Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, 1 H-NMR, 13 C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin.
The article presents a process research
study of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic
acid (1), a crucial intermediate
in the synthesis of baloxavir marboxil. The original four-step sequence
exhibited various limitations, such as low yield (43%), the use of
problematic solvents, a large excess of costly reagents, safety concerns,
and impurity control difficulties. To address these challenges, process
optimization was carried out to achieve the desired goals for large-scale
industrial production. Optimization of the enamine 4b synthesis was performed, resulting in the development of an azeotropic
removal method for the byproduct methanol. This improvement led to
minimized ring-opening impurity 15 and a significant
reduction in the consumption of the condensation reagent. Furthermore,
a simplified one-pot two-step oxidation sequence was devised to streamline
the process for the synthesis of compound 1. This optimization
involved controlling the formation of hydrolytic impurity 16 and its downstream aldol condensation form 17. The
optimized process was successfully demonstrated on a 600 g scale with
a product purity of 99.9%, and the overall yield was substantially
improved, rising from 43 to 66%.
Trityl olmesartan ethyl ester (TOEE), a key intermediate of the launched angiotensin II receptor blocker olmesartan medoxomil, was built using two blocks via an N-alkylation reaction, wherein the imidazole N-1 isomer of this intermediate was the only isomeric product reported previously. Unexpectedly, from a sample of laboratory trials, an undesired impurity (a level of 0.2− 0.3%) sharing the same molecular mass with TOEE was detected and assumed to be an N-3 regioisomeric impurity of TOEE. Accordingly, a five-step lactone ring-opening synthetic route was designed and successfully used to obtain this impurity, whose structure perfectly matched the NMR and mass spectra. Subsequent characterization by SCXRD directly confirmed the initial speculation of it being an N-3 regioisomer, which was reported for the first time. Next, two downstream impurities toward the active pharmaceutical ingredient (API) were synthesized, in which the N-3 impurity of API proved to be inseparable with the API molecule under the European Pharmacopoeia chromatography method, introducing a risk of impurity identification. Sequential investigations focusing on impurity tracing and control strategies of the downstream impurities were conducted to meet the quality control requirements.
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