(R*,S*)-(±)-1-(2-{[2,8-Bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-yl)ethanone methanol monosolvate

Raoni S B Gonçalves; Marcus V N de Souza; Solange M S V Wardell; James L Wardell; Edward R T Tiekink

doi:10.1107/S1600536811038128

. 2011 Sep 30;67(Pt 10):o2714–o2715. doi: 10.1107/S1600536811038128

(R,S)-(±)-1-(2-{[2,8-Bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidin-1-yl)ethanone methanol monosolvate

Raoni S B Gonçalves ^a, Marcus V N de Souza ^a, Solange M S V Wardell ^b, James L Wardell ^c,^‡, Edward R T Tiekink ^d,^*

PMCID: PMC3201357 PMID: 22065251

Abstract

The title mefloquine derivative has been crystallized as its 1:1 methanol solvate, C₁₉H₁₈F₆N₂O₂·CH₃OH. Each of the methinehydroxyl residue [the C—C—C—O torsion angle is −16.35 (17) °] and the piperidinyl group [distorted chair conformation] lies to one side of the quinolinyl ring system. The hydroxyl and carbonyl groups lie to either side of the molecule, enabling their participation in intermolecular interactions. Thus, the hydroxyl and carbonyl groups of two centrosymmetrically related molecules are bridged by two methanol molecules via O—H⋯O hydrogen bonds, leading to a four-molecule aggregate. These are linked into a supramolecular chain along the a axis via C—H⋯O interactions involving the hydroxyl-O atom. The chains assemble into layers that interdigitate along the c axis being connected by C—H⋯F interactions.

Related literature

For background to the use of quinoline derivatives, including mefloquine derivatives, for the treatment of tuberculosis, see: de Souza et al. (2009 ▶); Candea et al. (2009 ▶); Danelishvili et al. (2005 ▶); Kunin & Ellis (2008 ▶); Jayaprakash et al. (2006 ▶); Bermudez et al. (2004 ▶). For related structural studies of mefloquine derivatives, see: Wardell et al. (2010 ▶, 2011 ▶).

Experimental

Crystal data

C₁₉H₁₈F₆N₂O₂·CH₄O
M _r = 452.40
Triclinic,
a = 9.4719 (2) Å
b = 10.1223 (3) Å
c = 11.9227 (3) Å
α = 114.567 (1)°
β = 90.343 (2)°
γ = 102.795 (2)°
V = 1007.61 (4) Å³
Z = 2
Mo Kα radiation
μ = 0.14 mm⁻¹
T = 120 K
0.20 × 0.08 × 0.08 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2007 ▶) T _min = 0.883, T _max = 1.000
20055 measured reflections
4602 independent reflections
4038 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.110
S = 1.02
4602 reflections
288 parameters
2 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.33 e Å⁻³

Data collection: COLLECT (Hooft, 1998 ▶); cell refinement: DENZO (Otwinowski & Minor, 1997 ▶) and COLLECT; data reduction: DENZO and COLLECT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and DIAMOND (Brandenburg, 2006 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811038128/hb6409sup1.cif

e-67-o2714-sup1.cif^{(23.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811038128/hb6409Isup2.hkl

e-67-o2714-Isup2.hkl^{(220.8KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811038128/hb6409Isup3.cml

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
O1—H1o⋯O3ⁱ	0.84 (2)	1.87 (2)	2.7121 (18)	177 (2)
O3—H3o⋯O2ⁱⁱ	0.85 (2)	1.83 (2)	2.6667 (17)	168 (2)
C7—H7⋯O1ⁱⁱⁱ	0.95	2.49	3.3280 (18)	147
C17—H17a⋯F6^iv	0.99	2.51	3.3123 (17)	138

Open in a new tab

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

Acknowledgments

The use of the EPSRC X-ray crystallographic service at the University of Southampton, England, and the valuable assistance of the staff there is gratefully acknowledged. JLW acknowledges support from CAPES and FAPEMIG (Brazil).

supplementary crystallographic information

Comment

Tuberculosis (TB) is considered a global health emergency by the World Health Organization (WHO). Quinoline derivatives have been reported to exhibit substantial anti-mycobacterial activities and can be considered a promising area for the discovery of new anti-TB agents (de Souza et al., 2009; Candea et al., 2009). The quinoline derivative, mefloquine, ((R*, S*)-(±)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol, which has been used for a long time as an anti-malarial drug, has recently received considerable attention as an anti-mycobacterial drug. This substance has been found to possess substantial activities against Gram-positive bacteria (Kunin & Ellis, 2008) and Mycobacterium species (Danelishvili et al., 2005; Jayaprakash et al., 2006; Bermudez et al., 2004). However, there remains a need for more active and more resistant compounds. With this in mind, the acetoamido derivative of mefloquine, (R*, S*)-(±)-α-2-N-acetopiperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol, (I), has been prepared in continuation with biological and structural studies (Wardell et al., 2010; Wardell et al., 2011). Herein, we report its crystal structure.

In (I), Fig. 1, the asymmetric unit comprises a neutral mefloquine derivative and a methanol molecule of solvation. In the organic molecule, the methine-hydroxyl group is twisted out the least-squares plane through the quinolinyl ring (r.m.s. deviation = 0.008 Å) to which it is attached as seen in the value of the C2—C3—C12—O1 torsion angle of -16.35 (17) °. The piperidinyl group, with a distorted chair conformation, lies to one side and is directed away from the quinolinyl residue. Within the molecule, the hydroxyl and carbonyl groups are directed away from each other allowing for their participation in intermolecular hydrogen bonding interactions.

The formation of a centrosymmetric four molecule aggregate mediated by O—H···O hydrogen bonding, Table 1, is the most notable feature of the crystal packing. The hydroxyl group forms a donor O—H···O hydrogen bond with the solvent methanol molecule which in turn forms a O—H···O hydrogen bond with the carbonyl-O2 atom of a symmetry related molecule. In this way a centrosymmetric 18-membered {···OCNC₂OH···OH···}₂ synthon is formed. The four-molecule aggregates are linked into a linear supramolecular chain along the a-direction via C—H···O interactions where the acceptor atom is the mefloquine-hydroxyl group, Table 1 and Fig. 2. Chains assemble into layers in the ab plane and inter-digitate along the c axis, enabling the formation of C—H···F interactions, Table 1 and Fig. 3.

Experimental

To a stirred solution of mefloquine (3.0 mmol) and triethylamine (7.5 mmol) in anhydrous THF (5 ml), acetyl chloride (6 mmol) was added drop wise at 273 K. The mixture stirred at room temperature for 2 h and after complete conversion of the starting material, as indicated by TLC, THF was evaporated under reduced pressure. The residue was dissolved in CH₂Cl₂ and washed with water (3 x 10 ml). The organic layer was separated, dried over anhydrous MgSO₄, filtered, and solvent was evaporated under reduced pressure to give the desired product, which was recrystallized from MeOH as colourless blocks. M.pt. 458–460 K. IR ν_max (cm^-1; KBr pellets): 1682 (NC═O); 1189, 1150, 1115 (C—F).