866783-13-3

Basic information

• Product Name: (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride
• Synonyms: (1S)-4,5-Dimethoxy-1-(Methylaminomethyl)-Benzocyclobutane Hcl;(1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride;(7S)-3,4-Dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-methanamine hydrochloride;(1S)-4,5-Dimethoxy-1-(methylaminoethyl)benzocyclobutane HCl;(S)-N-[(4,5-diMethoxybenzocyclobut-1-yl)Methyl ]-N-MethylaMine h;(S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)MethanaMine;3,4-diMethoxy-N-Methyl-bicyclo[4.2.0]octa-1,3,5-triene-7-MethanaMine hydrochloride;Bicyclo[4.2.0]octa-1,3,5-triene-7-MethanaMine, 3,4-diMethoxy-N-Methyl-, hydrochloride
• CAS NO: 866783-13-3
• Molecular Formula: C₁₂H₁₇NO₂*ClH
• Molecular Weight: 243.73
• EINECS: 1592732-453-0
• Mol File: 866783-13-3.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 338.6 °C at 760 mmHg
• Flash Point: 158.6 °C
• Appearance: /
• Vapor Pressure: 6.95E-05mmHg at 25°C
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated), Water (Slightly)
• CAS DataBase Reference: (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride(866783-13-3)
• EPA Substance Registry System: (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride(866783-13-3)

Safety Data

• Hazardous Substances Data: 866783-13-3(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 866783-13-3 differently. You can refer to the following data:
1. (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride is an intermediate used in preparation of Ivabradine (I940500) which is a selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node.
2. (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane is an intermediate used in preparation of Ivabradine (I940500) which is a selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node.

InChI:InChI=1/C12H17NO2.ClH/c1-13-7-9-4-8-5-11(14-2)12(15-3)6-10(8)9;/h5-6,9,13H,4,7H2,1-3H3;1H/t9-;/m1./s1

Synthetic route

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine With acetic acid In ethanol at 20℃; for 0.5h; Stage #2: With hydrogenchloride at 15 - 20℃; for 1h;	95%
With hydrogenchloride In ethanol; ethyl acetate at 15 - 20℃; for 1h; Industry scale;	92%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate (1031767-75-5) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate In dichloromethane; water pH=10 - 11; Stage #2: With hydrogenchloride In ethanol; ethyl acetate at 0 - 5℃; pH=1 - 2;	94%

(7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide (1220993-43-0) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Stage #1: (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide With borane-THF In tetrahydrofuran at 20 - 50℃; Stage #2: With methanol In tetrahydrofuran at 0 - 5℃; for 0.25h; Stage #3: With hydrogenchloride In ethyl acetate at 0℃; for 2.5h; Reflux;	88%
Stage #1: (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide With borane-THF In tetrahydrofuran at 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol for 4h;	77%

ethyl ((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)carbamate (148870-55-7) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Stage #1: ethyl [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]carbamate With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Reflux; Stage #2: With hydrogenchloride In ethanol; ethyl acetate at 15 - 20℃; for 1h;	85%

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (1220993-44-1) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 2 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 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) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme

(R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (R)-(-)-1-(naphthyl)-ethylamine → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme

(S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride (1220993-45-2) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile (35249-62-8) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile (1214788-46-1) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.25 h / 20 °C 1.2: 12 h / 20 °C 2.1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 3.1: ethanol / 1 h / Reflux 4.1: sodium hydroxide / ethanol; water; dichloromethane / 1 h / 20 °C / pH 10 - 11 5.1: acetic acid / ethanol / 0.5 h / 20 °C 5.2: 1 h / 15 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 0.25 h / 20 °C 1.2: 12 h / 20 °C 2.1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 3.1: ethanol; Isopropyl acetate / 1 h / Reflux 4.1: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 5.1: acetic acid / ethanol / 0.5 h / 20 °C 5.2: 1 h / 15 - 20 °C View Scheme

(1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane dextro mandelate → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 2.1: acetic acid / ethanol / 0.5 h / 20 °C 2.2: 1 h / 15 - 20 °C View Scheme

C12H15NO3 → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 2.1: ethanol / 1 h / Reflux 3.1: sodium hydroxide / ethanol; water; dichloromethane / 1 h / 20 °C / pH 10 - 11 4.1: acetic acid / ethanol / 0.5 h / 20 °C 4.2: 1 h / 15 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 2.1: ethanol; Isopropyl acetate / 1 h / Reflux 3.1: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 4.1: acetic acid / ethanol / 0.5 h / 20 °C 4.2: 1 h / 15 - 20 °C View Scheme

({3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)(methyl)amine (148870-56-8) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethanol / 1 h / Reflux 2.1: sodium hydroxide / ethanol; water; dichloromethane / 1 h / 20 °C / pH 10 - 11 3.1: acetic acid / ethanol / 0.5 h / 20 °C 3.2: 1 h / 15 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: ethanol; Isopropyl acetate / 1 h / Reflux 2.1: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 3.1: acetic acid / ethanol / 0.5 h / 20 °C 3.2: 1 h / 15 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: 0.75 h / Reflux 2.1: water; dichloromethane / pH 10 - 11 2.2: 0 - 5 °C / pH 1 - 2 View Scheme

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 1-bromo-3-propanol (627-18-9) → 3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}methylamino]-1-propanol (1462470-47-8)

