# Process optimizations for the synthesis of an intermediate of dydrogesterone

## TL;DR

This paper presents an optimized and efficient process for synthesizing an intermediate of the progesterone drug dydrogesterone.

## Contribution

The study introduces a photoinitiated allylic bromination method that reduces reaction time and avoids traditional initiators.

## Key findings

- A three-step synthesis route was developed for the DG intermediate with simple operation and low energy consumption.
- Using a 365 nm LED lamp reduced bromination reaction time from 1.5 hours to 20 minutes while maintaining over 65% yield.
- The optimized process produces few by-products and is suitable for large-scale production.

## 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.

This works develops an efficient three-step synthesis of dydrogesterone intermidiate 9α,10β-pregest-5,7-diene-3,20-diethylene glycol ketone through ketal production, innovative photoinitiated allylic bromination, and elimination.