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
• Article Data: 13

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

Originator

Nicodel,Mitsui,Japan,1981

Uses

Different sources of media describe the Uses of 55985-32-5 differently. You can refer to the following data:
1. Vasodilator.
2. It is used for arterial hypertension, chronic, stable angina pectoris, preventing angina pectoris, and for ischemic-type abnormalities of brain blood flow.
3. Nicardipine is a dihydropyridine calcium channel blocker. Antianginal; antihypertensive. Neuroprotective & Neuroresearch products.

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

• 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 
• 76093-31-7 1-Ethoxymethyl-2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monomethyl ester 
• 101-98-4 2-(N-benzyl-N-methyl)amino-1-ethanol 
• 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 
• 74936-72-4 (-)-5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 
• 85677-95-8 2-hydroxyethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 
• 170748-98-8 3-nitroxypropyl 2-(3-cyanobenzylidene)acetoacetate 
• 88488-49-7 3-nitrooxypropyl 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 

Downstream Products

• 63675-72-9 nisoldipine 
• 335321-56-7 C₂₆H₂₃⁽²⁾H₆N₃O₆ 
• 59875-61-5 methyl 2-(N-methylamino)ethyl 4-(m-aminophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 
• 39562-70-4 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid ethyl methyl ester 
• 74936-72-4 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 
• 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 

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