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Synthetic route to hydroxychloroquine
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Md Abdul Motin
Synthetic route to hydroxychloroquine
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.
*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
Hydroxychloroquine and Chloroquine articles respectively of ScienceDirect.com. Original reference is "Drugs for Treating Protozoan Infections by R.S. Vardanyan, V.J. Hruby, 2006"
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.
*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
Hydroxychloroquine and Chloroquine articles respectively of ScienceDirect.com. Original reference is "Drugs for Treating Protozoan Infections by R.S. Vardanyan, V.J. Hruby, 2006"
@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 :)More
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 thisMore
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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.
Reference
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
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
Manuel Orlandi, Davide Brenna, Reentje Harms, Sonja Jost, and Maurizio Benaglia, Organic Process Research & Development 2018 22 (4), 430-445DOI: 10.1021/acs.oprd.6b00205
@NilayGhosh I didnt 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 thats all.More
@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.More
@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.More
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.More
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.
*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
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.
*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
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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.
Reference
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
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