Merck & Co., Inc.

A Redesigned, Efficient Synthesis of Aprepitant, the Active Ingredient in Emend®: A New Therapy for Chemotherapy-Induced Emesis

Innovation and Benefits: Emend^® is a drug that combats the nausea and vomiting often resulting from chemotherapy treatment. Merck now makes Emend^® using a new process that requires much less energy, raw materials, and water than the original process. With its new method, Merck eliminates approximately 41,000 gallons of waste per 1,000 pounds of the drug that it produces.

Summary of Technology: Emend^® is a new therapy for chemotherapy-induced nausea and vomiting, the most common side effects associated with the chemotherapeutic treatment of cancer. Emend^® has been clinically shown to reduce nausea and vomiting when used during and shortly after chemotherapy. Aprepitant is the active pharmaceutical ingredient in Emend^®.

Aprepitant, which has two heterocyclic rings and three stereogenic centers, is a challenging synthetic target. Merck's first-generation commercial synthesis required six synthetic steps and was based on the discovery synthesis. The raw material and environmental costs of this route, however, along with operational safety issues compelled Merck to discover, develop, and implement a completely new route to aprepitant.

Merck's new route to aprepitant demonstrates several important green chemistry principles. This innovative and convergent synthesis assembles the complex target in three highly atom-economical steps using four fragments of comparable size and complexity. The first-generation synthesis required stoichiometric amounts of an expensive, complex chiral acid as a reagent to set the absolute stereochemistry of aprepitant. In contrast, the new synthesis incorporates a chiral alcohol as a feedstock; this alcohol is itself synthesized in a catalytic asymmetric reaction. Merck uses the stereochemistry of this alcohol feedstock in a practical crystallization-induced asymmetric transformation to set the remaining stereogenic centers of the molecule during two subsequent transformations. The new process nearly doubles the yield of the first-generation synthesis. Much of the chemistry developed for the new route is novel and has wider applications. In particular, the use of a stereogenic center that is an integral part of the final target molecule to set new stereocenters with high selectivity is applicable to the large-scale synthesis of other chiral molecules, especially drug substances.

Implementing the new route has drastically improved the environmental impact of aprepitant production. Merck's new route eliminates all of the operational hazards associated with the first-generation synthesis, including those of sodium cyanide, dimethyl titanocene, and gaseous ammonia. The shorter synthesis and milder reaction conditions have also reduced the energy requirements significantly. Most important, the new synthesis requires only 20 percent of the raw materials and water used by the original one. By adopting this new route, Merck has eliminated approximately 41,000 gallons of waste per 1,000 pounds of aprepitant that it produces.

The alternative synthetic pathway for the synthesis of aprepitant as discovered and implemented by Merck is an excellent example of minimizing environmental impact while greatly reducing production costs by employing the principles of green chemistry. Merck implemented the new synthesis during its first year of production of Emend^®; as a result, Merck will realize the benefits of this route for virtually the entire lifetime of this product. The choice to implement the new route at the outset of production has led to a huge reduction in the cost to produce aprepitant, demonstrating quite clearly that green chemistry solutions can be aligned with cost-effective ones.

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