175591-22-7

Basic information

• Product Name: (betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine
• Synonyms: (2R,3R)-3-(3-Methoxyphenyl)-N,N-2-trimethylpentanamine;(betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine;Tapentadol InterMediate;BenzenepropanaMine, g-ethyl-3-Methoxy-N,N,b-triMethyl-, (bR,gR)-;(2R,3R)-3-(3-Methoxyphenyl)-N,N,2-triMethylpentan-1-aMine;(2S,3R)-1-(DiMethylaMino)-3-(3-Methoxyphenyl)-2-Methyl-3-pentanol;(betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropamine
• CAS NO: 175591-22-7
• Molecular Formula: C₁₅H₂₅NO
• Molecular Weight: 235.37
• Mol File: 175591-22-7.mol
• Article Data: 21

Chemical Properties

• Boiling Point: 308.9 °C at 760 mmHg
• Flash Point: 91.2 °C
• Appearance: /
• Density: 0.927
• PKA: 9.46±0.28(Predicted)
• CAS DataBase Reference: (betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine(CAS DataBase Reference)
• NIST Chemistry Reference: (betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine(175591-22-7)
• EPA Substance Registry System: (betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine(175591-22-7)

Safety Data

• Hazardous Substances Data: 175591-22-7(Hazardous Substances Data)

Usage

General Description

"(betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine" is a chemical compound with the molecular formula C15H25NO. It is a derivative of amphetamine and belongs to the class of psychoactive drugs. (betaR,gammaR)-gamma-Ethyl-3-methoxy-N,N,beta-trimethylbenzenepropanamine has stimulant effects on the central nervous system and can lead to increased alertness, concentration, and energy levels. It also has potential risks and side effects, including increased heart rate, elevated blood pressure, and insomnia. The exact mechanisms of action and long-term effects of this compound are not fully understood, and its use is regulated in many jurisdictions due to concerns about its potential for abuse and addiction.

Synthetic route

(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-4-en-1-amine (1367879-28-4) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol at 24℃; under 3750.38 Torr; for 22h;	99%
With hydrogen; 5%-palladium/activated carbon In methanol at 20℃; under 3375.34 Torr; for 16h;

(R),(R)-toluene-4-sulfonic acid 3-(3-methoxy-phenyl)-2-methyl-pentyl ester (1322723-68-1) + N,N-dimethylammonium chloride (506-59-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: N,N-dimethylammonium chloride With sodium hydroxide In dimethyl sulfoxide at 20 - 25℃; for 0.166667h; Stage #2: (R),(R)-toluene-4-sulfonic acid 3-(3-methoxy-phenyl)-2-methyl-pentyl ester In dimethyl sulfoxide at 50 - 55℃; for 2h;	95%

(2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol (809282-20-0) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol With methanesulfonic acid; sulfuric acid In tetrahydrofuran; cyclohexane at 25 - 78℃; for 3h; Stage #2: With palladium 10% on activated carbon; hydrogen In tetrahydrofuran; cyclohexane at 25 - 30℃; Autoclave; Inert atmosphere;	93.62%
Multi-step reaction with 2 steps 1.1: sulfuric acid / cyclohexane; tetrahydrofuran / 3 h / 25 - 80 °C 1.2: pH 8 - 9 2.1: hydrogen / palladium 10% on activated carbon / tetrahydrofuran / 25 - 30 °C / in an autoclave; Inert atmosphere 2.2: 0 - 5 °C / pH 9 - 10 View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid / tetrahydrofuran; cyclohexane / 3 h / 25 - 78 °C 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 25 - 30 °C / Autoclave; Inert atmosphere View Scheme

(2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-yl 4-methylsulfonate (1360589-13-4) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-yl 4-methylsulfonate With hydrogen; palladium 10% on activated carbon In tetrahydrofuran at 25 - 30℃; in an autoclave; Inert atmosphere; Stage #2: With sodium hydroxide In water at 0 - 5℃; pH=9 - 10; Product distribution / selectivity;	91%
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 25 - 30℃; Autoclave; Inert atmosphere;	91%

(βR,γR)-γ-ethyl-3-methoxy-β-methylbenzenepropanol (1322723-50-1) + N,N-dimethylammonium chloride (506-59-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: (βR,γR)-γ-ethyl-3-methoxy-β-methylbenzenepropanol With methanesulfonyl chloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: N,N-dimethylammonium chloride In dichloromethane at 30℃; for 2h;	91%

