Crystal structures of two alanyl­piperidine analogues

Mambourg, K.; Tumanov, N.; Henon, G.; Lanners, S.; Garcia-Ladona, J.; Wouters, J.

doi:10.1107/S2056989021010392

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ISSN: 2056-9890

Volume 77| Part 11| November 2021| Pages 1095-1098

https://doi.org/10.1107/S2056989021010392

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Crystal structures of two alanylpiperidine analogues

Kalina Mambourg,^a ^* Nikolay Tumanov,^a Gilles Henon,^a Steve Lanners,^a Javier Garcia-Ladona ^b and Johan Wouters ^a

^aDepartment of Chemistry, University of Namur, Rue de Bruxelles 61, Namur 5000, Belgium, and ^bAbaxys Therapeutics, Rue du Berceau 91, Villers-la-Ville 1495, Belgium
^*Correspondence e-mail: kalina.mambourg@unamur.be

Edited by L. Van Meervelt, Katholieke Universiteit Leuven, Belgium (Received 30 September 2021; accepted 7 October 2021; online 13 October 2021)

The structure of ethyl 1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylate, C₁₉H₂₈N₂O₅S, I, a compound of interest as activator of Ubiquitin C-terminal Hydrolase-L1 (UCH-L1), was determined by single-crystal X-ray diffraction (SCXRD) analysis. In order to find new activators, a derivative of compound I, namely, 1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylic acid, C₁₇H₂₄N₂O₅S, II, was studied. The synthesis and crystal structure are also reported. Despite being analogues, different crystal packings are observed. Compound II bears a carboxylic group, which favors a strong hydrogen bond. A polymorph risk assessment was carried out to study interactions in compound II.

Keywords: crystal structure; UCH-L1 activator; alanylpiperidine derivatives; polymorph risk assessment.

CCDC references: 2114340; 2114339

1. Chemical context

Ubiquitin C-terminal Hydrolase-L1 is a deubiquitinase that represents 2% of the neuronal soluble proteins in the brain and is involved in the neuropathogenesis of neurodegenerative diseases. Studies have shown that several mutations have an impact on the hydrolase activity of UCH-L1 (Leroy et al., 1998 ; Maraganore et al., 1999 ) and that its down-regulation is associated with idiopathic Parkinson's disease (Choi et al., 2004 ). Finding potentiators of UCH-L1 could be a therapeutic pathway for these diseases (Mitsui et al., 2010 ). Ethyl 1-[N-(methylsulfonyl)-N-(p-tolyl)-alanyl]piperidine-4-carboxylate was discovered through in silico drug screening as an activator of UCH-L1, with a hydrolase activity up to 111% at 63 µM (Mitsui et al., 2010). We studied the only known activator in the literature, compound I. Derivatives of compound I were then investigated as potential activators and compound II was obtained after a saponification. Compound II bears a carboxylic acid group, which opens up the possibility for co-crystallization and salification in order to modulate the physicochemical properties, such as the solubility. We report the crystal structures of these two compounds as well as a survey of the interactions observed in compound II.

2. Structural commentary

Both compounds crystallize as colorless plate-like crystals but in different space groups. Compound I crystallizes in the triclinic P $[\overline{1}]$ space groups and compound II in the monoclinic P2₁/n space group. The asymmetric units are shown in Fig. 1. Both compounds crystallize as a racemic mixture and have one molecule in the asymmetric unit in a similar conformation. The torsion angle N1—C1—C2—N2 is 156.2 (1) and −153.5 (1)° for I and II respectively. The only slight difference between the two compounds is the geometry of N2. In compound I, the distance between N2 and the plane formed by C2, C3 and C7 is 0.114 (2) Å whereas in compound II this distance is 0.014 (2) Å. A more planar arrangement of N2 in compound II is noticed, probably caused by the crystal packing. Single crystals represent the bulk samples as the powder patterns calculated from SCXRD data are similar to the experimental ones.

Figure 1
The asymmetric units of compounds I and II, with displacement ellipsoids drawn at the 50% probability level.

3. Supramolecular features

As compound I does not have any strong hydrogen-bond acceptors, only weak hydrogen bonds are observed in the crystal structure (see Table 1). The amide oxygen atom O1 participates in the formation of two intramolecular hydrogen bonds [ S₁¹(7) motifs; Etter et al., 1990 ]. The oxygen atom O4 is inter-connected with atom H12C of the sulfonyl methyl of an adjacent molecule [d(H⋯O) 2.44 Å; Table 1], forming an R₂²(8) hydrogen bond motif along the a-axis direction (Fig. 2). As compound I bears a tolyl moiety, π–π interactions were expected but were not observed in this crystal packing.

Table 1
Hydrogen-bond geometry (Å, °) for compound I

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C12—H12B⋯O1	0.96	2.50	3.210 (2)	130
C12—H12C⋯O4ⁱ	0.96	2.44	3.376 (2)	164
C14—H14⋯O1	0.93	2.48	3.177 (2)	132
Symmetry code: (i) .

Figure 2
Crystal packing of I with hydrogen bonds highlighted in green (a) showing one layer of molecules, viewed down the a axis and (b) showing adjacent layers of molecules.

Compound II bearing a carboxylic moiety instead of an ester has an impact on the hydrogen bonds and thus on the crystal packing. In compound II, a tubular arrangement (Fig. 3) can be observed, which is different from that of compound I. In compound II, a hydrogen-bonded ring with an R₂²(24) motif is formed by a strong hydrogen bond between H3 of the carboxylic acid group and O5 from an adjacent molecule [d(H⋯O) 1.88 (3) Å; Table 2]. In addition, two intramolecular [ S₁¹(7) motifs] and one intermolecular [ R₂²(10) motif] weak hydrogen bonds are detected. As in compound I, no π–π interactions are noticed in the crystal structure. A dimer synthon is observed in the crystal packing in both cases, but for compound I it is ensured by weak hydrogen bonds in contrast to compound II where the dimer is based on strong hydrogen bonds.

