Cefonicid Benzathine Salt: A Convenient, Lean, and High-Performance Protocol to Make an Old Cephalosporin Shine

Abstract

Cefonicid is a second-generation cephalosporin sold under the brand name Sintocef™. It is an injectable drug obtained via a freeze-drying process and is also available for oral preparations. The high-quality standard required is very challenging to satisfy, and current production protocols are characterized by steps that are lengthy and cumbersome, making the product unattractive for the international market. Industrial R&D is constantly working on the process optimization for API synthesis, with the aim of increasing productivity and decreasing production costs and waste. We herein report a new and efficient method for the synthesis of the cefonicid benzathine salt that provides a good yield and high product stability. The double-nucleophilic and lipophilic nature of N′,N″-dibenzylethylene diacetate enables the deformylation of the OH-protected group on the mandelic moiety and also enables product crystallization to occur. We demonstrate that the formyl group in the peculiar position has high reactivity, promoting an amidation reaction that deprotects a hydroxy group and generates a new C-N bond in the reaction by-product. Several amines and OH-protected groups have been studied, but none were able to replicate the excellent results of benzathine diacetate.

Towards Antibiotic Synthesis in Continuous-Flow Processes

“…We have covered the period of 2012–2022, as we highlight the key points and merits of applying this new technology for these important drugs. Most of the small molecules studied are off patent, are characterized by chemistry that was developed many years ago and have only been relaunched in some cases [ 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. We hope that flow chemistry can revive them with renewed vigor.…”

From Batch to the Semi-Continuous Flow Hydrogenation of pNB, pNZ-Protected Meropenem

“…In addition, the FDA and the European Medicines Agency (EMA) have strongly encouraged the study and implementation of this innovative, sustainable and environmentally friendly technology in API synthesis [ 95 , 96 ]. β-lactam chemistry has remained anchored to developments from many years ago and has only recently achieved renewal in a few cases [ 97 , 98 ]. With this revolution in place, MW-assisted flow chemistry could really upend acquired certainties in the near future.…”