230615-52-8

Usage

Uses

Used in Pharmaceutical Industry:
2,3,4,5-TETRAHYDRO-1H-1,5-METHANO-3-BENZAZEPINE HYDROCHLORIDE is used as an intermediate compound for the preparation of the main band impurity of Varenicline (V098490), a nicotinic α4β2 acetylcholine receptor partial agonist. 2,3,4,5-TETRAHYDRO-1H-1,5-METHANO-3-BENZAZEPINE HYDROCHLORIDE plays a crucial role in the development of medications that aid in smoking cessation, helping individuals overcome nicotine addiction and improve their overall health.

InChI:InChI=1/C11H13N.ClH/c1-2-4-11-9-5-8(6-12-7-9)10(11)3-1;/h1-4,8-9,12H,5-7H2;1H

Synthetic route

10-Aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene (69718-72-5) → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
With hydrogenchloride In methanol at 0 - 5℃; Solvent;	96%

3-benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine (230615-48-2) → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
With hydrogenchloride; hydrogen; palladium(II) hydroxide In methanol at 20 - 40℃; under 3677.86 - 4413.43 Torr;	89.24%
Stage #1: 3-benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine With ammonium formate; palladium(II) hydroxide In methanol for 0.5h; Inert atmosphere of nitrogen; Reflux; Stage #2: With hydrogenchloride In ethyl acetate at 0 - 5℃; for 1h; pH=1 - 2;

2-indanone (615-13-4) → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: acetic acid; bromine / 2 h / 25 °C / Cooling with ice 2.1: ethanol; water / 5 h / 20 °C 3.1: potassium hydroxide; water / ethanol / 4 h / 75 °C 4.1: acetic anhydride / 5 h / 100 °C 4.2: 3 h / 75 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 6 h / 20 °C / Cooling with ice 6.1: hydrogenchloride / methanol / 0 - 5 °C View Scheme

1,3-dibromo-indan-2-one (39094-23-0) → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ethanol; water / 5 h / 20 °C 2.1: potassium hydroxide; water / ethanol / 4 h / 75 °C 3.1: acetic anhydride / 5 h / 100 °C 3.2: 3 h / 75 °C 4.1: sodium tetrahydroborate / tetrahydrofuran / 6 h / 20 °C / Cooling with ice 5.1: hydrogenchloride / methanol / 0 - 5 °C View Scheme

C11H6N2O → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium hydroxide; water / ethanol / 4 h / 75 °C 2.1: acetic anhydride / 5 h / 100 °C 2.2: 3 h / 75 °C 3.1: sodium tetrahydroborate / tetrahydrofuran / 6 h / 20 °C / Cooling with ice 4.1: hydrogenchloride / methanol / 0 - 5 °C View Scheme

C11H8O5 → 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic anhydride / 5 h / 100 °C 1.2: 3 h / 75 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 6 h / 20 °C / Cooling with ice 3.1: hydrogenchloride / methanol / 0 - 5 °C View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) + 2-chloro-5-(chloromethyl)pyridine (70258-18-3) → C17H17ClN2

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In acetone for 6h; pH=10; Reflux;	78.2%

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) + C11H7BrF7NO → C22H19F7N2O

Conditions	Yield
With potassium carbonate; sodium iodide In acetonitrile at 60℃; for 18h;	70%

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) + 4-methoxy-3-(2,2,2-trifluoroacetamido)benzenesulfonyl chloride (1184086-20-1) → 2-methoxy-5-((1,2,4,5-tetrahydro-3H-1,5-methanobenzo[d]azepin-3-yl)sulfonyl)aniline

Conditions	Yield
Stage #1: 2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride; 4-methoxy-3-(2,2,2-trifluoroacetamido)benzenesulfonyl chloride With dmap; triethylamine In dichloromethane for 1h; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water for 16h; Inert atmosphere; Reflux;	65%

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) + trifluoroacetic anhydride (407-25-0) → 1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (230615-51-7)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Product distribution / selectivity;
With pyridine In dichloromethane at 0℃; for 0.166667h;
With pyridine In dichloromethane

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → (+/-)-2,2,2-trifluoro-1-(4-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone (230615-53-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → 1-(4-Iodo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (230615-77-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane 3: palladium-carbon / methanol 4: potassium iodide / sulfuric acid; water View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → 1-(4-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (230615-56-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane 3: palladium-carbon / methanol View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → 4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (230615-81-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane 2: acetyl chloride 3: 1,4-dioxane; methanol; water View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → 1-(4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (230615-80-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / dichloromethane 2: acetyl chloride View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → N-(10-Trifluorothioacetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-thioacetamide (357425-94-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane 3: palladium-carbon / methanol 4: triethylamine / dichloromethane 5: toluene View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-acetamide (230615-57-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane 3: palladium-carbon / methanol 4: triethylamine / dichloromethane View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → 1-(10-AZATRICYCLO[6.3.1.02,7]DODECA-2(7),3,5-TRIEN-4-YL)-1-ETHANONE HYDROCHLORIDE (230615-31-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane 2: acetyl chloride 3: 1,4-dioxane; methanol; water 4: methanol View Scheme

2,3,4,5-tetrahydro-1,5-methylene-1H-3-benzazepine hydrochloride (230615-52-8) → N1-[10-AZATRICYCLO[6.3.1.02,7]DODECA-2(7),3,5-TRIEN-4-YL]-ACETAMIDE HYDROCHLORIDE (230615-06-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: pyridine / dichloromethane 2: trifluorormethanesulfonic acid; nitric acid / dichloromethane 3: palladium-carbon / methanol 4: triethylamine / dichloromethane 5: sodium carbonate / methanol; water View Scheme

Upstream product

• 615-13-4 2-indanone 
• 39094-23-0 1,3-dibromo-indan-2-one 
• 69718-72-5 10-Aza-tricyclo[6.3.1.02.7]dodeca-2⁽⁷⁾,3,5-triene 
• 230615-48-2 3-benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine 

Downstream Products

• 230615-51-7 1-(10-aza-tricyclo[6.3.1.0^2,7]dodeca-2⁽⁷⁾,3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 
• 230615-53-9 1-(4-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 

Relevant academic research and scientific papers

Preparation method of varenicline key intermediate

The invention discloses a preparation method of a varenicline key intermediate. A target compound is prepared from indanone by the six steps of halogenation, cyanidation, hydrolysis, closed-loop reaction, reduction and hydrochloride formation. The preparation method has the advantages of easy availability of raw materials, mild reaction conditions, simple process, high yield, low cost, low environmental pollution and good utilization value in industrial production.

PROCESS FOR PREPARING VARENICLINE, VARENICLINE INTERMEDIATES, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

Provided herein is an improved, convenient, commercially viable and environmentally friendly process for the preparation of varenicline or a pharmaceutically acceptable salt thereof comprising reacting l-(4,5-diamino-10-aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien- 10-yl)-2,2,2-trifluoro-ethanone with chloroacetaldehyde in the pressence of an oxygen source. Provided further herein is an improved and industrially advantageous process for the preparation of l-(4,5-diamino-10-aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien-10-yl)-2,2,2- trifluoro-ethanone.

PROCESSES FOR THE PREPARATION OF VARENICLINE AND INTERMEDIATES THEREOF

The invention provides an improved process for the preparation and purification of Varenicline and intermediates for the preparation of Varenicline.