124750-92-1

Basic information

• Product Name: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID
• Synonyms: LOSARTAN CARBOXY ACID;AKOS 91941;2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID;’-biphenyl)-4-yl)methyl)-;1h-imidazole-5-carboxylicacid,2-butyl-4-chloro-1-((2’-(14-tetrazol-5-yl)(1,1;e-3174;exp3174;l-158641
• CAS NO: 124750-92-1
• Molecular Formula: C₂₂H₂₁ClN₆O₂
• Molecular Weight: 436.89
• Product Categories: Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Heterocycles
• Mol File: 124750-92-1.mol
• Article Data: 23

Chemical Properties

• Melting Point: 130-132°C
• Boiling Point: 707.8 °C at 760 mmHg
• Flash Point: 381.8 °C
• Appearance: Light-Yellow Solid
• Density: 1.41 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: Dimethylformamide, Dimethyl Sulfoxide, Methanol
• PKA: 0.79±0.50(Predicted)
• CAS DataBase Reference: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(124750-92-1)
• EPA Substance Registry System: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(124750-92-1)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 124750-92-1(Hazardous Substances Data)

Usage

Description

Losartan carboxylic acid is a physiologically active metabolite of losartan , produced by cytochrome P450 isoforms in the liver. Like the parent compound, losartan carboxylic acid is a potent AT1 antagonist (Kis = 0.57 and 0.67 nM for rat and human forms, respectively), producing a depressor response and vasodilatation. When administered intravenously, losartan carboxylic acid is more potent and has a longer duration of action than losartan. However, the metabolite has very low oral bioavailability. Losartan, but not its metabolite, inhibits platelet aggregation in vitro.

Chemical Properties

Light-Yellow Solid

Uses

Different sources of media describe the Uses of 124750-92-1 differently. You can refer to the following data:
1. A metabolite of Losartan
2. Losartan carboxylic acid is used as a metabolite of Losartan.

Definition

ChEBI: A biphenylyltetrazole that is losartan with the hydroxymethyl group at position 5 on the imidazole ring replaced with a carboxylic acid.

in vitro

e-3174 potently blocked the specific binding of [125i]-aii to vsmc isolated from rat aorta. e-3174 was able to dampen the platelet-derived growth factor-induced increase in cell dna synthesis and protein, which led to the blockade of the aii-induced increase in cell protein [1].

in vivo

rats were administrated e-3174 intravenously at a dose of l.0 mg/kg. after 6 hours, e-3174 markedly attenuated the cardiovascular effects of aii in rats. e-3174 induced a progressive fall in mean arterial pressure and a marked increase in renal flow only [2].

references

[1]. li, x. & widdop, r. angiotensin type i receptor antagonists cy-11974 and exp 3174 cause selective renal vasodilatation in conscious spontaneously hypertensive rats. clinical science, 1996; 91(2): 147-154. [2]. sachinidis, a., ko, y., weisser, p., zu bricbkwedde, m., dsing, r., & christian, r. et al. exp3174, a metabolite of losartan (mk954, dup753) is more potent than losartan in blocking the angiotensin ll-induced responses in vascular smooth muscle cells. journal of hypertension. 1993; 11(2): 155-162.

Synthetic route

2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-methyl]imidazole-5-carboxylic acid ethyl ester (947330-97-4) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With sodium hydroxide In ethanol at 90℃; for 20h;	90%

cozaar (124750-99-8) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Stage #1: cozaar With potassium permanganate In water at -5 - 50℃; for 16h; Stage #2: With hydrogenchloride In water pH=2 - 3;	89.1%
Stage #1: cozaar With potassium hydroxide In water at 2℃; for 2h; Stage #2: With sodium periodate; ruthenium trichloride In water; isopropyl alcohol at 4 - 20℃; for 22h; Stage #3: With phosphoric acid In water; isopropyl alcohol for 0.5h;
Stage #1: cozaar With ruthenium trichloride; potassium hydroxide; sodium periodate In water at 0℃; Stage #2: With phosphoric acid In water; isopropyl alcohol at 30℃; for 0.5h;

lorsartan (114798-26-4) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With pyridine; potassium permanganate; tetrabutyl-ammonium chloride In water; acetone at 40 - 50℃; for 1h; Product distribution / selectivity;	78%
With sodium periodate; ruthenium(III) trichloride hydrate; potassium hydroxide In water at 0℃;
Stage #1: lorsartan With sodium periodate; ruthenium (III) chloride monohydrate; potassium hydroxide In water at 0℃; Stage #2: In water; isopropyl alcohol at 25℃; for 2.5h; Stage #3: With phosphoric acid In water; isopropyl alcohol at 30℃; for 0.5h;
With cytochrome P450 2C9 Enzymatic reaction;
With cytochrome b5; NADPH In aq. phosphate buffer at 37℃; for 0.75h; Kinetics; Reagent/catalyst; Enzymatic reaction;

