8-Amino-6-chloroquinoline

The indirect deactivation in 2-amino-4-chloroquinoline (187) requires vigorous conditions (potassium hydroxide in hot ethylene glycol, or boiling propanolic propoxide for 16 hr) to displace the chloro group, which is stable to aqueous alkali and to hydriodic acid. The direct deactivation in 5-amino-2-chloro-3-cyano-6-methyl-pyridine (188) prevents reaction with alkoxide ion under conditions which produce smooth reaction of the des-amino analog. 

Blackie, M.A.L., Beagley, P., Chibale, K., Clarkson, C., Moss, J.R. and Smith, P.J. (2003) Synthesis and antimalarial activity in vitro of new heterobimetallic complexes Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines. Journal of Organometallic Chemistry, 688(1-2), 144-152. 

The noticeable rate enhancement due to a microwave-specific effect is consistent with a reaction mechanism in which the kinetic rate-determining step is nucleophilic attack of an amino group on the chloroquinoline ring (Scheme 3.16). 

Condensed derivatives are also known. Treatment of 2-amino-l,3,4-thiadiazoles with 2,3-dichloro-l,4-naphthoquinone or 6-chloroquinoline-5,8-dione yields 102 and 103, respectively (82H333, 91JIC529). 

The base is extracted with ether, dried with potassium carbonate, the ether removed by distillation and the residue fractionated. The 4-(5 -diethylaminopentyl-2 -amino)-7-chloroquinoline (BP 212 to 214C/0.2 mm) is obtained. On cooling the compound solidifies crystalline. It melts, recrystallized from benzene, at 88°C. The base combines with phosphoric acid to yield a diphosphate salt. 

In a further effort to develop better antimalarials by changing the substitution at the 4-amino function of chloroquine led to the discovery of hydroxychloroquine (5) with high antimalarial activity [11,12]. The search for newer 4-aminoquinoline drugs received a new dimension when Burckhalter et al. [13] discovered the antimalarial activity with some a-dialkylamino-o-cresols of the type 6 and 7. Consequently these authors prepared a large variety of Mannich bases attached to the 7-chloroquinolin-4-... 

Several examples have been reported of the preparation of 4,7-phenanthrolines from substituted 6-aminoquinolines by the Skraup and related reactions. In this way, 5-methoxy-, 5-chloro-, 3-methyl-6-methoxy-, l-methyl-, and l,2,3,4-tetrahydro-4-methyl-4,7-phenanthrolines have been synthesized while improvements have been made to the synthesis of the 3-methyl derivative. The Skraup reaction has also been applied to quaternary salts of 6-aminoquinolines. For example, 5-chloro-4-methyl-4,7-phenanthrolinium iodide (36) was obtained from the methiodide of 6-acetamido-8-chloroquinoline (35). Cyclizations starting from aminocarbostyrils have also been reported. Thus, 6-amino-1-methylcarbostyril (37) was condensed with paraldehyde in the presence of concentrated hydrochloric acid to afford 3,4-dihydro-4,8-dimethyl-3-oxo-4,7-phenanthroline (38), while under Skraup conditions, with glycerol as condensing agent, 6-amino-4-methylcarbostyril afforded 3,4-dihydro- l-methyl-3-oxo-4,7-phen-... 

Chemical Name 4-[(7-Chloro-4-quinolinyl)amino] -2-[(diethylamino)-methyl] phenol Common Name 4-(3 -diethylaminomethyl-4 -hydroxyanilino)-7-chloroquinoline... 

Parke, Davis workers have reported on the effects of introducing distal and proximal hydrazine moieties into the structures of active acridines and 4-aminoquinolines [266, 267]. Substitution of a hydrazine moiety for the amine function at the distal position of compounds such as azacrin, quin-acrine, and chloroquine, had a deleterious effect on antimalarial activity. Several such compounds containing proximal hydrazino functions, however, showed activity greater than chloroquine 4,4 -(l,4-piperazinediyldi-imino) bis (7-chloroquinoline) (74) and 7-chloro-4-[(4-methyl-l-piperazinyl)amino] quinoline (75) had quinine coefficients of 27 and 28 respectively against P. berghei compared to chloroquine s 11, but these compounds were highly... 

Chloroquine and three metabolites (desethylchloroquine, bisdesethylchloroquine [BDC], 4-amino-7-chloroquinoline [4AC]) were extracted from plasma and baseline resolved in under 10 min on a C,g colunm (2 = 343 nm) using a 28/72 acetonitrile/ water (20 mM heptanesulfonic acid with 700pL/L diethylamine to pH 4 with H3PO4) mobile phase [1499]. Peak shapes were excellent and detection limits of 2 ng/mL were reported. An interesting modification of the analysis of chloroquine, BDC and 4AC was a separation generated on a silica column (2 = 325 nm, ex 380 nm, em). The mobile phase was a 57/40/3 acetonitrile/methanol/ammonia mixture [1500]. Peak shapes were excellent. Detection limits of 4 ng/mL widi a linear concentration curve of 25-100 ng/mL were reported. Elution was complete in 15 min. 

Heating of 4-chloroquinolines with potassium fluoride (tetrabutylphosphonium fluoride) in DMSO affords only low yields of the corresponding 4-fluoro compounds [39, 40], however use of microwave irradiation (300 W) results in the formation of 2-fluoroquinolines from 2-chloroquinolines in 60-62 % yields [41], Replacement of the diaza group with the fluoride ion, the method which is widely used in heterocyclic chemistry, has also found its application to obtain fluo-roquinolines, as illustrated, for instance, by the syntheses of 3-fluoroquinoline from 3-aminoquinoline [42] and 3,5-difluoroquinoline from 3-fluoro-5-aminoquinoline, respectively [43], 3,7-Difluoro-6-methoxyquinoline 69, one of the key intermediates for the synthesis of antibacterial agents, has been obtained by the reaction of 3-amino-7-fluoro-6-methoxyquinoline with sodium nitrite in the presence of hydrogen borotetrafluoride (Scheme 26) [44],... 

Tricyclic system of benzo[/][l,7]naphthyridone 120 was obtained through the Gould-Jacobs cyclization of enamine 119, derived from 3-amino-6,8-difluoro-7-chloroquinoline 118 and diethyl ethoxymethylene malonate. The cyclization was carried out in diphenyl ether at 240 °C, providing a good yield of compound 120 (Scheme 59) [89],... 

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