Development of Novel Methods for Preparing Chiral Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) by Asymmetric Esterification

Abstract

A novel and efficient method for preparing chiral 2-arylalkanoic acid derivatives, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and naproxen, and their esters by asymmetric esterification is presented in this paper. A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic 2-arylalkanoic acids with achiral alcohols, using carboxylic anhydrides in the presence of chiral acyl-transfer catalysts. It was found that the combination of the modified benzotetramisole-type catalyst, (S)-β-Np-BTM, and a newly designed nucleophile, di(α-naphthyl)methanol, in the presence of a carboxylic anhydride, p-methoxybenzoic anhydride (PMBA) or pivalic anhydride (Piv₂O), is most suitable for producing the corresponding chiral esters from 2-arylpropionic acid derivatives, with high enantiomeric excess under very mild reaction conditions. Using this new chiral acylation system, fairly broad substrate scope could be realized despite the multi-functional groups on the aromatic ring of the substrate. It was also revealed that ortho-substituted aromatic compounds, especially, 2,5-disubstituted aromatic ones were the most suitable compounds for providing a high selectivity.