41234-23-5

Basic information

• Product Name: 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid
• Synonyms: 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid;DiMethoxybenzocyclobutane-1-carboxylic acid;4,5-DiMethoxybenzocyclobutane-1-carboxylicacid;3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid
• CAS NO: 41234-23-5
• Molecular Formula: C₁₁H₁₂O₄
• Molecular Weight: 206.1947
• Mol File: 41234-23-5.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 378.0±42.0 °C | Condition: Press: 760 Torr
• Appearance: /
• Density: 4.14±0.20 | Condition: Most Acidic Temp: 25 °C
• Storage Temp.: 2-8°C
• PKA: 4.14±0.20(Predicted)
• CAS DataBase Reference: 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid(41234-23-5)
• EPA Substance Registry System: 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid(41234-23-5)

Safety Data

• Hazardous Substances Data: 41234-23-5(Hazardous Substances Data)

Usage

General Description

4,5-Dimethoxybenzocyclobutene-1-carboxylic acid is a chemical compound with a cyclobutene ring and two methoxy groups attached to the benzene ring. It is often used in organic synthesis and medicinal chemistry as a precursor for the synthesis of various pharmaceutical compounds. 4,5-Dimethoxybenzocyclobutene-1-carboxylic acid may also have potential applications in materials science and as a building block in the synthesis of advanced materials. Additionally, it may have potential use in the development of new drugs and therapeutics due to its structural features and reactivity. The compound's unique structure and functional groups make it an important intermediate in the preparation of various biologically active molecules and materials with diverse properties.

Synthetic route

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
With potassium hydroxide In ethanol for 5h; Reflux;	95%
Stage #1: 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile With water; potassium hydroxide for 4h; Reflux; Stage #2: With hydrogenchloride In water at 20℃;	94%
With over-expressed nitrilase of Rhodococcus rhodochrous NCIMB 11216 In aq. phosphate buffer; ethanol at 30℃; for 2h; pH=7; Enzymatic reaction;	100 %Chromat.

(R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Stage #1: (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid With potassium hydroxide In water for 4h; Stage #2: With hydrogenchloride In water for 0.5h; Cooling with ice-water bath;	94%
With sodium ethanolate In ethanol for 18h; Reflux;
With acetic acid at 80 - 100℃; Reagent/catalyst;	56 g

dimethyl 4,5-dimethoxycyclobutabenzene-1,1(2H)-dicarboxylate (1069115-32-7) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Stage #1: dimethyl 4,5-dimethoxycyclobutabenzene-1,1(2H)-dicarboxylate With potassium cyanide In dimethyl sulfoxide at 130℃; for 12h; Inert atmosphere; Stage #2: With hydrogenchloride; water In diethyl ether; dimethyl sulfoxide at 20℃; for 1h;

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (+)-cinchonine → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water 2.1: potassium hydroxide / water / 4 h 2.2: 0.5 h / Cooling with ice-water bath View Scheme

3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile (35249-62-8) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -10 °C / Inert atmosphere 2.1: potassium hydroxide; water / 4 h / Reflux 2.2: 20 °C View Scheme

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile (1214788-46-1) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) + 3,4-Dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid amide (55171-70-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 2 h / 65 °C 2: nitrilase NIT 115 / aq. phosphate buffer; dimethyl sulfoxide / 72 h / 28 °C / pH 7 / Enzymatic reaction View Scheme

(R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile (1214788-46-1) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / isopropyl alcohol / 2 h / 65 °C 2: over-expressed nitrilase of Rhodococcus rhodochrous NCIMB 11216 / ethanol; aq. phosphate buffer / 2 h / 30 °C / pH 7 / Enzymatic reaction View Scheme

3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile (35202-54-1) → (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) + 3,4-Dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid amide (55171-70-5)

Conditions	Yield
With nitrilase NIT 110 In aq. phosphate buffer; dimethyl sulfoxide at 28℃; for 72h; pH=7; Reagent/catalyst; Enzymatic reaction;	A 15 %Chromat. B 24 %Chromat.
With nitrilase NIT 115 In aq. phosphate buffer; dimethyl sulfoxide at 28℃; for 72h; pH=7; Enzymatic reaction;	A 47 %Chromat. B 7 %Chromat.

