155974-00-8

Basic information

• Product Name: Ivabradine
• Synonyms: Ivabradine;3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methyl-amino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one;3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one;Ivabridine –;7-(3-((((R)-4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)Methyl)(Methyl)aMino)propyl)-2,3-diMethoxy-8,9-dihydro-5H-benzo[7]annulen-6(7H)-one;Ivabradine sulfate;Ivabradine(Hydrochloride form)
• CAS NO: 155974-00-8
• Molecular Formula: C₂₇H₃₆N₂O₅
• Molecular Weight: 468.58514
• Product Categories: API
• Mol File: 155974-00-8.mol
• Article Data: 28

Chemical Properties

• Boiling Point: 626.9 °C at 760 mmHg
• Flash Point: 332.9 °C
• Appearance: White crystalline powder
• Density: 1.146 g/cm³
• Vapor Pressure: 1.24E-15mmHg at 25°C
• Refractive Index: 1.56
• PKA: 8.77±0.50(Predicted)
• CAS DataBase Reference: Ivabradine(CAS DataBase Reference)
• NIST Chemistry Reference: Ivabradine(155974-00-8)
• EPA Substance Registry System: Ivabradine(155974-00-8)

Safety Data

• Hazardous Substances Data: 155974-00-8(Hazardous Substances Data)

Usage

Description

Ivabradine is a first selective and specific If inhibitor that was approved by EMEA for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm. It is the first agent to lower heart rate by inhibiting the cardiac pacemaker If current. The compound was discovered and developed by Servier and is currently being marketed in Ireland.

Uses

Used in Pharmaceutical Industry:
Ivabradine is used as a heart rate-lowering agent for patients with angina who have intolerance to beta blockers and/or heart failure. It works by selectively inhibiting the cardiac pacemaker If current, which helps to reduce the heart rate and alleviate symptoms of angina.
Used in Cardiology:
Ivabradine is used as a treatment for chronic stable angina pectoris in patients with normal sinus rhythm. By lowering the heart rate, it helps to improve blood flow and reduce the frequency and severity of angina attacks.
Used in Research and Development:
Ivabradine serves as a valuable compound for researchers studying the effects of If current inhibition on cardiac function and the potential development of new treatments for various heart conditions.

Synthesis

The convergent synthesis of ivabradine was accomplished by coupling the key benzocylclobutanyl amine 73 with oxadioxalane 76 in an in situ deprotection and amination as shown in Scheme 13. For the synthesis of the key amine 73, cyano group of compound 69 is reduced with borane-THF to give amine 70 in 90% yield, which was reacted with ethyl chloroformate to give carbamate 71 in 80% yield. Complete reduction of the carbamate was accomplished by refluxing with LAH in THF to give racemic methyl amine 72 in 92% yield, which was then resolved by crystallizing with N-acetyl –L-glutamic acid to give chiral salt 73. Prior to the next step, the amine is converted to the hydrochloride salt. The coupling partner 76 to make ivabradine was prepared from the azepinone 74 by first reacting with bromoethyldioxalane to give 75. The olefin in 75 was reduced by hydrogenating with palladium/carbon catalyst at 55°C to give 76. To the same pot, the amine 73 was added and hydrogenated to give reductive amination product ivabradine hydrochloride (X) in very good yields.

InChI:InChI=1/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1

Upstream product

• 148849-67-6 ivabradine hydrochloride 
• 1086026-42-7 (S)-7,8-dimethoxy-3-(3-(N-[(4,5-dimethoxybenzocyclobut-1-yl)methyl]-N-(methyl)amino)propyl)-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one oxalate 
• 1086026-31-4 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 
• 148870-59-1 3-[3-[[[-3,4-dimethoxybicyclo[4.2.0]octane-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepine-2-one 
• 120-20-7 2-(3,4-dimethoxyphenyl)-ethylamine 
• 98062-25-0 tert-butyl N-[2-(3,4-dimethoxyphenyl)ethyl]carbamate 
• 1325209-22-0 tert-butyl 3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-methyl}(methyl)amino]propyl-[2-(3,4-dimethoxyphenyl)ethyl]carbamate 
• 1325209-23-1 N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N'-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1,3-propanediamine 
• 1325209-24-2 N-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxyacetamide 
• 1325209-25-3 2-{{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)-amino]propyl}-[2-(3,4-dimethoxyphenyl)ethyl]amino}-2-oxoethyl acetate 
• 1325209-27-5 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1-(phenylsulphanyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 
• 1239343-05-5 (R,S)-7-(iodomethyl)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene 
• 85175-77-5 7,8-dimethoxy-3-<3-(methylamino)propyl>-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 
• 1239343-06-6 (R,S)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl methanesulphonate 

Downstream Products

• 148849-67-6 ivabradine hydrochloride 
• 1031767-75-5 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate 

Relevant articles and documents

NEW SALT OF IVABRADINE AND USES THEREOF

The present invention relates to novel salts and physical forms of ivabradine, methods for their formation, and uses thereof, such as in the treatment of myocardial ischemia and the like.

Synthetic method of ivabradine

The invention provides a synthetic method of ivabradine. The synthetic method of ivabradine comprises following steps: 1, a compound II and bromo chloropropane are subjected to alkylation reaction under the catalytic effect of a first alkali so as to obtain a compound III; 2, the compound III is subjected to hydrogenation reaction in a palladium on carbon and ammonium formate system so as to obtain a compound IV; 3, the compound IV and an iodination reagent are subjected to iodization reaction so as to obtain a compound V; 4, the compound V and the compound VI are subjected to condensation reaction under the catalytic effect of a second alkali so as to obtain a compound I. Operation is simple; reaction conditions are mild; the raw materials are commercially available; the synthetic methodis simple; cost is low; and the ivabradine synthesis difficulty is reduced greatly.

Ivabradine and its hydrochloride preparation method

The invention provides a preparation method for ivabradine and hydrochloride thereof. The preparation method for ivabradine comprises: step a1, enabling a compound shown as a formula III and a compound shown as a formula IV to have a nucleophilic substitution reaction in a polar aprotic solvent in the presence of an acid binding agent and a composite phase-transfer catalyst to generate ivabradine; and step b1, performing separation and purification on ivabradine obtained in the step a1. The composite phase-transfer catalyst is composed of a quaternary ammonium salt phase-transfer catalyst and a polyether phase-transfer catalyst with the mass ratio of 1-8:1, and X in the formula III is selected from Cl, Br, I, sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, p-methylbenzene sulfonyloxy, o-methylbenzene sulfonyloxy or m-methylbenzene sulfonyloxy. The method is capable of substantially shortening the time of nucleophilic substitution reaction, reducing reaction temperature, improving product purity and reducing production cost.