137863-90-2

Usage

Uses

Used in Pharmaceutical Industry:
Methyl N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valinate is used as an impurity in the production of Valsartan, a medication for treating high blood pressure (hypertension). As an impurity, it is essential to monitor and control its levels to ensure the safety and efficacy of the final drug product.
The compound's presence in Valsartan is significant because it can impact the drug's overall performance and patient safety. Therefore, its role in the pharmaceutical industry is crucial for maintaining the quality and reliability of antihypertensive medications.

Upstream product

• 137863-89-9 N-[(2'-cyanobiphenyl-4-yl)-methyl]-(L)-valine methyl ester 
• 638-29-9 n-valeryl chloride 
• 1198074-66-6 2-{[2'-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-biphenyl-4-ylmethyl]-pentanoyl-amino}-3-methyl-butyric acid methyl ester 
• 883223-08-3 (S)-methyl 3-methyl-2-((4-(4,4,5,5-tetramethyl-2,3,2-dioxaborolan-2-yl)benzyl)amino)butanoate 
• 883223-09-4 N-pentanoyl-N-[4-(4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolan-2'-yl)benzyl]-L-valinemethyl ester 
• 2042-37-7 o-cyanobromobenzene 
• 4070-48-8 L-Valine methyl ester 
• 138500-85-3 4-bromomethylphenylboronic acid pinacol ester 
• 67-56-1 methanol 
• 138642-62-3 2-Cyanophenylboronic acid 
• 589-15-1 1-bromomethyl-4-bromobenzene 
• 1189547-11-2 methyl N-pentanoyl-L-valinate 
• 87199-17-5 4-formylphenylboronic acid, 
• 4387-36-4 2-iodobenzonitrile 

Downstream Products

• 137863-17-3 methyl N-((2’-(1H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl)methyl)-N-pentanoyl-L-valinate 
• 137862-53-4 N-pentanoyl-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]-methyl]-(L)-valine 
• 443093-86-5 N-((2'-(cyano)-[1,1'-biphenyl]-4-yl)methyl)-N-pentanoyl-L-valine 
• 1298055-61-4 C₃₃H₃₆N₂O₃ 
• 1298055-65-8 C₁₂H₂₃N*C₂₄H₂₈N₂O₃ 
• 944467-25-8 N-valeryl-N-[(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl]-L-valine methyl ester 
• 934736-50-2 N-valeryl-N-[(2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl]-L-valine 
• 137862-53-4 valsartan 
• 1353844-74-2 N-(1-oxopentyl)-n-[[2'-(2-tributyltintetrazol-5-yl)-(1,1'-biphenyl)-4-yl]methyl]-(L)-valine methyl ester 

Relevant academic research and scientific papers

Improved synthesis of valsartan via nucleophilic aromatic substitution on aryloxazoline

A highly efficient approach to the synthesis of the angiotensin II receptor antagonist valsartan (Diovan), one of the most important agents used in antihypertensive therapy today is described. The formation of the aryl-aryl bond represents the key step of its synthesis, which has been done by simple nucleophelic aromatic substitution on aryloxazoline with good yield and purity. Copyright Taylor & Francis Group, LLC.

Synthesis method of valsartan intermediate

The invention relates to a synthesis method of a valsartan intermediate. The method comprises following steps: (1), a compound shown in the formula II is dissolved in an organic solvent firstly, an acid binding agent, sodium chloride or potassium chloride and water are added, the mixture is stirred uniformly, and a thermal insulation reaction is performed after valeryl chloride is dropwise added;(2), water is added for quenching after the reaction, alkaline washing, acid washing and alkaline washing are carried out in sequence, finally, a target product, namely, a compound shown in the formula I is obtained by reduced-pressure distillation, and the target product is N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester. According to the method, an appropriate amount of sodium chloride or potassium chloride is added to a reaction system, a hydrolysis reaction of valeryl chloride is inhibited by common-ion effect, so that the use amount of valeryl chloride is reduced,purity and yield of the product are increased, production cost is reduced, environmental pollution is reduced, and the method is more suitable for industrial production.

A method for preparing methyl valsartan

The invention provides a preparation method of valsartan. The preparation method has the technical effects that amide methyl ester and sodium azide are used as raw materials and are catalyzed by amine salt to carry out tetrazole formation reaction; side effects are minimized by controlling the reaction course; main products are furthest generated; unreacted raw materials are recycled and reused; the yield in the preparation method is increased by more than 10% relative to the yields in existing processes; compared with the existing processes, the method has the effect that plenty of high-toxicity wastewater is no longer generated, and is easy to be widely popularized industrially.

