7-Chloro-4-piperazinoquinoline

4, 7-Dichloroquinoline (2.00 g, 10.1 mmol) was combined with piperazine (4.35 g, 50.5 mmol, 5.0 equiv) and neat triethylamine (2.81 mL, 20.2 mmol, 2.0 equiv). The reaction flask was sealed under nitrogen and heated to 130 °C whereupon the solid material gradually melted to give a clear orange-yellow solution. After a period of time, a yellow precipitate was observed. The reaction was completed in approximately 4 hours as determined by TLC (5percent v/v methanol in dichloromethane was used as the solvent system). At this point, the reaction was cooled to room temperature before being diluted with dichloromethane (25 mL) and water (25 mL). The layers were separated and the organic layer was washed with water (3 x 25 mL). The combined aqueous washes were then back-extracted with dichloromethane (50 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (2.60 g). The crude material was purified by column chromatography over silica gel (dichloromethane/methanol: 100/0 to 98/2) to afford 2.44 g (9.85 mmol, 98percent yield) of the title compound as a yellow solid. The 1H and 13C spectra were consistent with published data. 1H NMR (300 MHz, CDCl3): δ 8.71 (d, J = 4.9 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 2.0, 9.0 Hz, 1H), 6.82 (d, J = 5.0 Hz, 1H), 3.17 (obscured br. s, 4H), 3.16 (obscured br. s, 4H); 13C NMR (75 MHz, CDCl3): δ 157.3, 151.9, 150.1, 134.7, 128.8, 126.0, 125.2, 121.9, 108.9, 53.5, 46.0; ESI-MS: m/z 248.Piperazine (3.20 g, 36.73 mmol), 4, 7-dichloroquinoline (1.5 g, 7.35 mmol) and KTo a suspension of 4, 7-Dichloro-quinoline (4) (50 g, 0.252 mol) in isopropyl alcohol (150 mL, 3 vol) was added piperazine (65.2 g, 0.757 mol) at ambient temperature. The reaction mixture was stirred under nitrogen at 90 °C for 16 h. The reaction mass was turned into a clear solution at the beginning and the solid precipitation was observed slowly. The progress of the reaction was monitored by TLC analysis. The reaction mass was cooled to room temperature and diluted with ethyl acetate (1L, 20 vol). The unreacted piperazine was precipitated and it was removed by filtration. The filtrated solid was washed with ethyl acetate (500 mL). The filtrate was washed with water (500 mL X 2), dried over solid sulphate and concentrated under reduced pressure to give a crude desired compound. The crude compound was purified by column chromatography using silica gel (60-120), eluent 5 percent methanol in dichloromethane to get the desired compound as a pale yellow solid. Yield; 50 g (80.6 percent)To a stirred solution of 4, 7-dichloroquinoline (1) (10 g, 50.49 mmol) in 150 mL ethanol was added piperazine (30.44 g, 353.44 mmol), the resulting solution was then refluxed for 12 h. On reaction completion (TLC) the reaction was then concentrated under vacuum to give a crude solid mixture which was taken up in 200 mL DCM and washed with saturated sodium bicarbonate solution until no piperazine was seen in the organic layer (TLC). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by recrystallization in 30percent DCM:Hexane as a white powder (9.7 g, 77.6percent) of compound 2: RPiperazine (30.4 g, 353.4 mmol) was added to a mixture of 4, 7-dichloro-quinoline 1 (10 g, 50.4 mmol) in ethanol (150 mL). Thereaction mixture was refluxed and stirred for 12 h. The solvent wasremoved in vacuo and the resulting solid mixture was dissolved indichloromethane (200 mL) and washed with saturated sodiumbicarbonate solution until the complete removal of piperazine inthe organic layer (TLC). The combined organic phases were driedover anhydrous Na2SO4, concentrated and then purified byrecrystallization in 30percent