65141-46-0

Basic information

• Product Name: Nicorandil
• Synonyms: n-[2-(nitroxy)ethyl]-3-pyridinecarboxamide;N-[2-(NITROOXY)ETHYL]-3-PYRIDINECARBOXAMIDE;NICORANDIL;PERISALOL;SIGMART;IKOREL;ADANCOR;2-nicotinamidoethylnitrate
• CAS NO: 65141-46-0
• Molecular Formula: C₈H₉N₃O₄
• Molecular Weight: 211.17
• EINECS: 265-514-1
• Product Categories: Pharmaceutical;Intermediates & Fine Chemicals;Pharmaceuticals;Potassium channel;Aromatics;Heterocycles;Ikorel;reagent;Cardiovascular APIs
• Mol File: 65141-46-0.mol
• Article Data: 11

Chemical Properties

• Melting Point: 92°C
• Boiling Point: 350.85°C (rough estimate)
• Flash Point: 230 °C
• Appearance: white to off-white/
• Density: 1.4271 (rough estimate)
• Vapor Pressure: 1.58E-08mmHg at 25°C
• Refractive Index: 1.7400 (estimate)
• Storage Temp.: Desiccate at +4°C
• Solubility: DMSO: >10mg/mL
• PKA: pKa 空 (Uncertain)
• Merck: 14,6521
• CAS DataBase Reference: Nicorandil(CAS DataBase Reference)
• NIST Chemistry Reference: Nicorandil(65141-46-0)
• EPA Substance Registry System: Nicorandil(65141-46-0)

Safety Data

• Hazard Codes: Xn
• Statements: 22-41
• Safety Statements: 26-39
• WGK Germany: 3
• RTECS: US4667600
• Hazardous Substances Data: 65141-46-0(Hazardous Substances Data)

Usage

Chemical Properties

Nicorandil is N-(2-hydroxyethyl)-nicotinamide nitrate (ester). It is a white crystalline powder or white needles with a faint, characteristic odour. It is freely soluble in methanol, ethanol, acetone or glacial acetic acid, slightly soluble in chloroform or water, almost insoluble in ether or benzene. Melting point 88.5-93.5 ℃. Acute toxicity LD50 rat (mg/kg): 1200-1300 orally, 800-1000 intravenously.

Uses

Nicorandil is a vasodilator used for the prophylaxis and treatment of angina. This medication widens blood vessels thus increasing the blood and oxygen flow to the heart. It is not currently available in the US.Nicorandil is a nitric oxide donor and ATP-sensitive potassium channel opener. A study showed that Nicorandil is able to protect against stress-induced cell death in dystrophin-deficient cardiomyocytes and also preserve cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury.

Definition

ChEBI: Nicorandil is a pyrimidinecarboxamide that is nicotinamide in which one of the hydrogens attached to the carboxamide nitrogen is replaced by a 2-(nitrooxy)ethyl group. It has both nitrate-like and ATP-sensitive potassium channel activator properties, and is used for the prevention and treatment of angina pectoris. It has a role as a vasodilator agent and a potassium channel opener. It is a pyridinecarboxamide and a nitrate ester. It derives from a nicotinamide.

Preparation

Nicorandil is obtained by treating nicotinic acid chloride hydrochloride with nitro-oxy-ethyl-amine nitrate in an organic solvent.Nicorandil was synthesized from 2-aminoethanol by a four step process. In order to protect the amino group during nitration, 2-aminoethanol was first treated with phthalic anhydride. The amide formed was then nitrated using a nitrating mixture and was subsequently deprotected by reacting with hydrazine hydrate. The 2- nitroxyethylamine obtained was condensed with nicotinoyl chloride in pyridine. Treatment with aqueous sodium bicarbonate solution gave nicorandil as free base.synthesis of Nicorandil

Brand name

SIGMART; PERISALOL

Biochem/physiol Actions

Nicorandil is a hybrid ATP-sensitive K+ (KATP) channel opener and nicotinamide nitrate NO donor. Nicorandil selectively activates SUR2B- versus SUR2A-containing KATP channels. It enhances endothelial NO synthase expression and protects against ischemic ventricular arrhythmias. By activating potassium channels, and donating nitric oxide to activate the enzyme guanylate cyclase, Nicorandil causes activation of GMP leading to both arterial and venous vasodilatation. Nicorandil is selective for vascular potassium channels, but has no significant action on cardiac contractility and conduction.

