Kilogram-Scale Synthesis of an Inhaled Corticosteroid

The development and implementation of a safe and scalable process for the manufacture of corticosteroid PF-4714224 (<b>1</b>) is described. Initial routes used to synthesise analogues from this series directly from fluocinolone acetonide (<b>2</b>) were unsuitable for large-scale use. Key aspects of the route are the efficient and simple method for the preparation of the steroid tetraol (<b>6</b>), acetal formation by reaction of the tetraol with a bisulphite adduct (<b>12</b>), and isolation of the product by sequential recrystallisations

Copper-Catalyzed Synthesis of Masked (Hetero)Aryl Sulfinates

Catalysis using substoichiometric copper facilitates the synthesis of masked (hetero)aryl sulfinates under mild, base-free conditions from aryl iodides and the commercial sulfonylation reagent sodium 1-methyl 3-sulfinopropanoate (SMOPS). The development of a tert-butyl ester variant of the SMOPS reagent allowed the use of aryl bromide substrates. The sulfones thus generated can be unmasked and functionalized in situ to form a variety of sulfonyl-containing functional groups

Development of the Synthetic Route to PF-06878031 Part 1: Selective Alkylation Route

The target compound PF-06878031 is a key structural fragment of a range of oral late-stage glucagon-like peptide-1 receptor agonists (GLP-1-RA) under development in our laboratories for the indications of type-2 diabetes mellitus (T2DM) and weight loss. This article describes the identification of a selective alkylation route and development of a process, capable of delivering multikilo quantities of PF-06878031. Process development afforded improved safety, increased yield, reduced step count, and lowered PMI. The new process has been scaled up at multiple facilities to generate >1.5MT of high purity PF-06878031

Development of the Synthetic Route to PF-06878031 Part 2: Amide Reduction Route

The target compound PF-06878031 is a key structural fragment of a range of oral late-stage glucagon-like peptide-1 receptor agonists (GLP-1-RA) under development in our laboratories for the indications of type 2 diabetes mellitus (T2DM) and weight loss. This article describes the identification of an amide reduction route, and development of a process, capable of delivering multikilo quantities of PF-06878031. The process development afforded improved safety, higher yield, a reduced step count, and a significant cost reduction. The new process has been scaled up at multiple facilities to generate >1.5MT of high-purity PF-06878031