Chemists simplify synthesis of drugs involving amide groups

Chemists from HSE University and the Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences (INEOS RAS) have developed a new method for synthesising amides, essential compounds in drug production. Using a ruthenium catalyst and carbon monoxide under precisely controlled reaction conditions, they successfully obtained the target product without by-products or complex purification steps. The method has already been tested for synthesising a key component of Vorinostat, a drug used to treat T-cell lymphoma. This approach could lower the cost of the drug by orders of magnitude. The paper has been published in the Journal of Catalysis. The study was supported by the Russian Science Foundation.

The amide bond is one of the fundamental bonds in chemistry. It forms during protein and peptide synthesis through a reaction between the α-amino group of one amino acid and the α-carboxyl group of another. This bond is present in substances used for drug production, as well as in many other compounds essential to medicine and materials science. However, its synthesis remains challenging, as conventional methods require multistep reactions, involve toxic reagents, and generate waste that must be properly managed. 

Chemists at HSE University and INEOS RAS have proposed an alternative synthesis approach in which nitroarenes—aromatic compounds with a nitro group (-NO₂) widely used in industry—are converted into amides in a single step. The reaction is highly efficient and does not generate by-products. The key element of the method is the catalyst, a ruthenium cluster compound, Ru₃(CO)₁₂, which accelerates the reaction and enables it to be performed with an exceptionally low metal content of just 16 ppm. 

'This means there are only 16 molecules of the catalyst per million molecules of the reagent. In fact, we use 62,500 times less catalyst than the amount of product,' comments Mikhail Losev, student at the HSE Faculty of Chemistry.

A reducing agent—a substance that donates electrons to other molecules, altering their structure—also plays a crucial role in the reaction. In this method, carbon monoxide (CO) acts as the reducing agent, facilitating the conversion of nitroarenes into amides without the need for additional reagents. Carbon monoxide has traditionally been viewed as a dangerous byproduct, but the scientists have demonstrated that it can be used as a valuable reagent in chemical synthesis. As a result, the process becomes more environmentally friendly and efficient: the reaction occurs without generating solid waste, and the resulting compounds do not require complex purification.

Typically, amides are produced in several steps. First, nitroarenes are converted into anilines. Then, carboxylic acids are made more chemically reactive using chloroanhydrides or carbodiimides. Only after that are the anilines combined with the acids to form amides.

'In conventional methods of amide synthesis, new reagents had to be added at each step, complicating the purification process and generating waste. We have managed to overcome these challenges: the reaction occurs in a single step, without unnecessary substances or by-products, and in some cases, the resulting product requires no further purification,' explains Denis Chusov, Professor at the Joint Department of Organoelement Chemistry with the Nesmeyanov Institute of Organoelement Compounds (RAS) of the HSE Faculty of Chemistry.

The scientists investigated how the reaction rate changes and which factors influence it, including the concentration of substances, temperature, and catalysts. It was found that initially, the reaction rate depends on the concentration of nitroarenes, as the subsequent reaction of aniline with acid activates the process. Later, the main limitation on the reaction rate is the regeneration of water, which is necessary to reduce the original nitroarene. This data not only helps increase the product yield but also enables the method to be adapted for industrial applications. 

'We tested the method in synthesising a key component of Vorinostat, a drug used to treat T-cell lymphoma,' notes Mikhail Losev. 'Our approach enabled us to obtain a compound with 99% purity without additional purification, while also reducing the amount of generated waste by orders of magnitude. According to our estimates, the cost of the drug using this synthesis could drop to less than one dollar per gram, whereas the current cost of Vorinostat from major suppliers can reach several hundred dollars per gram.'