123524-52-7

Basic information

• Product Name: Azelnidipine
• Synonyms: 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-[1-(diphenylmethyl)-3-azetidinyl] 5-(methylethyl) ester;AZELNIDIPINE;3-[1-(Diphenylmethyl)-3-azetidinyl]-5-(1-methylethyl-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate;AzelnidipineC33H34N406;AZELINIDIPINE;AZELNIDIPINE(FORR&DONLY);CS-905, RS-9054, 2-Amino-1,4-dihydro-6-methyl-4-(3 nitrophenyl)-3,5-pyridinedicarboxylic acid 3-[1-(diphenylmethyl)-3-azetidinyl] 5-(1-methylethyl) ester;Azelidipine
• CAS NO: 123524-52-7
• Molecular Formula: C₃₃H₃₄N₄O₆
• Molecular Weight: 582.65
• EINECS: 1806241-263-5
• Product Categories: API;Cardiovascular Drugs;Inhibitors
• Mol File: 123524-52-7.mol

Chemical Properties

• Melting Point: 120-126°C
• Boiling Point: 709.3 ºC at 760 mmHg
• Flash Point: 382.8 ºC
• Appearance: light yellowish powder
• Density: 1.33 g/cm³
• Vapor Pressure: 5.74E-20mmHg at 25°C
• Refractive Index: 1.658
• Storage Temp.: Room temp
• Solubility: DMSO: >10mg/mL
• PKA: 7.89(at 25℃)
• Merck: 14,907
• CAS DataBase Reference: Azelnidipine(CAS DataBase Reference)
• NIST Chemistry Reference: Azelnidipine(123524-52-7)
• EPA Substance Registry System: Azelnidipine(123524-52-7)

Safety Data

• Hazard Codes: Xn
• Statements: 22-41
• Safety Statements: 26-39
• WGK Germany: 3
• RTECS: US7968332
• Hazardous Substances Data: 123524-52-7(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Applications:
Azelnidipine is used as an antihypertensive agent for treating hypertension. It helps in reducing systolic and diastolic blood pressure in patients with mild-to-moderate hypertension, providing a sustained decrease in blood pressure without causing reflex tachycardia, a common side effect of this class of drugs.
Used in Ischemic Heart Disease Treatment:
Azelnidipine is used as a treatment for ischemic heart disease and cardiac remodeling after myocardial infarction. Its slow onset and long-lasting effect make it an effective option for managing these conditions.
Used in Metabolic Disorders Prevention:
Azelnidipine is used to reduce the risk of hyperglycemia-induced metabolic disorders. Studies show that treatment with Azelnidipine can help in preventing such complications.
Used in Atherosclerosis Inflammation Protection:
Azelnidipine may have a protective role in inflammation associated with atherosclerosis, making it a potential treatment option for patients with this condition.
Used in Cardiac Function Maintenance:
Azelnidipine is used to prevent a sudden drop in cardiac function after acute stress, providing support for maintaining cardiac function during critical situations.
Application Industry:
Pharmaceutical Industry: Azelnidipine is used in the development and production of antihypertensive medications, as well as treatments for ischemic heart disease, metabolic disorders, and atherosclerosis inflammation.
Brand Name:
Calblock

Originator

Sankyo (Japan)

Biological Activity

Azelnidipine, a novel dihydropyridine derivative, is a L-type calcium channel blocker and antihypertensive. Unlike other L-type calcium channel blockers, azelnidipine causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. Azelnidipine may have a protective role in inflammation in atherosclerosis.

Synthesis

A solution of benzhydrylamine (46) and epichlorohydrin (47) was mixed without adding solvent to give azetidinol 48 in 57% yield. DCC coupling between cyanoacetic acid (49) and azetidinol 48 in hot THF gave ester 50 in 93% yield. Cyanoester 50 was treated with ethanol and HCl gas in chloroform to give imidate HCl salt 51, which was treated with ammonia gas in chloroform and ammonium acetate in acetonitrile to give the corresponding amidinoacetate 52. A modified Hantzsch reaction was employed to construct the 2-amino-1,4- dihydropyridine core structure. Compound 52 was condensed with 2-(3-nitrobenzylidene)acetic acid isopropyl ester (55) in the presence of NaOMe in refluxing isopropanol to give the cyclized product, azelnidipine (V) in 74% yield. Benzylideneacetoacetate 55 was obtained through the Knoevenagel reaction employing 3-nitrobenzaldehyde (53) and isopropyl acetoacetate (54) in isopropanol containing a catalytic amount of piperidinium acetate at 45-55oC in 65% yield.

