172875-59-1Relevant articles and documents
Identification, Synthesis, and Comprehension of an Imidazole N-3 Regioisomeric Impurity of Olmesartan Medoxomil Key Intermediate
Huang, Kongcheng,Li, Xiao,Lu, Jianwu,Shi, Yinfei,Sun, Han,Sun, Xun,Wang, Xiaoxu,Wang, Yinquan,Weng, Weizhao,Wu, Taizhi,Yuan, Shun
, (2022/03/03)
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.
Preparation method of olmesartan medoxomil
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Paragraph 0039; 0040; 0041; 0042; 0043; 0044, (2017/02/09)
The invention discloses a preparation method of olmesartan medoxomil. The preparation method comprises the following steps of using 4-bromobenzaldehyde as a starting raw material, performing Suzuki coupling reaction with 2-(2'-triphenylmethyl tetrazole-5-yl)borophenylic acid (III), and reducing by NaBH4 (sodium borohydride), so as to obtain an olmesartan medoxomil intermediate of N-triphenylmethyl-5-(4'-hydroxymethyl biphenyl-2-yl)tetrazole (IV); directly reacting the intermediate (IV) and 2-propyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid ethyl ester, so as to obtain a compound VI; performing hydrolysis, esterification and deprotection, so as to obtain the olmesartan medoxomil. Compared with the prior art, the preparation method has the advantages that the obtaining of raw materials is easy, the amount of byproducts is fewer, the reaction line is shortened, the reaction condition is mild, the operation is simple, the total yield of product is improved, and the preparation method is suitable for industrialized production.
An improved process for the preparation of olmesartan medoxomil
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Page/Page column 5-6, (2008/06/13)
Olmesartan medoxomil of high purity (99.3-99.7% by HPLC ) is prepared using an improved process of its intermediate, namely- ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, comprising: Reacting ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with N-(Triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yl]tetrazole in an organic solvent in presence of a base and a phase transfer catalyst in non-aqueous system to give after workup, ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, which is further processed, by following improved reaction conditions in three steps to provide substantially pure [HPLC purity 99.3 to 99.7 %] olmesartan medoxomil. A further process relates to the purification of olmesartan medoxomil by treatment with isopropyl alcohol and methyl ethyl ketone.
