55985-32-5

Basic information

• Product Name: Nicardipine
• Synonyms: NicardipineBase;Nicardipine Hcl 54527-84-3 / Base;1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-[methy(phenyl-methyl)amino]ethyl ester hydrochloride;Nicardipine (base and/or unspecified salts);Methyl 2-(benzyl-methyl-amino)ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-[2-[methyl(benzyl)amino]ethyl]5-methyl ester;2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid 3-methyl 5-[2-[methyl(benzyl)amino]ethyl] ester;2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-[2-(N-methylbenzylamino)ethyl] ester
• CAS NO: 55985-32-5
• Molecular Formula: C₂₆H₂₉N₃O₆
• Molecular Weight: 479.52
• EINECS: 259-932-3
• Product Categories: Active Pharmaceutical Ingredients
• Mol File: 55985-32-5.mol

Chemical Properties

• Melting Point: 136-138 °C
• Boiling Point: 603.4 °C at 760 mmHg
• Flash Point: 318.7 °C
• Appearance: /
• Density: 1.23 g/cm³
• Solubility: Dichloromethane; Methanol
• PKA: 7.30±0.50(Predicted)
• CAS DataBase Reference: Nicardipine(CAS DataBase Reference)
• NIST Chemistry Reference: Nicardipine(55985-32-5)
• EPA Substance Registry System: Nicardipine(55985-32-5)

Safety Data

• Hazardous Substances Data: 55985-32-5(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Applications:
Nicardipine is used as an antihypertensive agent for the treatment of arterial hypertension. Its vasodilatory effect helps lower blood pressure and reduce the strain on the heart, providing relief from hypertension-related symptoms.
Used in Angina Management:
Nicardipine is used as an antianginal agent to prevent and manage angina pectoris, a condition characterized by chest pain due to insufficient blood supply to the heart. By dilating blood vessels, it improves blood flow to the heart muscle, alleviating angina symptoms.
Used in Neuroprotection and Neuroresearch:
Nicardipine is utilized in the field of neuroprotection and neuroresearch due to its ability to improve blood flow to the brain. It is particularly useful in treating ischemic-type abnormalities of brain blood flow, which can lead to conditions such as stroke or transient ischemic attacks (TIAs). Its vasodilatory properties help enhance cerebral blood flow, providing neuroprotective benefits and supporting research in neuroscience.

Originator

Nicodel,Mitsui,Japan,1981

Manufacturing Process

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of β-aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20:1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1-2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3'-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylester-5-β-(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°C to 140°C (decomposed).

Therapeutic Function

Vasodilator

Mechanism of action

Nicardipin relaxes smooth musculature of vessels, lowers resistance of coronary and peripheral vessels, increases blood flow in vessels of the brain, causes a moderate and stable hypotensive effect, and reduces the myocardial need for oxygen.

Synthesis

Nicardipine, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-methyl-2-[(methylphenylmethyl)- amino]ethyl ester 3,5-pirididincarboxylic acid (19.3.7), is synthesized in a manner analogous to the synthesis of nifedipine, the only difference being that in the Hantsch synthesis, two different β-dicarbonyl compounds are used simultaneously with o-nitrobenzaldehyde. During this, one of these in the enamine form of acetoacetic ester is simultaneously used as an amine component. A heterocyclization reaction is accomplished by reacting, the methyl ester of β-aminocrotonic acid with the 2-methyl-2-benzylaminoethyl ester of acetoacetic acid.

InChI:InChI=1/C26H29N3O6/c1-17-22(25(30)34-4)24(20-11-8-12-21(15-20)29(32)33)23(18(2)27-17)26(31)35-14-13-28(3)16-19-9-6-5-7-10-19/h5-12,15,24,27H,13-14,16H2,1-4H3

Synthetic route

2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-[2-(toluene-4-sulfonyloxy)-ethyl] ester (103785-48-4) + benzyl-methyl-amine (103-67-3) → Nicardipine (55985-32-5)

Conditions	Yield
for 8h; Heating;	77%

2-(N-benzyl-N-methyl)amino-1-ethanol (101-98-4) + (S)-1,1-Dibenzyl-3-[(R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3-carbonyloxy]-piperidinium; bromide → Nicardipine (55985-32-5)

Conditions	Yield
With potassium hydroxide In tetrahydrofuran at 25℃; for 24h;	67%

2-(N-benzyl-N-methyl)amino-1-ethanol (101-98-4) + (S)-1-Benzyl-3-[(R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3-carbonyloxy]-1-methyl-piperidinium; iodide → Nicardipine (55985-32-5)

Conditions	Yield
With potassium hydroxide In tetrahydrofuran at 25℃;	32%

2-(N-benzyl-N-methyl)amino-1-ethanol (101-98-4) + (S)-1-Allyl-1-benzyl-3-[(R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3-carbonyloxy]-piperidinium; bromide → Nicardipine (55985-32-5)

Conditions	Yield
With potassium hydroxide In tetrahydrofuran at 25℃;	26%

3-Imino-butyric acid methyl ester; compound with acetic acid + 2-Amino-4-(3-cyano-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-(3-nitrooxy-propyl) ester → Nicardipine (55985-32-5)

Conditions	Yield
With sodium methylate In isopropyl alcohol Heating;

(R)-2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-((S)-1-benzyl-piperidin-3-yl) ester 5-methyl ester → Nicardipine (55985-32-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / CHCl3 / Heating 2: 67 percent / KOH / tetrahydrofuran / 24 h / 25 °C View Scheme
Multi-step reaction with 2 steps 1: 95 percent / CHCl3 / Heating 2: 26 percent / KOH / tetrahydrofuran / 25 °C View Scheme
Multi-step reaction with 2 steps 1: 94 percent / acetone / 8 h / Heating 2: 32 percent / KOH / tetrahydrofuran / 25 °C View Scheme

