A novel route for the preparation of betamethasone from 9α-hydroxyandrost-4-ene-3,17-dione (9αOH-AD) by chemical synthesis and fermentation

Abstract

A novel and efficient synthesis of betamethasone has been developed from the readily available 9α-hydroxyandrost-4-ene-3,17-dione (9αOH-AD). The 16α-methyl was introduced stereoselectively with CH3Br and converted to the 16β-methyl, the 17-side chain was installed with 2-chlorovinyl ethyl ether in the place of the toxic KCN/HOAc, and a mild fermentation was employed for the 1,2-dehydrogenation, replacing the DDQ oxidation. By adjustments and improvements of the steps, this route produced betamethasone in 11 steps with a 22.9% overall yield, showing its potential for industrial application with relatively low toxicity and cost.