An Efficient Procedure for the Synthesis of 21-Acetoxypregna-1,4,9(11),16- tetraene-3,20-dione

Abstract

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Halogenated corticosteroids are widely used in medicine, and the global need of these steroidal APIs is estimated to be 40 – 70 tons, annually. Vietnam currently imports the pharmaceutical compounds up to 90%, in particular 100% of steroidal drugs. Currently, industrial production is based on the chemical syntheses of corticosteroids from either 16- dehydropregnenolone acetate (obtained from diosgenin) or androstenedione (obtained from phytosterol). The development of shorter synthetic schemes and more economically feasible technologies is of great significance. Introduction of 1(2)-double bond at the final stages of the corticosteroids synthesis results inpoor yield. 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione (tetraene acetate) is a key intermediate in the synthesis of highly active halogenated corticosteroids such as dexamethasone and other halogenated corticosteroids. 21-acetoxypregna-1,4,9(11),16- tetraene-3,20-dione is a key intermediate in the synthesis of dexamethasone from the readily available and cheap 9α-hydroxyandrost-4-ene-3,17-dione.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>The purpose of this study was the development of an efficient and shorter procedure for the synthesis of 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, which is a product of a bio-oxidative degradation of the side chain of phytosterols.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Pregnane side chain was constructed using cyanohydrin method. For 1(2)- dehydrogenation, selene dioxide was applied for the introduction of Δ1(2)-double bond. Other stages of the synthesis were epimerization, Stork’s iodination procedure and dehydration.</jats:p> </jats:sec> <jats:sec> <jats:title>Result:</jats:title> <jats:p>21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione was prepared from 9α- hydroxyandrostenedione in yield more than 46%.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>An efficient and practically feasible procedure for the synthesis of 21-acetoxypregna- 1,4,9(11),16-tetraene-3,20-dione from 9α-hydroxyandrostenedione, a key intermediate for the synthesis of 9-haloidated corticoids, has been developed. The procedure can be applied for the production of value-added 9-haloidated corticoids.</jats:p> </jats:sec>

Study on preparation of pregna‐4‐en‐17α,21‐diol‐3,20‐dione from androst‐4‐en‐3,17‐dione

“…We also published the synthetic methods of corticoids from phytosterol via key intermediate 9-OH-AD and proposed various efficient processes for the preparation of prednisolone, betamethasone, dexamethasone and their synthetic intermediate from 9-OH-AD. [8,9] An alternative approach to the preparation of corticoid from 17-ketosteroid undergoes S Reichstein as a key intermediate.…”