Sciencemadness Discussion Board

A theoretical total synthesis of chloroquine I thought up this afternoon

DrIronic101 - 19-3-2020 at 16:34



Attachment: chloroquine write-up.pdf (560kB)
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Dr.Bob - 19-3-2020 at 18:35

It is a reasonable route to consider. In step 3, 7-chloro-4-hydroxyquinolin, you are missing the key reagent, ethyl 3-ethoxybut-2-enoate, which is what builds the second ring. The ethyl benzoate is the solvent, not a reactant. Then there are a few more steps there to get to 7-chloro-4-hydroxyquinolin from the initial product.

One source claims that a similar compound is more effective and/or safe, which has a different side chain with a hydroxyl group instead of the dimethylamine.

From wikipedia:
"Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19,[48][49][unreliable medical source?] although these agencies noted important contraindications for people with heart disease or diabetes.[50][unreliable medical source?] In February 2020, both drugs were shown to effectively inhibit COVID-19 in vitro,[43]

but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.[51 - Yao, Xueting; Ye, Fei; Zhang, Miao; Cui, Cheng; Huang, Baoying; Niu, Peihua; Liu, Xu; Zhao, Li; Dong, Erdan; Song, Chunli; Zhan, Siyan. "In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)". Clinical Infectious Diseases. doi:10.1093/cid/ciaa237.]

Preliminary results from a multicenter trial, announced in a press conference, suggested that chloroquine is effective and safe in treating COVID-19 associated pneumonia, "improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course."[46]"

see also https://en.wikipedia.org/wiki/Hydroxychloroquine for more info:

"Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the treatment COVID-19.[31] [32] In vitro studies have demonstrated that hydroxychloroquine is more potent than chloroquine against SARS-CoV-2 with a more tolerable safety profile.[33]

On 16 March 2020, advisor to the French Government on COVID-19, Professor Didier Raoult, announced that a non-randomized unblinded trial[34] involving 24 patients from the south east of France supported the claim that hydroxychloroquine was an effective treatment for COVID-19.[35] The trial is yet to be peer-reviewed.[34] An amount of 600 mg of hydroxychloroquine (brand name Plaquenil) was administered to these patients every day for 10 days. They reported "a significant decrease in viral load".[34] The drug appeared to be responsible for a "rapid and effective speeding up of their healing process, and a sharp decrease in the amount of time they remained contagious".[36] 70% of patients were "considered cured", compared with 12.5% of those who did not receive hydroxychloroquine and azithromycin combination.[34] The antibiotic azithromycin - which is known to be effective against secondary infections from bacterial lung disease - led to even better outcomes. Professor Raoult said the results showed there was "a spectacular reduction in the number of positive cases" with the combination therapy. At 6 days, among patients given combination therapy, the percentage of cases still carrying SARS-CoV-2 was no more than 5%.[37][38]

On March 17 after testing in several hospitals around Italy the Italian Pharmaceutical Agency has included hydroxychloroquine in the list of drugs with positive preliminary results for treatment of coronavirus disease 2019.[39] "

Also, here are a few routes to chloroquine I found quickly, which mostly gow through 3-chloroaniline also, like the proposed route.


https://ars.els-cdn.com/content/image/3-s2.0-B97804445216685...

https://www.sciencedirect.com%2Ftopics%2Fchemistry%2Fchloroq...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749251/


AvBaeyer - 19-3-2020 at 19:15

Bob,

I am very curious about how the chloroquine compounds actually work. I had a good deal of experience working with these and similar compounds in my drug discovery days related to projects on secreted peptides and proteins. As it turns out (and is well known) chloroquine, which is a basic molecule, accumulates in acidic vesicles (eg lysomomes, transport vesicles and the like) and alters their internal pH. This in turn appears to alter intracellular transport of various cellular biomolecules which are transported along the cytoskeleton in these acidic vesicles usually for the purpose of secretion out of the cell. For me, this begs the question of what is happening to the virus inside the cell. Is it simply being trapped in the cell because transport mechanisms which it may use to escape the cell are being inhibited or is it being trapped AND destroyed? Measurement of plasma virus levels will not answer this question.

I wonder if a result similar to that of chloroquine/hydroxychloroquine would be observed in vitro with known proton pump inhibitors. Proton pumps transfer protons from the cytoplasm into the acidic vesicles to maintain their acidic pH. Since chloroquine is rapidly taken up in acidic vesicles it simply overwhelms the ability of the acidification mechanism.

Just some preliminary thoughts.

