Enabled Process To Synthesize Monobactam 1 for Early Development

摘要

An efficient process to synthesize Monobactam 1 from intermediates 2, 3, and 4 was developed. The process was initially enabled to deliver 500 g of 1 for exploratory toxicity studies and further improved to facilitate kilogram-scale production of the active pharmaceutical ingredient with enhanced quality and throughput. Highlights of the process encompass utilizing 1,1'-carbonyldiimidazole to construct a urea linker with good selectivity, oxidative cleavage to remove a 2,4-dimethoxybenzyl protecting group, two activation methods to form an amide bond, a high yielding reaction to introduce N-sulfonic moiety, and a global deprotection to remove all protecting groups. Practical procedures were developed to isolate intermediates en route by adding a concentrated substrate to antisolvents to obtain filterable amorphous solids with partial purification. Amberchrom CG161M resin was applied not only as a "resin-capture-release" tool to remove the bulk amount of water but also as an effective method to purify 1. Finally, a process isolating 1 pentahydrate (1 center dot 5H(2)O) as a crystalline solid from the acidic aqueous solution was developed based on zwitterionic crystallization methodology.