148849-67-6

Basic information

• Product Name: Ivabradine hydrochloride
• Synonyms: Ivabradine HCl;Ivabradine hydrochloride;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 hydrochloride;3-[3-[[[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one Hydrochloride;Corlentor;Procoralan;S-16257;(7,8-Dimethoxy 3-(3-(((1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one hydrochloride
• CAS NO: 148849-67-6
• Molecular Formula: C₂₇H₃₆N₂O₅*ClH
• Molecular Weight: 505.05
• EINECS: 1308068-626-2
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;API;Chiral Reagents;Heterocycles;Cardiovascular APIs;Inhibitors
• Mol File: 148849-67-6.mol
• Article Data: 24

Chemical Properties

• Melting Point: 193-196?C
• Boiling Point: 626.9 °C at 760 mmHg
• Flash Point: 332.9 °C
• Appearance: white to beige/
• Vapor Pressure: 1.24E-15mmHg at 25°C
• Storage Temp.: -20°C Freezer
• Solubility: H2O: ≥5mg/mL (warmed)
• Merck: 14,5247
• CAS DataBase Reference: Ivabradine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Ivabradine hydrochloride(148849-67-6)
• EPA Substance Registry System: Ivabradine hydrochloride(148849-67-6)

Safety Data

• Hazard Codes: N
• Statements: 50/53
• Safety Statements: 60-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 148849-67-6(Hazardous Substances Data)

Usage

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). .

Chemical Properties

White to Off-White Solid

Originator

Servier (France)

Uses

Different sources of media describe the Uses of 148849-67-6 differently. You can refer to the following data:
1. 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).
2. 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
3. angina therapeutic
4. Selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node. Antianginal

Definition

ChEBI: A hydrochloride obtained by combining ivabradine with one molar equivalent of hydrochloric acid. Used to treat patients with angina who have intolerance to beta blockers and/or heart failure.

Brand name

Procoralan

Biochem/physiol Actions

Ivabradine is used to treat chronic heart failure.

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.

Metabolism

Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is N-desmethyl-ivabradine (S 18982) with an exposure about 40% of that of the parent compound. This active metabolite undergoes further metabolism by CYP3A4. Excretion of metabolites occurs to a similar extent via faeces and urine.

InChI:InChI=1/C27H36N2O5.ClH/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;1H/t21-;/m1./s1

Synthetic route

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)

Conditions	Yield
Stage #1: 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; Stage #2: With hydrogenchloride In ethyl acetate; isopropyl alcohol at 0 - 10℃; for 1h;	93.5%
Stage #1: 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; ammonium formate In methanol at 25 - 30℃; Stage #2: With hydrogenchloride In dichloromethane	78%
With hydrogenchloride; hydrogen; palladium 10% on activated carbon In water at 45℃; under 7500.75 Torr; for 6h;
Multi-step reaction with 2 steps 1: hydrogenchloride / acetonitrile / 20 - 25 °C 2: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 30 - 35 °C / 3000.3 - 3750.38 Torr / Autoclave View Scheme
Stage #1: 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 In methanol at 25 - 30℃; under 5250.53 - 6000.6 Torr; Stage #2: With hydrogenchloride In dichloromethane; water	24.48 g

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)

Conditions	Yield
Stage #1: 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; Stage #2: 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;	85%
Stage #1: 3-(2-[1,3]-dioxolan-2-yl-ethyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one With palladium on activated charcoal; hydrogen In ethanol at 55℃; under 3750.38 Torr; Autoclave; Large scale; Stage #2: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With palladium on activated charcoal; hydrogen In ethanol; water at 85℃; under 22502.3 Torr; Autoclave; Large scale;	85%
Stage #1: 3-(2-[1,3]-dioxolan-2-yl-ethyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one With palladium on activated charcoal; hydrogen In ethanol at 20 - 55℃; under 3750380 Torr; Autoclave; Inert atmosphere; Stage #2: 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 63756400 Torr; Inert atmosphere;	85%

3-[2-(1,3-Dioxolan-2-yl)-ethyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-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)

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

ivabradine (155974-00-8) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
With hydrogenchloride In water; acetonitrile at 20℃; pH=2;	81%
With hydrogenchloride In acetonitrile at 60℃; pH=2 - 3;	80.1%
With hydrogenchloride In diethyl ether; acetonitrile Product distribution / selectivity;	78%

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 hydrochloride (1086026-38-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 30 - 35℃; under 3000.3 - 3750.38 Torr; for 18h; Autoclave;	80%

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)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 1.2: 2 h / 20 °C 2.1: potassium carbonate / water / 0.08 h 2.2: Inert atmosphere 3.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 12 h / 20 °C 2: hydrogenchloride; pyrographite / acetonitrile / 0.17 h / 70 °C / pH 2 - 3 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: potassium hydroxide; water / 4 h / Reflux 1.2: 20 °C 2.1: ethyl acetate / 1.25 h / 0 °C / Reflux 3.1: hydrogenchloride / dichloromethane; water / 0.08 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide; water / 4 h / Reflux 1.2: 20 °C 2.1: acetone / 0.5 h / Reflux; Cooling 3.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide; water / 4 h / Reflux 1.2: 20 °C 2.1: ethyl acetate / 1 h / 18 °C / Heating 3.1: hydrogenchloride / dichloromethane; water / 0.33 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: ethyl acetate / 1.25 h / 0 °C / Reflux 2.1: hydrogenchloride / dichloromethane; water / 0.08 h 3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4.1: dichloromethane; water / 0 - 10 °C 5.1: borane-THF / tetrahydrofuran / 20 - 50 °C 5.2: 0.25 h / 0 - 5 °C 5.3: 2.5 h / 0 °C / Reflux 6.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 6.2: 2 h / 20 °C 7.1: potassium carbonate / water / 0.08 h 7.2: Inert atmosphere 8.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 8 steps 1.1: acetone / 0.5 h / Reflux; Cooling 2.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4.1: dichloromethane; water / 0 - 10 °C 5.1: borane-THF / tetrahydrofuran / 20 - 50 °C 5.2: 0.25 h / 0 - 5 °C 5.3: 2.5 h / 0 °C / Reflux 6.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 6.2: 2 h / 20 °C 7.1: potassium carbonate / water / 0.08 h 7.2: Inert atmosphere 8.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 8 steps 1.1: ethyl acetate / 1 h / 18 °C / Heating 2.1: hydrogenchloride / dichloromethane; water / 0.33 h 3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4.1: dichloromethane; water / 0 - 10 °C 5.1: borane-THF / tetrahydrofuran / 20 - 50 °C 5.2: 0.25 h / 0 - 5 °C 5.3: 2.5 h / 0 °C / Reflux 6.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 6.2: 2 h / 20 °C 7.1: potassium carbonate / water / 0.08 h 7.2: Inert atmosphere 8.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 8 steps 1.1: ethyl acetate / 1 h / 18 °C / Heating 2.1: hydrogenchloride / dichloromethane; water / 0.33 h 3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4.1: dichloromethane; water / 0 - 10 °C 5.1: borane-THF / tetrahydrofuran / 20 - 50 °C 5.2: 0.25 h / 0 - 5 °C 5.3: 2.5 h / 0 °C / Reflux 6.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 6.2: 2 h / 20 °C 7.1: potassium carbonate / water / 0.08 h 7.2: Inert atmosphere 8.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 8 steps 1.1: ethyl acetate / Heating 2.1: hydrogenchloride / dichloromethane; water / 0.33 h 3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4.1: dichloromethane; water / 0 - 10 °C 5.1: borane-THF / tetrahydrofuran / 20 - 50 °C 5.2: 0.25 h / 0 - 5 °C 5.3: 2.5 h / 0 °C / Reflux 6.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 6.2: 2 h / 20 °C 7.1: potassium carbonate / water / 0.08 h 7.2: Inert atmosphere 8.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine → ivabradine hydrochloride (148849-67-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: hydrogenchloride / dichloromethane; water / 0.08 h 2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 3.1: dichloromethane; water / 0 - 10 °C 4.1: borane-THF / tetrahydrofuran / 20 - 50 °C 4.2: 0.25 h / 0 - 5 °C 4.3: 2.5 h / 0 °C / Reflux 5.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 5.2: 2 h / 20 °C 6.1: potassium carbonate / water / 0.08 h 6.2: Inert atmosphere 7.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (1220993-44-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 2.1: dichloromethane; water / 0 - 10 °C 3.1: borane-THF / tetrahydrofuran / 20 - 50 °C 3.2: 0.25 h / 0 - 5 °C 3.3: 2.5 h / 0 °C / Reflux 4.