dichloromethane/hexane, (yield: 9.7 g 77percent)of compound 2. Mp: 118e120 C; 1H NMR (300 MHz, CDCl3):d 8.72 (d, 1H, J 5.1 Hz), 8.06 (dd, 1H, J 2.1 and 9 Hz), 7.97 (t, 1H, J 9 Hz), 7.42 (dd, 1H, J 2.1 and 9.0 Hz), 6.83 (d, 1H, J 5.1 Hz), 3.33 (s, 1H), 3.14e3.21 (m, 8H); IR (KBr) nmax 3342, 3024, 1579, 823 cm1; FAB-MS (m/z): [M 1], 248; Anal. calcd for C13H14N3Cl:C 63.03, H 5.70, N 16.96percent; found: C 63.23, H 5.61, N 17.02percent.General procedure: The amino-functionalized quinolines (7) - (9) were synthesized using a reported method [33], as depicted in Scheme 2 and described as follows: A mixture of 4, 7-dichloroquinoline (4.95 g, 25 mmol) and a diamine (250 mmol; 10 eq.) was vigorously stirred upon heating at 80-135 °C for 24h. For the synthesis of the quinolines (10) and (11), a mixture of the quinoline and the diamine was dissolved in anhydrous dimethylformamide (DMF) after which the above described method was applied. The process was monitored by thin layer chromatography. After completion, the mixture was cooled to room temperature while stirring then basified with 1M NaOH (50 ml) and washed with distilled water (150 ml) thereafter the product was extracted with hot EtOAc (3 x 150 ml). The organic phase was dried over MgSOTo a suspension of 4, 7-dichloroquinoline (2.5g, 12.6mmol) and potassium carbonate (2.1, 15.1mmol) in acetonitrile (20mL) was added piperazine (1.1g, 12.6mmol) at 30°C. The reaction mixture was then heated to 80°C for 1–2h (monitored by TLC and LCMS for completion), cooled to 30°C. The mixture was then filtered through celite bed, and acetonitrile was evaporated in vacuo. The resultant residue was diluted with water (10mL) and dichloromethane (20mL) and the layers separated. The aqueous layer was re-extracted with dichloromethane (2×25mL). The combined organic extract was washed with brine, dried over sodium sulphate, and evaporated in vacuo. The resultant residue was the purified by column chromatography on neutral alumina using hexane: ethylacetate as eluent to give 7-chloro-4-(piperazin-1-yl)quinoline (1.9g, 61.3percent) as an off-white solid. A mixture of4, 7-dichloroquinoline (1) (0.505 mol), piperazine (2c) (1.5mol) and potassium iodide (0.12 mol) in isopropyl alcohol(20 ml) was refluxed for 10 h, and cooled to room temperature.The precipitated solid was filtered, washed withisopropyl alcohol and evaporated in vacuo. The crudeproduct, thus obtained was diluted further with dichloromethane(20 ml) and washed twice with water. The pH ofdichloromethane layer was adjusted using conc. HCl. Theseparated water layer was made alkaline with 10percent NaOHsolution and extracted again with dichloromethane. Theorganic layer was evaporated to dryness to get 7-chloro-4-piperazine-1-ylquinoline. Odourless off-white solid; solublein acetone, dichloromethane; melting range 161–162 °C;percentYield 50; Rf value 0.76 (dichloromethane: ethanol: 1:1);Spectroscopic analysis: λmax (in DMSO) 321.52 nm; FTIRSpectrum (νmax, in cm−1, film) 3250.01 (N–H stretching, 4NH piprazinyl), 3035.30 (aromatic C–H stretching, quinolyl), 2925.41–2830.10 (C–H stretching, 4CH2 piprazinyl), 1918.46–1496.85 (N–H bending, 4NH piprazinyl), 1452.82–1419.76 (C=C–C, aromatic ring stretching, quinolyl), 1373.06–1281.11 (C–N stretching), 1250.50–922.34(aromatic C–H in-plane bend), 1067.64 (C–Cl stretching, quinolyl–Cl), 867.05–618.50 (aromatic C–H out-of-planebend, quinolyl).

Molecular Weight:247.72
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:247.0876252
Monoisotopic Mass:247.0876252
Topological Polar Surface Area:28.2
Heavy Atom Count:17
Complexity:255
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes