Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor

Abstract

The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late-stage functionalization approach. An alternative synthesis was developed to satisfy the short-term material need for toxicological studies in animals. The new synthetic strategy was built on two key features, an intramolecular azomethine ylide [3 + 2] cycloaddition that allowed the efficient formation of molecular complexity from readily available starting materials and an enzymatic resolution that resulted in high optical purity of a key intermediate.

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…The discovery route for IID572 started from the carboxylic acid 17 derivative over eight steps to reach the final product with 0.9% overall yield [48,74]. A scale-up synthesis of the compound was recently developed from readily available materials over 19 steps, resulting in an overall yield of 1.7% [75] (Schemes 9 and 10). According to Scheme 9, the Boc protection of 2-(benzylamino)acetic acid (39) was achieved in quantitative yields followed by the coupling of the resultant compound with commercially available allylbenzylamine to obtain compound 40.…”

“…NaOH. The separation of the required enantiomer 44 was achieved by QLM lipase in high enantiomeric purity [75]. After the successful isolation of the pure enantiomer 44, Scheme 10 is followed to convert it to the target compound.…”

“…Thus, an intermediate alcohol 48 was obtained and then reacted with N-(benzyloxy)-2-nitrobenzenesulfonamide to form compound 49, which, after Boc deprotection, was converted to 51 after cyclic urea formation by phosgene. The benzyl deprotection in 51 followed by the sulfonation, solvation of the complex with tetrabutyl ammonium salt, and its subsequent exchange by Na yield the target compound IID572 [75] (Scheme 10). After the successful isolation of the pure enantiomer 44, Scheme 10 is followed to convert it to the target compound.…”