InChI:InChI=1/C33H34N4O6/c1-20(2)42-32(38)27-21(3)35-31(34)29(28(27)24-15-10-16-25(17-24)37(40)41)33(39)43-26-18-36(19-26)30(22-11-6-4-7-12-22)23-13-8-5-9-14-23/h4-17,20,26,28,30,35H,18-19,34H2,1-3H3

Synthetic route

3-oxo-2-(3-nitrophenylmethylene)butanoic acid isopropyl ester (39562-25-9) + 1-benzhydrylazetidin-3-yl 3-amino-3-iminopropanoate acetate → azelnidipine (123524-52-7)

Conditions	Yield
With sodium amide In toluene for 4h; Reflux;	90.01%
With sodium methylate In isopropyl alcohol for 4h; Heating;	74%
With sodium methylate In isopropyl alcohol for 4h; Heating / reflux;	74%

isopropyl 3-aminocrotonate (14205-46-0) + C26H23N3O5 → azelnidipine (123524-52-7)

Conditions	Yield
With sodium methylate In ethanol for 6h; Reflux;	89%

isopropyl acetoacetate (542-08-5) → azelnidipine (123524-52-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / piperidinium acetate / propan-2-ol / 1 h / 45 - 55 °C 2: 74 percent / sodium methoxide / propan-2-ol / 4 h / Heating View Scheme

3-nitro-benzaldehyde (99-61-6) → azelnidipine (123524-52-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid; piperidine / ethanol / 24 h / 20 - 30 °C 2: potassium hydroxide / ethanol; water / 6 h / Reflux 3: dicyclohexyl-carbodiimide / tetrahydrofuran / 10 h / 60 - 70 °C 4: sodium methylate / ethanol / 6 h / Reflux View Scheme

2-cyano-3-(3'-nitro-1'-phenyl)acrylic acid (5468-46-2) → azelnidipine (123524-52-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide / ethanol; water / 6 h / Reflux 2: dicyclohexyl-carbodiimide / tetrahydrofuran / 10 h / 60 - 70 °C 3: sodium methylate / ethanol / 6 h / Reflux View Scheme

C10H8N2O5 → azelnidipine (123524-52-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 10 h / 60 - 70 °C 2: sodium methylate / ethanol / 6 h / Reflux View Scheme

toluene-4-sulfonic acid (104-15-4) + azelnidipine (123524-52-7) → Azelnidipine tosylate

Conditions	Yield
In ethyl acetate at 25℃; for 1h;	100%

azelnidipine (123524-52-7) → Azelnidipine dihydrochloride

Conditions	Yield
With hydrogenchloride In chloroform at 25℃; for 0.0833333h; Product distribution / selectivity;	100%
With hydrogenchloride In water; ethyl acetate at 25℃; for 1h; Product distribution / selectivity;	92%

azelnidipine (123524-52-7) + benzenesulfonic acid (98-11-3) → Azelnidipine dibenzenesulfonate

Conditions	Yield
In ethyl acetate at 25℃; for 1h;	99%

methanesulfonic acid (75-75-2) + azelnidipine (123524-52-7) → Azelnidipine dimesylate

Conditions	Yield
In ethyl acetate at 25℃; for 1h;	97%

methanesulfonic acid (75-75-2) + azelnidipine (123524-52-7) → Azelnidipine trimesylate

Conditions	Yield
In ethyl acetate at 25℃; for 1h;	97%

naphthalene-2-sulfonate (120-18-3) + azelnidipine (123524-52-7) → Azelnidipine napsylate

Conditions	Yield
In ethyl acetate at 2 - 25℃; for 97h;	97%

(2E)-but-2-enedioic acid (110-17-8) + azelnidipine (123524-52-7) → 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester hemifumarate