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 4.2: 2 h / 20 °C 5.1: potassium carbonate / water / 0.08 h 5.2: Inert atmosphere 6.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 3 steps 1.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 1.2: 20 °C 2.1: borane-THF / tetrahydrofuran / 20 °C 2.2: 4 h 3.1: hydrogen; palladium on activated charcoal / ethanol / 55 °C / 3750.38 Torr / Autoclave; Large scale 3.2: 85 °C / 22502.3 Torr / Autoclave; Large scale View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine (1346558-07-3) → ivabradine hydrochloride (148849-67-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 3.1: dichloromethane; water / 0 - 10 °C 4.1: borane-THF / tetrahydrofuran / 20 - 50 °C 4.2: 0.25 h / 0 - 5 °C 4.3: 2.5 h / 0 °C / Reflux 5.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 5.2: 2 h / 20 °C 6.1: potassium carbonate / water / 0.08 h 6.2: Inert atmosphere 7.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 3.1: dichloromethane; water / 0 - 10 °C 4.1: borane-THF / tetrahydrofuran / 20 - 50 °C 4.2: 0.25 h / 0 - 5 °C 4.3: 2.5 h / 0 °C / Reflux 5.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 5.2: 2 h / 20 °C 6.1: potassium carbonate / water / 0.08 h 6.2: Inert atmosphere 7.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: acetone / 0.5 h / Reflux; Cooling 4.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1.25 h / 0 °C / Reflux 4.1: hydrogenchloride / dichloromethane; water / 0.08 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: potassium hydroxide / water / 4 h 1.2: 0.5 h / Cooling with ice-water bath 2.1: ethyl acetate / 1.25 h / 0 °C / Reflux 3.1: hydrogenchloride / dichloromethane; water / 0.08 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide / water / 4 h 1.2: 0.5 h / Cooling with ice-water bath 2.1: acetone / 0.5 h / Reflux; Cooling 3.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide / water / 4 h 1.2: 0.5 h / Cooling with ice-water bath 2.1: ethyl acetate / 1 h / 18 °C / Heating 3.1: hydrogenchloride / dichloromethane; water / 0.33 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide / water / 4 h 1.2: 0.5 h / Cooling with ice-water bath 2.1: ethyl acetate / 1 h / 18 °C / Heating 3.1: hydrogenchloride / dichloromethane; water / 0.33 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 9 steps 1.1: potassium hydroxide / water / 4 h 1.2: 0.5 h / Cooling with ice-water bath 2.1: ethyl acetate / Heating 3.1: hydrogenchloride / dichloromethane; water / 0.33 h 4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 5.1: dichloromethane; water / 0 - 10 °C 6.1: borane-THF / tetrahydrofuran / 20 - 50 °C 6.2: 0.25 h / 0 - 5 °C 6.3: 2.5 h / 0 °C / Reflux 7.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 7.2: 2 h / 20 °C 8.1: potassium carbonate / water / 0.08 h 8.2: Inert atmosphere 9.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (R)-(-)-1-(naphthyl)-ethylamine → ivabradine hydrochloride (148849-67-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: hydrogenchloride / dichloromethane; water / 0.33 h 2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 3.1: dichloromethane; water / 0 - 10 °C 4.1: borane-THF / tetrahydrofuran / 20 - 50 °C 4.2: 0.25 h / 0 - 5 °C 4.3: 2.5 h / 0 °C / Reflux 5.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 5.2: 2 h / 20 °C 6.1: potassium carbonate / water / 0.08 h 6.2: Inert atmosphere 7.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 3.1: dichloromethane; water / 0 - 10 °C 4.1: borane-THF / tetrahydrofuran / 20 - 50 °C 4.2: 0.25 h / 0 - 5 °C 4.3: 2.5 h / 0 °C / Reflux 5.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 5.2: 2 h / 20 °C 6.1: potassium carbonate / water / 0.08 h 6.2: Inert atmosphere 7.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1.25 h / 0 °C / Reflux 4.1: hydrogenchloride / dichloromethane; water / 0.08 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: acetone / 0.5 h / Reflux; Cooling 4.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: hydrogenchloride / water 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath 3.1: ethyl acetate / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