Table 2
Hydrogen-bond geometry (Å, °) for compound II

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O5ⁱ	0.90 (3)	1.88 (3)	2.7463 (15)	161 (2)
C17—H17A⋯O1	0.96	2.48	3.144 (2)	127
C4—H4B⋯O2ⁱ	0.97	2.52	3.471 (2)	167
C11—H11⋯O1	0.93	2.56	3.2558 (19)	132
Symmetry code: (i) .

Figure 3
Crystal packing of II showing the tubular arrangement viewed down the a axis. Hydrogen bonds are highlighted in green.

4. Database survey

Searches of the Cambridge Structural Database (CSD, version 5.42, update September 2021; Groom et al. 2016 ) were carried out with the exact structures of compounds I and II and with substructures containing the significant fragments (alanylpiperidine with and without the sulfonyl methyl and tolyl group). No comparable structures came out of this survey.

A polymorph risk assessment based on the hydrogen bonds in the CSD was carried out. This statistical analysis allows us to estimate which atoms are the donors and the acceptors for hydrogen bonds in the crystal structure (Chemburkar et al., 2000 ; Galek et al., 2007 ). This quantifies the probability of hydrogen-bond formation and thus the different probable polymorphs that can arise from a specific compound. The results are summarized in Table 3. A hydrogen-bonding interaction between two carboxylic groups is predicted with the highest probability. We did not observe the carboxylic dimer but rather this group interacting with one oxygen of the sulfonyl methyl. The analysis also predicts other plausible hydrogen-bonded networks (Fig. 4), one that is statistically slightly more likely to be formed than the current one. This suggests that another potential polymorph could be obtained. Thus, we undertook a polymorph screening by several crystallization experiments of compound II. The recrystallization solvents that we tested were cyclohexane, toluene, ethyl acetate, chloroform, dichloromethane, acetone, acetonitrile, 2-propanol, ethanol and methanol. They all lead to the same polymorph.

Table 3
Hydrogen-bond propensity calculation for compound II

Donor	Acceptor	Propensity
O3	O2	0.36
O3	O4	0.30
O3	O5	0.30

Figure 4
Hydrogen-bond propensity chart for compound II.

5. Synthesis and crystallization

Compound I: This was purchased from Evotech (Hamburg, Germany). The product was crystallized by slow evaporation from non-anhydrous ethyl acetate, which provided colorless plate-like crystals suitable for SCXRD. M.p. 442.2 K

Compound II: In a round-bottom flask, compound I (405.1 mg, 1.02 mmol, 1.0 eq) dissolved in 8 mL of THF was added to a solution of LiOH (81.9 mg, 3.40 mmol, 3.4 eq) dissolved in 5 mL of water. The mixture was stirred at room temperature for 8 h. The resulting mixture was washed with ether. The aqueous phase was then acidified with HCl 37% to a pH of 2 and extracted with dichloromethane. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield a white solid (351.0 mg, 93%). The product was crystallized by slow evaporation from methanol, which provided colorless plate-like crystals suitable for SCXRD. ¹H NMR (DMSO): 12.32 (s, 1H, carboxylic acid), 7.39 (d, 2H, CH_arom), 7.20 (d, 2H, CH_arom), 5.20 (s, 1H, CH_α), 4.03–3.15 (m, 4H, CH_pip), 2.96 (s, 3H, CH_SO2Me), 2.79 (m, 1H, CH_pip), 2.31 (s, 3H, CH_PheMe), 1.83–1.36 (m, 4H, CH_pip), 1.03 (d, 3H, CH_αMe) ¹³C NMR (DMSO): 169.1, 168.7, 138.2, 133.5, 132.0, 129.4, 53.3, 44.5, 41.3, 28.5, 20.7, 16.8. M.p. 496.2 K

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 4. All H atoms, except one of the -OH group in II, were refined using a riding model, with C—H = 0.93 (aromatic), 0.96 (methyl) or 0.98 Å (tertiary carbon). Coordinates of the hydrogen atom of the -OH group were refined. The isotropic atomic displacement parameters of the H atoms were set at 1.5U_eq of the parent atom for the methyl and alcohol groups, and at 1.2U_eq otherwise.

Table 4
Experimental details

	I	II
Crystal data
Chemical formula	C₁₉H₂₈N₂O₅S	C₁₇H₂₄N₂O₅S
M_r	396.49	368.44
Crystal system, space group	Triclinic, P $[\overline{1}]$	Monoclinic, P2₁/n
Temperature (K)	295	295
a, b, c (Å)	8.5368 (6), 9.6594 (6), 13.5173 (12)	12.1013 (2), 12.3092 (2), 12.4348 (3)
α, β, γ (°)	75.947 (6), 79.302 (6), 74.554 (5)	90, 100.546 (2), 90
V (Å³)	1033.47 (14)	1820.97 (6)
Z	2	4
Radiation type	Mo Kα	Mo Kα
μ (mm⁻¹)	0.19	0.21
Crystal size (mm)	0.79 × 0.18 × 0.05	0.77 × 0.18 × 0.11

Data collection
Diffractometer	Oxford Diffraction Xcalibur, Gemini Ultra R	Oxford Diffraction Xcalibur, Gemini Ultra R
Absorption correction	Analytical [CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), based on expressions derived by Clark & Reid (1995 )]	Analytical [CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), based on expressions derived by Clark & Reid (1995)]
T_min, T_max	0.923, 0.991	0.882, 0.980
No. of measured, independent and observed [I > 2σ(I)] reflections	13200, 6870, 4304	29518, 6284, 4779
R_int	0.026	0.026
(sin θ/λ)_max (Å⁻¹)	0.762	0.761

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.054, 0.158, 1.02	0.043, 0.126, 1.02
No. of reflections	6870	6284
No. of parameters	248	232
H-atom treatment	H-atom parameters constrained	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.38	0.29, −0.29
Computer programs: CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SHELXT2014 (Sheldrick, 2015a ), SHELXL2016 (Sheldrick, 2015b ), Mercury (Macrae et al., 2020 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC references: 2114340; 2114339

Crystal structure: contains datablocks I, II. DOI: https://doi.org/10.1107/S2056989021010392/vm2254sup1.cif

Supporting information file. DOI: https://doi.org/10.1107/S2056989021010392/vm2254Isup4.mol

Supporting information file. DOI: https://doi.org/10.1107/S2056989021010392/vm2254IIsup5.mol

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989021010392/vm2254Isup6.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989021010392/vm2254Isup6.cml

Structure factors: contains datablock II. DOI: https://doi.org/10.1107/S2056989021010392/vm2254IIsup7.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989021010392/vm2254IIsup7.cml

checkCIF report

Computing details top

For both structures, data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: publCIF (Westrip, 2010).