Conditions	Yield
In tetrahydrofuran; ethyl acetate at 25℃; for 0.833333h;	93%

azelnidipine (123524-52-7) → 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester monosulfate

Conditions	Yield
With sulfuric acid In acetone at 25℃; for 2.83333h;	92%

azelnidipine (123524-52-7) + citric acid (77-92-9) → Azelnidipine citrate (938439-89-5)

Conditions	Yield
In acetone at 25℃; for 1.16667h;	79%

azelnidipine (123524-52-7) → Azelnidipine dihydrobromide

Conditions	Yield
With hydrogen bromide In methanol; water at 25℃; for 1h;	78%

azelnidipine (123524-52-7) → (-)-Azelnidipine (722455-08-5) + (+)-Azelnidipine (722455-09-6)

Conditions	Yield
at 25℃; Purification / work up;

maleic acid (110-16-7) + azelnidipine (123524-52-7) → azelnidipine-maleic acid complex

Conditions	Yield
In ethanol; water at 25℃; Thermodynamic data; Temperature;

azelnidipine (123524-52-7) → 3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (918659-10-6)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 20℃; for 5h; Inert atmosphere;	800 mg

azelnidipine (123524-52-7) → aminoazelnidipine

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethyl acetate

azelnidipine (123524-52-7) → C33H36N4O8

Conditions	Yield
Stage #1: azelnidipine With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -10℃; for 0.666667h; Stage #2: With sodium hydrogensulfite In dichloromethane; water for 0.333333h; Temperature;

Upstream product

• 39562-25-9 3-oxo-2-(3-nitrophenylmethylene)butanoic acid isopropyl ester 
• 170749-59-4 1-benzhydrylazetidin-3-yl 3-amino-3-iminopropanoate acetate 
• 5468-46-2 2-cyano-3-(3'-nitro-1'-phenyl)acrylic acid 
• 99-61-6 3-nitro-benzaldehyde 
• 14205-46-0 isopropyl 3-aminocrotonate 
• 542-08-5 isopropyl acetoacetate 

Downstream Products

• 722455-08-5 (-)-Azelnidipine 
• 722455-09-6 (+)-Azelnidipine 
• 918659-10-6 3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate 
• 938439-89-5 Azelnidipine citrate 

Related news

Spectroscopic studies on the interaction of Azelnidipine (cas 123524-52-7) with bovine serum albumin08/01/2019

Interaction between azelnidipine and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy and circular dichroism (CD). Azelnidipine effectively quenched the intrinsic fluorescence of BSA via a combination of static and dynamic quenching, forming azelnidipine–BSA complex with...detailed

Enantioselective determination of Azelnidipine (cas 123524-52-7) in human plasma using liquid chromatography–tandem mass spectrometry07/31/2019

A sensitive and simple method was developed for determination of the enantiomers of azelnidipine, (R)-(−)-azelnidipine and (S)-(+)-azelnidipine, in human plasma using chiral liquid chromatography with positive ion atmospheric pressure chemical ionization tandem mass spectrometry. Plasma samples ...detailed

Effect of Azelnidipine (cas 123524-52-7) and amlodipine on single cell mechanics in mouse cardiomyocytes07/30/2019

Azelnidipine and amlodipine are dihydropyridine-type Ca2+ channel blockers for the treatment of hypertension. Although these drugs have high vasoselectivity and small negative inotropic effects in vivo, little is known regarding their direct effects on cellular contractility without humoral regu...detailed

Acute effects of intravenous nifedipine or Azelnidipine (cas 123524-52-7) on open-loop baroreflex static characteristics in rats07/29/2019

AimsTo assess the acute effects of intravenous azelnidipine, a third-generation L-type calcium channel blocker, on sympathetic outflow from the central nervous system and to compare the effects of intravenous azelnidipine with those of intravenous nifedipine.detailed

Olmesartan with Azelnidipine (cas 123524-52-7) versus with trichlormethiazide on home blood pressure variability in patients with type II diabetes mellitus07/28/2019

The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an ope...detailed

Solid state characterization of Azelnidipine (cas 123524-52-7)–oxalic acid co-crystal and co-amorphous complexes: The effect of different Azelnidipine (cas 123524-52-7) polymorphs07/27/2019

