A catalyst to create green pharmaceuticals
An international research team, led by Singapore’s Agency for Science, Technology and Research (A*STAR), has developed a more sustainable approach to a bond-forming reaction used in the pharmaceutical and fine chemical industries. The team used the solvent-free, catalytic reaction to produce high yields of a wide range of amides.
“Amide groups are widely found in pharmaceuticals,” said Anqi Chen from the A*STAR Institute of Chemical and Engineering Sciences. Examples include the antidepressant moclobemide, the cholesterol-lowering drug Lipitor, the anticancer drug Velcade and the anti-HIV drug Isentress.
Current routes used to synthesise amide-containing molecules are expensive and generate lots of waste, prompting the need for cheaper, greener approaches. An attractive alternative to conventional methods is transamidation - the catalytic reaction of a primary amide with an amine to make a secondary or tertiary amide. Ammonia is the only by-product of the process.
The team sought to demonstrate that the solid-state catalyst mesoporous niobium oxide is suitable for transamidation in the absence of solvents. The catalyst is simple and inexpensive to synthesise and does not require any noxious solvents. It has a highly regular spherical structure with a diameter of approximately 500 nm and acidity comparable to that of sulfuric acid. Team members at the National University of Singapore (NUS) had previously developed the catalyst for other reaction types.
The team tested the catalyst in reactions of a wide range of primary amides with various primary and secondary amines. Writing in the journal Advanced Synthesis & Catalysis, the researchers said the process provided “N-alkyl amides in good to excellent yields”. The team also used the catalyst to synthesise moclobemide and other drug-like molecules in gram quantities with excellent yields.
“Compared with other reported transamidation catalysts, the niobium catalyst has the advantages of a broad substrate scope, a good functional group tolerance and high yields of amide products,” said Chen.
“The catalyst can also be conveniently recovered after the reaction and re-used several times without appreciable loss of activity.”
The researchers believe the only downside of the process is that the reactions require a relatively high temperature - around 150°C. Thus, said Chen, “The promising results from this work should promote the development of more efficient catalysts that allow this valuable transformation to be carried out at lower temperatures to facilitate its application.”
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