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.

Keywords: API synthesis; N′,N″-dibenzylethylene diamine diacetate; amidation; cephalosporin; deformylation; process chemistry; sustainability.

Figure 1

7-ACA structure.

Figure 2

Amidation of OCA (2) from (R)-mandelic acid (1) and 7-SACA or 7-TACA intermediate (3).

Figure 3

DOX, methyl-DOX, and ethyl-DOX.

Figure 4

OCA decarboxylation.

Scheme 1

New protocol to obtain cefonicid benzathine salt (6).