6-BROMO-4-HYDROXYQUINOLINE

Tan powder

A mixture of 5-(((4-bromophenyl)amino )methylene)-2, 2-dimethyl-1 , 3-dioxane-4, 6-dione (50 g, 154 mmol) in 1, 2-dichlorobenzene (500 mL) was stirred at 188°C for 3.5 h. Thereaction was then cooled down to 0°C and stirred further for 3 h. The solid was collected byfiltration, and was then washed with methyl tert-butyl ether (100 mL) to give the title compoundas a brown solid (30.6 g, 87percent). The title compound was characterized by LC-MS and 1H NMRas shown below:LC-MS (ESI, pos. ion) m/z: 224 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 6.32 (d, J= 7.32 Hz, 1H), 7.48 (d, J= 9.08 Hz, 1H), 7.77(dd, J= 8.88 Hz, 2.32 Hz, 1H), 7.95 (d, J = 7.32 Hz, 1H), 8.34 (d, J = 2.28 Hz, 1H).The 5 - (( (4-bromophenyl) amino) methylene) - 2, 2-dimethyl -1, 3-dioxane -4, 6-dione (50g, 154mmol) in 1, 2-dichlorobenzene (500 ml) solution is heated to 188 °C, stirring for 3.5 hours, cooling to 0 °C, continue to stir 3 hours. Filtering, collecting solid, solid after armoruncle ether (100 ml) eluting, to obtain the title compound as brown solid (30.6g, 87percent).Diphenyl ether (519.9 g, 3.064 mol)Add to a 1000 mL three-necked flask, Preheat to 190 ° C, Compound 2a (50.1 g, 0.153 mol) was added slowly, Reaction for 15 min.TLC detection [V (dichloromethane): V (methanol) = 15:1] reaction junctionbundle, cool down, The reaction solution was poured into 600 mL of petroleum ether and stirred.Precipitating solids, Filtering, dry, Made a grayish yellow solid 29.9g, The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. . Deprotection and removal of the carboxylic acid10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.4.1.7 Add 6-bromo-4-oxo-2, 3-dihydroquinoline (0.01 mol) to a 25 ml reaction flask, add 15 ml of acetonitrile, concentrated sulfuric acid (0.02 mol), stir for 20 minutes, and slowly add potassium permanganate. (0.02 mol), the reaction was stirred at 85 ° C, the progress of the reaction was monitored by TLC, and the reaction was stopped after 5 hours. After the reaction solution is cooled to room temperature, it is poured into 50 ml of water, stirred and filtered to obtain a crude product of 6-bromo-4-hydroxyquinoline, which is separated by silica gel column chromatography (column chromatography silica gel 100-200 mesh, eluent oil) Ether: ethyl acetate = 1:4). The eluent was concentrated to give the product. The yield was 86percent, and the purity was 96percentCompound 1g (47.9 mmol, 10 g) was dissolved in diphenyl oxide and heated to 220 ℃ for 5 min. After cooling, the precipitated solid was filtered and washed with petroleum ether. Yield 83.5percent. HPLC purity: 96.7percent.A solution of Meldrum's acid (1) (32.4 g, 225.0 mmol) in trimethyl orthoformate (250 mL) was stirred and heated at reflux for 3 h under N2 to give 2. The solution was allowed to cool to ~50 C, and 4-bromoaniline (25.8 g, 150.0 mmol) in trimethyl orthoformate (80 mL) was added dropwise. The reaction mixture was heated at reflux for 2 h. After removal of the solvent in vacuo, the residue was diluted with hexanes, filtered, and the solid was washed with hexanes and dried to give Meldrum's acid derivative 3 as a yellow solid. Compound 3 was added slowly in small portions (~1.0 g each) to preheated (245 C) Ph2O (500 mL). Caution not to perform this addition too rapidly must be taken as gas violently evolves. The reaction mixture was stirred and heated at 250 C for 15 min, then allowed to cool to room temperature (rt) and diluted with hexanes, filtered. The solid was washed with hexanes, then 30% Et2O/hexanes. The crude product was purified by silica gel column chromatography (16:1-10:1 CH2Cl2/MeOH) to afford 4 (24.6 g, 73%) as a pale brown solid, mp 282-284 C (lit30 282-284 C). 1H NMR (DMSO-d6) delta 11.93 (br s, 1H, NH), 8.17 (d, J = 2.0 Hz, 1H, Ar-H), 7.96 (dd, J = 7.5, 6.0 Hz, 1H), 7.79 (dd, J = 9.0, 2.5 Hz, 1H, Ar-H), 7.53 (d, J = 8.5 Hz, 1H), 6.08 (d, J = 2.5 Hz, 1H, Ar-H).Step 2: 6-bromo-1, 4-dihydroquinolin-4-one (160b) Compound (160a) (535 mg, 1.64 mmol) was dissolved in hot diphenyl ether (10 mL) and heated under reflux for 30 minutes until the formation of gaseous products ceased. After cooling, pentane (8 mL) was added and the mixture was stirred 48 hours at room temperature. The precipitate was isolated by filtration and washed with pentane to afford compound (160b) (258 mg, 1.15 mmol, 70%).5- [(4-Bromophenylamino) methylene] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (50 g, 15411111101) was added to a 1-liter three-necked flask equipped with o-dichlorobenzene (500111, and the reaction was heated to 188 (reaction time 3.5 hoursSlowly cooled to 0 and stirred for 3 hours, filtered and the residue was washed with methyl tert-butyl ether (100 ml) to give a brown solid(30.6 g, 87%) as a crude product directly for the next step.Alternatively, step f may be a seventh compound as shown in 7d (2-fluoro-3-O-decladate-3-carbonyl-6-O-[3-[6'-(1', Preparation of 4'-dihydro-4'-oxoquinolyl]]-E-prop-2-enyl]erythromycin A 9-O-methylindole-11, 12-cyclocarbonateThe sixth compound (0.300 g, 0.412 mmol), palladium acetate (0.0278 g, 0.124 mmol), tris(o-methylphenyl)phosphorate (0.0752 g, 0.247 mmol),

Molecular Weight:224.05
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:222.96328
Monoisotopic Mass:222.96328
Topological Polar Surface Area:29.1
Heavy Atom Count:12
Complexity:227
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes