7-Chloro-4-(piperazin-1-yl)quinoline

Amol A Kulkarni; Christopher L King; Joseph M D Fortunak; Ray J Butcher

doi:10.1107/S1600536812014912

. 2012 Apr 21;68(Pt 5):o1497. doi: 10.1107/S1600536812014912

7-Chloro-4-(piperazin-1-yl)quinoline

Amol A Kulkarni ^a,^*, Christopher L King ^b, Joseph M D Fortunak ^b, Ray J Butcher ^b

PMCID: PMC3344606 PMID: 22590368

Abstract

There are two molecules in the asymmetric unit (Z′ = 2) of the title compound, C₁₃H₁₄ClN₃, Each molecule is linked by N—H⋯N hydrogen bonds to another of the same type in a chain in [110]. The crystal studied was a non-merohedral twin with components 0.622 (2) and 0.378 (2).

Related literature

The title compound is an important intermediate in the synthesis of the anti-malarial compound piperaquine {systematic name: 7-chloro-4-[4-[3-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]propyl]piperazin-1-yl]quinoline phosphoric acid}, see: Chen et al. (1982 ▶); Hien et al. (2004 ▶); Dongre et al. (2007 ▶).

Experimental

Crystal data

C₁₃H₁₄ClN₃
M _r = 247.72
Triclinic,
a = 7.0048 (6) Å
b = 7.8297 (8) Å
c = 21.4256 (19) Å
α = 91.371 (8)°
β = 91.292 (7)°
γ = 95.210 (8)°
V = 1169.55 (19) Å³
Z = 4
Cu Kα radiation
μ = 2.72 mm⁻¹
T = 123 K
0.43 × 0.35 × 0.12 mm

Data collection

Oxford Diffraction Xcalibur Ruby Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2007 ▶) T _min = 0.809, T _max = 1.000
6990 measured reflections
6990 independent reflections
5619 reflections with I > 2σ(I)
R _int = 0.000

Refinement

R[F ² > 2σ(F ²)] = 0.074
wR(F ²) = 0.228
S = 1.09
6990 reflections
316 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.65 e Å⁻³
Δρ_min = −0.60 e Å⁻³

Data collection: CrysAlis PRO (Oxford Diffraction, 2007 ▶); 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.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812014912/bt5836sup1.cif

e-68-o1497-sup1.cif^{(24.6KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812014912/bt5836Isup2.hkl

e-68-o1497-Isup2.hkl^{(342KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812014912/bt5836Isup3.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
N3A—H3AN⋯N1Aⁱ	0.92 (4)	2.18 (4)	3.083 (4)	166 (4)
N3B—H3BN⋯N1Bⁱ	0.99 (4)	2.12 (4)	3.088 (4)	166 (4)

Open in a new tab

Symmetry code: (i) Inline graphic .

Acknowledgments

AAK wishes to acknowledge RCMI, Howard University, Center for Drug Research and Development, Howard University and the District of Columbia Developmental Center for AIDS Research (P30AI087714). RJB wishes to acknowledge the NSF–MRI program (grant CHE-0619278) for funds to purchase the diffractometer. This project was supported by grant No. D34HP16042-03-03 from the Health Resources and Services Administration (HRSA).

supplementary crystallographic information

Comment

Recrystallization of the title compound from 2-propanol removes low levels (1–4%) of impurities that are present from the manufacturing process. Impurities in the desired product arise from the presence of 4,5-dichloroquinoline in 4,7-DCQ and are difficult to remove from the manufacturing process of commercial malaria drugs, including amodiaquine and piperaquine (Dongre et al., 2007).

In view of the pharmaceutical importance of this intermediate its crystal structure was determined. There are two molecules in the asymmetric unit (Z' = 2). Each molecule is linked by N—H···N hydrogen bonds to another of the same type in a chain in the b direction.

Experimental

A solution of 4,7-dichloroquinoline (10 g, 51 mmole, 1 equiv) and piperazine (13.05 g, 153 mmole, 3 equiv) in 2-propanol (25 ml) was heated to a gentle reflux for 4 h. The solution was cooled to room temperature. Ethyl acetate (50 ml) was added and the reaction mixture was stirred at room temperature for 14 h. It was then poured into a separatory funnel and was washed with water (3 X 50 ml). The organic layer was dried using anhydrous Na₂SO₄. Removal of the solvent in vacuo resulted in the isolation of the desired compound as pale yellow crystals. The crude product was recrystallized from 2-propanol to yield colorless crystals of the desired compound. mp 112–114 °C; ¹H-NMR (CDCl₃) d 8.68 (d, J = 4.8 Hz, 1H), 8. 01 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 3.12–2.93 (m, 8H).