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5) + (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid (1220993-44-1)

Conditions	Yield
Stage #1: (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid With (R)-1-phenyl-ethyl-amine In isopropyl alcohol for 1h; Reflux; Resolution of racemate; Stage #2: With hydrogenchloride; water Reagent/catalyst; Solvent; Time;	A n/a B 76.8%
Multi-step reaction with 2 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h View Scheme
Multi-step reaction with 2 steps 1: acetone / 0.5 h / Reflux; Cooling 2: hydrogenchloride / ethyl acetate; water / 0.08 h / pH 3 View Scheme

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 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

Conditions	Yield
In ethyl acetate Heating;	A n/a B 46%

(S)-1-phenyl-ethylamine (2627-86-3) + (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5) + C11H12O4*C8H11N

Conditions	Yield
In ethanol; 1,2-dichloro-ethane at 35℃; Solvent; Temperature; Reflux;	A n/a B 41.3%

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 3,4-Dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl chloride (343779-04-4)

Conditions	Yield
With oxalyl dichloride In benzene for 2h; Ambient temperature;

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → N-(3-butenyl)-4,5-dimethyoxybenzocyclobutenylmethylamine (73344-68-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → N-(3-butenyl)-4,5-dimethoxybenzocyclobutene 1-carboxamide (73344-66-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 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 4 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h 4: various solvent(s) / 18 h / Heating View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → trans-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline (73344-71-5, 73344-77-1)

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

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → trans-N-methyl-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline

Conditions	Yield
Multi-step reaction with 5 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h 4: various solvent(s) / 18 h / Heating 5: NaCNBH3, acetic acid / methanol; H2O View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → trans-N-ethyl-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline

Conditions	Yield
Multi-step reaction with 5 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h 4: various solvent(s) / 18 h / Heating 5: NaBH4 / benzene View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → cis-N-n-propyl-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline

Conditions	Yield
Multi-step reaction with 5 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h 4: various solvent(s) / 18 h / Heating 5: NaBH4 / benzene View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → trans-N-n-propyl-8,9-dimethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzisoquinoline

Conditions	Yield
Multi-step reaction with 5 steps 1: oxalyl chloride / benzene / 2 h / Ambient temperature 2: pyridine / CH2Cl2 / 1 h / Ambient temperature 3: LiAlH4, AlCl3 / diethyl ether / 2 h 4: various solvent(s) / 18 h / Heating 5: NaBH4 / benzene View Scheme

methanol (67-56-1) + (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → Methyl (R,S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate (1206230-25-2)

Conditions	Yield
With sulfuric acid for 2h; Reflux;

(S)-1-(1-Naphthyl)ethylamine (10420-89-0) + (R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine + (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid (S)-(-)-1-(naphthyl)-ethylamine (1346558-07-3)

Conditions	Yield
In ethyl acetate at 18℃; for 1h; Heating;	A n/a B n/a

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) + cinchonine (118-10-5, 485-70-1, 485-71-2, 550-54-9, 40134-63-2, 72402-55-2, 72402-56-3) → 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

Conditions	Yield
In ethyl acetate at 0℃; for 1.25h; Reflux;	A n/a B n/a

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) + cinchonidine (118-10-5, 485-70-1, 485-71-2, 550-54-9, 40134-63-2, 72402-55-2, 72402-56-3) → 3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine + (R)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid cinchonidine (1346558-10-8)

Conditions	Yield
In acetone for 0.5h; Reflux; Cooling;

