Intermediates 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%. 

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... 

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