Some Items of Interest to Process R&D Chemists and Engineers

Abstract

A review from process chemists Martin Eastgate and Michael Schmidt at Bristol-Myers Squibb and Keith Fandrick at Boehringer Ingelheim highlights the importance of synthetic strategy and the need for the development of new chemistry during process development (Nat. Rev. Chem. 2017, 1 (16), 1). Arguing strongly in favor of " disruptive innovation " , the authors highlight examples from their respective companies where the development of new reactions and processes resulted in a step change in synthetic efficiency compared to previous routes. Detailed case studies include JAK2 inhibitor BMS-911543, NRTI BMS-986001, HIV attachment inhibitor BMS-663068, and Pfizer's smoothened inhibitor PF-04449913. The review contains 55 references. ■ CONVERSION OF tert-BUTYL ESTERS TO ACID CHLORIDES USING THIONYL CHLORIDE Sammakia and co-workers at the University of Colorado at Boulder have described the direct conversion of tert-butyl esters into acid chlorides using thionyl chloride (J. Org. Chem. 2017, 82, 3245). The reaction is clean and high yielding, and other esters even isopropyl and benzylare unreactive under the conditions. Although 10−20 equiv of thionyl chloride were required, the reaction could generally be performed at room temperature, and the acid chloride can be obtained as a toluene solution after azeotropic removal of the unreacted thionyl chloride. A number of different functional groups and protecting groups were tolerated, and the reaction could also be performed on an amino acid derivative with minimal erosion of the enantiopurity. The method was developed when an acid chloride was required whose parent carboxylic acid was difficult to isolate, and it is potentially useful in similar cases or in telescoped reaction sequences.