Ethyl 1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylate (I) top

Crystal data top

C₁₉H₂₈N₂O₅S	Z = 2
M_r = 396.49	F(000) = 424
Triclinic, P1	D_x = 1.274 Mg m⁻³
a = 8.5368 (6) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.6594 (6) Å	Cell parameters from 3246 reflections
c = 13.5173 (12) Å	θ = 2.4–30.5°
α = 75.947 (6)°	µ = 0.19 mm⁻¹
β = 79.302 (6)°	T = 295 K
γ = 74.554 (5)°	Plate, colorless
V = 1033.47 (14) Å³	0.79 × 0.18 × 0.05 mm

Data collection top

Oxford Diffraction Xcalibur, Gemini Ultra R diffractometer	6870 independent reflections
Radiation source: fine-focus sealed X-ray tube	4304 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.026
Detector resolution: 10.3712 pixels mm^-1	θ_max = 32.8°, θ_min = 2.2°
ω scans	h = −12→10
Absorption correction: analytical [CrysAlisPro (Rigaku OD, 2018), based on expressions derived by Clark & Reid (1995)]	k = −13→14
T_min = 0.923, T_max = 0.991	l = −20→19
13200 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: dual
R[F² > 2σ(F²)] = 0.054	Hydrogen site location: mixed
wR(F²) = 0.158	H-atom parameters constrained
S = 1.02	w = 1/[σ²(F_o²) + (0.0633P)² + 0.1206P] where P = (F_o² + 2F_c²)/3
6870 reflections	(Δ/σ)_max < 0.001
248 parameters	Δρ_max = 0.34 e Å⁻³
0 restraints	Δρ_min = −0.37 e Å⁻³

