67165-56-4

Basic information

• Product Name: Diclofensine
• Synonyms: Diclofensine;4-(3,4-dichlorophenyl)-7-Methoxy-2-Methyl-3,4-dihydro-1H-isoquinoline hydrochloride;4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline;Ro8-4650;4-(3,4-Dichlorophenyl)-7-Methoxy-2-Methyl-1,2,3,4-tetrahydroisoquinoline
• CAS NO: 67165-56-4
• Molecular Formula: C₁₇H₁₇Cl₂NO
• Molecular Weight: 322.233
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;research chemical
• Mol File: 67165-56-4.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 422.595 °C at 760 mmHg
• Flash Point: 209.378 °C
• Appearance: /
• Density: 1.242
• Vapor Pressure: 2.38E-07mmHg at 25°C
• Refractive Index: 1.59
• PKA: 7.87±0.40(Predicted)
• CAS DataBase Reference: Diclofensine(CAS DataBase Reference)
• NIST Chemistry Reference: Diclofensine(67165-56-4)
• EPA Substance Registry System: Diclofensine(67165-56-4)

Safety Data

• Hazardous Substances Data: 67165-56-4(Hazardous Substances Data)

Usage

Uses

A stimulant; inhibits reuptake of dopamine and noradrenaline, is an effective antidepressant. Compound exhibits significant addictive properties.

InChI:InChI=1/C17H17Cl2NO/c1-20-9-12-7-13(21-2)4-5-14(12)15(10-20)11-3-6-16(18)17(19)8-11/h3-8,15H,9-10H2,1-2H3

Synthetic route

1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol (802051-24-7) → 4-(3,4-dichlorophenyl)-5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (692248-97-8) + Diclofensine (67165-56-4)

Conditions	Yield
Stage #1: 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol With sulfuric acid In dichloromethane at 0℃; for 28h; Stage #2: With sodium hydroxide In dichloromethane pH=9;	A 10% B 59%
Stage #1: 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol With sulfuric acid In dichloromethane at 0℃; for 28h; Stage #2: With sodium hydroxide In dichloromethane pH=~ 9;
Stage #1: 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol With sulfuric acid In dichloromethane; water at 0℃; for 28h; Stage #2: With sodium hydroxide In dichloromethane; water pH=~ 9;

1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanone (1254941-88-2) → Diclofensine (67165-56-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 2.1: sulfuric acid / dichloromethane; water / 28 h / 0 °C 2.2: pH ~ 9 View Scheme

1-(3-methoxyphenyl)-N-methylmethanamine (41789-95-1) → Diclofensine (67165-56-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dichloromethane / 1 h / 0 °C 1.2: 1 h / 0 °C 2.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 3.1: sulfuric acid / dichloromethane; water / 28 h / 0 °C 3.2: pH ~ 9 View Scheme

3-methoxy-benzaldehyde (591-31-1) → Diclofensine (67165-56-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / methanol; water / 2 h / 0 °C 2.1: dichloromethane / 1 h / 0 °C 2.2: 1 h / 0 °C 3.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 4.1: sulfuric acid / dichloromethane; water / 28 h / 0 °C 4.2: pH ~ 9 View Scheme

Diclofensine (67165-56-4) → (+)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline + (-)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline

Conditions	Yield
With CHIRALPAK AD Purification / work up; Resolution of racemate;
With Chiralpak AD column In diethylamine; isopropyl alcohol Purification / work up; Resolution of racemate;

carbonochloridic acid 1-chloro-ethyl ester (50893-53-3) + Diclofensine (67165-56-4) → C19H18Cl3NO3

Conditions	Yield
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In 1,2-dichloro-ethane Reflux;

Diclofensine (67165-56-4) → (-)-4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (50560-45-7) + (S)-diclofensine (50560-38-8)

Conditions	Yield
With Chiralpak AD column In n-heptane; diethylamine; isopropyl alcohol Purification / work up; Resolution of racemate;

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (1255925-44-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C View Scheme

