Sitagliptin, synthesis

Synthesis of Sitagliptin, the Active Ingredient in Januvia and Janumet ... 

The first large-scale synthesis of sitagliptin [8] afforded the desired compound in 45% yield over 9 steps from acid 9 and triazole 3. Triazole 3 was prepared in 26% yield by optimizing the route used for the discovery of 1 into a process which can be run safely on a multi-kilogram scale. 

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%. 

I 5 Synthesis of Sitagliptin, the Actiue Ingredient in Januaia and Janumet"... 

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]. 

The requirement for an acyl protecting group represented a major drawback for an asymmetric hydrogenation approach in the synthesis of sitagliptin, since it would likely introduce additional chemical steps in the sequence for protection and deprotection. The ideal situation would be to perform the asymmetric hydrogenation on an unprotected enamine. Unfortunately, this transformation was unprecedented when we started the development work on sitagliptin [22]. 

A comparison of the amount of waste produced per kilogram of sitagliptin manufactured by the two processes demonstrates the improved efficiency of the new route (Figure 5.6). Overall, the new route reduces the total waste output of the process by approximately 80%. This will result in over 220000 kg less waste per 1000 kg of sitagliptin produced. While the first-generation synthesis produced over 60 L of aqueous waste per kg of 1, the new route produces no aqueous waste only 2 liters of water per kg of sitagliptin is now required for its preparation. 

The first large-scale synthesis of sitagliptin afforded the desired compound in 45% yield over eight steps from acid 22 and triazole 17. 

Development of Efficient One-Pot Process in the Synthesis of Sitagliptin Application of Online-Infrared for Kinetic Studies to Probe the Reaction Mechanism... 

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