The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S=O, consistent with MsOH being crucial for high selectivity. The second is a novel C–H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel–Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.

An improved process for the synthesis of prasugrel hydrochloride with an overall yield of 58%, 99.9% purity, and meeting all other quality requirements is described.

New efficient and convenient approaches have been devised for the synthesis of sitagliptin impurities. As a part of impurity profile study of an antidiabetic drug substance sitagliptin 1, we encountered with six process related impurities. These impurities were detected by utilizing simple techniques such as high performance liquid chromatography (HPLC) and liquid chromatography‐mass spectrometry (LC–MS). All these impurities were synthesized and their presence in the sitagliptin sample was confirmed by co‐injection and matching the retention time with spiked impurities. The formation and control of these impurities during sitagliptin manufacture and synthesis of these impurities is discussed in detail. Synthesis of these impurities was accomplished by utilizing readily accessible starting materials, simple, convenient and concise reaction sequence.