We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H-3 antagonist, 1. The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbonyl-directed fluorination. The chemoselective addition of the magnesium ate complex to the ketoester benefited from tight stoichiometric control, short addition times, and lower reaction temperatures, and thus was amenable to rapid mixing and excellent heat transfer in a flow reactor.

Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1. The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.

Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and D-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN center dot HCl) and the active ester 1-({[4 ''(pentyloxy)-1,1':4',1 ''-terphenyl-4-yl]carbonyl}oxy)-1,H-1,2,3-ben- zotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.