|The efficiency of chloroquine as an antiviral against COVID-19 is still in doubt with clinical trials running. For some time now I have had plans to piece together a summary of synthetic details. It does not help that I am locked out of the library but even with access, I doubt I am going to find the definite synthetic scheme very soon. These bits and pieces will have to do. |
Hans Andersag is credited for the discovery of the compound far back in 1936 working for Bayer AG. His name appears on a 1941 patent with number US2233970A. It describes the reaction of 4,7-dichloroquinoline with 1-diethylamino-4-aminopentane for 7 hours at 180°C. The completion of the reaction is monitored by adding a sample to diluted nitric acid and observe absence of precipitate with sodium acetate solution. The product is isolated by distillation at 212°C and 2 mm. Being a patent, no reaction time is disclosed nor a reaction yield. In variations with other chloroquinolines or other amines, sodium hydroxide solutions are added to the mix or is phenol an additive. Phenol seems to be key to a successful synthesis, the phenoxide is assumed to be an intermediate.
Even though Andersag worked in Germany his entire life the patent owner is Winthrop Chemical Company of New York as "assignors". On the day the patent was granted, the United States were still a few months away from entering the war but Winthrop had "acquired" the American Bayer division already in 1918 (that other war) as part of the Alien Property Custodian Act. Winthrop eventually became Sterling Drug and is now part of GlaxoSmithKline.
Synthesis of 4,7-dichloroquinoline is a classic by itself, look no further than Organic Syntheses volume 28, 1948 here with reporters Charles C. Price and Royston M. Roberts. Starting materials are m-chloroaniline and ethyl ethoxymethylenemalonate and the reaction even has a nice reaction mechanism attached to it, the Gould-Jacobs reaction. Price was an accomplished chemist and incidentally also an advocate of a world government. Something we would like to have today? 1-diethylamino-4-aminopentane can be prepared from ethylene oxide, diethylamine and acetone according to one source (Link).
Fast forward to present corona days. Bayer is still producing chloroquine in large amounts (they call it Resochin) and has been donating some of their production (Link, Link). On a smaller scale Lee Cronin has entered the field and ordered one of his bots to get going. His protocol can be found on github. It describes 1-diethylamino-4-aminopentane, 4,7-dichloroquinolene (sic, must be a typo) and a sodium hydroxide solution. Since these are only the instructions, we have to wait for the bot to report back the results, hopefully in an equally open-source manner. On the DIY front we have NurdRage who has announced his or her chloroquine challenge on Twitter. Just wondering why he or she (we don't know, do we) is looking for nitrobenzene as precursor?