In present study, based on the two polymorphs (α and β form) of azelnidipine (AZE), 12 complexes of AZE and oxalic acid (OXA) were prepared by solvent-assisted grinding (SG) and neat powder grinding (NG) methods at the AZE/OXA molar ratios of 2:1, 1:1, and 1:2. The effect of the different poly...detailed

Inhibitory effects of losartan and Azelnidipine (cas 123524-52-7) on augmentation of blood pressure variability induced by angiotensin II in rats07/26/2019

Increased blood pressure variability has been shown to be associated with cardiovascular morbidity and mortality. Recently we reported that continuous infusion of angiotensin II not only elevated blood pressure level, but also increased blood pressure variability in a manner assumed to be indepe...detailed

Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by Azelnidipine (cas 123524-52-7) and manidipine07/24/2019

The inhibitory effects of antihypertensive drugs (dihydropyridine calcium channel blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors) on cytochrome P450 2J2 (CYP2J2) activity were examined. Amlodipine, azelnidipine, barnidipine, benidipine, cilnidipine, efon...detailed

Improved bioavailability of Azelnidipine (cas 123524-52-7) gastro retentive tablets-optimization and in-vivo assessment07/23/2019

Azelnidipine, dihydropyridine based calcium channel blocker has been used for treating ischemic heart disease and cardiac remodeling after myocardial infarction but it is having a low bioavailability due to its poor solubility. The present study is to investigate the formulation and evaluation o...detailed

Relevant articles and documents

Azelnidipine preparation method (by machine translation)

The invention relates to a blood pressure lowering medicine azhediping preparation method, which belongs to the field of medicine. The method of the traditional synthetic route trunk compound 4 of the improved synthetic conditions, of the original anhydrous reaction conditions is changed into the water under the conditions of the reaction, not only is easy to operate, but also to reduce the requirement of anhydrous reaction solvent, thus very suitable for industrial production. (by machine translation)

Preparation method of azelnidipine

The invention relates to a preparation method of azelnidipine, which comprises the following steps: carrying out Knoevenagel reaction on cyanoacetic acid and m-nitrobenzaldehyde used as starting materials to generate a compound 1; hydrolyzing cyano group of the compound 1 to generate a compound 2; carrying out esterification on the compound 2 and 1-diphenylmethyl-3-azetidin-ol under the action of DCC (N,N'-dicyclohexylcarbodiimide) to generate a compound 3; carrying out Hantzsch cyclization on the compound 3 and isopropyl 3-aminocrotonate under alkaline conditions to generate an azelnidipine crude product; and refining the crude product to obtain the azelnidipine fine product. The method is simple to operate and suitable for industrial production; and the reaction product is easy to separate.

OPTICALLY ACTIVE DIHYDROPYRIDINE DERIVATIVE

The optically active dihydropyridine derivative is (R)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester or a pharmacologically acceptable salt thereof.

Novel 2-amino-1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having N,N-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-positions

Novel 2-amino-1,4-dihydropyridine derivatives I, which contain N,N-dialkylaminoalkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their antihypertensive effects were evaluated in spontaneously hypertensive rats. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced into either the 3- or 5-ester side-chain of the 1,4-dihydropyridine ring. In particular, the compounds containing cyclic amino moieties at the 3-position showed greater potency than those with acyclic amino moieties. Chemical modification studies indicated that the two ester side-chains of 1,4-dihydropyridine at the 3- and 5-position might function in a different manner in relation to the antihypertensive activities. 3-(1-Benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxyl ate, I-43 (CS-905), exhibited potent and long-lasting antihypertensive effects with gradual onset of action, and is a promising candidate as an antihypertensive drug.

Dihydropyridine derivatives, their preparation and their use

2-(Amino or methyl)-6-(methyl or amino)-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid esters have a specific class of heterocyclic groups as thealcohol moiety. These compounds have a variety of valuable activities, including antihypertensive and Ca++ -blocking activities, leading to their use for the treatment of circulatory and coronary disorders. They may be prepared by condensation of appropriate substituted benzylideneacetoacetic acid esters with appropriate amidinoacetic acid esters.