 (9)	0.0211 (3)
C17	0.00234 (19)	0.36490 (10)	0.75741 (10)	0.0276 (3)
H17A	−0.1051	0.3590	0.7809	0.041*
H17B	0.0251	0.3095	0.7180	0.041*
H17C	0.0119	0.4258	0.7234	0.041*
N1	0.61752 (15)	0.71226 (9)	0.82667 (9)	0.0264 (3)
N2	0.24673 (13)	0.55010 (8)	0.75654 (7)	0.0180 (2)
O1	0.36798 (13)	0.77208 (7)	0.85314 (7)	0.0301 (2)
O2	0.04938 (11)	0.61587 (6)	0.83902 (6)	0.0208 (2)
O3	0.11272 (11)	0.36562 (6)	0.83085 (6)	0.0201 (2)
O1W	0.36093 (13)	0.76305 (8)	1.04178 (8)	0.0273 (2)
F1	−0.00782 (10)	0.52989 (5)	1.00457 (5)	0.02504 (18)
F2	−0.03398 (10)	0.37511 (6)	0.98714 (6)	0.0283 (2)
F3	−0.15420 (9)	0.47343 (6)	0.89841 (6)	0.02748 (19)
H1O	0.359 (3)	0.7767 (16)	0.9843 (17)	0.059 (7)*
H2O	0.424 (3)	0.8062 (16)	1.0675 (14)	0.052 (6)*
H1N	0.665 (2)	0.7341 (13)	0.8794 (13)	0.037 (5)*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C1	0.0274 (7)	0.0175 (6)	0.0230 (7)	−0.0043 (6)	−0.0012 (6)	0.0047 (5)
C2	0.0194 (6)	0.0223 (6)	0.0188 (7)	−0.0023 (5)	0.0006 (5)	0.0046 (5)
C3	0.0174 (6)	0.0292 (7)	0.0181 (7)	−0.0013 (6)	0.0009 (5)	0.0011 (5)
C4	0.0188 (6)	0.0302 (7)	0.0276 (8)	−0.0047 (6)	−0.0033 (5)	0.0056 (6)
C5	0.0195 (6)	0.0225 (6)	0.0183 (7)	−0.0003 (5)	−0.0010 (5)	0.0053 (5)
C6	0.0203 (6)	0.0201 (6)	0.0202 (7)	0.0014 (6)	0.0035 (5)	−0.0028 (5)
C7	0.0194 (7)	0.0225 (6)	0.0231 (7)	0.0030 (5)	0.0017 (5)	−0.0009 (5)
C8	0.0156 (6)	0.0182 (6)	0.0155 (6)	−0.0018 (5)	−0.0023 (5)	0.0001 (5)
C9	0.0185 (6)	0.0159 (5)	0.0166 (7)	−0.0001 (5)	0.0017 (5)	−0.0004 (5)
C10	0.0184 (6)	0.0206 (6)	0.0150 (7)	0.0014 (5)	0.0016 (5)	0.0023 (5)
C11	0.0246 (7)	0.0191 (6)	0.0194 (7)	0.0024 (6)	−0.0010 (5)	0.0001 (5)
C12	0.0256 (7)	0.0252 (6)	0.0199 (7)	−0.0031 (6)	−0.0012 (5)	−0.0013 (5)
C13	0.0181 (6)	0.0326 (7)	0.0229 (8)	0.0013 (6)	−0.0019 (6)	0.0034 (6)
C14	0.0221 (7)	0.0239 (6)	0.0275 (8)	0.0058 (6)	0.0004 (6)	0.0031 (5)
C15	0.0215 (6)	0.0177 (6)	0.0221 (7)	0.0004 (5)	0.0027 (6)	0.0008 (5)
C16	0.0220 (6)	0.0204 (6)	0.0210 (7)	0.0006 (6)	0.0035 (5)	0.0023 (5)
C17	0.0303 (7)	0.0235 (6)	0.0290 (8)	−0.0063 (6)	−0.0092 (6)	−0.0017 (6)
N1	0.0286 (6)	0.0264 (6)	0.0241 (7)	−0.0067 (5)	−0.0068 (5)	−0.0001 (5)
N2	0.0174 (5)	0.0188 (5)	0.0177 (6)	−0.0010 (5)	0.0009 (4)	0.0003 (4)
O1	0.0373 (6)	0.0251 (5)	0.0280 (6)	−0.0004 (5)	0.0005 (5)	−0.0024 (4)
O2	0.0187 (4)	0.0200 (4)	0.0238 (5)	0.0030 (4)	0.0021 (4)	0.0028 (4)