AvB

Dr.Bob - 20-3-2020 at 17:46

There are a few theories in the papers I saw, and there are new ones every day, but that is out of my area, so I can't intelligently comment on if any seem reasonable. I mostly did receptor ligands, so those I know, but I don't know if the anti-viral effect is by the same mechanism as the anti malaria effect, or another different mode. I have seen the pH change discussed in some of them, but did not see any evidence that I could understand. At least one paper discussed some inhibition of viral protein synthesis, I think, but not sure. But if it works, I am all for it, and happy to make some if needed, but at least there are good supplies of chloroquine and its derivatives.

clearly_not_atara - 20-3-2020 at 18:35

The problem with chloroquine as an antiviral therapy is that it tends to inhibit the host immune system just as much or more than it inhibits the virus. When chloroquine is used against malaria this doesn't matter because the immune response to malaria is generally not very effective anyway. I do not expect chloroquine itself to be useful in humans against coronavirus. However, derivatives of chloroquine may prove effective. I would be happy to be proven wrong. See:

https://umsu.ac.ir/uploads/165.pdf

Also, I don't think remdesivir is as hard to make as you're making it out. Triprotected sugars are common synthetic precursors and apparently alanine esters add only once to phenyl dichlorophosphate, based on what the Wikipedia synthesis shows.

With that said, I also don't expect anybody here to reasonably compete with professional chemists in the large-scale synthesis of antivirals. Even ignoring the question of education, we're just not used to working with the reagents they use; I don't have any intuition for whether some kind of ligated iridium complex would be a good idea for some reaction because I literally never think about those kinds of methods. Again, I would be happy to be proven wrong.

Dr.Bob - 21-3-2020 at 06:52

You would be surprised how many times new routes to compounds have come from small companies or individuals. Often they simply think of a better way to do a certain portion of the reaction, which avoids a bad step or protecting group. Sometimes it is just a whole new route from a more readily obtainable starting material. But professionals are not that much different from most of the people here. (I'm theoretically a professional, and the amount of chemistry that I don't know is frightening.) I have found new routes to compounds before, but often they just used an entirely different approach that avoided some issue from the previous way. Certainly, there are some groups that have done amazing things, like scale up new complex drugs in good yields, but often for simpler compounds, there is a way to go from 5 or 7 bad steps to 2 or 3 with some luck and planning.

Sigmatropic - 21-3-2020 at 09:40

Do you have some literature on the reaction your using to make the dichloroquinolone? It seems to me that reaction requires a dehydrative chlorinating agent (POCl3 and the like).

For an alternative check out phoshonium couplings (https://en.m.wikipedia.org/wiki/Phosphonium_coupling) for those two steps.

Fery - 21-3-2020 at 14:37

chloroquine + azithromycine combination should be helpful although it is not casual treatment (antivirotic)
chloroquine and hydroxychlorquine are used to treat not only malaria but also SLE (systemic lupus erythematosus) where immunosupressive effect is used - clearly_not_atara already pointed out to the immunosupressive effect
sometimes the virus itselt does not cause such devastating effect as the overreacting immunity trying to fight the virus - in this case it is necessary to partially suppress immunity for preventing immunity from destroying respiratory system
also some expectorants (acetylcysteine, ambroxol etc) could be helpful but again not casual treatment

Dr.Bob - 23-3-2020 at 16:35

There are a number of places looking at both chloroquine and hydrochloroquine as part of their CV therapy, and there are now shortages anticipated, so this is a real area of interest. I may look and see if I can find the right SMs to start, but a few might be tougher. The 3-chloroaniline should be easy to find, then the rest will be a bit harder.

There are now shortages of pretty much every drug that might have any effect as an anti-viral. Gilead has said that it cannot possibly provide enough for all of the requests for remdesivir that they have, so other sources are going to be needed, although it is not yet approved, so tough to do by normal channels. I don't think people understand how hard it is to scale up drugs over their "normal" amounts, as the equipment and skills to do that are not insignificant, although their are some compounds which might be easier to scale up. Having tried to scale up compounds before, I know it is not easy, but it is possible with a few weeks to make many compounds in 100 g amounts. I have even seen undergrad labs prepare real amounts of a few compounds for real research purposes (after better purification).

Here is another good post on the chloroquines:

https://blogs.sciencemag.org/pipeline/archives/2020/03/20/ch...

[Edited on 24-3-2020 by Dr.Bob]

DrIronic101 - 24-3-2020 at 15:08

Quote: Originally posted by Sigmatropic  
Do you have some literature on the reaction your using to make the dichloroquinolone? It seems to me that reaction requires a dehydrative chlorinating agent (POCl3 and the like).

For an alternative check out phoshonium couplings (https://en.m.wikipedia.org/wiki/Phosphonium_coupling) for those two steps.


I believe you're right on that note.

Dr.Bob - 26-3-2020 at 09:18

Here are some of the routes to hydroxychloroquine

Attachment: Hydroxychloroquine_Reaction_03_26_2020_131402.pdf (274kB)
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