The other key intermediate, 4,7-dichloroquinoline (5) is relatively cheaper, commercially available and having the ease to synthesis using varieties of starting materials. The most convenient synthetic approach for 5 involves the use of 7-chloroquinolin-4(1H)-one (12) which in turn can be obtained by the reaction of 3-chloroaniline (11) with either ethoxy methylene malonic ester (13) or diethyl ester of oxaloacetic acid (14) following thermal heterocyclization and ester hydrolysis to yield 12a followed by decarboxylation (Scheme 2C). In similar manner, reaction of methyl acrylate (15) in presence of stoichiometric tosyl chloride ( ) with 2-amino-4-chlorobenzoic acid 85 (11a) or reaction of ethyl 3-oxopropanoate 86 (17) with 11 gives 12. Alternatively, 12 can be prepared from reaction of 11 with Meldrum's acid (18) via demethoxylation of 12b. In another approach, the synthesis of 5 is reported from 7-chloroquinolin-4(1H)-one (12) using chlorinated trichloroisocyanuric acid salt in the presence of BMIMPF6 ionic liquid. In alternate strategy (Scheme 1; strategy 2), Chen et al. described the synthesis of enantiomeric 1 using 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (4) and 7-chloroquinolin-4-amine (8) to give (R)-HCQ and (S)-HCQ under reductive amination conditions following chiral resolution using 10-CSA and mandelic acid respectively (Scheme 3A). As discussed before, 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (4), a key intermediate for the synthesis of 2-((4-aminopentyl)(ethyl)amino)ethan-1-ol (2), is one of the major costs contributing factor for the overall synthesis of HCQ. Thus, its production is always looked upon for the economical large-scale up processes. With the current ongoing demand, availability of this key intermediate (4) and associated raw materials is critical for the bulk scale production to fulfill the global supply. The industrial route for the synthesis of 4 involves the protection-deprotection strategy using 5chloropentan-2-one (6) as a starting material followed by SN2 substitution with 2-(ethylamino)ethan-1-ol (7). Alternatively, Haijun and co-workers utilized multifaceted transition-metal-catalysis for direct SN2 reaction to give 4. Although this protocol abolished the additional protection-deprotection step, the yield was sub-optimal coupled with use of toxic xylene as a reaction medium. In this context, Tie et al. reported the green synthesis of 4 using TBAB (phase transfer catalyst) in Aq. alkaline (water) : chloroform medium with 92% yield. Recently, Yu et al. Irrespective the route of synthesis, the chief chemical required for synthesis of key intermediate 4 are haloketone, 5-chloropentan-2-one (6) and 2-(ethylamino)ethanol (7) (commercially available). The commonly reported methods for their synthesis utilizes cheap raw materials are summarized below in the Scheme 3C (a. ; b. ; c. ; d. ; e. ; f. 98 ; g. The other key intermediate 4-amino-7-chloroquinoline (8) can be obtained via amination of 4,7dichloroquinoline (5) using ammonium carbonate 124 or liquid ammonia 125 or ammonia gas. Although the yields are promising, the use of phenol as reaction medium requires careful handling especially on large scale production having high temperature. Additionally, in most of the cases, the hydrochloride salt of 8 was obtained as side product which further requires basic treatment, adding higher cost to the production. In a preliminary study Hollywoood et al. reported the use of qunolylazides (20) as an alternative where its photo irradiation causes the formation of 8 while synthesizing various bicyclic azepine derivatives. reported the synthesis of 8 from 4-methoxy-7-chloroquinoline (12b) via demethoxylation using ammonium acetate as amine source with 70% yield. Gemma et al. reported the synthesis of 8 using 7-chloro-4-hydrazinylquinoline (21) under microwave irradiation using NaBH4 under nickel catalysis with 87% yield. Aillerie et al. performed the copper catalysed cross-coupling reaction of 7-chloro-4-iodoquinoline (22) with ammonia (generated in situ from formamide) and ethanolamine for the synthesis of 8 (Scheme 3D).