4,7-Dichloroquinoline

4,7-Dichloroquinoline was first reported in a patent filed by IG Farben in 1937.{{cite patent |country=DE |number=683692 |status=patent |gdate=1939-11-13 |fdate=1937-10-08 |pridate=1937-10-08 |invent1 =Andersag, Hans |invent2 = Breitner, Stefan |invent3 = Jung, Heinrich |title=Process for the preparation of quinoline compounds containing amino groups with basic substituents in the 4-position |assign1= IG Farbenindustrie AG}} However, its synthesis was not investigated in detail until chloroquine was developed as an antimalarial drug.{{cite book |isbn=9780309092180 |doi=10.17226/11017|doi-access=free|editor-last1=Arrow|editor-first1=K.J.|editor-last2=Panosian|editor-first2=C.B.|editor-last3=Gelband|editor-first3=H.|title=Saving lives, buying time : economics of malaria drugs in an age of resistance|date=2004|publisher=National Academies Press|pmid=25009879|author1=Institute of Medicine (US) Committee on the Economics of Antimalarial Drugs|last2=Arrow|first2=K. J.|last3=Panosian|first3=C.|last4=Gelband|first4=H.}}{{rp|130–132}} A route to the intermediate starting from 3-chloroaniline was developed by chemists at Winthrop Chemical Co.{{cite journal |doi=10.1021/ja01205a036 |title=Some 7-Substituted 4-Aminoquinoline Derivatives |year=1946 |last1=Surrey |first1=Alexander R. |last2=Hammer |first2=Henry F. |journal=Journal of the American Chemical Society |volume=68 |pages=113–116 |pmid=21008327 }}

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The substituted aniline is condensed with the diethyl ester of oxaloacetic acid under mildly acidic conditions, forming an imine, which is cyclised to form the pyridine ring by heating in mineral oil. Hydrolysis and decarboxylation follows, before the hydroxy group in the 4-position is converted into the second chloro group using phosphoryl chloride.

The availability of 4,7-dichloroquinoline allowed alternative structural analogs of the 4-aminoquinoline type to be investigated, leading to the discovery of hydroxychloroquine in 1949.{{cite patent |country=US |number=2546658 |status=patent |gdate=1951-03-27 |fdate=1949-07-23 |pridate=1949-07-23 |invent1 =Surrey, Alexander R |title=7-chloro-4-[5-(N-ethyl-N-2-hydroxyethylamino)-2-pentyl] aminoquinoline, its acid addition salts, and method of preparation |assign1= Sterling Drug Inc.}}{{cite journal |doi=10.1021/ja01160a116 |title=The Preparation of 7-Chloro-4-(4-(N-ethyl-N-β-hydroxyethylamino)-1- methylbutylamino)-quinoline and Related Compounds |year=1950 |last1=Surrey |first1=Alexander R. |last2=Hammer |first2=Henry F. |journal=Journal of the American Chemical Society |volume=72 |issue=4 |pages=1814–1815 }}

By that time, chloroquine manufacturing processes had been established to allow its widespread use.{{cite journal|doi=10.1021/ie50472a002|first1=R.L. |last1=Kenyon|first2= J.A.|last2=Wiesner|first3=C.E.|last3=Kwartler|title=Chloroquine manufacture|date=1949-04-01|journal=Industrial & Engineering Chemistry|volume=41|issue=4|pages=654–662 }} 4,7-Dichloroquinoline has also been prepared by the Gould–Jacobs reaction using an alternative method of constructing the pyridine ring from 3-chloroaniline.{{OrgSynth|title = 4,7-Dichloroquinoline (Quinoline, 4,7-dichloro-)|collvol = 3|collvolpages = 272|volume = 28|pages = 38|year = 1948|prep = CV3P0272|first1 = Charles C.|last1 = Price|author-link=Charles C. Price|first2 = Royston M.|last2 = Roberts|doi = 10.15227/orgsyn.028.0038}}

The chlorine atom in the 4-position in the pyridine ring is much more reactive in nucleophilic aromatic substitution reactions{{cite journal |doi=10.1002/anie.201902216 |title=Concerted Nucleophilic Aromatic Substitution Reactions |year=2019 |last1=Rohrbach |first1=Simon |last2=Smith |first2=Andrew J. |last3=Pang |first3=Jia Hao |last4=Poole |first4=Darren L. |last5=Tuttle |first5=Tell |last6=Chiba |first6=Shunsuke |last7=Murphy |first7=John A. |journal=Angewandte Chemie International Edition |volume=58 |issue=46 |pages=16368–16388 |pmid=30990931 |pmc=6899550 }}

than the chlorine in the benzene ring. As a result, it can be replaced selectively to form derivatives at that position. A typical reaction with a specific primary amine gives chloroquine in high yield:

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Apart from its use in the manufacture of antimalarials already described, 4,7-dichloroquinoline is of continuing interest as an intermediate to new drug candidates.

{{cite journal |doi=10.1039/C5RA16361G |title=4-Aminoquinoline-hybridization en route towards the development of rationally designed antimalarial agents |year=2015 |last1=Raj |first1=Raghu |last2=Land |first2=Kirkwood M. |last3=Kumar |first3=Vipan |journal=RSC Advances |volume=5 |issue=101 |pages=82676–82698 |bibcode=2015RSCAd...582676R |url=https://scholarlycommons.pacific.edu/cgi/viewcontent.cgi?article=1797&context=cop-facarticles }}{{cite journal |doi=10.1002/med.21355 |doi-access=free |title=Development of Small-Molecule Antivirals for Ebola |year=2015 |last1=Janeba |first1=Zlatko |journal=Medicinal Research Reviews |volume=35 |issue=6 |page=1182 |pmid=26172225 |pmc=7168439 }}

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• {{cite book |isbn=9780813546469 |title=War and Disease: Biomedical Research on Malaria in the Twentieth Century |last1=Slater |first1=Leo |date=9 January 2009 |publisher=Rutgers University Press }}

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Category:Quinolines

Category:Chloroarenes