Synthetic route to hydroxychloroquine

Question

This drug hydroxychloroquine has become a new burning topic of discussion as a chemistry enthusiast:

I know that in an industrial preparation we need to account fpr a lot of factors like temperature, solvent, expenditure etc. I tried this, which did not seem good enough:

It seems that the nucleophilic aromatic substitution is not appropriate and the starting products chosen may not be commercially available. Can someone suggest a better yielding and more economical pathway?

Answer 1

This took a bit of thinking about but here is a viable route from commercially available bulk materials.

Start with nitroethane, deprotonate ($\ce{t-BuOK}$ in THF would be my choice, but $\ce{NaOEt/EtOH}$ should do it) and react with the commercially available dioxane protected 3-bromopropanal. Reduce the nitro group - alkyl nitro groups are tricky to reduce, I've found Hg/Al amalgam to be pretty good but others may have different conditions. There's a recent review of reductions$\ce{^{[1]}}$. The product of this will do the SNAr with 4,7-dichloroquinoline, I would try $\ce{K2CO3/MeCN}$ for this, but here are plenty of other possible conditions. This is a good point to purify, then reveal the masked aldehyde by acid hydrolysis and do a reductive amination with the commercially available N-Ethylethanolamine to give the desired product.

Reference

1. Manuel Orlandi, Davide Brenna, Reentje Harms, Sonja Jost, and Maurizio Benaglia, Organic Process Research & Development 2018 22 (4), 430-445 DOI: 10.1021/acs.oprd.6b00205

Answer 2

Note: Organic chemistry is not my field of expertise. This is just a supporting answer to Waylander's excellent answer which is purely based on online research. OP want some canonical answers and if people are interested in this question, I might as well place a bounty.

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One route I found is react 1-chloro-4-pentanone with 2-ethylaminoethanol to make aminoketone which undergoes reductive amination making 4-[ethyl(2-hydroxyethyl)amino]-1-methylbutylamine. Reacting this with 4,7-dichlroquinoline* makes the desired hydroxychloroquine.

*There are 3 methods to make 4,7-dichloroquinoline(see ref. below for more details). One of the method is as follows:

Take 3-chloroaniline and ethoxymethylenmalonic ester to make (3-choroanilino)-methylenemalonic ester, which then undergoes high-temperature heterocyclization to make the ethyl ester of 7-chloro-4-hydroxyquinolin-3-carboxylic acid. Hydrolyzing this with sodium hydroxide gives 7-chloro-4-hydroxyquinolin-3-decarboxylic acid, which when heated at 250–270°C is decarboxylated, forming 7-chloro-4-hydroxyquinoline. Treating this with phosphorus oxychloride gives 4,7-dichloroquinoline.

Reference

1. Hydroxychloroquine and Chloroquine articles respectively of ScienceDirect.com. Original reference is "Drugs for Treating Protozoan Infections by R.S. Vardanyan, V.J. Hruby, 2006"