A novel synthesis of olmesartan medoxomil and examination of its related impurities.
- Author:
Tai-Zhi WU
1
;
Xiao-Hua LIU
;
Fu-Li ZHANG
;
Mei-Hua XIE
Author Information
- Publication Type:Journal Article
- MeSH: Angiotensin II Type 1 Receptor Blockers; chemical synthesis; chemistry; Animals; Antihypertensive Agents; chemical synthesis; chemistry; pharmacology; Blood Pressure; drug effects; Imidazoles; chemical synthesis; chemistry; pharmacology; Molecular Structure; Olmesartan Medoxomil; Rats; Stereoisomerism; Tetrazoles; chemical synthesis; chemistry; pharmacology
- From: Acta Pharmaceutica Sinica 2006;41(6):537-543
- CountryChina
- Language:Chinese
-
Abstract:
AIMTo develop a new synthetic route for olmesartan medoxomil.
METHODSOlmesartan 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.
RESULTSSynthesis 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%.
CONCLUSIONA novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.