73344-75-9

Basic information

• Product Name: C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE
• Synonyms: C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE;3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-methanamine;4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane;Bicyclo[4.2.0]octa-1,3,5-triene-7-MethanaMine, 3,4-diMethoxy-;(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methanamine;Ivabradine Impurity 18;4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane HCl;(4,5-DIMETHOXY-1,2-DIHYDROCYCLOBUTABENZEN-1-YL)METHANAMINE
• CAS NO: 73344-75-9
• Molecular Formula: C₁₁H₁₅NO₂
• Molecular Weight: 193.24
• Mol File: 73344-75-9.mol

Chemical Properties

• Boiling Point: 309℃
• Flash Point: 153℃
• Appearance: /
• Density: 1.113
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE(CAS DataBase Reference)
• NIST Chemistry Reference: C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE(73344-75-9)
• EPA Substance Registry System: C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE(73344-75-9)

Safety Data

• Hazardous Substances Data: 73344-75-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE is used as a key intermediate in the synthesis of ent-Ivabradine Hydrochloride (I940505), a selective bradycardic agent with a direct effect on the pacemaker If current of the sinoatrial node. It is utilized for its ability to regulate heart rate and provide antianginal benefits, making it a valuable compound in the development of cardiovascular medications.
Additionally, due to its unique structure and functional groups, C-(3,4-DIMETHOXY-BICYCLO[4.2.0]OCTA-1(6),2,4-TRIEN-7-YL)-METHYLAMINE may have potential applications in other areas of the pharmaceutical industry, such as the development of new drugs with novel mechanisms of action or the improvement of existing drug delivery systems. However, further research and development would be required to explore these possibilities.

Synthetic route

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9)

Conditions	Yield
With ammonia; hydrogen; nickel In methanol at 60℃; under 22502.3 Torr; Industry scale;	100%
With ammonia; hydrogen In methanol at 20℃; under 2327.23 Torr; for 12h; Solvent; Reagent/catalyst;	98%

formic acid (64-18-6) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → C12H15NO3

Conditions	Yield
Stage #1: formic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.25h; Stage #2: (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine In tetrahydrofuran at 20℃; for 12h; Reagent/catalyst; Temperature; Solvent;	90%

N-acetyl-(S)-glutamic acid (1188-37-0) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-(aminomethyl)-benzocyclobutane N-acetyl-L-glutamate (869856-08-6)

Conditions	Yield
In ethanol; water at 20℃; Heating / reflux; Industry scale;	40%

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + (S)-ibuprofen (51146-56-6) → C11H15NO2*2C13H18O2

Conditions	Yield
In acetonitrile at 20℃; for 24h; Solvent;	40%

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + (S)-ibuprofen (51146-56-6) → C11H15NO2*2C13H18O2 + C11H15NO2*2C13H18O2

Conditions	Yield
In acetonitrile at 20 - 42℃; for 20h; Temperature; Time; Solvent;	A 38% B n/a

diallylcarbonate (15022-08-9) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + allyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate + allyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With Pseudomonas cepacia lipase II In 2-methyltetrahydrofuran at 30℃; for 42h;	A n/a B n/a C 35% D n/a
With lipase from Pseudomonas fluorescens In tert-butyl methyl ether at 30℃; for 24h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a

DBC (3459-92-5) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + benzyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With Pseudomonas cepacia lipase II In 2-methyltetrahydrofuran at 30℃; for 24h;	A n/a B n/a C 30%

but-3-enoyl chloride (1470-91-3) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → N-<(4,5-dimethoxybenzocyclobutenyl)methyl>-3-butenamide (73348-43-3)

Conditions	Yield
With pyridine In dichloromethane	29%

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → cis-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline (73344-71-5, 73344-77-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 29 percent / pyridine / CH2Cl2 2: 57 percent / various solvent(s) / 18 h / Heating 3: LiAlH4, AlCl3 / diethyl ether / 2.25 h / Ambient temperature View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → cis-N-n-propyl-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline

Conditions	Yield
Multi-step reaction with 4 steps 1: 29 percent / pyridine / CH2Cl2 2: 57 percent / various solvent(s) / 18 h / Heating 3: LiAlH4, AlCl3 / diethyl ether / 2.25 h / Ambient temperature 4: NaBH4 / benzene View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → cis-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinolin-3-one (73344-76-0, 73344-85-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 29 percent / pyridine / CH2Cl2 2: 57 percent / various solvent(s) / 18 h / Heating View Scheme

diallylcarbonate (15022-08-9) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + allyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate + allyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With lipase from Pseudomonas Cepacia In tert-butyl methyl ether at 30℃; for 24h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a
With Pseudomonas cepacia lipase II In tert-butyl methyl ether at 30℃; for 24h;	A n/a B n/a C n/a

DBC (3459-92-5) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + benzyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate + benzyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With lipase from Pseudomonas Cepacia In tert-butyl methyl ether at 30℃; for 24h; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a
With Pseudomonas cepacia lipase II In tert-butyl methyl ether at 30℃; for 24h;	A n/a B n/a C n/a

