Merck synthesis sitagliptin

The first example is the Merck G3 [87] plan for sitagliptin hydrogen phosphate, an antidiabetic pharmaceutical used to treat juvenile type II diabetes. The synthesis scheme is shown in the following and the corresponding synthesis tree diagram is given in Figure 11.24. 

FIGURE 11.24 Synthesis tree for Merck G2 (2005) plan for sitagliptin hydrogen phosphate. 

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. 

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... 

An impressive example of a biotransformation process in aqueous media supplemented with a water-misdble cosolvent can be found in the transaminase-catalyzed synthesis of the sitagliptin key intermediate (S)-40 developed jointly by Codexis and Merck researchers (Scheme 2.16) [ 18,19]. As might be expeded, the ketone substrate was only soluble in water at less than 1 g/L. Various cosolvents were evaluated and both methanol and DMSO were suitable candidates with resped to both enzyme performance and increase of ketone solubility. The latter was ultimately chosen, and the final process operates at 50% (v/v) DMSO, which allows a remarkable substrate input of 200 g/L of ketone 39. This... 

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 most important application of enzymatic transamination has recently been demonstrated for the synthesis of SItagliptin (Januvia ) [48], a commercial DPP-4 inhibitor from Merck for the treatment of diabetes. Merck and Codexis started from a TA enzyme with... 

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