A New Efficient Synthesis of Ospemifene

December 6, 2017
Adeline Siew, PhD

Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

The method developed by Cambrex uses standard plant equipment and requires only two synthetic steps and one recrystallization, minimizing waste and use of solvents.

Cambrex was awarded the 2017 CPhI Pharma Award for Excellence in Pharma: API Development for developing a novel method to synthesize ospemifene more efficiently. According to Jonathan Knight, vice-president, New Product Development, Cambrex, the major challenges with the original published route were mainly associated with the number of chemical steps, which typically involved seven to eight steps. “This obviously has an effect on the amount of production equipment used, as well as the overall solvent requirements,” Knight said. He added that another important consequence of a multi-step synthesis was the formation of unwanted impurities at each intermediate stage, which increased the need for in-process analysis and often resulted in extensive purification, which had ramifications in the overall waste and environmental impact. “The original route was not ‘atom efficient’ in design, meaning that it lost molecular weight at the end of the synthesis, and that has a direct effect on yield and processing time, which can dramatically impact the cost of goods,” he explained. Knight spoke to Pharmaceutical Technology about the approach taken by Cambrex in this API development project. 

PharmTech:

How did Cambrex go about developing a more efficient process?

Knight:

Cambrex’s approach was always to develop an ‘atom efficient’ process. What we mean by this is to try to make the synthesis not only as short as possible but also to avoid protection–deprotection steps, and build the molecular weight during the synthesis. We also look at ‘process efficiency,’ which includes minimizing the number of chemical steps, and in particular, the isolated steps, while keeping the concentration as high as possible.

The goals that we set from the start were to develop a process that is robust, with a short route of synthesis and good capacity utilization. We wanted to start from commercially available raw materials and develop a process that is sustainable from an environmental standpoint. All these goals were achieved; many actually exceeded our expectations, and the result was to reduce a seven-step synthesis to a two-step synthesis.

PharmTech:

Can you tell us about the new method developed by Cambrex and what competitive edge it brings to the table?

Knight:

Cambrex actually developed three novel routes to the target API, each building upon the previous one. The third route, and the one for which we won the prize, is a two-step synthesis, in which both steps are coupling steps (increasing the molecular weight), starting from cheap and commercially available raw materials. The first step is run neat (i.e., no added solvents), which gives a high capacity of more than 400 g/L, as well as a 95% yield and 99.7% purity without the need for crystallization. The total processing time, including workup, is less than 24 hours. The second step is a McMurry Coupling, which was more challenging than the first step to develop due to the amount of potential impurities that could be formed. Following an extensive critical parameter study and formal design-of-experiment (DOE) study, the second step was successfully developed.  This step results in a robust, high-yielding process meeting the tight specification after only one recrystallization.

Based upon the publically available information of the original route, the novel Cambrex route has shown clear advantages that have resulted in a strong improvement in the process and a dramatic reduction in the synthesis costs. These improvements include the overall reduction of the number of chemical steps from seven to two (resulting in a significant increase in yield and plant efficiency); the demonstration of a robust, reproducible process that only requires one crystallization to achieve an overall purity of 99.9%; and a significant (>75%) reduction in waste.