(7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide (1220993-43-0) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: borane-THF / tetrahydrofuran / 20 - 50 °C 1.2: 0.25 h / 0 - 5 °C 1.3: 2.5 h / 0 °C / Reflux 2.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 2.2: 2 h / 20 °C 3.1: potassium carbonate / water / 0.08 h 3.2: Inert atmosphere 4.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 2 steps 1.1: borane-THF / tetrahydrofuran / 20 °C 1.2: 4 h 2.1: hydrogen; palladium on activated charcoal / ethanol / 55 °C / 3750.38 Torr / Autoclave; Large scale 2.2: 85 °C / 22502.3 Torr / Autoclave; Large scale View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride (1220993-45-2) → ivabradine hydrochloride (148849-67-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: dichloromethane; water / 0 - 10 °C 2.1: borane-THF / tetrahydrofuran / 20 - 50 °C 2.2: 0.25 h / 0 - 5 °C 2.3: 2.5 h / 0 °C / Reflux 3.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 3.2: 2 h / 20 °C 4.1: potassium carbonate / water / 0.08 h 4.2: Inert atmosphere 5.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

dehydro-ivabradine oxalate (1346558-08-4) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / water / 0.08 h 1.2: Inert atmosphere 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile (35249-62-8) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C 3.1: ethyl acetate / 1.25 h / 0 °C / Reflux 4.1: hydrogenchloride / dichloromethane; water / 0.08 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C 3.1: acetone / 0.5 h / Reflux; Cooling 4.1: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C 3.1: ethyl acetate / 1 h / 18 °C / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme
Multi-step reaction with 10 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C 3.1: ethyl acetate / Heating 4.1: hydrogenchloride / dichloromethane; water / 0.33 h 5.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 6.1: dichloromethane; water / 0 - 10 °C 7.1: borane-THF / tetrahydrofuran / 20 - 50 °C 7.2: 0.25 h / 0 - 5 °C 7.3: 2.5 h / 0 °C / Reflux 8.1: potassium carbonate; sodium iodide / 1-methyl-pyrrolidin-2-one / 20 - 60 °C / Inert atmosphere 8.2: 2 h / 20 °C 9.1: potassium carbonate / water / 0.08 h 9.2: Inert atmosphere 10.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / water / 6 h / 45 °C / 7500.75 Torr View Scheme

7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine (20925-64-8) + (S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylpropan-1-amine (1031767-71-1) → ivabradine hydrochloride (148849-67-6)

Conditions

Yield

Stage #1: 7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine With potassium tert-butylate In dimethyl sulfoxide for 1.08333h; Inert atmosphere; Stage #2: (S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylpropan-1-amine In dimethyl sulfoxide at 25 - 30℃; Stage #3: With hydrogenchloride In isopropyl alcohol; acetonitrile at 15 - 20℃; for 12h; pH=1 - 2; Inert atmosphere;

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine camphorsulphonic acid salt → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide 1.2: 5 h / 20 °C / Inert atmosphere 2.1: potassium tert-butylate / dimethyl sulfoxide / 1.08 h / Inert atmosphere 2.2: 25 - 30 °C 2.3: 12 h / 15 - 20 °C / pH 1 - 2 / Inert atmosphere View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / 20 °C 2.1: potassium tert-butylate / dimethyl sulfoxide / 1 h / 20 °C 2.2: 20 °C 3.1: hydrogenchloride / diethyl ether; acetonitrile View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / 20 °C 2.1: potassium tert-butylate / dimethyl sulfoxide / 0.5 h / 20 °C 2.2: 20 °C 3.1: hydrogen; acetic acid / 20% palladium hydroxide-activated charcoal / ethanol / 5 h / 20 °C / 3750.38 Torr 4.1: hydrogenchloride / diethyl ether; acetonitrile View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / 48 h / 85 - 90 °C 2: hydrogenchloride / acetonitrile / 20 - 25 °C 3: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 30 - 35 °C / 3000.3 - 3750.38 Torr / Autoclave View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid / ethanol / 0.5 h / 20 °C 1.2: 1 h / 15 - 20 °C 2.1: triethylamine / acetonitrile / 12 h / 20 °C 3.1: hydrogenchloride; pyrographite / acetonitrile / 0.17 h / 70 °C / pH 2 - 3 View Scheme

