Water-Compatible Acylation Reactions with Acid Chlorides Using a Flow Microreactor

Abstract

In this study, we used a flow microreactor for acylation with acid chlorides in a homogeneous aqueous medium, suppressing hydrolysis and providing up to 87% yield. Quenched-flow analysis indicated an associative transition state. This method applies to amines, phenols, thiols, and pharmaceuticals. Acylation of oseltamivir proceeds with a throughput of 2.1 g h -1 , demonstrating scalability and practicality.Condensation reactions that form amide bonds are essential in medicinal chemistry and peptide synthesis (Figure 1A). [1][2][3] According to recent analyses, amide bond formation reactions account for approximately 16% of all the transformations used in the synthesis of new drug candidates, which indicates their importance in drug discovery. 4 Although amidation is usually carried out in organic solvents, interest in aqueous media has been increasing, especially for reactions with water-soluble compounds such as pharmaceuticals and biomolecules. [5][6][7][8][9][10][11][12][13][14] From the viewpoint of green chemistry, aqueous systems are considered more environmentally friendly and practical. Activated esters and condensation reagents are often used for amidation in water; however, many of them have low reactivity and require long reaction times. 12,15,16 Therefore, the development of highly reactive reagents for rapid amide bond formation in aqueous media is strongly desired.