1020157-01-0

Usage

Chemical Properties

White Solid

Upstream product

• 80841-78-7 4-chloromethyl-5-methyl-1,3-dioxol-2-one 
• 133051-88-4 N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole 
• 676-58-4 methylmagnesium chloride 
• 1048948-16-8 4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-(2-(trityltetrazol-5-yl)phenyl)phenylmethyl)-imidazole-5-carboxylic acid, sodium salt 
• 172875-59-1 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate 
• 144689-93-0 ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate 
• 124750-59-0 2-propyl-4,5-bis(methoxycarbonyl)-imidazole 
• 752179-89-8 1-((2'-(2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 
• 51802-42-7 2-propylimidazole-4,5-dicarbonitrile 
• 144689-94-1 diethyl 2-(n-propyl)-1H-imidazole-4,5-dicarboxylate 
• 58954-23-7 2-propyl-1H-imidazole-4,5-dicarboxylic acid 

Downstream Products

• 144689-63-4 olmesartan 
• 144689-63-4 olmesartan medoxomil 

Relevant academic research and scientific papers

Development of efficient one-pot three-component assembly of trityl olmesartan medoxomil

We have elaborated a one-pot three-component assembly of trityl olmesartan medoxomil starting from commercially available ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate, 5-(4′-(bromomethyl)-[1,1′-biphenyl]-2-yl)-1-trityl-1H-tetrazole and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one intermediates. The developed and optimized one-pot process provides 72–75% yield of trityl olmesartan medoxomil over three steps, which represents in average ca. 90% yield per synthetic step, on a 300 g scale. The process is conducted in simple fashion and provides highly pure trityl olmesartan medoxomil (up to 97.5% by HPLC), which can be easily converted to olmesartan medoxomil that fully complies with all ICH requirements. Furthermore, the described process significantly improves the primary process to trityl olmesartan medoxomil by drastic reduction of required unit operations and application of single reaction solvent through the reaction sequence. Moreover, the amount of used organic solvents was notably reduced. The developed process has provided solid bases for industrial production of trityl olmesartan medoxomil.

Synthesis and physicochemical characterization of the process-related impurities of olmesartan medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole intermediates in sartan syntheses exist?

During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H, 13C and 15N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.

METHOD FOR PRODUCING HIGH PURITY OLMESARTAN MEDOXOMIL

PROBLEM TO BE SOLVED: To provide a method for producing high purity olmesartan medoxomil. SOLUTION: There is provided a method for producing trityl olmesartan medoxomil which comprises: (a) a step of saponifying trityl olmesartan ethyl ester with a base in a water-soluble organic solvent; and (b) a step of reacting the product in the step a) and 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolane in the presence of 0.5-fold more moles of an alkali metal iodide salt with respect to trityl olmesartan ethyl ester. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPO&INPIT

PROCESS FOR (5-METHYL-2-OXO-1,3-DIOXOLEN-4-YL)METHYL4-(1-HYDROXY-1-METHYLETHYL)-2-PROPYL-1-[4-[2-TETRAZOL-5-YL)PHENYL]PHENYL]METHYLIMIDAZOLE-5-CARBOXYLATE

The present invention relates to an improved process for the preparation of (5-methyl-2-oxo- 1,3-dioxolen-4-yl)methyl4-(1-hydroxy- 1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methyl imidazole-5-carboxylate.

An improved process for the preparation of olmesartan medoxomil

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.

PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL

A process for preparing olmesartan medoxomil.

Nonpeptide angiotensin II receptor antagonists: Synthesis, biological activities, and structure - Activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2′-1H-tetrazol-5-ylbiphenyl-4-yl) -methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.