(S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylpropan-1-amine (1031767-71-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / dimethyl sulfoxide / 1 h / 20 °C 1.2: 20 °C 2.1: hydrogenchloride / diethyl ether; acetonitrile View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / dimethyl sulfoxide / 0.5 h / 20 °C 1.2: 20 °C 2.1: hydrogen; acetic acid / 20% palladium hydroxide-activated charcoal / ethanol / 5 h / 20 °C / 3750.38 Torr 3.1: hydrogenchloride / diethyl ether; acetonitrile View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 3-(3-chloropropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (85175-65-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine; 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one With potassium carbonate; sodium iodide In acetone at 20 - 65℃; Stage #2: With triethylamine; acetyl chloride In toluene Stage #3: With hydrogenchloride In water; toluene pH=2 - 3; Product distribution / selectivity;

3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepine-2-one (85175-59-3) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / 48 h / 85 - 90 °C 2: hydrogenchloride / acetonitrile / 20 - 25 °C 3: 5%-palladium/activated carbon; hydrogen / methanol / 18 h / 30 - 35 °C / 3000.3 - 3750.38 Torr / Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate / water / 30 °C 1.2: 55 - 60 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / 25 - 30 °C / 5250.53 - 6000.6 Torr View Scheme
Multi-step reaction with 3 steps 1.1: sodium iodide / butanone / 8 h / Reflux 2.1: potassium carbonate / water / 30 °C 2.2: 24.5 h / 30 - 60 °C 3.1: ammonium formate; palladium 10% on activated carbon; hydrogen / methanol / 25 - 30 °C View Scheme

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile (1214788-46-1) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 2 h / 65 °C 2.1: nitrilase of Rhodococcus erythropolis NCIMB11215 / aq. phosphate buffer; dimethyl sulfoxide / 96 h / 30 °C / pH 7.3 / Enzymatic reaction 3.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 3.2: 20 °C 4.1: borane-THF / tetrahydrofuran / 20 °C 4.2: 4 h 5.1: hydrogen; palladium on activated charcoal / ethanol / 55 °C / 3750.38 Torr / Autoclave; Large scale 5.2: 85 °C / 22502.3 Torr / Autoclave; Large scale View Scheme
Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 2 h / 65 °C 2.1: nitrilase of Rhodococcus rhodochrous NCIMB11216 / aq. phosphate buffer; dimethyl sulfoxide / 96 h / 30 °C / pH 7.3 / Enzymatic reaction 3.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 3.2: 20 °C 4.1: borane-THF / tetrahydrofuran / 20 °C 4.2: 4 h 5.1: hydrogen; palladium on activated charcoal / ethanol / 55 °C / 3750.38 Torr / Autoclave; Large scale 5.2: 85 °C / 22502.3 Torr / Autoclave; Large scale View Scheme
Multi-step reaction with 5 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 2 h / 65 °C 2.1: over-expressed nitrilase of Rhodococcus rhodochrous NCIMB 11216 / aq. phosphate buffer; dimethyl sulfoxide / 6 h / 30 °C / pH 7 / Enzymatic reaction 3.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 3.2: 20 °C 4.1: borane-THF / tetrahydrofuran / 20 °C 4.2: 4 h 5.1: hydrogen; palladium on activated charcoal / ethanol / 55 °C / 3750.38 Torr / Autoclave; Large scale 5.2: 85 °C / 22502.3 Torr / Autoclave; Large scale View Scheme

ethyl ((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)carbamate (148870-55-7) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / Reflux 1.2: 1 h / 15 - 20 °C 2.1: hydrogen; palladium on activated charcoal / water; ethanol / 85 °C / 22502.3 Torr / Autoclave View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + (1S)-10-camphorsulfonic acid (3144-16-9) + ivabradine (155974-00-8) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate (1031767-75-5) + ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine; (1S)-10-camphorsulfonic acid; ivabradine In toluene; acetonitrile at 20℃; for 1h; Stage #2: With hydrogenchloride In water; toluene; acetonitrile at 0 - 5℃; for 2h;