O3	0.0211 (5)	0.0182 (4)	0.0211 (5)	−0.0020 (4)	−0.0017 (4)	−0.0023 (4)
O1W	0.0307 (6)	0.0256 (5)	0.0256 (6)	−0.0068 (5)	0.0051 (5)	−0.0049 (4)
F1	0.0294 (4)	0.0237 (4)	0.0220 (4)	0.0044 (3)	0.0064 (3)	−0.0012 (3)
F2	0.0337 (5)	0.0227 (4)	0.0286 (5)	−0.0006 (4)	0.0105 (4)	0.0069 (3)
F3	0.0172 (4)	0.0350 (5)	0.0302 (5)	−0.0007 (4)	0.0029 (3)	0.0035 (4)

Geometric parameters (Å, °)

C1—O1	1.2305 (18)	C9—O3	1.4120 (15)
C1—N1	1.3416 (19)	C9—C10	1.5330 (18)
C1—C2	1.529 (2)	C9—C16	1.5498 (18)
C2—C5	1.5218 (18)	C10—C15	1.3898 (18)
C2—C3	1.5392 (18)	C10—C11	1.3971 (19)
C2—H2	1.0000	C11—C12	1.3913 (19)
C3—C4	1.5321 (19)	C11—H11	0.9500
C3—C7	1.5328 (19)	C12—C13	1.3857 (19)
C3—H3	1.0000	C12—H12	0.9500
C4—N1	1.464 (2)	C13—C14	1.384 (2)
C4—H4A	0.9900	C13—H13	0.9500
C4—H4B	0.9900	C14—C15	1.3964 (19)
C5—N2	1.4664 (16)	C14—H14	0.9500
C5—H5A	0.9900	C15—H15	0.9500
C5—H5B	0.9900	C16—F3	1.3357 (16)
C6—N2	1.4699 (17)	C16—F1	1.3393 (15)
C6—C7	1.5242 (19)	C16—F2	1.3473 (14)
C6—H6A	0.9900	C17—O3	1.4412 (16)
C6—H6B	0.9900	C17—H17A	0.9800
C7—H7A	0.9900	C17—H17B	0.9800
C7—H7B	0.9900	C17—H17C	0.9800
C8—O2	1.2273 (15)	N1—H1N	0.933 (19)
C8—N2	1.3490 (17)	O1W—H1O	0.88 (2)
C8—C9	1.5546 (17)	O1W—H2O	0.88 (2)
O1—C1—N1	127.29 (14)	O3—C9—C16	107.02 (10)
O1—C1—C2	125.57 (13)	C10—C9—C16	108.50 (10)
N1—C1—C2	107.12 (13)	O3—C9—C8	114.85 (10)
C5—C2—C1	114.46 (12)	C10—C9—C8	108.42 (10)
C5—C2—C3	116.05 (11)	C16—C9—C8	109.16 (10)
C1—C2—C3	102.91 (11)	C15—C10—C11	119.53 (12)
C5—C2—H2	107.7	C15—C10—C9	121.31 (12)
C1—C2—H2	107.7	C11—C10—C9	119.14 (11)
C3—C2—H2	107.7	C12—C11—C10	120.38 (12)
C4—C3—C7	110.46 (12)	C12—C11—H11	119.8
C4—C3—C2	101.82 (11)	C10—C11—H11	119.8
C7—C3—C2	111.79 (11)	C13—C12—C11	119.80 (12)
C4—C3—H3	110.8	C13—C12—H12	120.1
C7—C3—H3	110.8	C11—C12—H12	120.1
C2—C3—H3	110.8	C14—C13—C12	120.12 (13)
N1—C4—C3	102.48 (11)	C14—C13—H13	119.9
N1—C4—H4A	111.3	C12—C13—H13	119.9
C3—C4—H4A	111.3	C13—C14—C15	120.39 (13)
N1—C4—H4B	111.3	C13—C14—H14	119.8
C3—C4—H4B	111.3	C15—C14—H14	119.8
H4A—C4—H4B	109.2	C10—C15—C14	119.77 (12)
N2—C5—C2	110.77 (11)	C10—C15—H15	120.1
N2—C5—H5A	109.5	C14—C15—H15	120.1
C2—C5—H5A	109.5	F3—C16—F1	107.42 (10)
N2—C5—H5B	109.5	F3—C16—F2	106.30 (10)
C2—C5—H5B	109.5	F1—C16—F2	106.33 (10)
H5A—C5—H5B	108.1	F3—C16—C9	113.68 (11)
N2—C6—C7	109.59 (10)	F1—C16—C9	113.76 (11)
