866783-12-2

Basic information

• Product Name: (S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)-N-MethylMethanaMine
• Synonyms: (S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)-N-MethylMethanaMine;(S)-1-(3,4-DiMethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)-N-MethylMethanaMine
• CAS NO: 866783-12-2
• Molecular Formula: C₁₂H₁₇NO₂
• Molecular Weight: 207.26888
• Mol File: 866783-12-2.mol
• Article Data: 8

Chemical Properties

• Appearance: /
• Storage Temp.: 2-8°C
• CAS DataBase Reference: (S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)-N-MethylMethanaMine(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)-N-MethylMethanaMine(866783-12-2)
• EPA Substance Registry System: (S)-(4,5-diMethoxy-1,2-dihydrocyclobutabenzen-1-yl)-N-MethylMethanaMine(866783-12-2)

Safety Data

• Hazardous Substances Data: 866783-12-2(Hazardous Substances Data)

Usage

Uses

(S)-N-((3,4-Dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)methyl)-N-methylacetamide is a derivative of (1S)-4,5-Dimethoxy-1-[(methylamino)methyl]benzocyclobutane (D461760, HCl); an intermediate in the synthesis of Ivabradine (I940500, HCl) which is a selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node. Also an antianginal.

Synthetic route

(1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane N-acetyl-L-glutamic acid → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
With sodium hydroxide In ethanol; dichloromethane; water at 20℃; for 1h; pH=10 - 11;	99%

(1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane dextro mandelate → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
With sodium hydroxide In dichloromethane; water at 20℃; for 1h; pH=10 - 11;	96%

ethyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate (869856-10-0) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Stage #1: ethyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 1h; Heating / reflux; Stage #2: With sodium hydroxide; water In tetrahydrofuran at 15℃;	93%

(7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide (1220993-43-0) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Stage #1: (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide With sodium tetrahydroborate; iodine In tetrahydrofuran for 24h; Reflux; Stage #2: With hydrogenchloride; water pH=3;	90%
With lithium aluminium tetrahydride In tetrahydrofuran for 0.5h; Reflux;	46%

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

Conditions	Yield
With sodium hydroxide In water; ethyl acetate at 25℃; for 0.166667h;	n/a

C12H17NO2*C20H18O8 → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
With sodium hydroxide In water

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium hydroxide / ethanol / 5 h / Reflux 2.1: (R)-1-phenyl-ethyl-amine / isopropyl alcohol / 1 h / Reflux; Resolution of racemate 3.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 20 °C 4.1: iodine; sodium tetrahydroborate / tetrahydrofuran / 24 h / Reflux 4.2: pH 3 View Scheme
Multi-step reaction with 5 steps 1.1: borane-THF / tetrahydrofuran / 12 h / 20 °C 1.2: 1 h 2.1: triethylamine / dichloromethane / 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 4.1: ethanol / Resolution of racemate 5.1: sodium hydroxide / ethyl acetate View Scheme
Multi-step reaction with 3 steps 1.1: nitrilase of Rhodococcus erythropolis NCIMB11215 / aq. phosphate buffer; dimethyl sulfoxide / 96 h / 30 °C / pH 7.3 / Enzymatic reaction 2.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 2.2: 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / Reflux View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (R)-1-phenyl-ethyl-amine / isopropyl alcohol / 1 h / Reflux; Resolution of racemate 2.1: triethylamine; chloroformic acid ethyl ester / tetrahydrofuran / 20 °C 3.1: iodine; sodium tetrahydroborate / tetrahydrofuran / 24 h / Reflux 3.2: pH 3 View Scheme

1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene (53207-00-4) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; cyclohexane / 0.25 h / -60 °C 1.2: 1 h 2.1: sodium amide / 2 h / 20 °C 3.1: borane-THF / tetrahydrofuran / 12 h / 20 °C 3.2: 1 h 4.1: triethylamine / dichloromethane / 20 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 6.1: ethanol / Resolution of racemate 7.1: sodium hydroxide / ethyl acetate View Scheme

3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile (35249-62-8) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium amide / 2 h / 20 °C 2.1: borane-THF / tetrahydrofuran / 12 h / 20 °C 2.2: 1 h 3.1: triethylamine / dichloromethane / 20 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 5.1: ethanol / Resolution of racemate 6.1: sodium hydroxide / ethyl acetate View Scheme

1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine hydrochloride (35202-55-2) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 3: ethanol / Resolution of racemate 4: sodium hydroxide / ethyl acetate View Scheme

ethyl ((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)carbamate (148870-55-7) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 2: ethanol / Resolution of racemate 3: sodium hydroxide / ethyl acetate View Scheme