Diclofensine (67165-56-4) → 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline (1254941-99-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere 6: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 19.33 h / 0 - 20 °C 7: methanol / 1 h / Reflux View Scheme
Multi-step reaction with 9 steps 1.1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2.1: hydrogen bromide / water; acetic acid / 8 h / Reflux 3.1: pyridine / dichloromethane / 1 h / -78 - 0 °C 4.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5.1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6.1: methanol / 1 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8.1: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sonication 9.1: hydrogenchloride / ethanol; water / 1 h / 20 °C 9.2: pH 8 - 9 View Scheme

Diclofensine (67165-56-4) → tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1254942-01-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere 6: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 19.33 h / 0 - 20 °C 7: methanol / 1 h / Reflux 8: N,N-dimethyl-formamide / 1 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6: methanol / 1 h / Reflux 7: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sonication View Scheme

Diclofensine (67165-56-4) → (+)-tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate + (-)-tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Conditions	Yield
Multi-step reaction with 9 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere 6: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 19.33 h / 0 - 20 °C 7: methanol / 1 h / Reflux 8: N,N-dimethyl-formamide / 1 h / 20 °C 9: Chiralpak AS-H column / methanol; carbon dioxide; triethylamine / Resolution of racemate View Scheme
Multi-step reaction with 9 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6: methanol / 1 h / Reflux 7: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sonication 9: Chiralpak AS-H column / methanol; carbon dioxide; triethylamine / Resolution of racemate View Scheme

Diclofensine (67165-56-4) → (+)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline monohydrochloride

Conditions	Yield
Multi-step reaction with 10 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere 6: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 19.33 h / 0 - 20 °C 7: methanol / 1 h / Reflux 8: N,N-dimethyl-formamide / 1 h / 20 °C 9: Chiralpak AS-H column / methanol; carbon dioxide; triethylamine / Resolution of racemate 10: hydrogenchloride / ethanol; dichloromethane / 2 h / 70 °C / Reflux View Scheme
Multi-step reaction with 10 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6: methanol / 1 h / Reflux 7: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sonication 9: Chiralpak AS-H column / methanol; carbon dioxide; triethylamine / Resolution of racemate 10: hydrogenchloride / ethanol; dichloromethane / 2 h / 70 °C / Reflux View Scheme

Diclofensine (67165-56-4) → (+)-7-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline L-tartrate

Conditions	Yield
Multi-step reaction with 10 steps 1.1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2.1: hydrogen bromide / water; acetic acid / 8 h / Reflux 3.1: pyridine / dichloromethane / 1 h / -78 - 0 °C 4.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5.1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6.1: methanol / 1 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8.1: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 1 h / 80 °C / Inert atmosphere; Sonication 9.1: hydrogenchloride / ethanol; water / 1 h / 20 °C 9.2: pH 8 - 9 10.1: activated carbon / ethanol / 4 h / 20 - 70 °C View Scheme
Multi-step reaction with 8 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere 6: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 19.33 h / 0 - 20 °C 7: methanol / 1 h / Reflux 8: activated carbon / ethanol / 4 h / 20 - 70 °C View Scheme

Diclofensine (67165-56-4) → 2-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile

Conditions

Yield

Multi-step reaction with 6 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / 2.25 h / 0 °C / Reflux 6: methanol / 1 h / Reflux View Scheme

Diclofensine (67165-56-4) → 5-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

Conditions

Yield

Multi-step reaction with 8 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 4: boron tribromide / dichloromethane / -78 - 0 °C 5: pyridine / dichloromethane 6: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / dimethyl sulfoxide / 2.5 h / 80 °C / Inert atmosphere 7: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 8: potassium carbonate / ethanol; dichloromethane View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (1255925-09-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 5: methanol / 1 h / Reflux View Scheme

Diclofensine (67165-56-4) → 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (1255924-39-0)

Conditions

Yield

Multi-step reaction with 6 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 5: methanol / 1 h / Reflux 6: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 2 h / 90 °C / Inert atmosphere View Scheme

Diclofensine (67165-56-4) → (+)-4-(3,4-dichlorophenyl)-7-(pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 7 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 6 h / 80 °C / Inert atmosphere 6: hydrazine hydrate / palladium 10% on activated carbon / ethanol / 5 h / 75 °C 7: trifluoroacetic acid / dichloromethane / 1 h / 20 °C View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-7-methoxy-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