DBC (3459-92-5) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + benzyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate + benzyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With lipase from Pseudomonas fluorescens In tert-butyl methyl ether at 30℃; for 24h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a
With Pseudomonas cepacia lipase II In tert-butyl methyl ether at 30℃; for 24h;	A n/a B n/a C n/a D n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + Diethyl carbonate (105-58-8) → ethyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate (869856-10-0) + ethyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With lipase from Pseudomonas Cepacia In 2-methyltetrahydrofuran at 30℃; for 48h; Inert atmosphere; Enzymatic reaction; Overall yield = 44 %; enantioselective reaction;	A n/a B n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + Diethyl carbonate (105-58-8) → ethyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate (869856-10-0) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + ethyl {[(7R)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate

Conditions	Yield
With lipase from Pseudomonas Cepacia In 2-methyltetrahydrofuran at 30℃; for 96h; Concentration; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a
With Pseudomonas cepacia lipase II In 2-methyltetrahydrofuran at 30℃; for 96h; Enzymatic reaction;	A n/a B n/a C n/a
With Pseudomonas cepacia lipase II In 2-methyltetrahydrofuran at 30℃; for 24h; Enzymatic reaction;	A n/a B n/a C n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + Diethyl carbonate (105-58-8) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + ethyl {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}carbamate (869856-10-0) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5)

Conditions	Yield
With lipase from Pseudomonas Cepacia In 2-methyltetrahydrofuran at 30℃; for 24h; Solvent; Concentration; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a
With Pseudomonas cepacia lipase II In 2-methyltetrahydrofuran at 30℃; for 24h; Enzymatic reaction;	A n/a B n/a C n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + ethyl acetate (141-78-6) → (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + (S)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide + (R)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide

Conditions	Yield
With lipase PS IM at 30℃; for 4h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + ethyl acetate (141-78-6) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + (S)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide + (R)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide

Conditions	Yield
With lipase from Pseudomonas fluorescens at 30℃; for 4h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + 1-phenylethyl acetate (93-92-5, 50373-55-2) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + (S)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide + (R)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)acetamide

Conditions	Yield
With lipase from Pseudomonas Cepacia In tert-butyl methyl ether at 30℃; for 96h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + chloroacetic acid ethyl ester (105-39-5) → C13H16ClNO3 + C13H16ClNO3

Conditions	Yield
With lipase from Pseudomonas Cepacia In tert-butyl methyl ether at 30℃; for 96h; Catalytic behavior; Reagent/catalyst; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) + chloroacetic acid ethyl ester (105-39-5) → C13H16ClNO3

Conditions	Yield
With lipase from Pseudomonas fluorescens In tert-butyl methyl ether at 30℃; for 96h; Inert atmosphere; Enzymatic reaction;

methyl methoxyacetate (6290-49-9) + (±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane (869856-07-5) + (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (1422007-49-5) + (S)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)-2-methoxyacetamide + (R)-N-((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)-2-methoxyacetamide

Conditions	Yield
With lipase from Pseudomonas Cepacia In tert-butyl methyl ether at 30℃; for 96h; Catalytic behavior; Reagent/catalyst; Resolution of racemate; Inert atmosphere; Enzymatic reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a

(±)-(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

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → ivabradine hydrochloride (148849-67-6)

Conditions	Yield
Multi-step reaction with 7 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 6.1: triethylamine / acetonitrile / 12 h / 20 °C 7.1: hydrogenchloride; pyrographite / acetonitrile / 0.17 h / 70 °C / pH 2 - 3 View Scheme
Multi-step reaction with 7 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 6.1: triethylamine / acetonitrile / 12 h / 20 °C 7.1: hydrogenchloride; pyrographite / acetonitrile / 0.17 h / 70 °C / pH 2 - 3 View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → ivabradine (155974-00-8)

Conditions	Yield
Multi-step reaction with 6 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 6.1: triethylamine / acetonitrile / 12 h / 20 °C View Scheme
Multi-step reaction with 6 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 6.1: triethylamine / acetonitrile / 12 h / 20 °C View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane N-acetyl-L-glutamic acid

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane dextro mandelate

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

(±)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine (73344-75-9) → ({3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)(methyl)amine (148870-56-8)

Conditions	Yield
Multi-step reaction with 2 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 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

Upstream product

• 35202-54-1 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile 

Downstream Products

• 1422007-49-5 (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methylamine 
• 869856-07-5 (1S)-4,5-dimethoxy-1-(ammoniummethyl)benzocyclobutane 
• 866783-12-2 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine 
• 148849-67-6 ivabradine hydrochloride 
• 155974-00-8 ivabradine 
• 148870-56-8 ({3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl)(methyl)amine 
• 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

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

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

PROCESS FOR THE SYNTHESIS OF (IS)-4,5-DIMETHOXY-1-(METHYLAMINOMETHYL)-BENZOCYCLOBUTANE AND ADDITION SALTS THEREOF, AND TO THE APPLICATION THEREOF IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID

Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid, and hydrates thereof.