172875-59-1

Basic information

• Product Name: N-Trityl Olmesartan Ethyl Ester
• Synonyms: N-Trityl Olmesartan Ethyl Ester;ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate
• CAS NO: 172875-59-1
• Molecular Formula: C₄₅H₄₄N₆O₃
• Molecular Weight: 716.86926
• Mol File: 172875-59-1.mol

Chemical Properties

• Appearance: /
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Slightly, Heated)
• CAS DataBase Reference: N-Trityl Olmesartan Ethyl Ester(CAS DataBase Reference)
• NIST Chemistry Reference: N-Trityl Olmesartan Ethyl Ester(172875-59-1)
• EPA Substance Registry System: N-Trityl Olmesartan Ethyl Ester(172875-59-1)

Safety Data

• Hazardous Substances Data: 172875-59-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
N-Trityl Olmesartan Ethyl Ester is used as a key intermediate in the synthesis of Olmesartan medoxomil for the treatment of hypertension. Its role in the production process is essential, as it contributes to the development of a medication that helps regulate blood pressure and improve the quality of life for patients suffering from high blood pressure.
As an intermediate, N-Trityl Olmesartan Ethyl Ester plays a significant role in the chemical reactions that lead to the final formulation of Olmesartan medoxomil. Its presence in the synthesis process ensures the production of a safe and effective medication for hypertension management.

Upstream product

• 133051-88-4 N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole 
• 144689-93-0 ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate 
• 58954-23-7 2-propyl-1H-imidazole-4,5-dicarboxylic acid 
• 144689-94-1 diethyl 2-(n-propyl)-1H-imidazole-4,5-dicarboxylate 
• 124750-51-2 N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole 
• 1122-91-4 4-bromo-benzaldehyde 
• 143722-25-2 2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)-phenylboronic acid 
• 135050-95-2 2'-<2-(triphenylmethyl)-1H-tetrazol-5-yl><1,1'-biphenyl>-4-methanol 
• 51802-42-7 2-propylimidazole-4,5-dicarbonitrile 

Downstream Products

• 144689-23-6 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 144689-63-4 olmesartan medoxomil 
• 1027174-22-6 5-(1-Hydroxy-1-methyl-ethyl)-2-propyl-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester 
• 1020157-01-0 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate 
• 172875-70-6 5-Isopropenyl-2-propyl-3-[2'-(2-trityl-2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid ethyl ester 

Relevant articles and documents

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

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 high-purity triphenyl olmesartan ethyl ester

The invention provides a preparation method of a high-purity olmesartan medoxomil intermediate triphenyl olmesartan ethyl ester. The provided preparation method specifically comprises the steps that in a first solvent, in the presence of a combined catalyst and potassium carbonate, a compound shown in a formula 2 and a compound shown in a formula 3 react with each other to obtain a compound shownin a formula 1, wherein the combined catalyst is composed of polyethylene glycol and 2-methylpyrrolidone. The preparation method can significantly reduce the content of the impurities shown in a formula 4 and formula 5 in the product intermediate shown in the formula 1, and improve the purity of the intermediate shown in the formula 1.

Preparation method of olmesartan medoxomil

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.

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.

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.

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.