3-nitrooxypropyl acetoacetate (88488-49-7) → Nicardipine (55985-32-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 38 percent / piperidine / benzene / 11 h / Heating 2: 30 percent / sodium methoxide / propan-2-ol / Heating 3: sodium methoxide / propan-2-ol / Heating View Scheme

3-nitroxypropyl 2-(3-cyanobenzylidene)acetoacetate (170748-98-8) → Nicardipine (55985-32-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 30 percent / sodium methoxide / propan-2-ol / Heating 2: sodium methoxide / propan-2-ol / Heating View Scheme

2-hydroxyethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (85677-95-8) → Nicardipine (55985-32-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / 1.) Et3N; 2.) H2O / tetrahydrofuran / 1.) 1 h; 2.) 0.5 h 2: 77 percent / 8 h / Heating View Scheme

(+)-2,6-dimethyl-3-methoxysulfonyl-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine → Nicardipine (55985-32-5)

Nicardipine (55985-32-5) + allyl bromide (106-95-6) → Allyl-benzyl-{2-[5-methoxycarbonyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3-carbonyloxy]-ethyl}-methyl-ammonium; iodide

Conditions	Yield
In chloroform Heating;	99%

Nicardipine (55985-32-5) + methyl iodide (74-88-4) → Benzyl-{2-[5-methoxycarbonyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3-carbonyloxy]-ethyl}-dimethyl-ammonium; iodide

Conditions	Yield
In acetone Heating;	93%

Nicardipine (55985-32-5) → 3-{2-[benzyl(methyl)amino]ethyl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (59875-58-0)

Conditions	Yield
With potassium phosphate; ethylenediaminetetraacetic acid; Emulgen 911; human liver cytochrome b5; human liver HL 39 lipid extract; rabbit liver NADPH-P-450 reductase; yeast P-450 IIIA4; magnesium chloride In water Rate constant; other human liver enzymes;
With nitric acid at 55 - 60℃; Yield given;

Nicardipine (55985-32-5) → 2-(N-benzyl-N-methylamino)ethyl methyl 4-(m-aminophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (59875-59-1)

Conditions	Yield
With hydrogen; nickel In tetrahydrofuran Ambient temperature; Yield given;

Nicardipine (55985-32-5) + C4H9N2O2*ClH → 3-{2-[benzyl(methyl)amino]ethyl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (59875-58-0)

Conditions	Yield
With Britton-Robinson buffer In water; N,N-dimethyl-formamide at 37℃; pH=7.4; Kinetics;

Nicardipine (55985-32-5) → 2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-(benzyl-formyl-amino)-ethyl] ester 5-methyl ester + 3-{2-[benzyl(methyl)amino]ethyl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (59875-58-0) + 2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-benzylamino-ethyl) ester 5-methyl ester (54527-90-1)

Conditions	Yield
In methanol Product distribution; Quantum yield; Further Variations:; Solvents; wavelengths; presence of air; Irradiation;

Nicardipine (55985-32-5) → 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (74936-72-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 99 percent / CHCl3 / Heating 2: 72 percent / NaOH / H2O / 40 °C View Scheme

Nicardipine (55985-32-5) → 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid ethyl methyl ester (39562-70-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / acetone / Heating 2: 92 percent / KOH / ethanol / 25 °C View Scheme

Nicardipine (55985-32-5) → methyl 2-(N-methylamino)ethyl 4-(m-aminophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (59875-61-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / Raney- Ni / tetrahydrofuran / Ambient temperature 2: hydrogen / 10percent Pd/C / methanol / Ambient temperature View Scheme

Nicardipine (55985-32-5) → C26H23(2)H6N3O6 (335321-56-7)

Conditions	Yield
With water-d2; trifluoroacetic anhydride In chloroform-d1; [(2)H6]acetone at 57℃; for 168h;

nifedipine (21829-25-4) + Nicardipine (55985-32-5) → nisoldipine (63675-72-9)

Nicardipine (55985-32-5) → (-)-Nicardipine + (+)-Nicardipine

Conditions	Yield
With Chiralpak IC In hexane; isopropyl alcohol Reagent/catalyst; Solvent; Resolution of racemate;

Upstream product

• 101-98-4 2-(N-benzyl-N-methyl)amino-1-ethanol 
• 88488-49-7 3-nitrooxypropyl acetoacetate 
• 85677-95-8 2-hydroxyethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 
• 74936-72-4 (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 
• 74936-72-4 (+)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 
• 76093-31-7 1-Ethoxymethyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monomethyl ester 
• 76093-31-7 1-Ethoxymethyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monomethyl ester 
• 170748-98-8 3-nitroxypropyl 2-(3-cyanobenzylidene)acetoacetate 
• 119065-61-1 (R)-2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-((S)-1-benzyl-piperidin-3-yl) ester 5-methyl ester 
• 103785-48-4 2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-[2-(toluene-4-sulfonyloxy)-ethyl] ester 
• 103-67-3 benzyl-methyl-amine 

Downstream Products

• 59875-58-0 3-{2-[benzyl(methyl)amino]ethyl} 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate 
• 59875-59-1 2-(N-benzyl-N-methylamino)ethyl methyl 4-(m-aminophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 
• 54527-90-1 2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-(2-benzylamino-ethyl) ester 5-methyl ester 
• 74936-72-4 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 
• 39562-70-4 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid ethyl methyl ester 
• 59875-61-5 methyl 2-(N-methylamino)ethyl 4-(m-aminophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 
• 335321-56-7 C₂₆H₂₃⁽²⁾H₆N₃O₆ 
• 63675-72-9 nisoldipine 

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