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Intensified azeotropic distillation – A novel, industrially viable approach to direct amidation

*Corresponding author
1. School of Chemical Engineering and Advanced Materials, Merz Court, Newcastle University, Newcastle-upon-Tyne, NE1 7RU, United Kingdom
2. LyraChem Ltd. St Thomas Street Stables, St Thomas Street, Newcastle-upon-Tyne, NE1 4LE, United Kingdom


Intensifying the boil up rate of azeotropic reactive distillation offers a novel and industrially viable means of increasing the rate of condensation reactions. The strategy can be as effective as using a catalyst and may lend itself to continuous operation. When applied to the condensation of carboxylic acids and amines such intensification provides an environmentally-benign route to a variety of amides. The impact of intensified azeotropic distillation on direct amidation using both a production scale batch reactor and a cascade of CSTRs is discussed and compared.


Amide bond formation is one of the ubiquitous reactions of Nature. It is also present in the synthesis of nearly two thirds of drug candidates in the pharmaceutical industry (1). Traditionally amide synthesis is achieved via carboxylic acid activation (e.g. acyl chlorides or mixed anhydrides) or with the help of a coupling agent (2). However, in both cases, poor atom economy is achieved, stoichiometric amounts of wastes are generated and the routes involve several process operations. Consequently it comes as no surprise that amidation was voted as a priority research area for improvement by the ACS Green Chemistry Institute Pharmaceutical Roundtable (3). Recent progress in catalysed direct amidation utilising the corresponding carboxylic acids and a