Simple and Convenient Synthesis of 21‐Thioalkylether Derivatives of Methyl 16‐Prednisolone Carboxylates

Abstract

The antedrug approach for corticosteroids has been described as a fundamentally sound approach for the development of safer anti‐inflammatory and anti‐asthmatic therapy. However, the derivatization of prednisolone and its congeners have been considered to be major pitfalls, because their syntheses are complicated by the presence of numerous carboxylate esters and hydroxyl functions in the steroid nucleus. A simple and direct synthesis of 21‐thioalkylether derivatives of methyl 16‐prednisolonecarboxylates is described. The 21‐mesylate of the methyl 16‐prednisolonecarboxylate and 9‐fluoro‐17‐dehydro methyl 16‐prednisolonecarboxylate were reacted with Na‐thioalkoxides to furnish the desired thioethers in good yields. A previously published method for the methanolysis of 16‐cyanoprednisolone to methylcarboxylate has been reexamined, and the conditions are explained clearly. The reaction conditions for all these reactions were critical.

Keywords:

• antedrug
• methanolysis
• 16‐methylcarboxylates
• prednisolone
• 21‐thioethers

Acknowledgments

This research was supported in part by National Institute of Health Grants RO1 AM 21627, MBRS GM 008111, and RCMI G12 RR003020.