Conditions	Yield
Multi-step reaction with 3 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-ol

Conditions	Yield
Multi-step reaction with 4 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 4: boron tribromide / dichloromethane / -78 - 0 °C View Scheme

Diclofensine (67165-56-4) → C19H15Cl3F3NO5S

Conditions	Yield
Multi-step reaction with 4 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux View Scheme

Diclofensine (67165-56-4) → (+)-4-(3,4-dichlorophenyl)-7-(6-(difluoromethoxy)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 9 steps 1.1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2.1: hydrogen bromide / water; acetic acid / 8 h / Reflux 3.1: pyridine / dichloromethane / 1 h / -78 - 0 °C 4.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5.1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6.1: methanol / 1 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere; Sonication 9.1: hydrogenchloride / ethanol; water / 20 °C 9.2: pH 8 - 9 View Scheme

Diclofensine (67165-56-4) → (+)-4-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 10 steps 1.1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2.1: hydrogen bromide / water; acetic acid / 8 h / Reflux 3.1: pyridine / dichloromethane / 1 h / -78 - 0 °C 4.1: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5.1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6.1: methanol / 1 h / Reflux 7.1: dmap; triethylamine / dichloromethane / 4 h / 20 °C 8.1: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 2 h / 80 °C / Inert atmosphere; Sonication 9.1: hydrogenchloride / water / 2.5 h / 20 °C 10.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 10.2: pH ~ 9 View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 6 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 4: boron tribromide / dichloromethane / -78 - 0 °C 5: pyridine / dichloromethane 6: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / dimethyl sulfoxide / 2.5 h / 80 °C / Inert atmosphere View Scheme

Diclofensine (67165-56-4) → 5-(4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrazin-2-amine

Conditions

Yield

Multi-step reaction with 7 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 4: boron tribromide / dichloromethane / -78 - 0 °C 5: pyridine / dichloromethane 6: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / dimethyl sulfoxide / 2.5 h / 80 °C / Inert atmosphere 7: caesium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-2-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate

Conditions	Yield
Multi-step reaction with 5 steps 1: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / 1,2-dichloro-ethane / Reflux 2: methanol / 1 h / Reflux 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 4: boron tribromide / dichloromethane / -78 - 0 °C 5: pyridine / dichloromethane View Scheme

Diclofensine (67165-56-4) → 7-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 5 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water / 1 h / 80 °C / Inert atmosphere View Scheme

Diclofensine (67165-56-4) → C22H26BCl2NO2

Conditions	Yield
Multi-step reaction with 4 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere View Scheme

Diclofensine (67165-56-4) → 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline

Conditions

Yield

Multi-step reaction with 6 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6: methanol / 1 h / Reflux View Scheme

Diclofensine (67165-56-4) → tert-butyl 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1255925-45-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: Chiralpak AD column / diethylamine; isopropyl alcohol / Resolution of racemate 2: hydrogen bromide / water; acetic acid / 8 h / Reflux 3: pyridine / dichloromethane / 1 h / -78 - 0 °C 4: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dimethyl sulfoxide / 1 h / 80 °C / Inert atmosphere 5: N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 0.92 h / 0 °C / Reflux 6: methanol / 1 h / Reflux 7: dmap; triethylamine / dichloromethane / 4 h / 20 °C View Scheme

Upstream product

• 802051-24-7 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol 
• 1254941-88-2 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanone 
• 41789-95-1 1-(3-methoxyphenyl)-N-methylmethanamine 
• 591-31-1 3-methoxy-benzaldehyde 

Downstream Products

• 1254941-99-5 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline 
• 1254942-01-2 tert-butyl 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 
• 1255924-39-0 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide 
• 1255925-45-1 tert-butyl 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate 

Relevant articles and documents

ARYL, HETEROARYL, AND HETEROCYCLE SUBSTITUTED TETRAHYDROISOQUINOLINES AND USE THEREOF

Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.

CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF

Novel [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinolines are described in the present invention. These compounds and crystalline forms SA1 and N-2 are used in the treatment of various neurological and physiological disorders. Methods of making these compounds and crystalline forms SA-1 and N-2 are also described in the present invention.