Aprepitant - Synthesis

Synthesis

Shortly after Merck initiated research into the reducing the severity and likelihood of CINV, researchers discovered that aprepitant is effective in prevention. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps, many of which needed dangerous chemicals such as sodium cyanide, dimethyltitanocene, and gaseous ammonia. In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous by products such as methane and magnesium chloride. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decide to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.

The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.

The new process begins by enantiopure trifluoromethylated phenyl ethanol (Red) being joined to a racemic morpholine precursor (Blue). This results in the wanted isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine, the base of the drug, is formed.

The second step involves the fluorophenyl group (Black) being attached to the morpholine ring (Blue). Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added (Green) to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.

This more streamlined route not only yields around 76% more aprepitant than the original process but also reduces the operating cost by a significant amount. In addition to this the new process also reduces the amount of solvent and reagents required by about 80% and saved an estimated 340,000L per a ton of aprepitant produced.

As a result of the improvements in the efficiency and reduction of environmental impacts of the synthesis of aprepitant, several social benefits have occurred. The most noticeable of which is a reduction in the price of the drug. This has resulted in a greater number of patients having access to it, which therefore has caused a decrease in the number of people that undergo chemotherapy experiencing CINV. The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimation of hazardous chemicals from the procedure.