(3S,4S)-3-Ethyl-4-hydr­oxy-3-(3-methoxy­phen­yl)-1-methyl­azepan-1-ium d-tartrate dihydrate

Xing-Hai Wang; Bo Chao; Zhui-Bai Qiu

doi:10.1107/S1600536808005898

. 2008 Apr 2;64(Pt 5):o784. doi: 10.1107/S1600536808005898

(3S,4S)-3-Ethyl-4-hydroxy-3-(3-methoxyphenyl)-1-methylazepan-1-ium d-tartrate dihydrate

Xing-Hai Wang ^a, Bo Chao ^a, Zhui-Bai Qiu ^a,^*

PMCID: PMC2961245 PMID: 21202277

Abstract

In the title compound, C₁₆H₂₆NO₂ ⁺·C₄H₅O₆ ⁻·2H₂O, a meptazinol derivative, three C atoms of the azepane ring are disordered over two positions, with site-occupancy factors of 0.80 and 0.20; the major disorder component adopts a twist-chair conformation, while the minor component has a chair conformation. The benzene ring is axially substituted on the heterocyclic ring, resulting in a folded conformation of the cation. The absolute configuration was determined with reference to d-tartaric acid. The crystal structure is stabilized by an extensive network of intra- and intermolecular O—H⋯O hydrogen bonds.

Related literature

For the synthesis of the racemate of the title compound, see: Hao et al. (2005 ▶). For conformational studies of seven-membered rings, see: Eliel et al. (1994 ▶); Entrena et al. (2005 ▶). For the analgesic activity and clinical use of meptazinol, see: Holmes (1985 ▶). For related literature, see: Bill et al. (1983 ▶).

Experimental

Crystal data

C₁₆H₂₆NO₂ ⁺·C₄H₅O₆ ⁻·2H₂O
M _r = 449.49
Orthorhombic,
a = 7.146 (3) Å
b = 10.812 (4) Å
c = 29.338 (11) Å
V = 2266.7 (15) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 293 (2) K
0.20 × 0.15 × 0.12 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.979, T _max = 0.988
11334 measured reflections
2855 independent reflections
2173 reflections with I > 2σ(I)
R _int = 0.076

Refinement

R[F ² > 2σ(F ²)] = 0.061
wR(F ²) = 0.163
S = 1.04
2855 reflections
319 parameters
19 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.43 e Å⁻³
Δρ_min = −0.26 e Å⁻³

Data collection: SMART (Bruker, 2000 ▶); cell refinement: SAINT (Bruker, 2000 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL and ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: SHELXTL and local programs.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808005898/wn2243sup1.cif

e-64-0o784-sup1.cif^{(24.9KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808005898/wn2243Isup2.hkl

e-64-0o784-Isup2.hkl^{(140.2KB, hkl)}

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
O5—H5⋯O4	0.82	2.15	2.623 (5)	116
O6—H6⋯O9	0.82	1.91	2.641 (5)	149
O9—H9X⋯O2	0.83 (2)	2.00 (2)	2.823 (5)	171 (6)
O10—H10X⋯O5	0.82 (2)	1.98 (2)	2.790 (5)	173 (6)
C7A—H7A⋯O1	0.97	2.56	3.149 (8)	119
C6B—H6B1⋯O1	0.97	1.91	2.46 (3)	113
O9—H9Y⋯O7ⁱ	0.83 (2)	1.85 (2)	2.680 (5)	171 (7)
O3—H3⋯O8ⁱ	0.82	1.73	2.516 (4)	160
O5—H5⋯O10ⁱⁱ	0.82	2.27	2.983 (5)	145
O10—H10Y⋯O4ⁱⁱⁱ	0.82 (2)	2.02 (4)	2.739 (5)	145 (6)
C16—H16⋯O7^iv	0.93	2.50	3.417 (6)	171
C7B—H7B1⋯O6^iv	0.97	2.51	3.176 (7)	126
C6B—H6B2⋯O1^v	0.97	2.39	3.056 (17)	125

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) .

Acknowledgments

This work is funded in part by the National Natural Science Foundation of China (grant No. 30472088).

supplementary crystallographic information

Comment

Meptazinol is a selective µ agonist with additional central anticholinergic activity, which has been used for treating pain associated with labour and kidney problems (Holmes, 1985). Many studies have shown meptazinol to have an advantage over other opioid analgesics because of its lack of adverse cardiorespiratory effects and low addiction liability (Bill et al., 1983); this makes it an ideal precursor for further investigation. During the course of our structural optimization of meptazinol, the title compound was synthesized by introducing an OH group at the 4-position, followed by resolution with D-tartaric acid.

The absolute configuration of the azepane ring atoms is N1(R), C3(S) and C4(S), according to the reference molecule D-tartaric acid. The O—H functionalities, carboxyl group and H₂O are known to be efficient donor and acceptor groups for hydrogen bonding, and they form an extensive hydrogen-bond network, which stabilizes the structure. The 3-methoxyphenyl substituent at C3 is trans to the OH group at C4 and cis to the N—H bond, resulting in a folded conformation of the cation.

The major disorder component adopts a twist-chair conformation, while the minor component has a chair conformation. The twist-chair conformation of seven-membered rings is known to be more stable than the chair conformation (Entrena et al., 2005). Thus, the relative proportion of both conformers observed within the crystal structure may reflect the statistical partitioning of the two populations of azepane structures corresponding to different energetic states.

Experimental

The title compound was prepared by standard procedures upon optical resolution of the racemate with D-tartaric acid. The synthesis of the racemic compound was described by Hao et al. (2005).