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.21006 (5)	0.11226 (4)	0.49970 (3)	0.04597 (14)
O1	0.20546 (16)	0.42592 (12)	0.58010 (10)	0.0542 (3)
O2	0.2688 (3)	−0.0438 (2)	1.00683 (16)	0.1150 (8)
O3	0.1551 (3)	0.16259 (18)	1.06193 (12)	0.0894 (5)
O4	0.21136 (17)	0.03480 (13)	0.42186 (11)	0.0618 (4)
O5	0.25664 (18)	0.02943 (13)	0.59697 (11)	0.0624 (4)
N1	0.33461 (16)	0.22121 (13)	0.45549 (10)	0.0404 (3)
N2	0.3882 (2)	0.31933 (16)	0.69243 (11)	0.0543 (4)
C1	0.4352 (2)	0.24222 (16)	0.52607 (12)	0.0407 (3)
H1	0.484975	0.145601	0.564865	0.049*
C2	0.3309 (2)	0.33501 (16)	0.60307 (13)	0.0435 (4)
C3	0.2942 (3)	0.4081 (2)	0.76676 (14)	0.0622 (5)
H3A	0.212739	0.487753	0.733487	0.075*
H3B	0.367076	0.450568	0.791143	0.075*
C4	0.2099 (3)	0.3155 (2)	0.85723 (15)	0.0598 (5)
H4A	0.126979	0.283509	0.834039	0.072*
H4B	0.155721	0.374364	0.908049	0.072*
C5	0.3330 (3)	0.1809 (2)	0.90679 (14)	0.0595 (5)
H5	0.409068	0.216659	0.934903	0.071*
C6	0.4334 (3)	0.0960 (2)	0.82547 (15)	0.0631 (5)
H6A	0.517049	0.016237	0.856466	0.076*
H6B	0.362540	0.054116	0.798864	0.076*
C7	0.5139 (3)	0.1963 (2)	0.73772 (15)	0.0617 (5)
H7A	0.590425	0.233317	0.763271	0.074*
H7B	0.574515	0.141684	0.685678	0.074*
C8	0.2494 (3)	0.0852 (2)	0.99538 (17)	0.0714 (6)
C9	0.0650 (4)	0.0879 (3)	1.1529 (2)	0.1069 (10)
H9A	0.004626	0.029494	1.132728	0.128*
H9B	0.140898	0.023064	1.198758	0.128*
C10	−0.0456 (5)	0.1958 (4)	1.2040 (2)	0.1357 (14)
H10A	0.012297	0.263307	1.213528	0.204*
H10B	−0.091589	0.148539	1.269779	0.204*
H10C	−0.131975	0.248210	1.163132	0.204*
C11	0.5719 (2)	0.31422 (19)	0.46630 (14)	0.0503 (4)
H11A	0.636931	0.256036	0.418334	0.075*
H11B	0.639730	0.321567	0.513158	0.075*
H11C	0.525388	0.410564	0.429625	0.075*
C12	0.0118 (2)	0.2217 (2)	0.5200 (2)	0.0700 (6)
H12A	−0.017746	0.283965	0.455966	0.105*
H12B	0.008836	0.280954	0.568219	0.105*
H12C	−0.064229	0.159986	0.546811	0.105*
C13	0.3206 (2)	0.31143 (16)	0.35381 (13)	0.0431 (4)
C14	0.2231 (2)	0.45197 (18)	0.33966 (14)	0.0543 (4)
H14	0.166814	0.491483	0.396039	0.065*
C15	0.2097 (3)	0.5336 (2)	0.24101 (16)	0.0641 (5)
H15	0.144679	0.628604	0.232086	0.077*
C16	0.2899 (3)	0.4784 (2)	0.15543 (15)	0.0617 (5)
C17	0.3898 (3)	0.3385 (2)	0.17173 (16)	0.0675 (6)
H17	0.447572	0.299605	0.115395	0.081*
C18	0.4060 (3)	0.25519 (19)	0.26953 (14)	0.0569 (5)
H18	0.474265	0.161520	0.278607	0.068*
C19	0.2674 (4)	0.5688 (3)	0.04839 (17)	0.0908 (8)
H19A	0.162225	0.569619	0.032294	0.136*
H19B	0.351973	0.526722	−0.000565	0.136*
H19C	0.273737	0.667492	0.045582	0.136*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.0381 (2)	0.0362 (2)	0.0636 (3)	−0.00995 (16)	−0.00197 (19)	−0.01207 (17)
O1	0.0444 (7)	0.0491 (6)	0.0645 (8)	0.0048 (5)	−0.0079 (6)	−0.0194 (5)
O2	0.157 (2)	0.0689 (11)	0.1072 (15)	−0.0226 (12)	0.0015 (14)	−0.0131 (10)
O3	0.1050 (15)	0.0800 (10)	0.0695 (10)	−0.0174 (10)	0.0144 (9)	−0.0133 (8)
O4	0.0598 (9)	0.0532 (7)	0.0829 (9)	−0.0212 (6)	−0.0043 (7)	−0.0280 (6)
O5	0.0629 (9)	0.0520 (7)	0.0669 (8)	−0.0211 (6)	−0.0053 (7)	0.0039 (6)
N1	0.0352 (7)	0.0367 (6)	0.0492 (7)	−0.0082 (5)	−0.0054 (6)	−0.0089 (5)
N2	0.0541 (10)	0.0534 (8)	0.0517 (8)	0.0017 (7)	−0.0076 (7)	−0.0191 (6)
C1	0.0333 (8)	0.0376 (7)	0.0507 (9)	−0.0047 (6)	−0.0051 (7)	−0.0119 (6)
C2	0.0389 (9)	0.0382 (7)	0.0527 (9)	−0.0075 (6)	−0.0036 (7)	−0.0114 (6)
C3	0.0761 (15)	0.0538 (10)	0.0557 (11)	−0.0053 (10)	−0.0049 (10)	−0.0226 (8)
C4	0.0598 (13)	0.0600 (11)	0.0568 (11)	−0.0007 (9)	−0.0072 (9)	−0.0214 (9)
C5	0.0600 (13)	0.0647 (11)	0.0542 (11)	−0.0060 (9)	−0.0145 (9)	−0.0170 (8)
C6	0.0635 (14)	0.0587 (10)	0.0620 (12)	0.0094 (9)	−0.0241 (10)	−0.0167 (9)
C7	0.0490 (12)	0.0749 (12)	0.0598 (11)	0.0038 (9)	−0.0152 (9)	−0.0247 (9)
C8	0.0784 (17)	0.0663 (13)	0.0668 (13)	−0.0071 (11)	−0.0187 (12)	−0.0122 (10)
C9	0.114 (3)	0.0948 (18)	0.0859 (19)	−0.0194 (18)	0.0136 (18)	0.0053 (15)
C10	0.125 (3)	0.143 (3)	0.092 (2)	−0.013 (2)	0.033 (2)	0.009 (2)
C11	0.0363 (9)	0.0539 (9)	0.0644 (11)	−0.0139 (7)	−0.0001 (8)	−0.0200 (8)
C12	0.0332 (10)	0.0571 (11)	0.1202 (19)	−0.0110 (8)	0.0035 (11)	−0.0288 (11)
C13	0.0396 (9)	0.0410 (8)	0.0493 (9)	−0.0094 (7)	−0.0059 (7)	−0.0105 (6)
C14	0.0528 (11)	0.0484 (9)	0.0554 (10)	0.0016 (8)	−0.0105 (9)	−0.0109 (8)
C15	0.0567 (13)	0.0568 (11)	0.0695 (13)	0.0007 (9)	−0.0188 (10)	−0.0030 (9)
C16	0.0607 (13)	0.0713 (12)	0.0540 (11)	−0.0235 (10)	−0.0112 (10)	−0.0024 (9)
C17	0.0791 (16)	0.0693 (12)	0.0534 (11)	−0.0223 (11)	0.0062 (10)	−0.0168 (9)
C18	0.0627 (13)	0.0471 (9)	0.0573 (11)	−0.0109 (8)	0.0035 (9)	−0.0143 (8)
C19	0.092 (2)	0.1060 (19)	0.0624 (14)	−0.0224 (16)	−0.0167 (14)	0.0085 (13)

Geometric parameters (Å, º) top

S1—O5	1.4285 (14)	C7—H7A	0.9700
S1—O4	1.4286 (13)	C7—H7B	0.9700
S1—N1	1.6278 (13)	C9—C10	1.428 (4)
S1—C12	1.7526 (19)	C9—H9A	0.9700
O1—C2	1.227 (2)	C9—H9B	0.9700
O2—C8	1.188 (3)	C10—H10A	0.9600
O3—C8	1.324 (3)	C10—H10B	0.9600
O3—C9	1.462 (3)	C10—H10C	0.9600
N1—C13	1.445 (2)	C11—H11A	0.9600
N1—C1	1.476 (2)	C11—H11B	0.9600
N2—C2	1.346 (2)	C11—H11C	0.9600
N2—C3	1.464 (2)	C12—H12A	0.9600
N2—C7	1.466 (2)	C12—H12B	0.9600
C1—C11	1.519 (2)	C12—H12C	0.9600
C1—C2	1.537 (2)	C13—C14	1.380 (2)
C1—H1	0.9800	C13—C18	1.381 (2)
C3—C4	1.516 (3)	C14—C15	1.382 (3)
C3—H3A	0.9700	C14—H14	0.9300
C3—H3B	0.9700	C15—C16	1.379 (3)
C4—C5	1.535 (3)	C15—H15	0.9300
C4—H4A	0.9700	C16—C17	1.384 (3)
C4—H4B	0.9700	C16—C19	1.514 (3)
C5—C8	1.514 (3)	C17—C18	1.381 (3)
C5—C6	1.526 (3)	C17—H17	0.9300
C5—H5	0.9800	C18—H18	0.9300
C6—C7	1.521 (3)	C19—H19A	0.9600
C6—H6A	0.9700	C19—H19B	0.9600
C6—H6B	0.9700	C19—H19C	0.9600

