Development of a Practical Large-Scale Synthesis of Denagliptin Tosylate

Abstract

A large-scale synthesis of denagliptin tosylate has been developed. The efficiency of the synthesis has been improved from the initially scaled route by changing the order of steps (performing a dehydration at a late stage). The key step of the synthesis is a single-step peptide coupling/dehydration, mediated by n-propanephosphonic acid cyclic anhydride. The challenges of developing this synthesis into a robust and practical manufacturing route are described.

A Unified Strategy for Kainoid Synthesis

“…The carboxylic acid in 24 was converted into the primary amine (in 26) by first forming primary amide 25 via a mixed anhydride, [25] followed by reduction with AlH 3 . The carboxylic acid in 24 was converted into the primary amine (in 26) by first forming primary amide 25 via a mixed anhydride, [25] followed by reduction with AlH 3 .…”

“…The reaction mixture was gradually warmed to room temperature over 1 h, where it was stirred for another 2 h. Then, additional [(but-3-en-1-yloxy)methyl]benzene (1.23 g, 7.57 mmol) and Grubbs catalyst (64.2 mg, 0.0756 mmol) were added at room temperature. [25] Di-tert-butyl dicarbonate (2.40 g, 11.0 mmol) and pyridine (574 μL, 7.15 mmol) were added to a solution of (2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-(prop-1-en-2-yl)hex-4-enoic acid (24; 1.92 g, 5.51 mmol) in ethyl acetate (19 mL) at room temperature. The organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:2) to give 20 (1.32 g, 65.5 %) as a pale yellow oil.…”

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

“…183 The final manufacturing step of denagliptin, an API developed to treat diabetes mellitus, is forming a tosylate salt in ethanol, as illustrated in Scheme 50. 184 There is potential for the formation of a potentially genotoxic p-toluenesulfonic acid ester with the alcoholic solvent. Teasdale et al carried out a detailed study to understand the mechanism, kinetics, and processing parameters of sulfonate ester formation 179,185,186 Note that these studies discuss the reactions between alcohols and sulfonic acids only and not sulfonyl halides.…”

Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review

“…In the analytical point of view, the actual QL should be much more sensitive than the PGIs concentration limit. In addition to this, certain drug substances may generate PGIs via degradation or storage and are to be separated from process impurities to achieve specificity in the analysis . Besides the sensitivity and specificity, the other challenges in PGIs determination includes (i) diverse structural types of PGIs that require the application of various analytical techniques, (ii) PGIs without structural features are not favorable to common analytical detectors, (iii) chemically reactive or unstable PGIs lead to low recovery and poor sensitivity, and require special handling techniques, (iv) interference of sample matrix resulted by enhanced test concentration of API to achieve lower detection limits .…”