Clinical Use

Nicorandil is used for the prevention and treatment of chronic stable angina. It is usually used when angina becomes difficult to control by other drugs and is given as an additional treatment.

Drug interactions

Potentially hazardous interactions with other drugs Avanafil, sildenafil, tadalafil and vardenafil: enhanced hypotensive effect - avoid. Riociguat: possible enhanced hypotensive effect - avoid.

Metabolism

Metabolism of nicorandil is mainly by denitration of the molecule into the nicotinamide pathway. About 20% of a dose is excreted in the urine mainly as metabolites

Mode of action

The coronary vasodilating activity of nicorandil is considered to be the consequence of the increasing cyclic GMP production by stimulating guanylyl cyclase in the coronary vascular smooth muscle, similar to other nitrates/nitrites (in vitro). In addition, other mechanisms such as hyperpolarization of the cell membrane were investigated concerning its coronary blood flowincreasing and coronary vasospasmolytic effects.The vasorelaxant effect of nicorandil in isolated blood vessels is suppressed by an ATP-sensitive K channel blocker or a guanylate cyclase inhibitor. Moreover, in a canine model of acute heart failure, the cardiac haemodynamics-improving effect of the drug (e.g. effect of increasing the aortic blood flow) was suppressed by an ATP-sensitive K channel blocker. Furthermore, the drug caused an increase in the cGMP content in isolated blood vessels. These facts suggest that the vasodilating effect of the drug is related to the effect of opening the ATP-sensitive K channel, as well as to the effect of increasing production of cGMP.

InChI:InChI=1/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12)

Synthetic route

N-(2-hydroxyethyl)nicotinamide (6265-73-2) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With nitric acid; urea; europium(III) trifluoromethanesulfonate at 70℃; for 6h; Schlenk technique;	86%
With nitric acid; propionic acid; propionic acid anhydride at 0 - 30℃; for 3.5h; Temperature;	85.9%
With nitric acid at -5℃; for 2h;	40%
Stage #1: N-(2-hydroxyethyl)nicotinamide With nitric acid; acetic anhydride; acetic acid at 15 - 22℃; Inert atmosphere; Stage #2: With ammonia In water at 5 - 35℃; for 1h; Product distribution / selectivity;

2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) + isopentyl nitrite (110-46-3) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
In 1,4-dioxane at 100℃; for 5h;	80%

2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With tert.-butylnitrite; oxygen In 1,4-dioxane at 60℃; Sealed tube; Green chemistry;	73%

tert.-butylnitrite (540-80-7) + 2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
In toluene at 100℃; for 5h;	60%

pyridine-3-carbonyl chloride hydrochloride (20260-53-1) + 2-nitroxyethylammonium nitrate (4665-58-1) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With pyridine at 5 - 20℃; Inert atmosphere;
Stage #1: pyridine-3-carbonyl chloride hydrochloride; 2-nitroxyethylammonium nitrate With pyridine at 5 - 20℃; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In chloroform

3-pyridinecarboxylic acid ethyl ester (614-18-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 18 h / 20 - 55 °C 2: nitric acid / 2 h / -5 °C View Scheme

pyridine-3-carbonitrile (100-54-9) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: zinc(II) chloride / chlorobenzene / 36 h / Inert atmosphere; Reflux 2: tert.-butylnitrite; oxygen / 1,4-dioxane / 60 °C / Sealed tube; Green chemistry View Scheme

3-pyridinecarboxaldehyde (500-22-1) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetra-N-butylammonium tribromide / ethanol / 1 h / 20 °C 2: 1,4-dioxane / 5 h / 100 °C View Scheme

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + salicylic acid (69-72-7) → C8H9N3O4*C7H6O3

Conditions	Yield
In water; acetonitrile Solvent;	95%
In water at 20℃; for 48h;	55.9%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + N-(2-nitroxyethyl)isonicotinamide (65141-47-1) + palladium dichloride → trans-[(2-nitroxyethyl)isonicotinamide-N'][(2-nitroxyethyl)nicotinamide-N]dichloropalladium(II)

