Process optimizations for the synthesis of an intermediate of dydrogesterone

Abstract

Dydrogesterone (DG) is a potent progesterone drug that can be used to treat almost all progesterone-deficiency in women. However, there are few reports on DG process studies, and the by-products are unclear, which make the process optimization challenging. In this paper, we report the process optimization studies for the synthesis of 9α,10β-pregest-5,7-diene-3,20-diethylene glycol ketone (1), an intermediate of DG. Starting from the natural raw progesterone, the intermediate 1 was synthesised via a three-step process involving ketal protection, allylic bromination and elimination. We synthesised and characterised the main by-products in the process route, and explored the effects of conditions such as feed amount, temperature and types of bases on the yield and selectivity. Compared with traditional thermal initiation, we employed a 365 nm LED lamp to initiate the allylic bromination, avoiding the need to add initiators during thermal initiation. The photoinduced reaction time was markedly diminished from 1.5 h to 20 min, while maintaining a bromination yield of over 65%. The optimized process route of intermediate 1 is featured with simple operation, short time, low energy consumption, few by-products, and easy to scale up production, which is critical for enhancing the production efficiency and reducing the environmental impact of DG.