({3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)(methyl)amine (148870-56-8) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / Resolution of racemate 2: sodium hydroxide / ethyl acetate View Scheme
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux 2: sodium hydroxide / ethanol; water; dichloromethane / 1 h / 20 °C / pH 10 - 11 View Scheme
Multi-step reaction with 2 steps 1: ethanol; Isopropyl acetate / 1 h / Reflux 2: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 View Scheme

[{(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 (866783-12-2)

Conditions	Yield
With sodium hydroxide In ethyl acetate

3,4-dimethoxy-benzaldehyde (120-14-9) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: sodium tetrahydroborate; methanol / 0.33 h / 0 °C 2.1: acetic acid / 0.5 h / 0 °C 2.2: 0 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; cyclohexane / 0.25 h / -60 °C 3.2: 1 h 4.1: sodium amide / 2 h / 20 °C 5.1: borane-THF / tetrahydrofuran / 12 h / 20 °C 5.2: 1 h 6.1: triethylamine / dichloromethane / 20 °C 7.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 8.1: ethanol / Resolution of racemate 9.1: sodium hydroxide / ethyl acetate View Scheme

(3,4-dimethoxyphenyl)methanol (93-03-8) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: acetic acid / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; cyclohexane / 0.25 h / -60 °C 2.2: 1 h 3.1: sodium amide / 2 h / 20 °C 4.1: borane-THF / tetrahydrofuran / 12 h / 20 °C 4.2: 1 h 5.1: triethylamine / dichloromethane / 20 °C 6.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / Reflux 7.1: ethanol / Resolution of racemate 8.1: sodium hydroxide / ethyl acetate View Scheme

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile (1214788-46-1) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

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: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / Reflux 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: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / Reflux 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: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / Reflux 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-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / Reflux View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

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

C12H15NO3 → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 2: ethanol / 1 h / Reflux 3: sodium hydroxide / ethanol; water; dichloromethane / 1 h / 20 °C / pH 10 - 11 View Scheme
Multi-step reaction with 3 steps 1: boron trifluoride-tetrahydrofuran complex / tetrahydrofuran / 8 h / 0 - 20 °C 2: ethanol; Isopropyl acetate / 1 h / Reflux 3: sodium hydroxide / water; dichloromethane / 1 h / 20 °C / pH 10 - 11 View Scheme

C12H15NO3 → [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2)

Conditions	Yield
With hydrogenchloride In ethanol; water at 0 - 5℃; for 10h; pH=3 - 4; Inert atmosphere; Large scale;	1.17 kg

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one acetate → ivabradine (155974-00-8)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 85 - 88℃; for 8h;	99.1%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 2-(3-bromopropyl)isoindole-1,3-dione (5460-29-7) → 2-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-1H-isoindole-1,3(2H)-dione (1393427-01-4)

Conditions	Yield
With potassium carbonate In acetone for 24h; Reflux;	97%

[{(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 (866783-12-2) + 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
With potassium carbonate In N,N-dimethyl-formamide at 25 - 45℃; for 12h;	91%
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine With potassium carbonate In N,N-dimethyl-formamide at 25 - 30℃; for 0.583333h; Stage #2: 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one In N,N-dimethyl-formamide at 40 - 45℃; for 12h;	70%
In acetone for 18h; Reflux;	67%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 1,3-dihydro-3-(iodopropyl)-7,8-dimethoxy-2H-benzazepin-2-one → 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 potassium carbonate In N,N-dimethyl-formamide at 40 - 45℃; for 12h; Inert atmosphere;	85%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal (85175-82-2) → ivabradine (155974-00-8)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine; 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal In ethanol at 85℃; for 1h; Autoclave; Inert atmosphere; Stage #2: With trimethylamine-N-oxide; C34H51FeNO6SSi2; hydrogen In ethanol at 85℃; under 3750.38 Torr; for 16h; Reagent/catalyst; Autoclave; Inert atmosphere;	79%
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine; 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal With triethylamine at 20℃; for 1h; Inert atmosphere; Stage #2: With formic acid at 85℃; for 18h;	62%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 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
With potassium carbonate at 20℃; Product distribution / selectivity;	56%

trans-3-(4-chloro-2-butenyl)-7,8-dimethoxy-1,3-dihydro-2H-benzo[d]azepin-2-one + [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → (S)-3-{(E)-4-[(3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)methylamino]buten-2-yl}-7,8-dimethoxy-2-oxo-1,3-dihydro-benzo[d]azepin-2-one (1260094-34-5)

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 48h; Inert atmosphere;	40%

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 2-bromoethanol (540-51-2) → 2-[{[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]ethanol (1132077-43-0)

Conditions	Yield
With potassium carbonate In acetonitrile Heating / reflux;

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + cyanomethyl bromide (590-17-0) → [{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]acetonitrile (1132077-49-6)

Conditions	Yield
With sodium carbonate In 4-methyl-2-pentanone Heating / reflux;

