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

Hydroxychloroquine structure

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:

Proposed synthesis

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?

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  • $\begingroup$ Assemble the amino sidechain first and use that in the SNAr with the di-chloroquinoline $\endgroup$ – Waylander Apr 17 '20 at 10:35
  • $\begingroup$ @Waylander would both the pathways make a difference? $\endgroup$ – An enthusiast Apr 17 '20 at 11:46
  • $\begingroup$ Yes, I think so.the SNAr will be a high- yielding reaction. I think your reductive am with the 4-aminoquinoline will be poor. $\endgroup$ – Waylander Apr 17 '20 at 11:48
  • $\begingroup$ But I had the doubt that may be both the aryl halides would compete for SnAr $\endgroup$ – An enthusiast Apr 17 '20 at 11:51
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    $\begingroup$ Convergent syntheses are higher yielding than linear syntheses. Follow @Waylander. $\endgroup$ – user55119 Apr 17 '20 at 16:25
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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.

enter image description here

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
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  • $\begingroup$ @ Waylander I unaccepted because I want the question to reach to larger amounts of people. Because very few people see an answered question. But meant nothing else $\endgroup$ – An enthusiast Apr 23 '20 at 12:13
  • $\begingroup$ @Adithya You can attract more people by placing a bounty onto your question. If an answer suits your need, you can award the bounty. But you must have reputation points of at least 75 to attain that privilege. So, try asking/answering a few questions to have some rep. points. $\endgroup$ – Nilay Ghosh Apr 25 '20 at 12:13
  • $\begingroup$ @NilayGhosh I didn't want to get reputation points. I just wanted a canonical answer which makes me learn more. More people answering will increase what I learn. Reputation points are always secondary to me. The answer by Waylander was quite amusing to me I wanted to know more of such reactions. I think in someway or the other we can help other people by combining the knowledge. That was my point of view that's all. $\endgroup$ – An enthusiast Apr 26 '20 at 6:39
  • $\begingroup$ @Waylander: A Chem Abst search did not locate effective methods for alkylation of nitroethane with primary alkyl halides. In other cases, C vs. O alkylation is always an issue. However, condensation of nitroethane with aliphatic aldehydes is efficient. (DOI:10.1021/ol800224k). I would offer addition of 2-(ethylamino)-ethanol to acrolein followed by base-catalyzed condensation of the resultant aldehyde with nitroethane. Then, hydrogenate both the double bond and nitro group. $\endgroup$ – user55119 Apr 26 '20 at 17:56
  • $\begingroup$ Thank you for that thought. I do not have any database access so cannot check a lot of reactions. I am not a fan of hydrogenating aliphatic nitro groups as they give low yields in my experience. $\endgroup$ – Waylander Apr 26 '20 at 18:00
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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.


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.

enter image description here

*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.

enter image description here

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"
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  • $\begingroup$ thanks for taking intrest on my question. I just had one doubt regarding the Decarboxylation of compound 37.1.1.6. I know that picolinic acid will be decarboxylated on heating will the same happen with this $\endgroup$ – An enthusiast Apr 26 '20 at 11:21
  • $\begingroup$ @Adithya Yes, it should but then again, I am no expert in organic chemistry. Let other expert users clarify this. HCQ is a burning topic nowadays and I believe it will attract more people :) $\endgroup$ – Nilay Ghosh Apr 26 '20 at 11:31
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    $\begingroup$ 5-Chloropentan-2-one is accessible from levulinic acid, 4-oxopentanoic acid. chemistry.stackexchange.com/questions/126004/… $\endgroup$ – user55119 Apr 26 '20 at 15:44

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