ChemInform Abstract: 6‐Hydroxyethylpenems ‐ 10 Years After

Abstract

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

“…A number of methods for construction of carba- and thiopenems have been reported in the synthetic chemistry literature. − Key strategies include C–C, ,,− C–N, and C–S − bond formation for preparation of the five-membered ring. However, many of the methods that have proven successful for carbapenems are not applicable to thiopenems.…”

“…Penems, a class of β-lactam antibiotics, have been the subject of intense research over the last three decades. − Sulopenem ( 1 ) is a novel 2-thioalkyl penem that was in development for a broad range of indications (Figure ). , In order to support this research program, a practical process for the large-scale preparation of this antibacterial was required.…”

“…Identification of a Potential Commercial Route. The combination of a high daily intravenous dose, a challenging β-lactam structure, and an aggressive clinical development plan for sulopenem (1) required the identification of scalable technology for the manufacture of rapidly escalating quantities of active pharmaceutical ingredient (API). To enable early alignment of suppliers for custom raw materials, 4acetoxyazetidinone (9) and the proprietary chiral sulfoxide 10 were selected as building blocks for all potential commercial processes (Figure 2).…”

“…To enable early alignment of suppliers for custom raw materials, 4acetoxyazetidinone (9) and the proprietary chiral sulfoxide 10 were selected as building blocks for all potential commercial processes (Figure 2). 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 firstand second-generation syntheses. 9 Conserving the same end-game strategy also minimized the potential for introducing new process-related impurities.…”

Development of a Second-Generation Process to Antibacterial Candidate Sulopenem

“…In 2003, development of sulopenem resumed as multidrug resistant bacteria threatened to render existing therapies ineffective. − The combination of a high-dose daily intravenous delivery, a challenging β-lactam structure, and an aggressive clinical development plan for this candidate required the identification of scalable technology for the manufacture of increasing quantities of active pharmaceutical ingredient (API). Because sulopenem exhibits antibacterial activity and contains a β-lactam structural motif related to that seen in penicillin, − all GMP manufacture was carried out in a dedicated single-product facility to eliminate cross-contamination concerns, as recommended by ICH Q7A. , This added considerable cost and complexity to the API development effort.…”