Product Name

  • Name

    Ivabradine hydrochloride

  • EINECS 638-798-3
  • CAS No. 148849-67-6
  • Article Data24
  • CAS DataBase
  • Density
  • Solubility
  • Melting Point 193-196?C
  • Formula C27H36N2O5.HCl
  • Boiling Point 626.9 °C at 760 mmHg
  • Molecular Weight 505.054
  • Flash Point 332.9 °C
  • Transport Information
  • Appearance
  • Safety 60-61
  • Risk Codes 50/53
  • Molecular Structure Molecular Structure of 148849-67-6 (Ivabradine hydrochloride)
  • Hazard Symbols N
  • Synonyms 2H-3-Benzazepin-2-one,3-[3-[[(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-,monohydrochloride, (S)-;
  • PSA 60.47000
  • LogP 4.04990

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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
With palladium on activated charcoal; hydrogen In ethanol; water at 85℃; under 22502.3 Torr; Autoclave;85%
ivabradine
155974-00-8

ivabradine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(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

ivabradine hydrochloride

Conditions
ConditionsYield
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

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

dehydro-ivabradine oxalate

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine

(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

(S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylpropan-1-amine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

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

ivabradine hydrochloride

Conditions
ConditionsYield
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

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(S)-3-chloro-N-((3,4-dimethoxybicyclo[4.2,0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylpropan-1-amine

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine

3-(3-chloropropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
85175-65-1

3-(3-chloropropyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepine-2-one

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

ethyl ((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)carbamate

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine

(1S)-10-camphorsulfonic acid
3144-16-9

(1S)-10-camphorsulfonic acid

ivabradine
155974-00-8

ivabradine

A

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

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate

B

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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;
...Expand
(3,4-Dimethoxyphenyl)acetic acid
93-40-3

(3,4-Dimethoxyphenyl)acetic acid

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

Conditions
ConditionsYield
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

embonic acid disodium salt

ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

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

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
ConditionsYield
In water for 0.5h;66.5%
ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

ivabradine
155974-00-8

ivabradine

Conditions
ConditionsYield
With sodium hydroxide In water Product distribution / selectivity;
ivabradine hydrochloride
148849-67-6

ivabradine hydrochloride

{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

{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

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

Ivabradine hydrochloride Chemical Properties

Molecular Structure of Ivabradine HCl (CAS NO.148849-67-6):

IUPAC Name: 3-[3-[[(7S)-3,4-Dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one hydrochloride 
Molecular Formula: C27H36N2O5.HCl
Molecular Weight: 505.05
H-Bond Donor: 1
H-Bond Acceptor: 6 
Flash Point: 332.9 °C
Enthalpy of Vaporization: 92.79 kJ/mol
Boiling Point: 626.9 °C at 760 mmHg
Vapour Pressure: 1.24E-15 mmHg at 25 °C
Product Categories: Intermediates & Fine Chemicals; Pharmaceuticals 
SMILES: Cl.O=C2N(CCc1cc(OC)c(OC)cc1C2)CCCN(C[C@@H]4c3cc(OC)c(OC)cc3C4)C
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
InChIKey: HLUKNZUABFFNQS-ZMBIFBSDBJ

Ivabradine hydrochloride Uses

 Ivabradine HCl (CAS NO.148849-67-6) is used as selective bradycardic agent with direct effect on the pacemake, if current of the sinoatrial node.

Ivabradine hydrochloride Specification

 Ivabradine HCl (CAS NO.148849-67-6), its Synonyms are (7,8-Dimethoxy 3-(3-(((1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one hydrochloride ; Ivabradine hydrochloride ; 2H-3-Benzazepin-2-one, 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-, monohydrochloride ; 2H-3-Benzazepin-2-one, 3-(3-(((3,4-dimethoxybicyclo(4.2.0)octa-1,3,5-trien-7-yl)methyl)methylamino)propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-, monohydrochloride, (S)- .

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