TESTOSTERONE

Development of a Chemoenzymatic Process for Dehydroepiandrosterone Acetate Synthesis

Anna Fryszkowska†, Justine Peterson†, Nichola L. Davies†, Colin Dewar†, George Evans†, Matthew Bycroft†, Neil Triggs†, Toni Fleming†, Srikanth Sarat Chandra Gorantla‡, Garrett Hoge†, Michael Quirmbach§, Upadhya Timmanna‡, Srinivas Reddy Poreddy‡, D. Naresh Kumar Reddy‡, Vilas Dahanukar‡, and Karen E. Holt-Tiffin*†

† Chirotech Technology Centre, Dr. Reddy’s Laboratories EU Ltd., 410 Cambridge Science Park, Cambridge CB4 0PE,United Kingdom

‡ Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India

§ Dr. Reddy’s Laboratories SA Elisabethenanlage, 11CH-4051 Basel, Switzerland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00215

Publication Date (Web): July 05, 2016

Copyright © 2016 American Chemical Society

*E-mail: keholt.tiffin@drreddys.com.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00215

Dehydroepiandrosterone (DHEA, 2) is an important endogenous steroid hormone in mammals used in the treatment of a variety of dysfunctions in female and male health,1 as well as an intermediate in the synthesis of steroidal drugs, such as abiraterone acetate which is used for the treatment of prostate cancer.2−4 In this manuscript we describe a novel, concise, and cost-efficient route toward DHEA (2) and DHEA acetate (3) from 4-androstene-3,17-dione (4-AD, 1). Crucial to success was the identification of a ketoreductase from Sphingomonas wittichii for the highly regio- and stereoselective reduction of the C3-carbonyl group of 5-androstene-3,17-dione (5) to the required 3β-alcohol (2, >99% de). The enzyme displayed excellent robustness and solvent stability under high substrate concentrations (up to 150 g/L).

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