63675-72-9

Basic information

• Product Name: Nisoldipine
• Synonyms: 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-isobutyl ester;Nikameal;Ninobarucin;Nisomynard;3-Methyl 5-(2-Methylpropyl) (4R)-2,6-diMethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;Nisoldipine (Sular);3,5-Pyridinedicarboxylicacid, 1,4-dihydro-2,6-diMethyl-4-(2-nitrophenyl)-, 3-Methyl 5-(2-Methylpropyl)ester;Nisoldipine-d4
• CAS NO: 63675-72-9
• Molecular Formula: C₂₀H₂₄N₂O₆
• Molecular Weight: 388.41
• EINECS: 264-407-7
• Product Categories: Calcium channel;Cardiovascular APIs;Active Pharmaceutical Ingredients;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 63675-72-9.mol

Chemical Properties

• Melting Point: 147-148°C
• Boiling Point: 503.3 °C at 760 mmHg
• Flash Point: 258.2 °C
• Appearance: yellow/
• Density: 1.205 g/cm³
• Vapor Pressure: 2.95E-10mmHg at 25°C
• Refractive Index: 1.544
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: >10mg/mL
• PKA: 2.67±0.70(Predicted)
• Merck: 14,6565
• CAS DataBase Reference: Nisoldipine(CAS DataBase Reference)
• NIST Chemistry Reference: Nisoldipine(63675-72-9)
• EPA Substance Registry System: Nisoldipine(63675-72-9)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22
• Safety Statements: 36
• WGK Germany: 3
• RTECS: US7975600
• Hazardous Substances Data: 63675-72-9(Hazardous Substances Data)

Usage

Manufacturing Process

Boiling a solution of 12.7 g of 2'-nitrobenzylideneacetoacetic acid methyl ester and 7.1 g of β-amino-crotonic acid isopropyl ester in 50 ml of methanol for 10 hours yielded 2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid 3-methyl ester-5-isopropyl ester of melting point 174°C (from ethanol). Yield 48% of theory.

Therapeutic Function

Coronary vasodilator

Biochem/physiol Actions

L-type (CaV1.2) calcium channel blocker; dihydropyridine-type calcium channel blocker with selectivity for smooth muscle (CaV1.2b) over cardiac muscle (CaV1.2a). Arterial vasodilator and antihypertensive agent.

InChI:InChI=1/C20H24N2O6/c1-11(2)10-28-20(24)17-13(4)21-12(3)16(19(23)27-5)18(17)14-8-6-7-9-15(14)22(25)26/h6-9,11,18,21H,10H2,1-5H3

Synthetic route

2-(2-nitrobenzylidene)-acetoacetic acid-i-butyl ester (61312-59-2) + methyl 3-aminocrotonate (21731-17-9) → nisoldipine (63675-72-9)

Conditions	Yield
With dmap In cyclohexane at 75 - 85℃; for 26h; Heating / reflux;	52.9%

2'-nitrobenzylideneacetoacetic acid methyl ester (111304-31-5) + isobutyl 3-aminocrotonate → nisoldipine (63675-72-9)

Conditions	Yield
In 1,2-dimethoxyethane; toluene at 80 - 105℃; for 15 - 25h;

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

methyl (S)-3-[(2-methoxy-methylpyrrolidin-1-yl)-imino]-butyrate + isobutyl 2-(2-nitrobenzylidene)-acetoacetate + 2,3-dimethyl-2,3-diaminobutane (20485-44-3) → nisoldipine (63675-72-9)

Conditions	Yield
With n-butyllithium; ammonium chloride In tetrahydrofuran; methanol; hexane; dichloromethane	1.4 g (30%)

isobutyl acetoacetate (7779-75-1) + 2-nitro-benzaldehyde (552-89-6) → nisoldipine (63675-72-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: alumina / neat (no solvent) / 120 °C / Microwave irradiation; Green chemistry 2: 0.15 h / 90 °C / Microwave irradiation View Scheme

2-(2-nitrobenzylidene)-acetoacetic acid-i-butyl ester (61312-59-2) + methyl 3-aminocrotonate (14205-39-1) → nisoldipine (63675-72-9)

Conditions	Yield
at 90℃; for 0.15h; Microwave irradiation;

nisoldipine (63675-72-9) → (+/-)-3-Isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrosophenyl)pyridine-3,5-dicarboxylate

Conditions	Yield
In acetonitrile Irradiation;	95%
at 25℃; for 720h; Decomposition; Photolysis;
With air In methanol Quantum yield; Further Variations:; Solvents; Reagents; Irradiation;

nisoldipine (63675-72-9) → 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester (103026-83-1, 136389-72-5, 136389-74-7)

Conditions	Yield
With lead(IV) acetate In dichloromethane; acetic acid at 20℃; for 1h;	76%
Stage #1: nisoldipine With hydrogenchloride In water Stage #2: In water at 20℃; for 5h;	72.1%
With nitric acid at 100℃; for 1h;	63%

nisoldipine (63675-72-9) → 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester (103026-83-1, 136389-72-5, 136389-74-7) + (+/-)-3-Isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrosophenyl)pyridine-3,5-dicarboxylate + 2,2'-Bis(3-isobutyloxycarbonyl-5-methoxycarbonyl-2,6-dimethyl-4-pyridyl)-azobenzene-N,N'-dioxide

Conditions	Yield
In ethanol for 144h; Irradiation;

nisoldipine (63675-72-9) → (+)-(S)-methyl 2-methylpropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate + (-)-(R)-methyl 2-methylpropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate

Conditions	Yield
With α1-acid glycoprotein HPLC column resolution of racemate;
With Chiralpak IC In hexane; butan-1-ol Reagent/catalyst; Solvent; Resolution of racemate;
With isopropylamine In tetrahydrofuran; methanol; isopropyl alcohol at 35℃; under 103432 Torr; Resolution of racemate; Supercritical conditions;

nisoldipine (63675-72-9) + C4H9N2O2*ClH → 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester (103026-83-1, 136389-72-5, 136389-74-7)

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

Upstream product

• 61312-59-2 2-(2-nitrobenzylidene)-acetoacetic acid-i-butyl ester 
• 14205-39-1 methyl 3-aminocrotonate 
• 7779-75-1 isobutyl acetoacetate 
• 552-89-6 2-nitro-benzaldehyde 
• 20485-44-3 2,3-dimethyl-2,3-diaminobutane 
• 21829-25-4 nifedipine 
• 55985-32-5 Nicardipine 
• 111304-31-5 2'-nitrobenzylideneacetoacetic acid methyl ester 
• 21731-17-9 methyl 3-aminocrotonate 

Downstream Products

• 103026-83-1 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester 
• 87375-91-5 (+/-)-3-Isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrosophenyl)pyridine-3,5-dicarboxylate 
• 103573-38-2 (+)-(S)-methyl 2-methylpropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate 
• 103573-38-2 (-)-(R)-methyl 2-methylpropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate 

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AN IMPROVED PROCESS FOR THE PREPARATION OF PURE NISOLDIPINE

Nisoldipine is prepared by the process according to this invention by cyclocondensing 3-Aminocrotonoic acid isobutyl ester with 2-(2-nitrobenzylidene)-3-oxo-butyric acid methyl ester in the presence of a water immiscible organic solvent such as toluene and an aprotic organic solvent. The reaction product is recovered after refluxing with diisopropyl ether. Water miscible aprotic solvent may be selected from ethers and glycol ethers.

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