Abstract
This manuscript describes a highly efficient and practical method for the synthesis of exquisite EP4-receptor agonist ONO-4819 that is expected for a therapeutic agent of metabolic bone diseases. The first generation stereoselective synthesis of ONO-4819 was developed using a commercially available THP-protected Corey-lactone as a starting material. Although the first generation synthesis was suitable for manufacturing more than 500 g of ONO-4819 for an initial study, it suffered from several drawbacks, one of which was a transformation to introduce sulfur-containing C4 side chain accompanied by the formation of three troublesome byproducts. In the second generation study, the authors have developed an improved synthetic route to introduce sulfur-containing C4 side chain using pure γ-thiobutyrolactone to suppress those side-products. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting group for hydroxyl functions are used for precise process controls of all intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity has been developed.