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 4-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-yl)-4-oxobutanal (1132078-18-2) → N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-4-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-N-methyl-4-oxobutan-1-amine (1132108-38-3)

Conditions	Yield
Stage #1: [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine; 4-(7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-yl)-4-oxobutanal With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 4h; Stage #2: With sodium hydroxide; water In dichloromethane

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

Conditions	Yield
In isopropyl alcohol at 20℃; for 14h; Inert atmosphere; Reflux;

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + Acetyl-D,L-glutaminsaeure (5817-08-3) → 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine N-acetylglutamate

Conditions	Yield
In ethanol at 20 - 80℃; for 16h; Inert atmosphere;

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → ivabradine (155974-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / 20 °C 2.1: potassium tert-butylate / dimethyl sulfoxide / 1 h / 20 °C 2.2: 20 °C View Scheme
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 2 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 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

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → 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 / 20 °C 2.1: potassium tert-butylate / dimethyl sulfoxide / 0.5 h / 20 °C 2.2: 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 24 h / Reflux 2.1: hydrazine hydrate / ethanol / 4 h / Reflux 3.1: hydrogen / palladium 10% on activated carbon / ethanol; water / 12 h / 20 °C / 760.05 Torr 4.1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 5.1: hydrogenchloride; water; acetic acid / 1 h / 25 °C 5.2: pH 9 / Cooling with ice View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methylpropane-1,3-diamine (1393427-02-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 24 h / Reflux 2: hydrazine hydrate / ethanol / 4 h / Reflux View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N'-(2,2-dimethoxyethyl)-N-methylpropane-1,3-diamine (1393427-03-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 24 h / Reflux 2: hydrazine hydrate / ethanol / 4 h / Reflux 3: hydrogen / palladium 10% on activated carbon / ethanol; water / 12 h / 20 °C / 760.05 Torr View Scheme

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) → N-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide (1393427-04-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 24 h / Reflux 2: hydrazine hydrate / ethanol / 4 h / Reflux 3: hydrogen / palladium 10% on activated carbon / ethanol; water / 12 h / 20 °C / 760.05 Torr 4: triethylamine / dichloromethane / 3 h / 0 - 20 °C 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;

[{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine (866783-12-2) + 7,8-dimethoxy-3-[3-iodopropane]-1,3-dihydro-2H-3-benzazepin-2-one (148870-57-9) → ivabradine (155974-00-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 18 h / Reflux 2: acetic acid; hydrogen; palladium(II) hydroxide / 24 h / 20 °C / 3675.37 Torr View Scheme

Upstream product

• 73344-75-9 (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine 
• 1220993-44-1 (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid 
• 1214788-46-1 (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile 
• 93-03-8 (3,4-dimethoxyphenyl)methanol 
• 120-14-9 3,4-dimethoxy-benzaldehyde 
• 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 
• 148870-55-7 ethyl [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]carbamate 
• 35202-55-2 1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine hydrochloride 
• 35249-62-8 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile 
• 53207-00-4 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene 
• 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 
• 1220993-43-0 (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 

Downstream Products

• 155974-00-8 ivabradine 
• 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 
• 1031767-75-5 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine d-camphorsulfonate 
• 148849-67-6 ivabradine hydrochloride 
• 1393427-04-7 N-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-N-(2,2-dimethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide 
• 866783-13-3 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride 

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.

Process for the enzymatic synthesis of (7S)-3,4-dimethoxybicyclo[4.2.0]OCTA-1,3,5-triene-7-carboxylic acid and application in the synthesis of ivabradine and salts thereof

Process for the enzymatic synthesis of the compound of formula (I): comprising enantioselective enzymatic hydrolysis of the nitrile of formula (IV): using the nitrilase of Rhodococcus rhodochrous of EMBL accession number EF467367.1, and the application of such a process in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid.

New synthetic route to (1s)-4,5-dimethoxy-1-[(methylamino)methyl] benzocyclobutane, a key intermediate of ivabradine

An efficient process for the preparation of (1S)-4,5-dimethoxy-1- [(methylamino)methyl] benzocyclobutane (S)-3 as ivabradine intermediate, which was obtained in 56% yield, is described. The salient feature of this process is the racemization of the undesired (1R)-4,5-dimethoxy-1,2- dihydrocyclobutabenzene-1-carboxylic acid (R)-12, and the overall yield of (S)-12 was improved to 70% by three resolutions of the racemized acid with R-(α)-phenylethanamine. The reduction of amide (S)-13 was achieved with NaBH4-I2 in refluxing tetrahydrofuran, giving the corresponding amine (S)-3 in 90% yield. The improved synthetic route described herein is cost-efficient, environmentally friendly and feasibile for scale-up production.