Conditions	Yield
With conc. HCl In ethanol; water aq. soln. of PdCl2 added to a soln. of equimolar amts. of the ligands ina mixt.of EtOH:H2O (3:1) at 20-30°C; then conc. HCl added to pH 2-2.5; stirred for 2 h; ppt. filtered off, washed with water and EtOH, and dried in air; elem. anal.;	94%

potassium tetrachloroplatinate(II) (10025-99-7) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → PtCl2(C8H9N3O4)2 (203808-46-2)

Conditions	Yield
In water ppt. washing (H2O, EtOH, Et2O); elem. anal.;	92%

rhodium(II) pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → [(NC5H4C(O)NHCH2CH2ONO2)2Rh2(OOCC(CH3)3)4] (186506-79-6)

Conditions	Yield
In tetrahydrofuran room temperature, pure Ar atmosphere; soln. evapn. to 1/3, crystals filtration off, air drying, recrystn. (THF); elem. anal.;	90%

iodomethyl isopropylcarbamate (1402915-01-8) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridine-1-ium iodide (1402916-59-9)

Conditions	Yield
In acetonitrile at 20℃;	88%
In acetonitrile at 20℃;	88%

sodium tetrachloroplatinate(II) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) + N-(2-nitroxyethyl)isonicotinamide (65141-47-1) → trans-[(2-nitroxyethyl)isonicotinamide-N'][(2-nitroxyethyl)nicotinamide-N]dichloroplatinum(II) (365515-47-5)

Conditions	Yield
In ethanol; water aq. soln. of Pt complex added to a soln. of equimolar amts. of the ligands in 60% aq. EtOH at 20-30°C; stirred for 11 h; ppt. filtered off, washed with water and EtOH, and dried in air; elem. anal.;	86%

iodomethyl diisopropylcarbamate (353736-55-7) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	85%

iodomethyl 1-piperidinyl carbamate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 3-((2-(nitrooxy)ethyl)carbamoyl)-1-(((piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	84%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + ethoxycarbonyloxymethyl iodide (82619-14-5) → 1-(((ethoxycarbonyl)oxy)methyl)-3 -((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	77%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + 1-hydroxy-2-naphthoic acid (86-48-6) → nicorandil 1-hydroxy-2-naphthoic acid

Conditions	Yield
In water at 20℃; for 48h;	75.8%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + copper(ll) bromide (7789-45-9) → (NC5H4C(O)NHCH2CH2ONO2)2CuBr2 (186506-76-3)

Conditions	Yield
In tetrahydrofuran pure Ar atmosphere, stirring (3 h), volume reduction (30-40°C, 0.1 torr), cooling to 5°C; ppt. washing (CH2Cl2), vacuum drying, recrystn. (2x, THF); elem. anal.;	70.5%

copper(II) pivalate dimer + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → [(NC5H4C(O)NHCH2CH2ONO2)2Cu2(OOCC(CH3)3)4] (186506-77-4)

Conditions	Yield
In tetrahydrofuran; benzene THF soln. of ligand addn. to benzene soln. of Cu-compd., pure Ar atmosphere; volume redn., recrystn. (THF); elem. anal.;	70%

isopropyloxycarbonyloxymethyl iodide (258841-42-8) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	60%

2,5-dihydroxybenzoic acid. (490-79-9) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → C7H6O4*C8H9N3O4

Conditions	Yield
In water at 20℃; for 48h;	54.7%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + tert-butyl (iodomethyl) carbonate (184373-03-3) → 1-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
	54%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + 3-Carboxyphenol (99-06-9) → C7H6O3*C8H9N3O4

Conditions	Yield
In water at 20℃; for 48h;	42%

[Ni9(HOOCCMe3)4(μ4-O)3(μ3-OH)3(μ-O,O-OOCCMe3)(μ-O,O'-OOCCMe3)7(μ3-O,O,O'-OOCCMe3)3(μ4-O,O,O',O'-OOCCMe3)] + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (C5H4NC(O)NHCH2CH2ONO2)4Ni2((CH3)3CCOO)4(OH)*C4H8O*2H2O

Conditions	Yield
In toluene stirring (20°C, 0.5 h); evapn., extn. (THF/benzene), crystn. (5°C); elem. anal.;	40%

