6-Bromo-7-fluoroquinoline

Light Yellow Solid

The starting material, 3-fluoro-4-bromoaniline (20 g, 0.105 mol) And catalyst sodium 3-nitrobenzenesulfonate (28 g, 0.124 mol, 1.2 eq) was added to a mixed solution of concentrated sulfuric acid (60 ml) and water (24 ml), heated to an internal temperature of 120 ° C, Glycerol (29 g, 0.315 mol, 3 eq) was added slowly and the reaction was warmed to 130-140 ° C overnight after the addition was complete and allowed to cool. The reaction solution was poured into crushed ice, concentrated ammonia to pH 8, extracted with dichloromethane, washed with water, After drying, column chromatography purified to give a yellow solid 20.3g, yield 85.8percent.4-Bromo-3-fluoroaniline (D-1, 5.0 g, 26.3 mmol) and sodium 3-nitrobenzenesulfonate (7.1 g, 31.6 mmol)were added to the mixture of HStep 1: A mixture of compound A (90 g, 0.60 mol), glycerol (1800 g, 1.9 mol), ferrous sulfate (27 g, 0.0954 mol), nitrobenzene (99 mL, 0.95 mol) and concentrated sulfuric acid (261 mL, 4.77 mol) was heated at 130° C. for 14 h. The reaction mixture was allowed to cool to room temperature and basified to pH about 8 by 28percent NHIntermediate 2: (7-fluoroquinolin-6-yl)methanamine Step 1 : 6-Bromo-7-fluoroquinoline: To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml) con. sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 'H- NMR (δ ppm, CDC1Step 1: Intermediate 2: 6-Bromo-7-fluoro-quinoline; [0302] A mixture of 4-bromo-3-fluoroaniline (2.85 g, 15 mmol), ferric sulfate (0.95 g, 6.25 mmol), glycerol (5.66 g, 61 mmol), nitrobenzene (0.93 mL, 9.1 mmol), and concentrated sulfuric acid (2.61ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 7h. Nitrobenzene was then evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid, and a dark brown precipitate separated, which was collected and purified by flash chromatography (silica gel, petroleum/ethyl acetate= 8/1) to give 1.44 g of 6-bromo-7-fluoro-quinoline as white crystals (42.5percent yield).A mixture of 4-bromo-3-fluoro-phenylamine (2.85 g, 15 m mole), ferrous sulfate (0.95 g), glycerol (5.658 g, 4.5 ml), nitrobenzene (1.125 g, 0.93 ml) and concentrated sulfuric acid (2.61 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 7 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum: ethyl acetate= 8:1) to return compound title as white crystals (1.44 g, 42.5percent).Intermediate E and F 7-Fluoro-quinoline-6-carbaldehyde and 7-(7-Fluoro-quinolin-6-yl)-methylamine 6-bromo-7-fluoro quinoline (i) To a suspension of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol) in concentrated sulfuric acid (290 ml.) was added glycerol (220 g, 2.39 mol, 4.5 eq.) followed by ferrous sulfate (30 g, 0.2 eq.). The reaction mixture was heated at 130 To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml), con.sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 'H-NMR (δ ppm, CDC1General procedure: In a pressure tube, 5-bromo-1 H-indazole (400 mg, 2 mmol), bis(pinacolato)diboron (773 mg, 3 mmol) and KOAc (598 mg, 6 mmol) were dissolved in 40 mL of dry DMF and sparged with argon for 10 mi Pd(dppf)012 (149 mg, 0.2 mmol) was added in one portion, and the reactionmixture was sparged with argon for additional 3 mm. The pressure tube was capped and the reaction mixture was heated at 10000 overnight. After full conversion (monitored by LOMS), the reaction mixture was filtered throught Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and co-evaporated with silica. Product was purified by column chromatography, eluting with hexane:EtOAc (0-50%) to afford the title product asa white solid (0.5 g, 2 mmol, quant.). ESI-MS: 245.1 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) 613.15 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.61 (dd, J = 8.4, 1.1 Hz, 1H), 7.52 (dt, J = 8.4, 1.0 Hz, 1H), 1.31 (s, 12H).

Molecular Weight:226.04
XLogP3:3
Hydrogen Bond Acceptor Count:2
Exact Mass:224.95894
Monoisotopic Mass:224.95894
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes