Molnupiravir Powder CAS 2349386-89-4

Synthesis method of Molnupiravir

As a new generation of anti-COVID-19 products, Molnupiravir has recently been reported to effectively reduce the hospitalization and mortality of infected patients. The product has the advantages of high metabolic stability, high bioavailability, high lung distribution rate, broad spectrum and low toxicity. The compound was originally developed by Merck, and the synthetic route was developed in 2019. The highest yield was only 17% in five steps. The team of Professor Li Zhiyu, Dean of School of Pharmacy, China Pharmaceutical University, published a short message in the 11th issue of English Journal of Pharmacy in 2021 to study the synthesis process of molnupiravir, in order to obtain a route that is easy to scale up, simple to operate and more economical.

In the research process, through exploring the reaction conditions, the key hydroxylamine intermediate can be obtained through one-step condensation reaction, which avoids the problem of complicated operation and low yield in the original route. In addition, during the final hydrolysis of protecting groups, the author found that trifluoroacetic acid can remove acetone fork with high yield and high selectivity. The final synthetic route has the advantages of easily available raw materials, mild reaction conditions, simple operation, high yield and easy industrial production.

references：

Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning

Zhen Qin, Bin Dong, Renbing Wang, Dechun Huang, Jubo Wang*, Xi Feng, Jinlei Bian*, Zhiyu Li*

Acta Pharm Sin B 2021;11(11):3678-3682

What is the mechanism of action of Molnupiravir?

Cytosine nucleoside is the basic raw material for RNA synthesis.

Molnupiravir powder is an analog of cytosine nucleoside, which will be mistaken for cytosine nucleoside by viral RNA polymerase (RdRp) and embedded in newly synthesized RNA, causing "lethal mutation" making the virus unable to replicate further.

Molnupiravir is the same as endogenous cytosine nucleoside.

Molnupiravir and its active metabolite (NHC) are not the main inhibitors or inducers of drug-metabolizing enzymes and transporters.

Molnupiravir is a compound similar to Remdesivir, and both products work by mimicking ribonucleotides (the main components of RNA molecules). During the process of virus replication, the molecules of these drugs can be mixed into the viral RNA chain to replace the nucleic acid base sequence generated during the original normal replication of some viruses, causing errors in the nucleic acid sequence of virus replication, and the accumulation of these fatal nucleic acid alignment errors, that is, differential mutation, can finally prevent virus replication, amplification and spread.

What is the difference between remdesivir, Molnupiravir and Paxlovid?

At present, there are three recognized products for treating COVID-19 in the world, namely Remdesivir developed by Gilead, Molnupiravir developed by Merck and Paxlovid developed by Pfizer. These products all have antiviral effects and are used to inhibit the replication of Covid-19 in human body, but their pharmacological effects are different.

1. Molnupiravir

Molnupiravir powder can pair with A and G at the same time, so it will make the transcription of the virus wrong and turn into other RNA chains. The clinical data of Molnupiravir can reduce the severe disease rate and mortality rate by 50%, and the effect is good. However, the risk of this product is that there is a certain chance of mutating into a new and more powerful virus after the virus disaster, and this product may also participate in normal DNA replication and cause genetic mutation in the human body itself. Therefore, under the condition that the risk of this product is not conclusive, doctors are more cautious in using it, and it is also forbidden for pregnant women to use it.

2.Paxlovid

Paxlovid is actually a combination of two products (Paxlovid/Ritonavir). Paxlovid inhibits virus replication by inhibiting the activity of a protease, but Paxlovid is easily metabolized by P450 enzyme, so Ritonavir should be used to inhibit the activity of P450 enzyme to maintain the concentration of Paxlovid in blood. There are many taboos in the use of Paxlovid, because many things depend on P450 enzyme metabolism, so when using Paxlovid, we should stop using these products or find substitutes, and people with poor liver and kidney function had better not use them. However, Paxlovid has the best data in clinical trials, which can reduce the serious illness rate and mortality rate by 90%, so it is the first choice to treat COVID-19.

3.Remdesivir

Simply put, Remdesivir will be transformed into GS-441524 after entering human body, disguised as nucleotide, and compete with other nucleotides to participate in virus replication. When GS-441524 molecule is inserted into the transcription product, the transcription will be terminated early, thus inhibiting the transcription process of virus RNA. However, the data of Remdesivir in clinical trials is not very good, and it has little effect on the severity rate and mortality rate, but it will shorten the course of disease and get better faster.

Many cat owners should be familiar with Remdesivir. The famous life-saving drug GS-441524, which is also a coronavirus, is redesivir after phosphorylation.

According to the pharmacology of the above three products, it can be seen that the principles of Remdesivir and Molupiravir are similar, both of which interfere with virus replication. In theory, Molupiravir should also be used to treat cat abdominal transmission, and the effect should be better. So some people abroad really tried to use Molupiravir to treat cat abdominal transmission. According to an article by FIP Warriors, they obtained a data from a Molupiravir manufacturer, which included 286 cases of cat abdominal transmission from all over the world, of which 28 cases were cured after using Molupiravir for six weeks, 258 cases were cured after using Molupiravir for eight weeks, no one died, and there was no recurrence after 3-5 months.