O5—S1—O4	118.43 (8)	O2—C8—O3	123.4 (2)
O5—S1—N1	106.30 (8)	O2—C8—C5	125.1 (2)
O4—S1—N1	108.16 (8)	O3—C8—C5	111.50 (18)
O5—S1—C12	108.50 (11)	C10—C9—O3	108.7 (2)
O4—S1—C12	107.33 (10)	C10—C9—H9A	110.0
N1—S1—C12	107.71 (8)	O3—C9—H9A	110.0
C8—O3—C9	119.1 (2)	C10—C9—H9B	110.0
C13—N1—C1	122.65 (12)	O3—C9—H9B	110.0
C13—N1—S1	117.57 (11)	H9A—C9—H9B	108.3
C1—N1—S1	118.92 (10)	C9—C10—H10A	109.5
C2—N2—C3	119.21 (16)	C9—C10—H10B	109.5
C2—N2—C7	126.42 (15)	H10A—C10—H10B	109.5
C3—N2—C7	112.45 (15)	C9—C10—H10C	109.5
N1—C1—C11	110.73 (13)	H10A—C10—H10C	109.5
N1—C1—C2	111.57 (13)	H10B—C10—H10C	109.5
C11—C1—C2	109.61 (12)	C1—C11—H11A	109.5
N1—C1—H1	108.3	C1—C11—H11B	109.5
C11—C1—H1	108.3	H11A—C11—H11B	109.5
C2—C1—H1	108.3	C1—C11—H11C	109.5
O1—C2—N2	121.94 (15)	H11A—C11—H11C	109.5
O1—C2—C1	120.33 (15)	H11B—C11—H11C	109.5
N2—C2—C1	117.58 (15)	S1—C12—H12A	109.5
N2—C3—C4	110.73 (15)	S1—C12—H12B	109.5
N2—C3—H3A	109.5	H12A—C12—H12B	109.5
C4—C3—H3A	109.5	S1—C12—H12C	109.5
N2—C3—H3B	109.5	H12A—C12—H12C	109.5
C4—C3—H3B	109.5	H12B—C12—H12C	109.5
H3A—C3—H3B	108.1	C14—C13—C18	119.67 (16)
C3—C4—C5	111.24 (18)	C14—C13—N1	121.20 (15)
C3—C4—H4A	109.4	C18—C13—N1	119.13 (14)
C5—C4—H4A	109.4	C13—C14—C15	119.47 (17)
C3—C4—H4B	109.4	C13—C14—H14	120.3
C5—C4—H4B	109.4	C15—C14—H14	120.3
H4A—C4—H4B	108.0	C16—C15—C14	122.01 (18)
C8—C5—C6	112.44 (17)	C16—C15—H15	119.0
C8—C5—C4	111.67 (19)	C14—C15—H15	119.0
C6—C5—C4	110.22 (16)	C15—C16—C17	117.39 (18)
C8—C5—H5	107.4	C15—C16—C19	120.6 (2)
C6—C5—H5	107.4	C17—C16—C19	122.0 (2)
C4—C5—H5	107.4	C18—C17—C16	121.65 (19)
C7—C6—C5	110.66 (16)	C18—C17—H17	119.2
C7—C6—H6A	109.5	C16—C17—H17	119.2
C5—C6—H6A	109.5	C13—C18—C17	119.76 (17)
C7—C6—H6B	109.5	C13—C18—H18	120.1
C5—C6—H6B	109.5	C17—C18—H18	120.1
H6A—C6—H6B	108.1	C16—C19—H19A	109.5
N2—C7—C6	109.70 (17)	C16—C19—H19B	109.5
N2—C7—H7A	109.7	H19A—C19—H19B	109.5
C6—C7—H7A	109.7	C16—C19—H19C	109.5
N2—C7—H7B	109.7	H19A—C19—H19C	109.5
C6—C7—H7B	109.7	H19B—C19—H19C	109.5
H7A—C7—H7B	108.2

O5—S1—N1—C13	176.09 (11)	C2—N2—C7—C6	−103.4 (2)
O4—S1—N1—C13	47.92 (13)	C3—N2—C7—C6	60.5 (2)
C12—S1—N1—C13	−67.78 (14)	C5—C6—C7—N2	−57.7 (2)
O5—S1—N1—C1	−14.24 (14)	C9—O3—C8—O2	−2.2 (4)
O4—S1—N1—C1	−142.40 (12)	C9—O3—C8—C5	−179.8 (2)
C12—S1—N1—C1	101.89 (14)	C6—C5—C8—O2	6.3 (4)
C13—N1—C1—C11	−25.36 (19)	C4—C5—C8—O2	130.8 (3)
S1—N1—C1—C11	165.51 (11)	C6—C5—C8—O3	−176.2 (2)
C13—N1—C1—C2	97.02 (16)	C4—C5—C8—O3	−51.7 (3)
S1—N1—C1—C2	−72.11 (15)	C8—O3—C9—C10	−171.3 (3)
C3—N2—C2—O1	3.0 (3)	C1—N1—C13—C14	−76.6 (2)
C7—N2—C2—O1	165.98 (18)	S1—N1—C13—C14	92.68 (17)
C3—N2—C2—C1	178.66 (15)	C1—N1—C13—C18	103.66 (19)
C7—N2—C2—C1	−18.4 (3)	S1—N1—C13—C18	−87.07 (18)
N1—C1—C2—O1	−28.1 (2)	C18—C13—C14—C15	1.3 (3)
C11—C1—C2—O1	94.89 (19)	N1—C13—C14—C15	−178.45 (17)
N1—C1—C2—N2	156.17 (14)	C13—C14—C15—C16	0.7 (3)
C11—C1—C2—N2	−80.81 (18)	C14—C15—C16—C17	−2.1 (3)
C2—N2—C3—C4	106.1 (2)	C14—C15—C16—C19	177.7 (2)
C7—N2—C3—C4	−59.1 (2)	C15—C16—C17—C18	1.7 (3)
N2—C3—C4—C5	54.5 (2)	C19—C16—C17—C18	−178.1 (2)
C3—C4—C5—C8	−178.38 (17)	C14—C13—C18—C17	−1.7 (3)
C3—C4—C5—C6	−52.6 (2)	N1—C13—C18—C17	178.02 (17)
C8—C5—C6—C7	179.54 (18)	C16—C17—C18—C13	0.2 (3)
C4—C5—C6—C7	54.2 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C12—H12B···O1	0.96	2.50	3.210 (2)	130
C12—H12C···O4ⁱ	0.96	2.44	3.376 (2)	164
C14—H14···O1	0.93	2.48	3.177 (2)	132

Symmetry code: (i) −x, −y, −z+1.