(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

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

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

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 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 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 7 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 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-triene-7-carboxylic acid (1220993-44-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethyl acetate / 1.25 h / 0 °C / Reflux 2: hydrogenchloride / dichloromethane; water / 0.08 h View Scheme
Multi-step reaction with 2 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h View Scheme
Multi-step reaction with 2 steps 1: ethyl acetate / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (1220993-48-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethyl acetate / 1.25 h / 0 °C / Reflux 2: hydrogenchloride / water View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide (1220993-43-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethyl acetate / 1.25 h / 0 °C / Reflux 2: hydrogenchloride / dichloromethane; water / 0.08 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4: dichloromethane; water / 0 - 10 °C View Scheme
Multi-step reaction with 4 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4: dichloromethane; water / 0 - 10 °C View Scheme
Multi-step reaction with 4 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C 4: dichloromethane; water / 0 - 10 °C View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → (S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1.3,5-triene-7-carboxylic acid chloride (1220993-45-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethyl acetate / 1.25 h / 0 °C / Reflux 2: hydrogenchloride / dichloromethane; water / 0.08 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C View Scheme
Multi-step reaction with 3 steps 1: ethyl acetate / 1 h / 18 °C / Heating 2: hydrogenchloride / dichloromethane; water / 0.33 h 3: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 15 - 25 °C View Scheme

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → dehydro-ivabradine oxalate (1346558-08-4)

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

(R,S)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid (41234-23-5) → 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 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: nitric acid / ethanol; water 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: nitric acid / ethanol; water 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: nitric acid / ethanol; water 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: nitric acid / ethanol; water 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: nitric acid / ethanol; water View Scheme

Upstream product

• 1069115-32-7 dimethyl 4,5-dimethoxycyclobutabenzene-1,1(2H)-dicarboxylate 
• 35202-54-1 3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile 
• 1220993-48-5 (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid 
• 35249-62-8 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile 
• 1214788-46-1 (R)-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)nitrile 

Downstream Products

• 866783-13-3 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]-N-methylmethanamine hydrochloride 
• 148849-67-6 ivabradine hydrochloride 
• 1086026-31-4 3-{3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-(methyl)amino]propyl}-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one 
• 1220993-43-0 (7S)-3,4-dimethoxy-N-methylbicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 
• 866783-12-2 [{(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl}methyl](methyl)amine 
• 1220993-48-5 (R)-4,5-dimethoxy-1,2-dihydrocyclobutabenzene-1-carboxylic acid 

Relevant articles and documents

Method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane

The invention relates to a method for synthesizing (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane. The method provided by the invention does not need complicated high-cost column chromatographic methods for product purification or other special equipment, is good in operability, mild and safe in process, simple in reaction operation and beneficial for industrial production; and halogenated hydrocarbons are used as a solvent and are easy to recover and to use indiscriminately, and S-1-phenylethylamine is used as a resolving agent and is low in price and easy to recover, so production cost is greatly reduced. According to the invention, the synthesis is performed in organic acid, so racemization pollution is low, and environmentally friendliness is achieved; and the produced (1S)-4,5-dimethoxy-1-(carbonylaminomethyl)benzocyclobutane has few impurities and high chiral purity, wherein yield can reach 80-90% and HPLC purity is no less than 99%, so product quality is good.

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.

Process for the preparation of functionalised benzocyclobutenes, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

Process for the preparation of compounds of formula (IV): wherein R1, R2, R3 and R4, which may be identical or different, each represent a hydrogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group, a fluorine atom, a chlorine atom, a protected amine group, a protected hydroxyl group, an alkoxycarbonyl group in which the alkoxy group is linear or branched (C1-C6), or a CF3 group, or R1═R4═H and R2 and R3 together with the carbon atoms carrying them form a 1,3-dioxolane group, R5 represents a saturated or unsaturated, linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)hydroxyalkyl group in which the hydroxyl function is protected, or a CO2R7 group in which R7 is a linear or branched (C1-C6)alkyl group,R6 represents a cyano group or a CO2R8 group in which R8 is a linear or branched (C1-C6)-alkyl group.Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.