losartan potassium (124750-99-8) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Stage #1: losartan potassium With pyridine; potassium permanganate; tetrabutyl-ammonium chloride In water; acetone at 40 - 50℃; for 1h; Stage #2: With hydrogenchloride In water; acetone Product distribution / selectivity;	72%
Stage #1: losartan potassium With potassium hydroxide In water at 2℃; for 2h; Stage #2: With sodium periodate; ruthenium trichloride In water at 4 - 6.5℃; for 19h;

cozaar (124750-99-8) → 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6) + 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With manganese(IV) oxide In water at 80 - 180℃; for 0.833333h; microwave irradiation;	A 0.253 mmol B 64%
With manganese(IV) oxide In water at 80 - 180℃; for 0.25h; microwave irradiation;	A 60% B n/a

2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With potassium permanganate; potassium hydroxide In water; N,N-dimethyl-formamide at 20 - 30℃; for 2h; Large scale;

2-n-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide; sodium hydroxide / toluene / 20 h / 60 °C 2: sodium azide; trimethylamine hydrochloride / toluene; 1-methyl-pyrrolidin-2-one / 43 h / 60 °C 3: sodium hydroxide / ethanol / 20 h / 90 °C View Scheme

4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide; sodium hydroxide / toluene / 20 h / 60 °C 2: sodium azide; trimethylamine hydrochloride / toluene; 1-methyl-pyrrolidin-2-one / 43 h / 60 °C 3: sodium hydroxide / ethanol / 20 h / 90 °C View Scheme

Upstream product

• 133910-00-6 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde 
• 124750-99-8 cozaar 
• 114798-36-6 EXP 3179 
• 947330-97-4 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-methyl]imidazole-5-carboxylic acid ethyl ester 
• 114772-54-2 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 
• 114798-36-6 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde 
• 124750-99-8 losartan potassium 
• 114798-26-4 lorsartan 
• 114798-26-4 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 

Downstream Products

• 1070174-98-9 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl]-1H-imidazole-5-carboxylic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester 
• 2387-23-7 1,3-Dicyclohexylurea 
• 1070174-99-0 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-1H-imidazole-5-carboxylic acid 2-(methylsulfonylthio)ethyl ester 
• 1185768-61-9 (3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl {[(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)carbonyl]amino}acetate 
• 1370339-86-8 2-n-butyl-5-chloro-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid[3-(3,4-bis-benzyloxyphenyl)propyl]amide 
• 1200445-28-8 1-(((3R,3aR,6R,6aR)-6-(5,6-bis(nitrooxy)hexanoyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)carbonyloxy)ethyl 1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylate 
• 1186124-18-4 1-[({[(R)-5-(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 1186123-58-9 1-[({[(R)-5-(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 947331-05-7 Allisartan 
• 947331-10-4 2-butyl-4-chloro-1-((2'-(2-trityl-2H-tetrazol-5-yl)[biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid 
• 1034453-56-9 (5S)-5,6-bis(nitrooxy)hexyl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 960231-60-1 2-butyl-4-chloro-1-{[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid 
• 913611-26-4 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid hydrochloride 
• 1185768-56-2 (S)-((R)-5,6-bis(nitrooxy)hexyl) 2-(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxamido)-3-phenylpropanoate 

Relevant articles and documents

Design, synthesis and antihypertensive evaluation of novel codrugs with combined angiotensin type 1 receptor antagonism and neprilysin inhibition

The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.

MANUFACTURING METHOD OF LOSARTAN METABOLITE EXP-3174

The present invention provides a manufacturing method capable of manufacturing a losartan metabolite EXP-3174 with high purity and high yield using inexpensive starting materials and under mild reaction conditions. The losartan metabolite EXP-3174 is represented by chemical formula 5.

Preparing method for EXP-3174

The invention discloses a preparing method for EXP-3174. The preparing method is characterized in that losartan is used as a starting raw material and is prepared into EXP-3174 through two-step oxidation. The preparing method has the greatest advantages that a reaction is moderate, the number of side reactions is small, aftertreatment is simple, and EXP-3174 with the purity of 99.9% can be obtained without column chromatography isolation.