Chiral sitagliptin synthesis

Overall, the chiral auxiliary approach to sitagliptin using (S)-PGA to install the amino group via diastereoselective hydrogenation resulted in a reduction of three chemical steps in the overall synthesis. This new synthetic approach essenhally followed the same convergent strategy (Route A on Scheme 5.8), but represented a big improvement over our previous route. The convergent approach made sense since the triazole heterocycle was a valuable intermediate that required an elaborate preparation with a modest yield of 26%. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Merck has discovered a more efficient catalytic synthesis for sitagliptin, a chiral (3-amino acid derivative that is the active ingredient in their new treatment for type 2 diabetes, Januvia . This revolutionary synthesis creates 220 pounds less waste for each pound of sitagliptin manufactured, and increases the overall yield by nearly 50%. Over the lifetime of Januvia , Merck expects to eliminate the formation of at least 330 million pounds of waste, including nearly 110 million pounds of aqueous waste. 

G., and Hughes, G. (2010) Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science, 329, 305-309,... 

C.K. Savile, l.M. laney, E.C. MundorlF, J.C. Moore, S. Tam, W.R. larvis, l.C. Colbeck, A. Kreb-ber, F.l. Fleitz, 1. Brands, P.N. Devine, G.W. Huisman, G.J. Hughes, Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329 (2010)... 

Chiral amine compounds with high optical purities can be difficult to prepare by many types of traditional catalysts. One well-known enzymatic synthesis of chiral amines involves TAs [6,47]. The to-TA transfers an amine group from an amino donor onto the ketone moiety of the amino acceptor (Figure 7.6). The most popular example, which won the presidential green chemistry award in 2010, has been the development of an co-TA by Merck and Codexis for an (R)-selective TA to synthesize sitagliptin (Januvia ) [48]. 

The chemical synthesis of sitagliptin [25,26] involved an as5mmetric hydrogenation of an enamine at high pressure using a rhodium-based chiral catalyst [27]. The chemical process suffers from inadequate stereoselectivity and a product stream contaminated with rhodium, necessitating additional purification steps at the expense of yield to upgrade both enantiomeric excess and chemical purity. 

A more concise route to chiral amines would be direct synthesis from the ketone via direct asymmetric reductive amination. This has been developed successfully for the conversion of (3-ketoesters to chiral (3-amino acid esters and demonstrated in the manufacture of sitagliptin, a DPP-IV inhibitor for... 

---