Conditions	Yield
With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 50℃; for 24h;	96%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 7,8-dimethoxy-3-(3-iodopropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one → ivabradine (155974-00-8)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 7,8-dimethoxy-3-(3-iodopropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one In N,N-dimethyl-formamide at 20℃; for 6h;	95.8%
With triethylamine In acetonitrile at 20℃; for 12h;

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one (148870-57-9) → 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)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With potassium carbonate In water at 30℃; Stage #2: 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one In water at 30 - 60℃; for 24.5h; Reagent/catalyst;	94%
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With potassium carbonate In N,N-dimethyl-formamide at 25 - 30℃; for 1h; Stage #2: 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one In N,N-dimethyl-formamide at 5 - 25℃; for 4h;	75%
With potassium carbonate In acetone at 55 - 58℃; for 3h;
In acetone for 18h; Reflux;

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 1,3-chlorobromopropane (109-70-6) → (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)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With potassium carbonate In water at 40℃; Stage #2: 1.3-chlorobromopropane In water at 40℃; for 5h;	94%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + C17H26ClNO5 → C29H42N2O7

Conditions	Yield
With potassium carbonate; sodium iodide for 6h; Reflux;	91%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepine-2-one (85175-59-3) → 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)

Conditions	Yield
With tetrabutylammomium bromide; sodium carbonate; sodium iodide In toluene at 108 - 110℃; for 10h; Temperature; Solvent; Reagent/catalyst;	86%
With potassium carbonate; sodium iodide In acetone for 28h; Reflux; Large scale;	82.54%

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%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one (148870-57-9) → 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one hydrochloride

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride With potassium carbonate In ethyl acetate at 25 - 30℃; for 1h; Stage #2: 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one In ethyl acetate at 5 - 25℃; for 6h; Stage #3: With palladium 10% on activated carbon; hydrogen In ethyl acetate at 65 - 70℃; for 6h;	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%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one (148870-57-9) → 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)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride; 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one With potassium carbonate In water; toluene at 70℃; Inert atmosphere; Stage #2: With hydrogenchloride In water	80%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepine-2-one (85175-59-3) + oxalic acid (144-62-7) → dehydro-ivabradine oxalate (1346558-08-4)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride; 3-(3-chloropropyl)-1,3-dihydro-7,8-dimethoxy-2H-3-benzazepine-2-one With potassium carbonate; sodium iodide In 1-methyl-pyrrolidin-2-one at 20 - 60℃; Inert atmosphere; Stage #2: oxalic acid In methanol at 20℃; for 2h;	76%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + (2-{2-[(3-chloropropyl)amino]ethyl}-4,5-dimethoxyphenyl)acetonitrile (1462470-52-5) → {2-[2-({3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)-amino]propyl}amino)ethyl]-4,5-dimethoxyphenyl}acetonitrile (1462470-53-6)

Conditions	Yield
With triethylamine In acetonitrile for 6h; Reflux;	66%

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) + 3-(7,8-Dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-propanenitrile (1246638-04-9) → N-{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-N-methylpropanimidamide (1246638-11-8)

Conditions	Yield
Stage #1: 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride; 3-(7,8-Dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-propanenitrile With triethylamine; copper(l) chloride In methanol for 24h; Inert atmosphere; Reflux; Stage #2: With sodium hydroxide In methanol; dichloromethane; water at 20℃;	46%

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

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) → 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)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride (866783-13-3) → 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3-dihydro-benzo[d]azepine-2-one nitrate (1346558-09-5)

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: nitric acid / ethanol; water View Scheme

Upstream product

• 148870-55-7 ethyl [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]carbamate 
• 1031767-75-5 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate 
• 148870-56-8 ({3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)(methyl)amine 
• 73344-75-9 (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine 
• 1214788-46-1 (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile 
• 35249-62-8 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile 
• 1220993-45-2 (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride 
• 1220993-43-0 (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 
• 1220993-48-5 (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-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 
• 1220993-44-1 (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid 
• 41234-23-5 (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid 
• 35202-54-1 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile 
• 866783-12-2 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine 

Downstream Products

• 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 
• 148849-67-6 ivabradine hydrochloride 
• 155974-00-8 ivabradine 
• 1462470-53-6 {2-[2-({3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)-amino]propyl}amino)ethyl]-4,5-dimethoxyphenyl}acetonitrile 
• 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

AN IMPROVED PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

: Disclosed herein is an improved process for the preparation of Ivabradine and pharmaceutically acceptable salts thereof. The invention more particularly disclosesthe synthesis of key intermediates viz.,(S)-N-[(4,5-dimethoxybenzocydobut-l-yl)-methyl]-N- (methyl)amine hydrochloride of Formula-II and 3-(3-Iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzapin-2-one of Formula-III, and its use in industrial synthesis of Ivabradine and pharmaceutically acceptable salts thereof.

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.).

INDUSTRIAL PROCESS FOR THE SYNTHESIS OF IVABRADINE SALTS

Process for the synthesis of Ivabradine salts of formula (I) the chemical name of which is: 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene- 7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one salts (HQ=HCl, HBr, HI, HNO3, HClO4, (COOH)2), and new intermediates thereof. Certain crystalline forms of the acid addition salts of Ivabradine (I) with nitric acid (I, HQ=HNO3), hydrobromic acid (I, HQ=HBr), hydroiodic acid (I, HQ=HI), oxalic acid (I, HQ= (COOH)2) and perchloric acid (I, HQ=HClO4)).