1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylic acid (II) top

Crystal data top

C₁₇H₂₄N₂O₅S	F(000) = 784
M_r = 368.44	D_x = 1.344 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71073 Å
a = 12.1013 (2) Å	Cell parameters from 8359 reflections
b = 12.3092 (2) Å	θ = 2.7–31.5°
c = 12.4348 (3) Å	µ = 0.21 mm⁻¹
β = 100.546 (2)°	T = 295 K
V = 1820.97 (6) Å³	Plate, colorless
Z = 4	0.77 × 0.18 × 0.11 mm

Data collection top

Oxford Diffraction Xcalibur, Gemini Ultra R diffractometer	6284 independent reflections
Radiation source: fine-focus sealed X-ray tube	4779 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.026
Detector resolution: 10.3712 pixels mm^-1	θ_max = 32.7°, θ_min = 2.2°
ω scans	h = −18→18
Absorption correction: analytical [CrysAlisPro (Rigaku OD, 2018), based on expressions derived by Clark & Reid (1995)]	k = −18→17
T_min = 0.882, T_max = 0.980	l = −17→18
29518 measured reflections

Refinement top

Refinement on F²	Primary atom site location: dual
Least-squares matrix: full	Secondary atom site location: dual
R[F² > 2σ(F²)] = 0.043	Hydrogen site location: difference Fourier map
wR(F²) = 0.126	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ²(F_o²) + (0.0593P)² + 0.3685P] where P = (F_o² + 2F_c²)/3
6284 reflections	(Δ/σ)_max = 0.001
232 parameters	Δρ_max = 0.29 e Å⁻³
0 restraints	Δρ_min = −0.29 e Å⁻³

