Development of a Triphenylmethyl Alkylation Pre-Column Derivatization Method for HPLC Quantitative Analysis of Chemically Unstable Halogenated Compounds.

The primary limitations of the quantitative analysis of thermally labile halogenated compounds by traditional gas chromatography (GC) are the inadequacy of identifying the insufficiently volatile impurity (often with a high boiling point) and the difficulty in obtaining a standard substance with a reliable standardized assay. Taking the 4-(Chloromethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Cl, 1) as an example, we reported a triphenylmethanamino-derivatization method to overcome the challenges of the assay determination of such species. During the quantification of 1, the presence of GC-undetectable polymeric impurity 10 poses a critical challenge in assessing the material quality. Moreover, the standard substance of 1 is not available on the market due to its inherent instability during storage and handling, further complicating the quantitative analysis. In this work, a precolumn HPLC-UV derivatization method based on triphenylmethanamino-alkylation was developed to quantitatively analyze 1. The resulting derivative 2 exhibits excellent crystallinity and superior physical and chemical stability and possesses effective chromophores for UV detection. The conversion from analyte 1 to derivative 2 demonstrates desirable reactivity and purity, facilitating quantitative analysis using the external standard method. The chemical derivatization-chromatographic detection method was optimized and validated, demonstrating its high specificity, good linearity, precision, accuracy, and stability. This method offers a valuable alternative to the general quantitative NMR (qNMR) detection technique, which exhibits reduced specificity in the presence of increased levels of impurities in compound 1.

Synthesis and Characterization of Process-Related Impurities of Antidiabetic Drug Linagliptin.

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, ¹H-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.

[A novel synthesis of olmesartan medoxomil and examination of its related impurities].

AIM: To develop a new synthetic route for olmesartan medoxomil. METHODS: Olmesartan medoxomil was prepared from ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate via hydrolysis and lactonization to afford 4,4- dimethyl-2-propyl-4,6-dihydrofuro [3,4-d]-1H-imidazole-6-one which was condensed with 2-(triphenylmethyl)-5-[4'-(bromomethylbiphenyl)-2-yl] tetrazole, followed by esterification with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and deprotection. The chemical structure of the major impurity in condensation reaction is the regio-isomer in the imidazole moiety, and confirmed by single crystal X-ray diffraction. The corresponding regio-isomer of olmesartan medoxomil was synthesized from the impurity by similar method. Optimization of the condensation conditions reduced the impurity to a negligible quantity. RESULTS: Synthesis of olmesartan medoxomil by the new route gave a product of 60% yield and above 99.0% purity. The content of olmesartan medoxomil regio-isomer was effectively controlled to less than 0.1%. CONCLUSION: A novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.