(3,4-Dimethoxyphenyl)acetic acid (93-40-3) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: toluene / 30 h / Reflux 2.1: hydrogenchloride; sulfuric acid / water / 4 h / 25 - 30 °C / Reflux 3.1: potassium hydroxide / N,N-dimethyl-formamide / 0.25 h / 0 - 5 °C 3.2: 3 h / 0 - 5 °C 4.1: potassium carbonate / water / 30 °C 4.2: 55 - 60 °C 5.1: hydrogen; palladium 10% on activated carbon / methanol / 25 - 30 °C / 5250.53 - 6000.6 Torr View Scheme

embonic acid disodium salt (6640-22-8, 7681-47-2, 15537-67-4) + ivabradine hydrochloride (148849-67-6) → 3-{3-[{ [(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one hemi 4,4’-methanediylbis(3-hydroxynaphthalene-2-carboxylic) acid

Conditions	Yield
In water for 0.5h;	66.5%

ivabradine hydrochloride (148849-67-6) → ivabradine (155974-00-8)

Conditions	Yield
With sodium hydroxide In water Product distribution / selectivity;

ivabradine hydrochloride (148849-67-6) → {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 (1462470-54-7)

Conditions	Yield
With water; sodium hydroxide In acetonitrile at 80℃; for 1h;

Upstream product

• 866783-13-3 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride 
• 155974-00-8 ivabradine 
• 35202-54-1 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile 
• 41234-23-5 (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid 
• 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 
• 1220993-44-1 (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid 
• 1346558-07-3 (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine 
• 1220993-48-5 (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid 
• 1220993-43-0 (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 
• 1220993-45-2 (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride 
• 1346558-08-4 dehydro-ivabradine oxalate 
• 35249-62-8 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile 
• 20925-64-8 7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine 
• 1031767-71-1 (S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1⁽⁶⁾,2,4-trien-7-yl)methyl)-N-methylpropan-1-amine 

Downstream Products

• 155974-00-8 ivabradine 
• 1462470-54-7 {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 

Relevant articles and documents

Preparation method of high-purity ivabradine hydrochloride and intermediate thereof

The invention discloses a preparation method of high-purity ivabradine hydrochloride and an intermediate thereof. According to the invention, a specific refining method is adopted; by-products generated in the preparation process are effectively removed, wherein the byproducts refer to an impurity shown in a formula I and an impurity shown in a formula II. Results confirm that the purity of the ivabradine intermediate shown in the formula IV is remarkably improved, and the contents of the impurity compound shown in the formula I and the impurity shown in the formula II in the ivabradine intermediate shown in the formula IV are controlled within the range of less than 0.1%, so that the purity of the subsequently prepared ivabradine hydrochloride can be improved. And in the process of preparing ivabradine hydrochloride by using the prepared ivabradine intermediate shown in the formula IV, impurities shown in the formula II are further removed by re-utilizing a recrystallization mode of amixed solution of acetyl chloride, acetone and ethanol. The impurity shown in the formula I and the impurity shown in the formula II obtained by separation can be used as impurity reference substances for quality control of an ivabradine raw material and a preparation thereof.

(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.

Exploiting the Biocatalytic Toolbox for the Asymmetric Synthesis of the Heart-Rate Reducing Agent Ivabradine

Several chemoenzymatic routes have been evaluated for the production of the heart-rate reducing agent ivabradine. Lipases and ω-transaminases have been identified as useful biocatalysts for the preparation of key enantiopure precursors. The lipase-catalysed kinetic resolution by alkoxycarbonylation of a racemic primary amine and subsequent chemical reduction of the resulting carbamate provided an N-methylated (S)-amine, one step away from ivabradine. Alternatively, the dynamic kinetic resolution by asymmetric bioamination of an aldehyde precursor enabled, in a four-step sequence, the preparative scale synthesis of enantiopure ivabradine in 50% overall yield. (Figure presented.).