Synthesis with C-acyl Meldrums Acid as the A-Acylating Agent

The interactions of sitagliptin with DPP4 (dotted lines) are discussed in the text (reproduced from [10], with the permission of the American Chemical Society) 

All these stmctural data on the interactions at the active site of DPP4 revealed (1 )-1 to be the champion in the design of potent inhibitors of this target protein. The most important aspects of the synthetic chemistry behind this biological achievement are presented in the next section. 

3 Synthesis with C-acyl Meldrum s Acid as the A -Acylating Agent 

Sitagliptin was discovered through optimization of p-amino acid-derived inhibitors of DPP4, particularly in relation to metabolic stability and the pharmacokinetic properties of its predecessors 2 and 3 [10]. 

The approach to 3-trifluoromethyl-tetrahydro-l,2,4-triazaolo-/4,3-a/-pyrazine (3-trifluoromethyl-l,2,4-triazaolo-piperazine), the heterocyclic portion of the sitagliptin molecule, requires construction of the annulated ring on 2-chloropyrazine 4 to yield the intermediate 7. The latter is selectively hydrogenated in step iv to 8, maintaining the five-membered heteroaromatic ring. 

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