Special details top

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.58667 (2)	0.35673 (2)	0.60942 (2)	0.03513 (9)
O1	0.68078 (9)	0.19851 (8)	0.41698 (10)	0.0531 (3)
O2	1.04956 (12)	0.60661 (11)	0.37887 (13)	0.0780 (4)
O3	1.13713 (10)	0.46783 (11)	0.31848 (13)	0.0732 (4)
H3	1.195 (2)	0.509 (2)	0.352 (2)	0.110*
O4	0.50845 (8)	0.37442 (9)	0.68112 (8)	0.0479 (2)
O5	0.65804 (8)	0.44541 (8)	0.59029 (9)	0.0501 (2)
N1	0.51748 (8)	0.32221 (9)	0.48974 (8)	0.0344 (2)
N2	0.73982 (9)	0.33804 (10)	0.32395 (10)	0.0447 (3)
C1	0.56084 (10)	0.35539 (10)	0.39054 (10)	0.0359 (2)
H1	0.580679	0.432597	0.397240	0.043*
C17	0.67424 (14)	0.24889 (13)	0.66359 (13)	0.0555 (4)
H17A	0.726630	0.233560	0.616194	0.083*
H17B	0.629402	0.185582	0.669483	0.083*
H17C	0.714621	0.268508	0.734742	0.083*
C2	0.66661 (10)	0.29079 (11)	0.37903 (10)	0.0392 (3)
C3	0.83897 (11)	0.27729 (13)	0.30503 (13)	0.0488 (3)
H3A	0.832698	0.263103	0.227419	0.059*
H3B	0.842307	0.208002	0.342640	0.059*
C4	0.94599 (11)	0.34095 (12)	0.34608 (11)	0.0427 (3)
H4A	1.009763	0.302094	0.327725	0.051*
H4B	0.957054	0.347251	0.425085	0.051*
C5	0.94003 (11)	0.45455 (12)	0.29524 (11)	0.0438 (3)
H5	0.933185	0.446018	0.215935	0.053*
C6	0.83536 (12)	0.51356 (12)	0.31663 (13)	0.0510 (3)
H6A	0.841595	0.526101	0.394520	0.061*
H6B	0.829392	0.583548	0.280182	0.061*
C7	0.73079 (12)	0.44690 (14)	0.27497 (12)	0.0510 (4)
H7A	0.665534	0.483641	0.292748	0.061*
H7B	0.720557	0.440587	0.196007	0.061*
C8	1.04549 (13)	0.51874 (13)	0.33621 (12)	0.0489 (3)
C9	0.47176 (12)	0.34023 (14)	0.28791 (12)	0.0489 (3)
H9A	0.458064	0.264097	0.275037	0.073*
H9B	0.497692	0.371751	0.226417	0.073*
H9C	0.403409	0.375286	0.297628	0.073*
C10	0.42232 (10)	0.25039 (10)	0.48451 (10)	0.0364 (2)
C11	0.43049 (14)	0.14088 (12)	0.46161 (15)	0.0541 (4)
H11	0.498708	0.111490	0.451688	0.065*
C12	0.33581 (16)	0.07526 (14)	0.45357 (15)	0.0641 (4)
H12	0.341460	0.001934	0.437384	0.077*
C13	0.23387 (13)	0.11605 (14)	0.46894 (12)	0.0553 (4)
C14	0.22767 (12)	0.22528 (14)	0.49295 (13)	0.0519 (4)
H14	0.159834	0.254119	0.504670	0.062*
C15	0.32057 (10)	0.29283 (12)	0.49995 (11)	0.0423 (3)
H15	0.314406	0.366372	0.514958	0.051*
C16	0.13157 (17)	0.0435 (2)	0.45871 (17)	0.0843 (7)
H16A	0.085792	0.066468	0.509939	0.126*
H16B	0.155060	−0.030246	0.473939	0.126*
H16C	0.088916	0.048332	0.385744	0.126*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.03062 (14)	0.03481 (15)	0.03976 (16)	−0.00400 (11)	0.00588 (11)	−0.00067 (11)
O1	0.0514 (6)	0.0410 (5)	0.0722 (7)	0.0074 (4)	0.0248 (5)	0.0058 (5)
O2	0.0771 (9)	0.0640 (8)	0.0943 (10)	−0.0098 (7)	0.0193 (7)	−0.0239 (7)
O3	0.0402 (6)	0.0697 (8)	0.1097 (11)	−0.0137 (5)	0.0139 (6)	−0.0303 (7)
O4	0.0448 (5)	0.0571 (6)	0.0436 (5)	−0.0033 (4)	0.0129 (4)	−0.0075 (4)
O5	0.0436 (5)	0.0481 (5)	0.0563 (6)	−0.0190 (4)	0.0033 (4)	0.0010 (4)
N1	0.0293 (4)	0.0375 (5)	0.0373 (5)	−0.0058 (4)	0.0082 (4)	−0.0016 (4)
N2	0.0353 (5)	0.0490 (6)	0.0530 (6)	0.0044 (5)	0.0171 (5)	0.0037 (5)
C1	0.0321 (5)	0.0382 (6)	0.0387 (6)	−0.0001 (5)	0.0102 (4)	0.0020 (5)
C17	0.0548 (8)	0.0583 (9)	0.0515 (8)	0.0155 (7)	0.0051 (7)	0.0093 (7)
C2	0.0345 (6)	0.0428 (6)	0.0414 (6)	0.0005 (5)	0.0103 (5)	−0.0025 (5)
C3	0.0366 (6)	0.0525 (8)	0.0609 (9)	0.0005 (6)	0.0184 (6)	−0.0099 (7)
C4	0.0360 (6)	0.0486 (7)	0.0450 (7)	0.0029 (5)	0.0114 (5)	−0.0049 (5)
C5	0.0388 (6)	0.0551 (8)	0.0387 (6)	−0.0029 (6)	0.0107 (5)	0.0008 (6)
C6	0.0493 (8)	0.0481 (8)	0.0591 (8)	0.0065 (6)	0.0190 (7)	0.0149 (6)
C7	0.0397 (7)	0.0658 (9)	0.0499 (8)	0.0079 (6)	0.0147 (6)	0.0195 (7)
C8	0.0490 (8)	0.0517 (8)	0.0469 (7)	−0.0062 (6)	0.0107 (6)	−0.0010 (6)
C9	0.0407 (7)	0.0635 (9)	0.0411 (7)	0.0017 (6)	0.0039 (5)	0.0014 (6)
C10	0.0327 (5)	0.0359 (6)	0.0404 (6)	−0.0076 (5)	0.0059 (5)	0.0002 (5)
C11	0.0499 (8)	0.0397 (7)	0.0735 (10)	−0.0066 (6)	0.0131 (7)	−0.0083 (7)
C12	0.0713 (11)	0.0434 (8)	0.0759 (11)	−0.0228 (8)	0.0088 (9)	−0.0078 (7)
C13	0.0513 (8)	0.0660 (9)	0.0443 (7)	−0.0296 (7)	−0.0026 (6)	0.0081 (7)
C14	0.0316 (6)	0.0692 (10)	0.0534 (8)	−0.0112 (6)	0.0038 (5)	0.0085 (7)
C15	0.0320 (6)	0.0447 (7)	0.0500 (7)	−0.0045 (5)	0.0066 (5)	0.0028 (5)
C16	0.0732 (12)	0.1026 (16)	0.0695 (11)	−0.0573 (12)	−0.0065 (9)	0.0100 (11)

Geometric parameters (Å, º) top

S1—O4	1.4309 (10)	C5—C8	1.508 (2)
S1—O5	1.4385 (10)	C5—C6	1.5252 (19)
S1—N1	1.6249 (10)	C5—H5	0.9800
S1—C17	1.7543 (15)	C6—C7	1.517 (2)
O1—C2	1.2300 (16)	C6—H6A	0.9700
O2—C8	1.2018 (19)	C6—H6B	0.9700
O3—C8	1.3269 (19)	C7—H7A	0.9700
O3—H3	0.90 (3)	C7—H7B	0.9700
N1—C10	1.4438 (15)	C9—H9A	0.9600
N1—C1	1.4834 (15)	C9—H9B	0.9600
N2—C2	1.3470 (17)	C9—H9C	0.9600
N2—C7	1.4677 (19)	C10—C15	1.3829 (18)
N2—C3	1.4688 (17)	C10—C11	1.3850 (19)
C1—C9	1.5238 (18)	C11—C12	1.390 (2)
C1—C2	1.5356 (17)	C11—H11	0.9300
C1—H1	0.9800	C12—C13	1.377 (3)
C17—H17A	0.9600	C12—H12	0.9300
C17—H17B	0.9600	C13—C14	1.382 (2)
C17—H17C	0.9600	C13—C16	1.513 (2)
C3—C4	1.5198 (19)	C14—C15	1.3882 (18)
C3—H3A	0.9700	C14—H14	0.9300
C3—H3B	0.9700	C15—H15	0.9300
C4—C5	1.531 (2)	C16—H16A	0.9600
C4—H4A	0.9700	C16—H16B	0.9600
C4—H4B	0.9700	C16—H16C	0.9600

