Merck & Co., Inc.

Codexis, Inc

Greener Manufacturing of Sitagliptin Enabled by an Evolved Transaminase

Innovation and Benefits: Merck and Codexis have developed a second-generation green synthesis of sitagliptin, the active ingredient in Januvia^TM, a treatment for type 2 diabetes. This collaboration has lead to an enzymatic process that reduces waste, improves yield and safety, and eliminates the need for a metal catalyst. Early research suggests that the new biocatalysts will be useful in manufacturing other drugs as well.

Summary of Technology: Sitagliptin is the active ingredient in Januvia^TM, an important treatment for type 2 diabetes that is in high demand worldwide. The current manufacturing process includes a novel and efficient asymmetric catalytic hydrogenation of an unprotected enamine. The process has some inherent liabilities however: inadequate stereoselectivity requires a crystallization step, and high-pressure hydrogenation (at 250 psi) requires expensive, specialized manufacturing equipment, and a rhodium catalyst.

Merck and Codexis were independently aware that transaminase enzymes could, in principle, improve the manufacturing process for sitagliptin by converting a precursor ketone directly to the desired chiral amine. Merck's tests of available transaminases failed to identify an enzyme with any detectable activity on the sitagliptin ketone.

Collaboration between Merck and Codexis has lead to an improved, greener route for the manufacture of sitagliptin. Starting from an R-selective transaminase with some slight activity on a smaller, truncated methyl ketone analog of the sitagliptin ketone, Codexis evolved a biocatalyst to enable a new manufacturing process to supplant the hydrogenation route. The evolved transaminase had a compounded improvement in biocatalytic activity of over 25,000-fold, with no detectable amounts of the undesired, S-enantiomer of sitagliptin being formed. The streamlined, enzymatic process eliminates the high-pressure hydrogenation, all metals (rhodium and iron), and the wasteful chiral purification step. The benefits of the new process include a 56 percent improvement in productivity with the existing equipment, a 10–13 percent overall increase in yield, and a 19 percent reduction in overall waste generation.

Evolved transaminases are proving to be a general tool for the synthesis of R-amines directly from ketones, constituting an important new green methodology, one of the key transformations identified by the American Chemical Society Green Chemistry Institute's Pharmaceutical Roundtable. Merck and Codexis have used scientific innovation to benefit the environment, meet the manufacturing demands of an important drug in growing demand, and potentially enable a broad class of chemistry. During 2009, Merck scaled up the new process to pilot scale. Plans to commercialize this technology are moving forward.

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