124751-00-4

Basic information

• Product Name: 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole
• Synonyms: (2-Butyl-4-chloro-1-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H-imidazol-5-yl)methanol;2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole;[phenyl(phenylsulfanylsulfonyl)methyl]benzene;[phenyl-(phenylthio)sulfonyl-methyl]benzene;N-Trityl Losartan;(2S)-1-[(2S)-2-[[(1S)-3-cyclohexyl-1-(ethoxycarbonyl)propyl] aMino]propanoyl]pyrrolidine-2-carboxylic acid;[2-Butyl-4-chloro-1-[[2'-[2-(triphenylMethyl)-2H-tetrazol-5-yl]biphenyl-4-yl]Methyl]-1H-iMidazol-5-yl]Methanol;2-Butyl-4-chloro-1-[[2'-[1-(triphenylMethyl)-1H-tetrazol-5-yl][1,1'-biphenyl-4-yl]Methyl]-1H-iMidazole-5-Methanol
• CAS NO: 124751-00-4
• Molecular Formula: C₄₁H₃₇ClN₆O
• Molecular Weight: 665.24
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 124751-00-4.mol

Chemical Properties

• Melting Point: 122-124°C
• Boiling Point: 856.6±75.0 °C(Predicted)
• Appearance: /
• Density: 1.22±0.1 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Chloroform
• PKA: 13.66±0.10(Predicted)
• CAS DataBase Reference: 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole(124751-00-4)
• EPA Substance Registry System: 2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole(124751-00-4)

Safety Data

• Hazardous Substances Data: 124751-00-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole is used as an intermediate in the preparation of Losartan impurities. It plays a crucial role in the synthesis of Losartan, a medication used to treat hypertension and other cardiovascular conditions. By controlling the presence of this impurity, the purity and efficacy of Losartan can be maintained, ensuring the safety and effectiveness of the drug for patients.
As an impurity in Losartan:
2-Butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1H-2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole is used as an impurity in Losartan for quality control purposes. Monitoring and controlling the levels of this impurity in the final drug product is essential to ensure the safety and efficacy of Losartan as an antihypertensive medication. This impurity can be used as a reference material for analytical methods and testing procedures to verify the purity and quality of Losartan batches produced by pharmaceutical companies.

Upstream product

• 79047-41-9 2-n-butyl-4-chloro-5-hydroxymethylimidazole 
• 124750-51-2 N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole 
• 905456-96-4 C₄₁H₃₈N₆O 
• 76-83-5 trityl chloride 
• 124750-99-8 losartan potassium 
• 120568-18-5 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxaldehyde 
• 83857-96-9 2-n-butyl-4-chloro-1H-imidazol-5-carboxaldehyde 
• 124750-53-4 N-triphenylmethyl-5-(4'-methylbiphenyl-2-yl)tetrazole 
• 894806-36-1 2-n-butyl-4-chloro-1-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)benzyl]-1 H-imidazole-5-methanol 
• 143945-72-6 N-trityl-5-(2-bromophenyl)tetrazole 
• 894806-35-0 (4-((2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl)phenyl)-boronic acid 
• 114798-26-4 lorsartan 
• 124750-99-8 cozaar 

Downstream Products

• 124750-99-8 cozaar 
• 114798-26-4 lorsartan 
• 596-31-6 methoxytriphenylmethane 
• 120568-18-5 2-Butyl-4-chloro-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxaldehyde 
• 114798-94-6 2-butyl-4-chloro-5-(methoxymethyl)-1-[[2'-[tetrazole-5-yl]biphenyl-4-yl]methyl]imidazole 
• 727718-93-6 2-butyl-4-chloro-5-(azidomethyl)-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]-1H-imidazole 

Relevant articles and documents

Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.

Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy- triazole-pyridine-substituted losartan for imaging AT1 receptors

The 2-[18F]fluoro-3-pent-4-yn-1-yloxypyridine ([ 18F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [18F]FPyKYNE to azide-modified tetrazole-protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30 min. Upon co-administration with AT 1R blocker candesartan (2.5, 5 and 10 mg/kg), a dose-dependent reduction (47-65%) in tracer uptake was observed in the kidney, while no difference was observed following AT2R blocker PD123,319 (5 mg/kg), indicating binding selectivity for AT1R over AT2R and potential for imaging AT1R using PET.

Synthesis and evaluation of [18F]FETLOs and [18F]AMBF3LOS as novel 18F-labelled losartan derivatives for molecular imaging of angiotensin II type 1 receptors

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI)

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.

[11C] Methyl-losartan as a potential ligand for PET imaging angiotensin II AT1 receptors

The renin-angiotensin system regulates blood pressure via activation of the angiotensin II type 1 receptor (AT1R). The AT1R is involved in the pathology of cardiac and renal diseases such as heart failure and diabetic nephropathy. The aim of this study was to synthesize and characterize the O-[11 C]methylated derivative of the clinically used AT1 receptor blocker losartan as a novel AT1R PET imaging radioligand. [11 C]Methyl-losartan was reliably synthesized (n ≥ 40) via methylation of tetrazole-protected losartan followed by deprotection using HCl in an overall yield of 30%-60% (decay-corrected from [11 C]MeI). Radiochemical purity was >99% and specific activity 700-3600 mCi/μmol. Copyright 2011 John Wiley & Sons, Ltd. [11 C]Methyl-losartan has been synthesized in three steps: 1) protection of the tetrazole group, 2) [11 C]methylation of hydroxyl group, and 3) deprotection in acidic conditions. Copyright

A PROCESS FOR PREPARATION OF 2-N-BUTYL -4-CHLORO - 1 - {[2`- (2-TRIPHENYLMETHYL - 2H - TETRAZOLE - 5- YL) - 1, 1’ - BIPHENYL-4-YL] METHYL}-LH- IMIDAZOIE-5-METHANOL (INTERMEDIATE OF LOSARTAN)

The present invention relates to a process for preparation of N-substituted heterocyclic derivative,2-n-Butyl-4-chloro- 1 - { [2' -(2-triphenylmethyl-2H-tetrazole-5-yl)- 1,1' -biphenyl -4-yl] methyl} -lH-imidazole-5-methanol, an important intermediate in the synthesis of Losartan and its pharmaceutically acceptable salts using phase transfer catalyst and minimal number of solvents with improved yield.

METHOD FOR THE PRODUCTION OF LOSARTAN

The invention relates to a novel method for the production of losartan, an imidazol derivative with the chemical name 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl}imidazol and the pharmacologically active salts thereof. The invention also relates to novel intermediate products which are suitable for the production of losartan, and to novel methods for the production of intermediate compounds which are suitable for the production of losartan. One aspect of the invention is a method for the production of a compound of general formula (I), which can arise as an intermediate step in the inventive representation of losartan.

Crystalline form of losartan potassium

A compound that is a crystalline Form III of losartan potassium is provided. Also provided are compositions containing the compound and methods for its preparation.

PREPARATION OF NEW PHARMACEUTICALLY SUITABLE SALT OF LOSARTAN AND FORMS THEREOF WITH NEW PURIFICATION AND ISOLATION METHODS

Pharmaceutically suitable crystalline and amorphous alkali and earth-alkali salts of 2-n-butyl-4-chloro-5-h idroxymethyl-1-[[2'-(1 H-tetrazole-5-yl)[1.1'-biphenyl]-4-yl]-1 H-imidazole have been prepared and new manufacturing, purification and isolation procedure for said salts in high purity have been described. Stable pharmaceutical compositions containing new crystalline potassium salts of 2-n-butyl-4-chloro-5-hidroxymethyl-1-[[2'-(1 H-tetrazole-5-yl)[1.1'-biphenyl]-4-yl]-1 H-imidazole have been prepared.