O4—S1—O5	118.24 (6)	C7—C6—C5	110.50 (13)
O4—S1—N1	108.76 (6)	C7—C6—H6A	109.5
O5—S1—N1	105.74 (6)	C5—C6—H6A	109.5
O4—S1—C17	107.33 (7)	C7—C6—H6B	109.5
O5—S1—C17	107.40 (7)	C5—C6—H6B	109.5
N1—S1—C17	109.13 (7)	H6A—C6—H6B	108.1
C8—O3—H3	105.0 (16)	N2—C7—C6	110.97 (12)
C10—N1—C1	122.13 (10)	N2—C7—H7A	109.4
C10—N1—S1	118.32 (8)	C6—C7—H7A	109.4
C1—N1—S1	119.22 (8)	N2—C7—H7B	109.4
C2—N2—C7	126.82 (11)	C6—C7—H7B	109.4
C2—N2—C3	119.62 (12)	H7A—C7—H7B	108.0
C7—N2—C3	113.53 (11)	O2—C8—O3	122.04 (15)
N1—C1—C9	111.04 (10)	O2—C8—C5	125.76 (15)
N1—C1—C2	111.26 (10)	O3—C8—C5	112.20 (13)
C9—C1—C2	109.42 (11)	C1—C9—H9A	109.5
N1—C1—H1	108.3	C1—C9—H9B	109.5
C9—C1—H1	108.3	H9A—C9—H9B	109.5
C2—C1—H1	108.3	C1—C9—H9C	109.5
S1—C17—H17A	109.5	H9A—C9—H9C	109.5
S1—C17—H17B	109.5	H9B—C9—H9C	109.5
H17A—C17—H17B	109.5	C15—C10—C11	119.68 (12)
S1—C17—H17C	109.5	C15—C10—N1	119.04 (11)
H17A—C17—H17C	109.5	C11—C10—N1	121.26 (12)
H17B—C17—H17C	109.5	C10—C11—C12	119.43 (15)
O1—C2—N2	122.37 (12)	C10—C11—H11	120.3
O1—C2—C1	120.17 (11)	C12—C11—H11	120.3
N2—C2—C1	117.44 (11)	C13—C12—C11	121.70 (16)
N2—C3—C4	110.77 (12)	C13—C12—H12	119.1
N2—C3—H3A	109.5	C11—C12—H12	119.1
C4—C3—H3A	109.5	C12—C13—C14	118.04 (13)
N2—C3—H3B	109.5	C12—C13—C16	120.88 (18)
C4—C3—H3B	109.5	C14—C13—C16	121.08 (18)
H3A—C3—H3B	108.1	C13—C14—C15	121.38 (15)
C3—C4—C5	111.06 (12)	C13—C14—H14	119.3
C3—C4—H4A	109.4	C15—C14—H14	119.3
C5—C4—H4A	109.4	C10—C15—C14	119.76 (14)
C3—C4—H4B	109.4	C10—C15—H15	120.1
C5—C4—H4B	109.4	C14—C15—H15	120.1
H4A—C4—H4B	108.0	C13—C16—H16A	109.5
C8—C5—C6	111.72 (13)	C13—C16—H16B	109.5
C8—C5—C4	111.47 (12)	H16A—C16—H16B	109.5
C6—C5—C4	109.92 (11)	C13—C16—H16C	109.5
C8—C5—H5	107.9	H16A—C16—H16C	109.5
C6—C5—H5	107.9	H16B—C16—H16C	109.5
C4—C5—H5	107.9

O4—S1—N1—C10	−39.35 (11)	C8—C5—C6—C7	−179.78 (12)
O5—S1—N1—C10	−167.31 (9)	C4—C5—C6—C7	−55.49 (15)
C17—S1—N1—C10	77.45 (11)	C2—N2—C7—C6	125.15 (15)
O4—S1—N1—C1	147.15 (9)	C3—N2—C7—C6	−56.90 (16)
O5—S1—N1—C1	19.20 (11)	C5—C6—C7—N2	56.02 (16)
C17—S1—N1—C1	−96.05 (11)	C6—C5—C8—O2	−1.4 (2)
C10—N1—C1—C9	20.64 (16)	C4—C5—C8—O2	−124.79 (17)
S1—N1—C1—C9	−166.13 (9)	C6—C5—C8—O3	179.68 (13)
C10—N1—C1—C2	−101.50 (13)	C4—C5—C8—O3	56.26 (17)
S1—N1—C1—C2	71.73 (12)	C1—N1—C10—C15	−106.70 (14)
C7—N2—C2—O1	179.61 (14)	S1—N1—C10—C15	80.01 (14)
C3—N2—C2—O1	1.8 (2)	C1—N1—C10—C11	71.61 (17)
C7—N2—C2—C1	1.4 (2)	S1—N1—C10—C11	−101.69 (14)
C3—N2—C2—C1	−176.43 (12)	C15—C10—C11—C12	0.5 (2)
N1—C1—C2—O1	28.24 (17)	N1—C10—C11—C12	−177.77 (14)
C9—C1—C2—O1	−94.83 (15)	C10—C11—C12—C13	−0.7 (3)
N1—C1—C2—N2	−153.51 (11)	C11—C12—C13—C14	0.0 (3)
C9—C1—C2—N2	83.42 (15)	C11—C12—C13—C16	179.38 (17)
C2—N2—C3—C4	−125.84 (14)	C12—C13—C14—C15	0.9 (2)
C7—N2—C3—C4	56.05 (17)	C16—C13—C14—C15	−178.47 (15)
N2—C3—C4—C5	−54.68 (15)	C11—C10—C15—C14	0.4 (2)
C3—C4—C5—C8	179.52 (11)	N1—C10—C15—C14	178.68 (12)
C3—C4—C5—C6	55.07 (15)	C13—C14—C15—C10	−1.1 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O5ⁱ	0.90 (3)	1.88 (3)	2.7463 (15)	161 (2)
C17—H17A···O1	0.96	2.48	3.144 (2)	127
C4—H4B···O2ⁱ	0.97	2.52	3.471 (2)	167
C11—H11···O1	0.93	2.56	3.2558 (19)	132

Symmetry code: (i) −x+2, −y+1, −z+1.

Hydrogen-bond propensity calculation for compound II top

Donor	Acceptor	Propensity
O3	O2	0.36
O3	O4	0.30
O3	O5	0.30

Acknowledgements

This work was performed on XRD equipment from the PC2 platform at UNamur and PXRD equipment has been funded by FRS–FNRS. The authors thank Laurie Bodard for her help on the polymorph risk assessment.

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