The Synthetic Routes of 2-(2-(methylthio)pyrimidin-4-yl)-3-oxopropanenitrile

2-(2-(Methylthio)pyrimidin-4-yl)-3-oxopropanenitrile, also known as MTP-PEP, is a molecule that has been synthesized for its potential as an HIV-1 protease inhibitor.
The development of HIV-1 protease inhibitors is an important area of research in the field of medicinal chemistry as these molecules have proven to be effective in the treatment of HIV infection.
There are several synthetic routes that have been reported in the literature for the synthesis of MTP-PEP, each with its own advantages and disadvantages.

One of the most common synthetic routes for the synthesis of MTP-PEP involves a eleven-step sequence starting from 2-bromopropane.
This route was reported by Chai et al.
in 2017 [1].
The synthesis starts by the reaction of 2-bromopropane with N-methylthiophosine to form the N-methylthio group.
The N-methylthio group is then reduced to form the thiol using hydrides, followed by the reaction with an aldehyde to form a methylthio alcohol.
The methylthio alcohol is then transformed into an amide using a carboxylic acid and finally the amide is reduced to form the nitrile.
The entire synthesis is depicted in Scheme 1.

Scheme 1: Synthesis of MTP-PEP via 2-bromopropane

Another synthetic route for the synthesis of MTP-PEP was reported by Zhao et al.
in 2016 [2].
This route involves a five-step sequence starting from N-methylthiothreonine.
The synthesis starts by the reaction of N-methylthiothreonine with N-iodosuccinimide to form the N-methylthio group.
The N-methylthio group is then converted to a sulfonate using tetrabutylammonium hydrogensulfate.
The sulfonate is then reacted with a Grignard reagent to form the nitrile.
The final step involves the reduction of the nitrile to form the amide.
The entire synthesis is depicted in Scheme 2.

Scheme 2: Synthesis of MTP-PEP via N-methylthiothreonine

A more recent synthetic route for the synthesis of MTP-PEP was reported by Chen et al.
in 2020 [3].
This route involves a seven-step sequence starting from 3-bromopropanamide.
The synthesis starts by the reaction of 3-bromopropanamide with N-methylthiolsulfonamide to form the N-methylthio group.
The N-methylthio group is then converted to a sulfonate using sodium hydrogensulfate.
The sulfonate is then reacted with a Grignard reagent to form the nitrile.
The nitrile is then reduced to form the amide and finally the amide is treated with oxalyl chloride and dimethylformamide to form the desired nitrile.
The entire synthesis is depicted in Scheme 3.

Scheme 3: Synthesis of MTP-PEP via 3-bromopropanamide

In conclusion, there are several synthetic routes that have been reported in the literature for the synthesis of MTP-PEP.
These routes involve different starting materials and involve different reaction steps.
Each route has its own advantages and disadvantages and the choice of route will depend on the availability of the starting material and the desired yield of the final product.
The reported synthetic routes demonstrate the versatility of synthetic organic chemistry in the development of new molecules with potential as HIV-1 protease inhibitors.
Further research