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

Luu D Huy; Nguyen T Diep; Tran K Vu; Tatiana S Savinova; Marina V Donova

doi:10.2174/1386207323666200219122644

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

Comb Chem High Throughput Screen. 2020;23(3):225-231. doi: 10.2174/1386207323666200219122644.

Authors

Luu D Huy¹, Nguyen T Diep¹, Tran K Vu², Tatiana S Savinova³, Marina V Donova⁴

Affiliations

¹ Institute of Chemistry, Vietnam Academy of Science and Technology, 18- Hoang Quoc Viet, Cau giay, Hanoi, Vietnam.
² School of Chemical Engineering, Hanoi University of Science and Technology, No 1, Dai Co Viet, Hai Ba Trung- Hanoi, Vietnam.
³ M. V. Lomonosov Moscow State University, Faculty of Chemistry Build. 3, 1 Lenin Hills, 119991 Moscow, Russian Federation.
⁴ Federal Research Center «Pushchino Center for Biological Research of the Russian Academy of Sciences», G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Prospekt 5, 142290, Moscow Region, Russian Federation.

PMID: 32072895
DOI: 10.2174/1386207323666200219122644

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Result: 21-Acetoxypregna-1,4,9(11),16-tetraene-3,20-dione was prepared from 9α- hydroxyandrostenedione in yield more than 46%.

Conclusion: 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.

Keywords: 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione; 9α-hydroxyandrostenedione; acetoxylation; dehydration; dehydrogenation; hydrocyanation..

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androstenedione / chemistry*
Hydrogenation
Molecular Conformation
Stereoisomerism

Substances

Androstenedione