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 in November for symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm. This 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.

Definition

ChEBI: A member of the class of benzazepines that is 7,8-dimethoxy-1,3,4,5-tetrahydro-3-benzazepin-2-one in which the amide hydrogen is replaced by a [{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl} group. Use (as its hydrochloride salt) to treat patients with angina who have intolerance to beta blockers and/or heart failure.

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

• 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 
• 866783-12-2 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine 
• 85175-82-2 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal 
• 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 
• 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 
• 148849-67-6 ivabradine hydrochloride 
• 1346558-08-4 dehydro-ivabradine oxalate 
• 148849-68-7 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one hydrochloride 
• 73344-75-9 (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine 
• 866783-13-3 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride 
• 37895-73-1 1,2-dibromo-4,5-dimethoxybenzene 
• 91-16-7 1,2-dimethoxybenzene 

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

(1 S) - 4, 5 - dimethoxy - 1 - [(methylamino) methyl] benzocyclobutane preparation of hydrochloride salts of method

The invention provides a preparation method of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride, which specially comprises the following step: carrying out reduction and salting-out on 4,5-dimethoxybenzocyclobutyl-1-methyl formamide in an inert solvent to finally obtain the (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride (I). The reaction is simple to operate, has the advantages of mild reaction conditions, clean and accessible raw/auxiliary materials, low overall cost, high chemical and enantiomer purity and the like, and therefore, is suitable for industrial production.

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 preparation method of a pharmaceutically acceptable salt thereof

The invention discloses a preparation method for ivabradine. The method includes: in the presence of a noble metal catalyst and a hydrogen transfer reagent, subjecting 3-3{-[{[(7S)-3, 4-dimethoxy benzocyclobutene-7-]methyl}(methyl)amino-propyl]- 7, 8-dimethoxy-1, 3-dihydro-2-hydro-3-benzoazepine-2-one to hydrogen transfer reaction, and after complete reaction, conducting aftertreatment to obtain the ivabradine. The method provided by the invention avoids strict requirements for equipment in hydrogenation reaction, also effectively reduces side effect, and increases the reaction yield.