Some substituted benz[c]acridines and benzo[h]quinoline derivatives are synthesized and may be useful as antimalarials.4-Hydroxy-1-naphthylamine-HCl, m. 265-7° (decomposition), is converted into 75% 4-acetamido-1-naphthol (I) and methylated in 90% yield to 4-acetamido-1-methoxynaphthalene (II).II is hydrolyzed by refluxing with 1 N HCl in MeOH for 6 h. to give 90% 4-methoxy-1-naphthylamine-HCl (III), m. 278-9° (decomposition).Neutralization of III with Na2CO3 gives 4-methoxy-1-naphthylamine (IV).When 40 g. II is hydrogenated in 600 cc. dioxane at 130-40° and 1500-2000 lb. H pressure in the presence of 5 g. U.O.P. Ni catalyst (V), 70-85% 4-acetamido-1-methoxy-5,6,7,8-tetrahydronaphthalene (VI), crystals from EtOH, m. 188-9°, is obtained.Refluxing of VI with alc. HCl for 6 h. gives 95% (4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)amine-HCl, m. 250-3° (decomposition); free base (VII), m. 61°, oxidizes rapidly in air and turns purple.An attempt to prepare VII by reducing 1-methoxy-4-nitroso-5,6,7,8-tetrahydronaphthalene failed because on nitrosation of 1-methoxy-5,6,7,8-tetrahydronaphthalene the MeO group is hydrolyzed, giving 68.5% 4-nitroso-5,6,7,8-tetrahydro-1-naphthol (VIII), m. 161-3°.Reduction of VIII by dissolving it in concentrated NH4OH and passing H2S into the filtered solution gives 67% 4-amino-5,6,7,8-tetrahydro-1-naphthol (IX), m. 144-6° (decomposition).Acetylation of IX gives 90% 4-acetamido-5,6,7,8-tetrahydro-1-naphthol (X), m. 188-9°.X is also obtained in 75% yield when 28 g. I is hydrogenated in 250 cc. dry dioxane at 130° and 1400 lb. pressure in the presence of 5 g. V.Methylation of X with Me2SO4 gives VI.Ethylation of X gives 70% 4-acetamido-1-ethoxy-5,6,7,8-tetrahydronaphthalene (XI), m. 195-6°.VII (16.5 g.) is condensed with 16.2 g. 2,4-Cl2C6H3CO2H (XII) by refluxing in 100 cc. BuOH in the presence of 12 g. K2CO3 and 0.75 g. Cu bronze 7 h., with addition of 1 g. K2CO3 and 0.3 g. Cu bronze after 3 h. of heating.NaOH (25 cc. 20%) is added, the BuOH removed by steam distillation, and the solution saturated with CO2, causing the separation of 40% crude 4-chloro-N-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)anthranilic acid (XIII), m. 200-25°.XIII is cyclized by refluxing 22.8 g. in 82.5 cc. POCl3 for 4 h.After 1/2 of the POCl3 is distilled off, the reaction mixture is poured into a mixture of 650 cc. ice H2O, 500 cc. concentrated NH4OH, and 500 cc. CHCl3.The CHCl3 layer is separated, the aqueous solution repeatedly extracted with CHCl3, and the combined CHCl3 extracts are dried and evaporated, giving 39% 7,10-dichloro-5-methoxy-l,2,3,4-tetrahydrobenz[c]acridine (XIV), yellow crystals from C6H6-heptane, m. 190-1°.Condensation of IV with XII gives 4-chloro-N-(4-methoxy-1-naphthyl)anthranilic acid (XV), m. 275-80°, which is also obtained in 35-40% yield from III by addition of sufficient K2CO3 to liberate IV.In these reactions, an acidic byproduct, m. 225-42°, containing Cl but no N, is isolated but not identified.Refluxing XV with POCl3 gives 46% 7,10-dichloro-5-methoxybenz[c]acridine (XVI), m. 199-200°.XIV (3.32 g.) is dissolved in 10 g. PhOH at 120-5°, 1.74 g. MeCH(NH2)CH2CH2CH2NEt2 (XVII) is added, and the mixture heated 3 h.The hot solution is slowly dropped into a cold mixture of 50 cc. ether and 50 cc. 10% NaOH, causing the separation of a solid, m. 335°, which seems to be the acridone formed on hydrolysis of XIV, since on treatment with POCl3 XIV is formed.Extraction of the alk. solution with ether and repeated crystallization of the residue of the dried ether extract from heptane give 10-chloro-5-methoxy-7-phenoxy-1,2,3,4-tetrahydrobenz[c]acridine, yellow crystals, m. 193-5°.Evaporation of the heptane mother liquor gives the hydrated form, m. 90-3°, of 10-chloro-7-[(4 -diethylamino-1-methylbutyl) amino]-5-methoxy-1,2,3,4-tetrahydrobenz[c]acridine.Because it is impossible to obtain the anhydrous base in a crystalline form, it is converted into the di-HCl salt (XVIII).The hydrated di-HCl