Potential antimalarials. V. 2-p-Chlorophenyl-7-quinolinemethanols

Abstract

reaction was carried out and worked up as described for the preparation of Id to obtain 0.9 g (97%) of crude Ih, mp 16N-172°. It was recrystd from petroleum ether (bp 60-110°) to recover 0.2 g (22%) of pure Ih, mp 181-182.5°, exhibiting a single spot on tic (silica gel, Cells, Rt 0.481. Anal. (CitHioBiv C1NO): C, H, Br.An alkaline oxidation with hypoiodite6 cleaved the pure dibromo ketone Ih in 79% yield to 8-chloro-2-phenyl-5-quinolinecarboxylic acid (Ie) which did not depress the melting point, of an authentic sample of the acid.The monobromination of 0.026 mole of ig was attempted with 0.009 mole of KBr03. The product obtained, after repeated recrystallization from petroleum ether (bp 60-110°), had mp 118-128.5°. Based on its Br content (27.22%) and tic (silica gel, C«H«, Ri 0.35 and 0.45) it was a mixture of 64%, of monobromide Ii and 36%, of dibromide Ih.8-Chloro-a:-[ (dibuty lamino )methyl] -2-phenyl-5-quinoIinemethanol Hydrochloride (lie).-To the dry (KOH) Et20 solution of CH2N2 obtained from 21.5 g of A'-nitroso-p-toluenesulfonamide was added in small portions 6.06 g (0.02 mole) of powdered acyl chloride If over a period of 20 min at -5 to 0°. After 18 hr standing at 0°, there was added slowly to the reaction mixture a solution of 1.5 ml of 48% HBr and 15 ml of Et«0 and it was stirred for 2 hr at room temp. The two-phase reaction mixture was filtered, the residue was washed with II20 and dried to give 4.66 g of the crude 5-(a-bromoacetyi)-8-chloro-2-phenylquinoline (Ii).An additional 2.2 g was obtained from the ethereal layer. The combined crops were recrystd from 95% EtOH to give 5.36 g (74%) of Ii, mp 139-140°, exhibiting a single spot on tic (silica gel, Celle, Ri 0.32). Anal. (CnHnBrClNO): C, , N.The crude monobromo ketone Ii (0.014 mole) was reduced to crude a-bromomethyl-8-chlom-2-phenyl-5-quinolmemethanol (lid) in 92% yield and the latter (0.013 mole) was treated with 0.05 mole of Bu2NH as described for lib. The reaction mixture was cooled and filtered and the filter cake was washed with anhyd Et20. The Et20 filtrate was treated with 9 ml of f-PrOH-HC1 (gas) (containing 0.028 mole of HC1) to remove the unreacted Bu2NH. The crystalline Bu2NH-HCl was filtered and washed with Et20. The filtrate was evapd to dryness in vacuo. The residual oil was dissolved in ] 3 ml of AleOH, cooled, treated with 3 ml of i-PrOH-HCl (gas) containing 0.008 mole of HC1, dild with 135 ml of Et20, and chilled to give 0.87 g of white crystals, mp 170-172°. The mother liquor was evapd to dryness and the residue was treated with Et20. On filtration, followed by washing with Et20, there was obtained another crop of 2.52 g of white crystals, mp 165-170°. The combined crops were recrystd from -PrOH to recover 3.13 g (54%) of He, mp 171-172°. Anal. (C26H31C1N20-HC1): C, , N, Cl~.