Efficient Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate YG-056SP

Abstract

The development of an improved kilogram-scale synthesis of a novel oxazolidinone antibacterial candidate YG-056SP for the treatment of multidrug-resistant Gram-positive bacterial infection is described. The new process is highlighted by a step economical construction of the chiral N-methyloxazolidone, employing an asymmetric reduction of the carbonyl and methylamine substitution, followed by the cyclization with N,N′-carbonyldiimidazole. Another highlight is the safe construction of the fused ring with high optical purity. Epoxy intermediates were obtained by intramolecular ring closure, and reacted with phenol fragments, followed by reduction, protection, and an intramolecular tandem reaction to afford the fused ring. The endgame process features the completion of the Miyaura reaction and the Suzuki coupling reaction in one pot and tert-butyldimethylsilyl deprotection to make dibenzyl phosphate. Finally, cheap hydrochloric acid was used to deprotect the benzyl group, which delivered YG-056SP with a defined particle-size distribution suitable for preclinical studies after crystal transformation. Compared with the initial synthetic route, the overall yield of this optimized process increased significantly from 2.3 to 29.6%.