Development of a Second-Generation Process to Antibacterial Candidate Sulopenem

Abstract

The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium.

Development of a Practical and Convergent Process for the Preparation of Sulopenem

“…To enable early alignment of suppliers for custom raw materials, 4-acetoxyazetidinone ( 9 ) and the proprietary chiral sulfoxide 10 were selected as building blocks for all potential commercial processes (Figure ). Furthermore, we committed to targeting the late-stage thiopenem intermediate 8 , since the end-game chemistry for conversion of this compound to sulopenem ( 1 ) was well-established by the first- and second-generation syntheses . Conserving the same end-game strategy also minimized the potential for introducing new process-related impurities.…”

“…Difficulties in the construction and handling of starting materials for a key transformation complicated the vinyl halide cross-coupling and intramolecular imine formation strategies. Finally, other routes reached a proof-of-concept phase in the laboratory, but were either too lengthy (e.g., thiolactonization and enolate addition to thiocarbonate approaches) or technically challenging/costly for commercial-scale application (azomethine ylide and Eschenmoser sulfide contraction routes).…”

“…This was followed by acidification with acetic acid to give crude thiol 13 containing minimal disulfide 30 . Although thiol 13 proved incapable of addition to 26 directly, addition of nitrogen bases (e.g., triethylamine) promoted the reaction to provide thiopenem 8 (Scheme ), an advanced intermediate in the second-generation process to sulopenem ( 1 ) …”

“…Therefore, focus shifted to improvements in the end game. The end-game strategy utilized in both first- and second-generation syntheses of sulopenem ( 1 ) involved desilylation of the secondary hydroxyl group, followed by palladium-catalyzed deallylation to provide the free carboxylic acid (Scheme ). ,, …”

Development of a Safe and Scalable Process for the Preparation of Allyl Glyoxalate

“…The utility of glyoxylic acid esters in target oriented synthesis has been widely reported. − During the course of development of a clinical drug candidate, kilogram quantities of a glyoxalic acid ester were required. The ideal glyoxalate would need to be accessible on large scale, isolated and stored for extended periods with minimal loss of purity, and stable to the fairly strenuous processing conditions required in the downstream synthetic sequence.…”