Hydroxychloroquine is now prescribed in corona treatments in Europe even though the effectiveness of the drug as an antiviral is unsure (link). Antimalarial drug chloroquine was identified as a possible cure as early as the beginning of February but cousin hydroxychloroquine is considered less toxic. Existing users of the drug (sufferers of Lupus are mentioned) now watch in alarm as supplies rapidly dwindle away.
(RS)-2-(4-((7-chloroquinolin-4-yl)amino)pentyl(ethyl)amino)ethanol was patented in 1951 by Sterling Drug Inc of New York as an antimalarial drug but describes only two steps (link). An improved procedure was patented in 2005 by IPCA Laboratories of Mumbay (Link).
Acetyl butyrolactone is commercially available and step one is a hydrolysis / chlorination:
Step two is a ketone protection to an acetal:
With protection in place step 3 is an amination with 2-(N-ethyl)-aminoethanol:
Step 4 is the acetal deprotection step (the 110% yield is a patent text error but we may assume the yield is quantitative):
Step 5 is a reductive amination
The final step is reaction with 4,7-dichloroquinoline (also commercially available)
Key difference with the 1951 patent is the elimination of the use of phenol in the final step. The yield is higher but a reaction time of up to 50 hours is excessive by any standard. With an overall yield of 51% the production costs in terms of the two raw materials can be kept below 1 euro per gram. In a 2010 patent the final step is carried out at 20 bar of nitrogen with a reported 78% yield at 4 hours and 100°C. (Link) In a 2015 patent (Link) chloro-2 pentanone and 2-(N-ethyl)-aminoethanol are reacted directly without the need for a protecting-deproting step. Most recently in 2019 a continuous flow procedure was published (DOI).