Design and development of efficient synthetic strategies for novel β-lactam enhancer WCK 5153 effective against gram-negative pathogens

• Published in: Results in Chemistry Vol. 7; p. 101485
• Main Authors: Bhavsar, Satish, Pawar, Shivaji, Joshi, Sanjeev, Jadhav, Sunil, Mishra, Amit, Dond, Bharat, Kayastha, Abhijeet K, Yeole, Ravindra, Deshpande, Prasad, Bhagwat, Sachin, Patel, Mahesh
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2024; Elsevier
• Subjects: Antibacterial; Chiral separation; Crystallization; Itaconic acid; WCK 5153; Itaconic acid; Antibacterial; WCK 5153; Chiral separation; Crystallization
• ISSN: 2211-7156; 2211-7156
• DOI: 10.1016/j.rechem.2024.101485

[Display omitted] Continuous evolution in bacterial strains confines utility of frontline antibacterial agents due to development of multiple resistance mechanisms. Especially gram-negative multidrug bacterial resistance is foremost important topic of concern. The current manuscript details the development of different synthetic strategies for stereo-controlled synthesis of WCK 5153, a specific and high-affinity PBP2 binding, novel β-lactam enhancer (BLE) discovered through systematic structure activity (SAR) relationship. Earlier the synthesis of parent i.e. diastereomeric mixture WCK 5133 achieved from benzyl amine and chloromethyl trimethyl silane. Subsequently preparative HPLC helped to separate the diastereomers as WCK 5153 and WCK 5154 from parent WCK 5133. Based on potency differences synthesis of side chain for chiral isomer WCK 5153 accomplished through reaction of methyl itaconate and (R)-phenyl ethylamine to get optically pure methyl 5-oxo-1-((R)-1-phenylethyl) pyrrolidine-3-carboxylate. For removing the hurdle of chromatographic separation, crystallization of diastereomeric side chain; at acid intermediate, 5-oxo-1-((R)-1-phenylethyl)-R,S)-pyrrolidine-3-carboxylic acid was achieved. Reaction of Itaconic acid and (R)-phenyl ethylamine in methanol at 80 °C created an opportunity for separation through crystallization. This methodology completes the stereoselective synthesis of requisite hydrazide side chain in 11-steps.