salt, obtained in 30% yield, loses its H2O on prolonged heating at 140°/15 mm. over P2O5.XVIII has a transition point at 175-8° and m. 247-50° (decomposition).Reaction of XVI and XVII in the presence of phenol gives 10-chloro-5-methoxy-7-phenoxybenz[c]acridine, m. 182-3°.Condensation of XVI with XVII for 7 h. at 135° gives 41% 10-chloro-7-[(4-diethylamino-1-methylbutyl)amino]-5-methoxy-benz[c]acridine-2HCl, yellow crystals with 0.5 H2O from EtOH-iso-PrOH, m. 233-5° (decomposition) with a transition point at 215-16°.Skraup reaction by dropwise addition of 39 cc. concentrated H2SO4 to a hot solution of 31 g. X, 70 cc. glycerol, and 9.15 cc. PhNO2 over a period of 1 h., refluxing of the mixture for 2 h., and pouring it onto 500 cc. ice cause the separation of an acid-insoluble tar which is filtered off.The filtrate is neutralized with 15% NaOH, giving a white precipitate which is distilled at 1 mm.Recrystallization of the distillate gives 25-30% 6-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline, plates from EtOH, m. 257-8° (HCl salt m. 270-2° (decomposition)).Condensation of VII.HCl with Na Et ethoxalylacetate (XIX) according to Mueller and Hamilton (C.A. 38, 3982.7) gives 93% di-Et (4-methoxy-5,6,7,8-tetrahydro-1-naphthylimino)succinate (XX), crystals from MeOH-H2O, m. 54°.Ring closure of XX by dropping it into mineral oil, preheated to 250°, gives 75% 2-carbethoxy-4-hydroxy-6-methoxy-7,8,9,10-tetrahydrobenzo[h]quinoline (XXI), m. 212-14°.When 20 g. XXI is heated with 500 cc. 10% NaOH on a steam bath for 2 h. and the mixture acidified with HCl, 90% 2-carboxy analog (XXII), m. 263-4° (decomposition), is obtained.Decarboxylation of 2 g. XXII by heating it with 0.5 g. CuO.Cr2O3 catalyst 10 min. at 250°, extraction of the reaction mixture with 10% NaOH, and saturation of the filtered solution with CO2 give 60-70% 4-hydroxy-6-methoxy-7,8,9,10-tetrahydrobenzo[h]quinoline (XXIII), m. 257-8°.Refluxing 2 g. XXIII with POCl3 2 h., distilling off of a part of the POCl3, pouring the reaction mixture onto ice, adding 5 cc. concentrated HCl, decolorizing the mixture, and neutralizing it at 20-30° with NH4OH give 75% 4-Cl analog (XXIV), crystals from MeOH-H2O, m. 107°.When 0.25 g. XXIV and 0.31 g. H2NCH2CH2CH2NEt2 (XXV) are refluxed 8 h., the reaction product washed with H2O, dissolved in ether, the ether extract washed with 5% NaOH, extracted with HCl, and the HCl extract made alk., 4-(3-diethylaminopropylamino)-6-methoxy-7,8,9,10-tetrahydrobenzo[h]quinoline (XXVI) seps. as an oil and crystallizes on long standing.XXVI is isolated in 70% yield as the di-HCl salt, very hygroscopic yellow crystals, m. 252-4° (decomposition).When III is treated with XIX according to M. and H. (loc. cit.), 85% di-Et (4-methoxy-1-naphthylimino)succinate, yellow crystals from MeOH, m. 77°, is obtained and when dehydrated by dropping into preheated mineral oil it gives 88% 2-carbethoxy-4-hydroxy-6-methoxybenzo[h]quinoline (XXVII), yellow crystals from a large volume of EtOH, m. 253-5° (decomposition), in addition to 20% alkali-insoluble product.Decarboxylation of XXVII in the same way as XXII gives 46.5% 4-hydroxy-6-methoxybenzo[h]quinoline (XXVIII), m. 269-70°.Treatment of XXVIII with POCl3 gives 31.5% 4-chloro-6-methoxybenzo[h]quinoline (XXIX), yellow crystals from MeOH-H2O, m. 101-2°.When XXIX is allowed to react with XXV and the reaction product is worked up as XXVI, 70% 4-(3-diethylaminopropylamino)-6-methoxybenzo[h]quinoline-2HCl (XXX), m. 246-8°, is obtained.Condensation of 3.37 g. VII with 4 g. AcCH2CO2Et 16 h. at room temperature gives 70% Et β-[(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-amino]crotonate, m. 81-2°, which, when added slowly to mineral oil heated at 260°, gives 78.5% 4-hydroxy-6-methoxy-2-methyl-7,8,9,10-tetrahydrobenzo[h]quinoline (XXXI), m. 273°.Refluxing 5.53 g. XXXI with 32 cc. POCl3 gives 51.5% of the 4-Cl analog, crystals from MeOH, m. 104-5°.Only XXX shows antimalarial activity on malaria-infected ducklings.
