7-{4-[(1,3-Benzodioxol-5-yl)meth­yl]piperazin-1-yl}-1-cyclo­propyl-6-fluoro-4-oxo-1,4-dihydro­quinoline-3-carb­oxy­lic acid

Shuo Wang; Guangzhi Shan; Huiyuan Guo; Mingliang Liu

doi:10.1107/S1600536812028711

. 2012 Jun 30;68(Pt 7):o2264. doi: 10.1107/S1600536812028711

7-{4-[(1,3-Benzodioxol-5-yl)methyl]piperazin-1-yl}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Shuo Wang ^a, Guangzhi Shan ^a, Huiyuan Guo ^a, Mingliang Liu ^a,^*

PMCID: PMC3394047 PMID: 22798912

Abstract

In the title structure, C₂₅H₂₄FN₃O₅, a strong intramolecular O—H⋯O hydrogen bond is present between the carboxy group at the 3-position and the carbonyl group at the 4-position. In the crystal, molecules are held together by weak C—H⋯O, C—H⋯F and π–π [centroid–centroid distance 3.6080 (8) Å] interactions. The 1,4-dihydroquinoline ring and cyclopropyl group are not in the same plane, making an interplanar angle of 57.52 (8)°.

Related literature

For the synthesis and properties of quinolone derivatives, see Basuri et al. (2011 ▶); Feng et al. (2011 ▶); Guo et al. (2011 ▶); Liu et al. (2010 ▶); Sharma et al. (2010 ▶); Xu et al. (2007 ▶). For the cryogenic cooler used in the data collection, see Cosier & Glazer (1986 ▶). For hydrogen bonding, see Desiraju & Steiner (1999 ▶).

Experimental

Crystal data

C₂₅H₂₄FN₃O₅
M _r = 465.47
Triclinic,
a = 8.6200 (5) Å
b = 9.7068 (9) Å
c = 13.7680 (13) Å
α = 79.089 (8)°
β = 76.000 (6)°
γ = 87.939 (6)°
V = 1097.52 (16) Å³
Z = 2
Cu Kα radiation
μ = 0.88 mm⁻¹
T = 118 K
0.55 × 0.35 × 0.15 mm

Data collection

Oxford Gemini S Ultra Sapphire CCD diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.645, T _max = 0.880
10407 measured reflections
3876 independent reflections
3518 reflections with I > 2σ(I)
R _int = 0.024

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.099
S = 1.04
3876 reflections
311 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.25 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; 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, PLATON (Spek, 2009 ▶) and publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812028711/fb2250sup1.cif

e-68-o2264-sup1.cif^{(31.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812028711/fb2250Isup2.hkl

e-68-o2264-Isup2.hkl^{(190KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812028711/fb2250Isup3.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
O3—H3⋯O2	0.992 (19)	1.563 (19)	2.5215 (13)	161.1 (17)
C20—H20⋯O13ⁱ	0.93	2.58	3.3206 (17)	137
C28—H28a⋯F1	0.97	2.18	2.8587 (15)	126
C32—H32b⋯O2ⁱⁱ	0.97	2.49	3.4144 (16)	158
C34—H34b⋯O3ⁱⁱⁱ	0.97	2.44	3.3853 (18)	165

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

Acknowledgments

This work was supported by New Teachers’ Fund for Doctor Stations, Ministry of Education (20101106120032) and the IMB Research Foundation.

supplementary crystallographic information

Comment

Ciprofloxacin, the most applied antibacterial agent worldwide (Basuri et al., 2011), is used extensively for the treatment of various bacterial infections including tuberculosis (Liu et al., 2010). However, extensive use and even abuse have brought increasing ciprofloxacin resistance to many Gram-positive and Gram-negative pathogens, as well as to Mycobacterium tuberculosis (Xu et al., 2007; Liu et al., 2010). Recently, as a part of our program which is aimed to increase potency and to overcome resistance of existing quinolones by their structural modifications, we have focused our attention on introducing various lipophilic groups, such as an isatin or a coumarin moieties, to ciprofloxacin (Feng et al., 2011; Guo et al., 2011). Some of the ciprofloxacin derivatives were found to have improved activity against drug-resistant Mycobacterium tuberculosis. Our results have suggested that the activity of fluoroquinolones against drug-resistant Mycobacterium tuberculosis is proportional to increment of lipophilicity in ciprofloxacin derivatives (Sharma et al., 2010).

The crystal structure of the title compound is reported here. The title compound shows remarkable improvement in lipophilicity by introduction of a lipophilic 3,4-methylenedioxyl benzyl group to the N atom which is situated on the C-7 piperazine ring of ciprofloxacin.

The title molecule is shown in Fig. 1. The 1,4-dihydroquinoline ring and cyclopropyl group (C31\C32\C33) are not in the same plane and the interplanar angle between them is 57.52 (8)°. The six-membered piperazine ring adopts a chair conformation. In the title structure, there is a strong intramolecular hydrogen bond O—H···O and a weak C-H···F interaction (Table 1; Fig. 2) (Desiraju & Steiner, 1999). The intermolecular interactions that are present in the structure are weak ones exclusively: a) C—H···O hydrogen bonds (Table 1) and b) π-electron ring — π-electron ring interactions in the structure as it is indicated by the distance 3.6080 (8) Å between the respective centroids of the benzene rings C7\C8\C17\C18\C12\C9 (symmetry codes x, y, z and 1-x, 1-y, -z).

Experimental

To a stirred solution of piperonyl alcohol (0.61 g, 4 mmol) in anhydrous methylene chloride (50 ml) at 0–5°C was added phosphorus tribromide (0.5 ml, 5 mmol) dropwise over a period of 15 min. The reaction mixture was stirred for additional 30 min at the 0–5°C, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethyl formamide (20 ml) and anhydrous potassium carbonate (0.83 g, 6 mmol) with ciprofloxacin hydrochloride (0.51 g, 1.4 mmol) were added to this solution. The reaction mixture was heated to 40°C and stirred at this temperature for 14 h and then diluted with methylene chloride (50 ml), washed with distilled water (50 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel), eluted by methylene chloride and methanol in proportion 10:1 (v/v) to yield the title compound (0.32 g, 17.2 wt. %) as transparent block-like light yellow crystals, the longest distance of which was about 4 mm. The measured sample was cut from a larger crystal. Melting point: 238–239°C. ¹H-NMR(DMSO, δ): 1.16–1.18 (2H, m, CH₂ cyclopropyl), 1.28–1.31(2H, m, CH₂cyclopropyl), 2.57–2.58 (4H, m, 2CH₂ piperazinyl), 3.30–3.33 (4H, m, 2CH₂ piperazinyl), 3.47 (2H, s, CH₂ Benzyl), 3.78–3.82 (1H, m, CH cyclopropyl), 5.99(2H, s, OCH₂O), 6.78–6.90(3H, m, CH benzyl), 7.55–7.57(1H, d, C8, J=8 Hz), 7.88–7.91(1H, d, C5, J=12 Hz),8.649(1H, s, C2), 15.21(1H, s, COOH). MS (ESI, m/z): 466 (M+H⁺). HRMS(ESI,m/z): C₂₅H₂₄FN₃O₅ Calculated:466.1769; Found:466.1772.