N2—C6—H6A	109.8	F2—C16—C9	108.86 (10)
C7—C6—H6A	109.8	O3—C17—H17A	109.5
N2—C6—H6B	109.8	O3—C17—H17B	109.5
C7—C6—H6B	109.8	H17A—C17—H17B	109.5
H6A—C6—H6B	108.2	O3—C17—H17C	109.5
C6—C7—C3	112.70 (11)	H17A—C17—H17C	109.5
C6—C7—H7A	109.1	H17B—C17—H17C	109.5
C3—C7—H7A	109.1	C1—N1—C4	113.73 (12)
C6—C7—H7B	109.1	C1—N1—H1N	123.0 (12)
C3—C7—H7B	109.1	C4—N1—H1N	123.2 (12)
H7A—C7—H7B	107.8	C8—N2—C5	118.94 (11)
O2—C8—N2	123.04 (12)	C8—N2—C6	127.93 (11)
O2—C8—C9	119.21 (11)	C5—N2—C6	113.02 (10)
N2—C8—C9	117.70 (11)	C9—O3—C17	117.12 (10)
O3—C9—C10	108.74 (10)	H1O—O1W—H2O	107.0 (19)
O1—C1—C2—C5	−33.31 (19)	C10—C11—C12—C13	−0.4 (2)
N1—C1—C2—C5	148.36 (12)	C11—C12—C13—C14	−0.5 (2)
O1—C1—C2—C3	−160.12 (13)	C12—C13—C14—C15	0.8 (2)
N1—C1—C2—C3	21.55 (13)	C11—C10—C15—C14	−0.67 (19)
C5—C2—C3—C4	−158.45 (12)	C9—C10—C15—C14	177.92 (12)
C1—C2—C3—C4	−32.67 (13)	C13—C14—C15—C10	−0.3 (2)
C5—C2—C3—C7	−40.53 (16)	O3—C9—C16—F3	−68.07 (13)
C1—C2—C3—C7	85.25 (13)	C10—C9—C16—F3	174.76 (11)
C7—C3—C4—N1	−86.77 (13)	C8—C9—C16—F3	56.79 (14)
C2—C3—C4—N1	32.10 (14)	O3—C9—C16—F1	168.56 (10)
C1—C2—C5—N2	−73.86 (14)	C10—C9—C16—F1	51.39 (13)
C3—C2—C5—N2	45.83 (16)	C8—C9—C16—F1	−66.59 (13)
N2—C6—C7—C3	−56.07 (15)	O3—C9—C16—F2	50.20 (13)
C4—C3—C7—C6	157.69 (12)	C10—C9—C16—F2	−66.97 (13)
C2—C3—C7—C6	45.08 (15)	C8—C9—C16—F2	175.06 (10)
O2—C8—C9—O3	129.59 (12)	O1—C1—N1—C4	−178.89 (14)
N2—C8—C9—O3	−52.90 (15)	C2—C1—N1—C4	−0.60 (15)
O2—C8—C9—C10	−108.58 (13)	C3—C4—N1—C1	−20.66 (15)
N2—C8—C9—C10	68.93 (14)	O2—C8—N2—C5	1.99 (19)
O2—C8—C9—C16	9.44 (16)	C9—C8—N2—C5	−175.41 (11)
N2—C8—C9—C16	−173.05 (11)	O2—C8—N2—C6	177.85 (12)
O3—C9—C10—C15	−14.71 (16)	C9—C8—N2—C6	0.44 (19)
C16—C9—C10—C15	101.35 (14)	C2—C5—N2—C8	119.23 (13)
C8—C9—C10—C15	−140.21 (12)	C2—C5—N2—C6	−57.22 (14)
O3—C9—C10—C11	163.89 (11)	C7—C6—N2—C8	−113.09 (14)
C16—C9—C10—C11	−80.05 (14)	C7—C6—N2—C5	62.97 (14)
C8—C9—C10—C11	38.39 (15)	C10—C9—O3—C17	−166.32 (11)
C15—C10—C11—C12	1.0 (2)	C16—C9—O3—C17	76.67 (13)
C9—C10—C11—C12	−177.60 (12)	C8—C9—O3—C17	−44.66 (15)

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
O1W—H1O···O1	0.88 (2)	1.96 (3)	2.8164 (16)	165 (2)
N1—H1N···O1Wi	0.933 (19)	2.037 (19)	2.8687 (17)	147.7 (16)
O1W—H2O···O2i	0.88 (2)	2.06 (2)	2.9111 (15)	162.8 (19)

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