Identification, Synthesis, and Comprehension of an Imidazole N-3 Regioisomeric Impurity of Olmesartan Medoxomil Key Intermediate

Abstract

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.

Cross-acyloin condensation of aldehydes catalysed by transketolase variants for the synthesis of aliphatic α-hydroxyketones

“…α-Hydroxyketones (acyloins) are highly valuable compounds for numerous applications in fine chemicals, 1 especially in pharmaceuticals, 2 where they are used as building blocks for the synthesis of drugs and pro-drugs, 3 such as olmesartan medoxomil, 4 used to treat high blood pressure. Although symmetrical (aromatic or aliphatic) α-hydroxyketones can be prepared by chemo-benzoin-type condensation reactions catalysed by N-heterocyclic carbenes (NHCs) coupled with a base, 5 this strategy is much less convenient for access to a broad range of unsymmetrical, aliphatic, and hydroxy-functionalised α-hydroxyketones, 6 owing to the difficulty controlling both chemo- and regio-selectivity.…”

“…H NMR (400 MHz, D 2 O): δ = 1.05 (t, 3H, J = 7.2 Hz, H-1), 2.67 (m, 2H, H-2), 3.64 (dd, 1H, J = 7.1 and 11 4. Hz, H-6a), 3.72 (dd, 1H, J = 5.8 and 11.4 Hz, H6b), 4.16 (m, 1H, H-5), 4.41 (d, J = 2.1 Hz, H-4);13 C NMR (101 MHz, D 2 O): δ = 6.7 (C-1), 31.9 (C-2), 62.2 (C-6), 71.7 (C5), 76.7 (C-4), 215.7 (C-3); β furanose anomer: 1 H NMR (400 MHz, D 2 O): δ = 0.96 (t, 3H, J = 7.5 Hz, H-1), 1.76 (m, 2H, H-2), 3.60 (dd, 1H, J = 4.8 and 9.7 Hz, H-6a), 3.90 (d, 1H, J = 5.4 Hz, H-4), 4.16 (m, 1H, H-6b), 4.34 (ddd, 1H, J = 5.4 and 10.9 Hz, H-5); 13 C NMR (101 MHz, D 2 O): δ = 6.9 (C1), 30.1 (C-2), 69.4 (C-6), 75.2 (C-5), 78.8 (C-4), 104.5 (C-3); α-furanose anomer: 1 H NMR (400 MHz, D 2 O): δ = 0.99 (t, 3H, J = 7.6 Hz, H-1), 1.76 (m, 2H, H-2), 3.86 (dd, 1H, J = 6.3 and 12.9 Hz, H-6a), 3.99 (d, 1H, J = 1.0 Hz, H-4), 4.24 (m, 2H, H-5 and H-6b); 13 C NMR (101 MHz, D 2 O): δ = 7.2 (C-1), 26.8 (C-2), 72.0 (C-6), 76.3 (C-5), 79.6 (C-4), 108.2 (C-3); m/z HRMS ESI-MS calcd for C 6 H 13 O 4 : 149.0808; found [M + H] + : 149.0807.…”