An improved, highly scalable methodology for the multigram-scale preparation of an important synthon, 17-β-(2-carboxyethyl)-1,3,5(10)- estratriene, is described. Previous approaches have failed to provide useful quantities of the analytically pure product because of facile retro-Michael breakdown of the-alkoxy carbonyl precursors during workup and isolation operations. The synthetic approach described herein has been designed specifically to sidestep this problematic breakdown process. This new scalable method of preparation overcomes a major hurdle in the exploration of structure-activity relationships centered around novel estradiol derivatives with bone-targeting properties and also provides a scalable process for subsequent developmental work.
Bibliographical noteFunding Information:
Financial support from Pradama, Inc. and the Kentucky Science and Technology Corporation is gratefully acknowledged. W.M.P., K.G.T., and P.A.C. have a financial interest in Pradama Inc.
Copyright 2010 Elsevier B.V., All rights reserved.
- Retro-Michael addition