4-HYDROXYQUINOLINE-3-CARBOXYLIC ACID ETHYL ESTER

4-Hydroxyquinoline-3-carboxylic acid ethyl ester [0217] A l L three-necked flask fitted with a mechanical stirrer was charged with 2- phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to 70 General procedure: Polyphosphoric acid (PPA) (2 equiv by weight) was added to corresponding intermediate 1 (40 mmol) to this phosphorousoxychloride (POCl3) (10 mmol) was added. The reaction mixture was heated to 75 °C for 8 h, monitored by TLC, after completion of the reaction. The reaction mixture was quenched slowly with 10percent sodium hydroxide solution by keeping it in an ice bath and the PH was adjusted to a pH ~ 7, the solid separated was filtered, dried and washed with diethyl ether (3*20 mL) to afford desired compound in good yield. 4.1.5.1. Ethyl 4-hydroxyquinoline-3-carboxylate (10a). Pale yellowsolid (5.64 g, 65percent); m.p: 276-278 C; ESI-MS was found at m/z 218.32 [M+H]+. 1H NMR (300 MHz, DMSO-d6, TMS):d 10.72 (brs, 1H), 8.91 (s, 1H), 8.46e7.78 (m, 4H), 4.29 (q, J 7.1 Hz, 2H), 1.29 (t, J 7.1 Hz, 3H).Aniline (1.02 mL, 0.011 mol) and diethyl ethoxymethylenemalonate (0.5-2 eq) were weighed into ethanol and heated at 100-200 ° C for three hours.Cool to room temperature, add phenyl ether, heat at 100-200 ° C for 30 min, cool to room temperature, After the reaction was completed, ice water was added, and ethyl acetate (100 mL × 2) was added, and the organic phase was combined, and the organic phase was washed with saturated brine.Dry over anhydrous sodium sulfate, filter, The organic phase was concentrated and the residue was purified by silica gel column chromatography1.6 g (76percent yield);Aniline (1.02 mL, 0.011 mol) and diethyl ethoxymethylenemalonate (0.5-2 eq) were weighed into ethanol and heated at 100-200 ° C for three hours.Cool to room temperature, add phenyl ether, heat at 100-200 ° C for 30 min, Cool to room temperature, After the reaction was completed, ice water was added, and ethyl acetate was extracted (100 mL × 2).The organic phase was combined and the organic phase was washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the organic phase.The residue was subjected to silica gel column chromatography to give the productWhite solid 1.6g (76percent yield);Weigh aniline (1.0 mL) and diethyl ethoxymethylenemalonate (2.2 mL) into an appropriate amount of ethanol, and heat to reflux threeAfter cooling to room temperature, add 40 mL of phenylethyl ether, reflux under heating for 1 hour, and cool to room temperature. After completion of the reaction, add ice water, extract with ethyl acetate (100 mL×2), combine the organic phase, and saturate the organic phase. The mixture was washed with brine, dried over anhydrous sodium sulfate.Weighed aniline (0.011 mol) and diethyl ethoxymethylenemalonate (0.012 mol) were added to 20 mL of ethanol and heated at 90 ° C for three hours. Cool to room temperature, add 40 mL of phenyl ether, heat at 100 ° C for 30 min, cool to room temperature.After the reaction was completed, ice water was added, and ethyl acetate was extracted (100 mL×2).The organic phase was combined and the organic phase was washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the organic phase.The residue was subjected to silica gel column chromatography to ethyl 4-hydroxy-2-hydro-quinoline-3-carboxylate (66percent yield)Weigh aniline (0.011 mol) and diethyl ethoxymethylenemalonate (0.012 mol) into 20 mL of ethanol.Heated at 90 oC for three hours, Cool to room temperature, add 40 mL of phenyl ether and heat at 100 °C for 30 min.After cooling to room temperature, after completion of the reaction, ice water was added, and ethyl acetate was extracted (100 mL×2), the organic phase was combined, and the organic phase was saturated.Washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated.The residue was subjected to silica gel column chromatography toield ethyl 4-hydroxy-2-hydro-quinoline-3-carboxylate (66percent yield)Synthesis of Lipophilic Group Modified Peptide Sequence Based on Nisvastatin; Scheme A; Scheme A; Ethyl 4-hydroxyquinoline-3-carboxylate (Al); [0183] Aniline (2.15g, 23mmol) and diethyl ethoxymethylene malonate (5g, 23mmol) were mixed neat and heated at 110°C for 2h then cooled and allowed to stand at room temperature for 15h. During this time the reaction mixture crystallized. [0184] Dowtherm A (70 mL) was heated to 255°C and the melted crystals were added and the mixture heated at 255°C for 20 min. The mixture was then poured into a stainless steel container cooled to 0°C with an ice bath. Hexanes were added to the cold solution to precipitate the product which was collected by filtration and rinsed with another portion of hexanes. The product was recrystallized from EtOH to give the product as a white solid. (1.6g, 7.3mmol, 32percent, M.P. 309C) that was used without further purification in the next step.Ethyl 3- (2-aminophenyl) -3-oxopropionate (20.7 g, 0.1 mol) was dissolved in 100 mL of N, N-dimethylformamide, N, N-dimethylformamide dimethyl acetal (24.0 g, 0.2 mol) was added thereto, and the reaction was carried out at 120 ° C for 4 hours.The reaction solution was cooled to 20 ° C and the solvent was concentrated under reduced pressure. The residue was added to 200 g of ice water and stirred for 2 h.Ethanol and water volume (30mLx2 times), 50 drying, with 160mL ethyl acetate and petroleum ether equal volume mixedWas purified by recrystallization to obtain 15.4 g of ethyl 4-hydroxyquinoline-3-carboxylate in 71percent yield as an off-white solid.Weigh aniline (1.0 mL) and diethyl ethoxymethanemalonate (2.2 mL), add to the appropriate amount of ethanol, heat to reflux for three hours, cool to room temperature, add 40 mL of phenyl ether, and reflux under heating for 30 min.After cooling to room temperature, after completion of the reaction, ice water was added and extracted with ethyl acetate (100 mL×2).The combined organic phase was washed with brine, dried over anhydrous sodium sulfateThe residue was subjected to silica gel column chromatography to give the product(86percent yield).