Ivabradine Hydrochloride

Base Information

• Chemical Name: Ivabradine Hydrochloride
• CAS No.: 148849-67-6
• Molecular Formula: C27H36N2O5^.HCl
• Molecular Weight: 505.054
• European Community (EC) Number: 638-798-3
• UNII: TP19837BZK
• DSSTox Substance ID: DTXSID2046913
• Wikidata: Q27158823
• NCI Thesaurus Code: C148546
• RXCUI: 1649479
• ChEMBL ID: CHEMBL2145077
• Mol file: 148849-67-6.mol

Synonyms:7,8-dimethoxy-3-(3-(((4,5-dimethoxybenzocyclobutan-1-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one;Corlanor;ivabradine;S 16257;S 16257 2;S 16257-2;S 162572;S 16260 2;S 16260-2;S 162602;S-16257;S-16257-2;S-16260-2;S16257;S162572;S162602

Chemical Property of Ivabradine Hydrochloride

Chemical Property:

• Vapor Pressure: 1.24E-15mmHg at 25°C
• Melting Point: 193-196?C
• Boiling Point: 626.9 °C at 760 mmHg
• Flash Point: 332.9 °C
• PSA: 60.47000
• LogP: 4.04990
• Storage Temp.: -20°C Freezer
• Solubility.: H2O: ≥5mg/mL (warmed)
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 10
• Exact Mass: 504.2391000
• Heavy Atom Count: 35
• Complexity: 663

Purity/Quality:

99%min ^*data from raw suppliers

Ivabradine hydrochloride ^*data from reagent suppliers

Safty Information:

• Pictogram(s): N
• Hazard Codes: N
• Statements: 50/53
• Safety Statements: 60-61

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)CC3CC4=CC(=C(C=C34)OC)OC.Cl
• Isomeric SMILES: CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)C[C@H]3CC4=CC(=C(C=C34)OC)OC.Cl
• Recent EU Clinical Trials: Ivabradine for PREVENTion of Myocardial Injury after Noncardiac Surgery (MINS) - PREVENT-MINS Trial
• Description: In an effort to develop angina agents without the unwanted negative inotropic and hypotensive effects associated with b-adrenergic blockers and calcium channel blockers, a new class of heart-rate reducing compounds that act specifically on the sinoatrial (SA) node has been explored. These bradycardic agents interact directly with the pacemaking cell of the SA node and the hyperpolarization- activated If , the primary pacemaking current. Ivabradine has evolved as a specific inhibitor of If current through its contact with f-channels on the intracellular side of the plasma membrane. As a consequence, ivabradine reduces the speed of diastolic depolarization and decreases heart rate. It has been approved for the treatment of chronic stable angina and provides a viable alternative to patients with a contraindication or intolerance of b-blockers. Evaluation is also underway for the potential treatment of ischemic heart disease. Using a patch-clamp technique on rabbit sinoatrial node cells, inhibition of If current ranged from 6% (0.03 mM) – 80% (10 mM). .
• Uses: Ivabradine hydrochloride has been used as a potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel (HCN)2 blocker in embryoid body (EB) and rat engineered heart tissue (EHT). Ivabradine HCl, a new If inhibitor with IC 50 of 2.9 μM which acts specifically on the pacemaker activity of the sinoatrial node, is a pure heart rate lowering agent angina therapeutic Selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node. Antianginal
• Clinical Use: Symptomatic treatment of chronic stable angina pectoris in patients with sinus rhythm Treatment of mild to severe chronic heart failure
• Drug interactions: Potentially hazardous interactions with other drugs Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone and disopyramide. Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid; increased risk of ventricular arrhythmias with erythromycin - avoid. Antifungals: concentration increased by ketoconazole - avoid; concentration increased by fluconazole - reduce initial ivabradine dose; concentration possibly increased by itraconazole - avoid. Antimalarials: increased risk of ventricular arrhythmias with mefloquine. Antipsychotics: increased risk of ventricular arrhythmias with pimozide. Antivirals: concentration possibly increased by ritonavir - avoid. Beta-blockers: increased risk of ventricular arrhythmias with sotalol. Calcium-channel blockers: concentration increased by diltiazem and verapamil - avoid. Grapefruit juice: ivabradine concentration increased. Pentamidine: increased risk of ventricular arrhythmias. St John’s wort: ivabradine concentration reduced - avoid.

Technology Process of Ivabradine Hydrochloride

There total 45 articles about Ivabradine Hydrochloride which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 93.5%

3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (1086026-31-4) → ivabradine hydrochloride (148849-67-6,148849-68-7)

Guidance literature:

3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one; With palladium 10% on activated carbon; hydrogen; acetic acid; at 15 - 25 ℃; for 23h;

With hydrogenchloride; In ethyl acetate; isopropyl alcohol; at 0 - 10 ℃; for 1h;

Reference yield: 85.0%

3-(2-[1,3]-dioxolan-2-yl-ethyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one + 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) → ivabradine hydrochloride (148849-67-6,148849-68-7)

Guidance literature:

3-(2-[1,3]-dioxolan-2-yl-ethyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one; With hydrogen; palladium on activated charcoal; In ethanol; at 55 ℃; under 3750.38 Torr;

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride; In ethanol; water; at 20 - 85 ℃; under 22502.3 Torr;

Reference yield: 85.0%

3-[2-(1,3-Dioxolan-2-yl)-ethyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (866462-51-3) + 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) → ivabradine hydrochloride (148849-67-6,148849-68-7)

Guidance literature:

With palladium on activated charcoal; hydrogen; In ethanol; water; at 85 ℃; under 22502.3 Torr; Autoclave;

DOI:10.1002/adsc.201601222

upstream raw materials:

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride

ivabradine

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid

Downstream raw materials:

ivabradine

{2-[2-({3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-4,3,5-trien-7-yl]methyl}(methyl)-amino]propyl}amino)ethyl]-4,5-dimethoxyphenyl}acetic acid

Refernces

• 1、 -. "Preparation method of high-purity ivabradine hydrochloride and intermediate thereof". Paragraph 0056-0062. . Retrieved 2019/12/02.
• 2、 -. "A high-purity hydrochloric acid Ivabradine preparation method (by machine translation)". Paragraph 0057; 0059-0062; 0063-0069. . Retrieved 2018/09/11.