Enabled Process To Synthesize Monobactam 1 for Early Development

Abstract

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•5H 2 O) as a crystalline solid from the acidic aqueous solution was developed based on zwitterionic crystallization methodology.

Potential Safety Hazards Associated with Using N,N-Dimethylformamide in Chemical Reactions

“…Sulfur trioxide (SO 3 )–DMF complex has found wide applications as a sulfonation reagent and been employed in large scale N-sulfations . However, it has been reported that a bottle of SO 3 –DMF complex exploded during storage .…”