Merck & Co., Inc.

Novel Green Synthesis for β-Amino Acids Produces the Active Ingredient in Januvia^TM

Innovation and Benefits: Merck discovered a highly innovative and efficient catalytic synthesis for sitagliptin, which is the active ingredient in Januvia^TM, the company's new treatment for type 2 diabetes. This revolutionary synthesis creates 220 pounds less waste for each pound of sitagliptin manufactured and increases the overall yield by nearly 50 percent. Over the lifetime of Januvia^TM, Merck expects to eliminate the formation of at least 330 million pounds of waste, including nearly 110 million pounds of aqueous waste.

Summary of Technology: Januvia^TM is a new treatment for type 2 diabetes; Merck filed for regulatory approval in December 2005. Sitagliptin, a chiral β-amino acid derivative, is the active ingredient in Januvia^TM. Merck used a first-generation synthesis of sitagliptin to prepare over 200 pounds for clinical trials. With modifications, this synthesis could have been a viable manufacturing process, but it required eight steps including a number of aqueous work-ups. It also required several high-molecular-weight reagents that were not incorporated into the final molecule and, therefore, ended up as waste.

While developing a highly efficient second-generation synthesis for sitagliptin, Merck researchers discovered a completely unprecedented transformation: the asymmetric catalytic hydrogenation of unprotected enamines. In collaboration with Solvias, a company with expertise in this area, Merck scientists discovered that hydrogenation of unprotected enamines using rhodium salts of a ferrocenyl-based ligand as the catalyst gives β-amino acid derivatives of high optical purity and yield. This new method provides a general synthesis of β-amino acids, a class of molecules well-known for interesting biological properties. Merck scientists and engineers applied this new method in a completely novel way: using it in the final synthetic step to maximize the yield in terms of the valuable chiral catalyst. The dehydro precursor to sitagliptin used in the asymmetric hydrogenation is prepared in an essentially one-pot procedure. Following the hydrogenation, Merck recovers and recycles over 95 percent of the valuable rhodium. The reactive amino group of sitagliptin is only revealed in the final step; as a result, there is no need for protecting groups. The new synthesis has only three steps and increases the overall yield by nearly 50 percent.

This strategy is broadly applicable to other pharmaceutical syntheses; Merck has used it to make several exploratory drug candidates. Implementing the new route on a manufacturing scale has reduced the amount of waste by over 80 percent and completely eliminated aqueous waste streams. This second-generation synthesis will create 220 pounds less waste for each pound of sitagliptin manufactured. Over the lifetime of the drug, Merck expects to eliminate the formation of 330 million pounds or more of waste, including nearly 110 million pounds of aqueous waste. Because Merck's new synthesis has reduced the amount of raw materials, processing time, energy, and waste, it is a more cost-effective option than the first-generation synthesis. The technology discovered, developed, and implemented by Merck for the manufacture of Januvia^TM is an excellent example of scientific innovation resulting in benefits to the environment.

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