A method of preparing the valsartan

The invention discloses a method for preparing valsartan. The method comprises the following steps: carrying out a first-step reaction on L-valine methyl-ester hydrochloride and 2-cyan-4'-bromomethyl biphenyl, of which the molar ratio is (1-2):1; carrying out a second-step reaction together with pentanoyl chloride; finally carrying out a third-step reaction, so as to obtain a valsartan crude product, wherein the first-step reaction comprises the following steps: by taking acetonitrile as a reaction solvent, carrying out neutral reaction on the L-valine methyl-ester hydrochloride and potassium carbonate; then adding the 2-cyan-4'-bromomethyl biphenyl to react; adding the 2-cyan-4'-bromomethyl biphenyl by 2-6 times, wherein the reaction temperature is 50-65 DEG C; the reaction time is 3-7 hours. By adopting the method for preparing the valsartan, the quantity of byproducts corresponding to valsartan impurities T in the product in the first step is controlled, so as to control the quantity of the valsartan impurities T; furthermore, the other conditions are correspondingly adjusted; generation of other unmanageable impurities also can be avoided. Thus, the high-purity valsartan product can be prepared.

COMPOSITIONS AND METHODS FOR THE TREATMENT OF HYPERTENSION AND MANAGEMENT OF DIABETIC KIDNEY DISEASE

The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing hypertension and diabetic kidney disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of diabetes related renal complications, hypertension, albuminuria, Heart Diseases, ESRD, Kidney GFR complications, Vascular Disease, Ventricular Septal Defect, vascular dilation, high blood pressure, congestive heart failure (CHF), post-myocardial infarction (MI).

Polymer-supported electron-rich oxime palladacycle as an efficient heterogeneous catalyst for the Suzuki coupling reaction

Various electron-rich oxime palladacycle resins designed as heterogeneous catalysts were employed for the Suzuki coupling reaction of aryl halides with arylboronic acids. The electron-richness of the oxime ligand was controlled by the substituted alkoxy groups. Evaluation based on the electronic effect of the catalysts revealed that the alkoxy-substituted oxime palladacycle resins showed better catalytic activity than palladated Kaiser oxime resin in the Suzuki coupling reactions and that the catalytic activity of oxime palladacycle resins increased as the electron-richness of oxime ligand increased. The most electron-rich oxime palladacycle resin exhibited an excellent catalytic performance for the synthesis of both biaryl and heterobiaryl compounds, despite its heterogeneous system. As a practical application of the catalyst, a valsartan precursor was synthesized in high yield under mild conditions. The electron-rich oxime resin could also be reused for up to 5 cycles while maintaining good catalytic activity in the Suzuki coupling reaction.

PROCESS FOR THE PREPARATION OF VALSARTAN

The present invention relates to a process for the preparation of pure Valsartan (I) substantially free from impurities of formulae (Ia), (Ib), and (Ic), which comprises: (i) condensing 2-(4′-bromomethylphenyl)benzonitrile of formula (II) with L-valine methyl ester hydrochloride of formula (V) in the presence of a base in a solvent to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (VI); (ii) treating the compound VI of step (i) with acid followed by treating with base to produce pure compound VI substantially free from dimeric impurity of formula (Via); (iii) reacting the pure compound of formula (VI) with n-valeryl chloride in the presence of a base to produce pure N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) substantially free from alkene impurity of formula (Vila); (iv) reacting the compound of formula (VII) with trialkyltin chloride and a metal azide in a solvent at a reflux temperature to produce N-(1-oxopentyl)-N-[[2′-(2-tributyltinte-trazol-5-yl)-(1,1′-biphenyl)-4-yl]methyl]-(L)-valine methyl ester of formula (VHIb) free from thermal degradation impurity (Villa); (v) hydrolyzing the compound of formula (VHIb) in the presence of alkaline conditions to produce Valsartan (I).

Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect

A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT1 receptor with an IC50 value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD50 value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD50 = 307.50 mg/kg) but higher than losartan (LD50 = 2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.

AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN

The present invention relates to a process for the preparation of pure Valsartan (I) substantially free from impurities of formulae (la), (lb), and (Ic), which comprises: (i) condensing 2-(4'-bromomethylphenyl)benzonitrile of formula (II) with L-valine methyl ester hydrochloride of formula (V) in the presence of a base in a solvent to produce N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (VI); (ii) treating the compound VI of step (i) with acid followed by treating with base to produce pure compound VI substantially free from dimeric impurity of formula (Via); (iii) reacting the pure compound of formula (VI) with n-valeryl chloride in the presence of a base to produce pure N-valeryl-N-[(2'-cyanobiphenyl-4-yl)methyl]- (L)-valine methyl ester (VII) substantially free from alkene impurity of formula (Vila); (iv) reacting the compound of formula (VII) with trialkyltin chloride and a metal azide in a solvent at a reflux temperature to produce N-(l-oxopentyl)-N-[[2'-(2- tributyltintetrazol-5-yl)-(l, l '-biphenyl)-4-yl]methyl]-(L)-valine methyl ester of formula (VHIb) free from thermal degradation impurity (Villa); (v) hydrolyzing the compound of formula (VHIb) in the presence of alkaline conditions to produce Valsartan (I).

AN IMPROVED PROCESS FOR THE PREPARATION OF N-PENTANOYL-N-[[2'-(1H-TETRAZOL-5-YI)[1,1'-BIPHENYL]-4-YI]METHYL]-L-VALINE

Disclosed herein is an improved process for the preparation of pure N-Pentanoyl-N-[[2'- (1h-Tetrazol-5-Y1)[1,1'-Biphenyl]-4-Yl]Methyl]-L-Valine employing highly active carbon.