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
• Article Data: 9

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

Description

Nisoldipine D4 is another long-acting dihydropyridine calcium channel blocker effective in the treatment of hypertension and angina pectoris. It is reported to have little or no cardiodepressive activity and to be more effective than nifedipine in reducing blood pressure in hypertensives. Nisoldipine has also been shown to be effective in the management of congestive heart failure. Reduction in dosage is necessary in patients with hepatic, but not renal impairment.

Chemical Properties

Nisoldipine D4 is Light Tan Crystals

Uses

Different sources of media describe the Uses of 63675-72-9 differently. You can refer to the following data:
1. Dihydropyridine calcium channel blocker. Antihypertensive and antianginal
2. urease inhibitor
3. Labeled Nisoldipine, intended for use as an internal standard for the quantification of Nisoldipine by GC- or LC-mass spectrometry.

Definition

ChEBI: A dihydropyridine that is 1,4-dihydropyridine which is substituted by methyl groups at positions 2 and 6, a methoxycarbonyl group at position 3, an o-nitrophenyl group at position 4, and an isobutoxycarbonyl group at position 5. The racemate, calcium channel blocker, is used in the treatment of hypertension and angina pectoris.

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.

Brand name

Sular (Sciele);Baymycard.

Therapeutic Function

Coronary vasodilator

General Description

In vitro studies show that the effects ofnisoldipine, 1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylic acid methyl 2-methylpropyl ester(Sular), on contractile processes are selective, with greaterpotency on vascular smooth muscle than on cardiac muscle.Nisoldipine is highly metabolized, with five majormetabolites identified. As with most of the dihydropyridines,the cytochrome P450 (CYP) 3A4 isozyme is mainlyresponsible for the metabolism of nisoldipine. The majorbiotransformation pathway appears to involve the hydroxylationof the isobutyl ester side chain. This particular metabolitehas approximately 10% of the activity of the parentcompound.

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

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

Downstream Products

• 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 
• 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 

Relevant articles and documents

METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS

In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.

THERAPY FOR COMPLICATIONS OF DIABETES

A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.

Method for treating resistant hypertension

A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.