1-iodoethyl diisopropylcarbamate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(1-((diisopropylcarbamoyl)oxy)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	35%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + methyl iodide (74-88-4) → 1-(2-(nicotinamido)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridine-1-indole iodide

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 336h; pH=7.0 - 9.0; Solvent; Cooling with ice;	2.25%

methyl bromide (74-83-9) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(2-(nicotinamido)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridine-1-indole iodide

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 240h; pH=7.0 - 9.0; Darkness;	1.9%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6)

Conditions	Yield
In sodium hydroxide at 60℃; for 5h;	60 mg
at 60℃; for 7h; Rate constant; Mechanism; Thermodynamic data; variation of pH; Δ Eexcit;

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 2-aminoethyl nicotinate nitrate (88598-33-8)

Conditions	Yield
With water at 70℃; for 4h;	40 mg

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → Polymer, M.w. 30,000-50,000; Monomer(s): N-(2-nitroxyethyl)nicotinamide + Polymer, M.w. 1000; Monomer(s): 2-(3-pyridyl)-4,5-dihydrooxazole

Conditions	Yield
at 70℃; for 72h; Polymerization;

cobalt pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (nicorandil)Co(μ-OOCCMe3)4Co(nicorandil) (251911-24-7)

Conditions	Yield
In tetrahydrofuran; toluene THF soln. of ligand addn. to THF soln. of Co-compd., boiling (15 min), solvent complete removal, residue dissoln. in boiling toluene, volume reduction (Ar flow), slow cooling to room temperature; ppt. sepn., washing (hexane), drying (Ar flow, room temperature);

cobalt pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (nicorandil)2(OOCCMe3)Co(μ-OH2)(μ-OOCCMe3)2Co(OOCCMe3)(nicorandil)2

Conditions	Yield
In water soln. of ligand addn. to soln. of Co-compd., soln. keeping at room temperature (5 d); solvent removal; elem. anal.;

Upstream product

• 20260-53-1 pyridine-3-carbonyl chloride hydrochloride 
• 4665-58-1 2-nitroxyethylammonium nitrate 
• 614-18-6 3-pyridinecarboxylic acid ethyl ester 
• 540-80-7 tert.-butylnitrite 
• 40055-37-6 2-(pyridin-3-yl)-4,5-dihydrooxazole 
• 110-46-3 isopentyl nitrite 
• 500-22-1 3-pyridinecarboxaldehyde 
• 100-54-9 pyridine-3-carbonitrile 
• 6265-73-2 N-(2-hydroxyethyl)nicotinamide 

Downstream Products

• 65141-45-9 nicorandil hydrochloride 
• 40055-37-6 2-(pyridin-3-yl)-4,5-dihydrooxazole 

Relevant articles and documents

Preparation method of Nicodil

The invention discloses a preparation method of Nicorandil, the preparation method comprises the following steps: directly synthesizing N-(2-ethoxyl) nicotinamide by taking nicotinamide as an initial raw material through a transamidation method, and nitrifying by using a mixture of non-fuming nitric acid, acetic anhydride and concentrated sulfuric acid to obtain Nicorandil. The method simplifies the existing synthesis process, is easy and convenient to operate and is more suitable for large-scale production; meanwhile, the yield of products obtained in each step of reaction is increased, the types and the dosage of reaction reagents are greatly reduced, and the production cost is lower. The technical problems of more reaction steps, high reagent consumption, low production efficiency, serious environmental pollution, poor quality of the prepared product and low yield of the existing preparation process are solved.

Practical catalytic nitration directly with commercial nitric acid for the preparation of aliphatic nitroesters

To pursue a sustainable and efficient approach for aliphatic nitroester preparation from alcohol, europium-triflate-catalyzed nitration, which directly uses commercial nitric acid, has been successfully developed. Gram scalability with operational ease showed its practicability.

Highly efficient synthesis of β-nitrate ester carboxamides through the ring-opening of 2-oxazolines

A novel method for the synthesis of β-nitrate ester carboxamides using non-corrosive tert-butyl nitrite (TBN) as the nitro source and easily available oxygen as the oxidant has been developed. Variously substituted 2-oxazolines were efficiently ring-opened to deliver the corresponding products in excellent yields. Notably, this reaction provides fast access to pharmaceuticals such as nicorandil.