(αR,βR)-β-ethyl-3-methoxy-N,N,α-trimethyl benzenepropanamide (1313374-09-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Cooling with ice;	90%
Stage #1: (αR,βR)-β-ethyl-3-methoxy-N,N,α-trimethyl benzenepropanamide With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Cooling with ice; Stage #2: With water; sodium hydroxide In tetrahydrofuran	90%
Stage #1: (αR,βR)-β-ethyl-3-methoxy-N,N,α-trimethyl benzenepropanamide With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene for 1h; Inert atmosphere; Reflux; Stage #2: With sodium hydroxide In water; toluene at 20℃; for 0.5h; Cooling with ice;	84%
Stage #1: (αR,βR)-β-ethyl-3-methoxy-N,N,α-trimethyl benzenepropanamide With dimethylsulfide borane complex In tetrahydrofuran at 20 - 80℃; for 3h; Inert atmosphere; Stage #2: With methanol In tetrahydrofuran at 0 - 5℃; for 0.5h;

(R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
With hydrogenchloride; hydrogen; palladium 10% on activated carbon In ethanol; water at 20℃; Inert atmosphere;	72%

formaldehyd (50-00-0) + (3S,4R)-4-(3-methoxyphenyl)-3-methylhexanoic acid → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
With formic acid In water at 85℃; for 3h;	70%

(R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) + (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane

Conditions	Yield
Stage #1: (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine With hydrogenchloride; hydrogen; 5%-palladium/activated carbon In ethanol; water under 750.075 - 3750.38 Torr; Stage #2: With sodium hydroxide; water In ethanol at 20℃; pH=10 - 12;

C17H24F3NO3 → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: C17H24F3NO3 With hydrogen; palladium 10% on activated carbon at 40℃; under 1520.1 Torr; for 4h; Stage #2: With sodium hydroxide; water at 20℃; for 0.166667h; Product distribution / selectivity;

C17H27NO3 → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: C17H27NO3 With hydrogen; palladium 10% on activated carbon at 40℃; under 1520.1 Torr; for 4h; Stage #2: With sodium hydroxide; water at 20℃; for 0.166667h; Product distribution / selectivity;

C19H29NO5 → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Stage #1: C19H29NO5 With hydrogen; palladium 10% on activated carbon at 40℃; under 1520.1 Torr; for 4h; Stage #2: With sodium hydroxide; water at 20℃; for 0.166667h; Product distribution / selectivity;

(Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine hydrochloride + (E)-(RS)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethylamine hydrochloride (197144-97-1) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) + (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane

Conditions	Yield
Stage #1: (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine hydrochloride; (E)-(RS)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethylamine hydrochloride With hydrogen; 5%-palladium/activated carbon In water at 45℃; under 750.075 - 3750.38 Torr; Stage #2: With sodium hydroxide In water Product distribution / selectivity;

(E)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine (809282-31-3) + (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine (809282-30-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) + (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In ethanol at 25℃; under 750.075 - 3750.38 Torr; Product distribution / selectivity;
With hydrogen; palladium 10% on activated carbon In ethanol; water at 25℃; under 750.075 - 3750.38 Torr; Product distribution / selectivity;
With hydrogen; 5%-palladium/activated carbon In ethanol; water at 25℃; under 750.075 - 3750.38 Torr; Product distribution / selectivity;
With hydrogen; 1% Pd/C In ethanol; water at 25℃; under 750.075 - 3750.38 Torr; Product distribution / selectivity;
Stage #1: (E)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine; (Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine With hydrogenchloride; hydrogen; 5%-palladium/activated carbon In ethanol; water at 25℃; under 750.075 - 3750.38 Torr; Stage #2: With sodium hydroxide In water; ethyl acetate at 20℃; pH=10 - 12; Product distribution / selectivity;

(2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol (809282-20-0) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) + (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane

Conditions	Yield
Stage #1: (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol With hydrogenchloride In water at 20 - 70℃; for 1.66667h; Stage #2: With sodium hydroxide; sodium chloride In water at 20℃; Stage #3: With sodium hydroxide; hydrogen; 1% Pd/C Product distribution / selectivity; more than 3 stages;
Stage #1: (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol With hydrogenchloride In water at 20 - 70℃; for 1.66667h; Stage #2: With sodium hydroxide; sodium chloride In water at 20℃; Stage #3: With sodium hydroxide; hydrogen; palladium dichloride Product distribution / selectivity; more than 3 stages;

(Z)-(2R)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethyl-amine (809282-30-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) + (2R,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentane

Conditions	Yield
With methanesulfonic acid; hydrogen; bis(norbornadiene)rhodium(l)tetrafluoroborate; (S)-Solphos In ethanol at 0 - 25℃; under 7500.75 - 15001.5 Torr; for 16.5 - 67.5h; Product distribution / selectivity;
With methanesulfonic acid; hydrogen; bis(norbornadiene)rhodium(l)tetrafluoroborate; 2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-1,1'-biphenyl In ethanol at 0 - 25℃; under 15001.5 Torr; for 20h; Product distribution / selectivity;
With methanesulfonic acid; hydrogen; bis(norbornadiene)rhodium(l)tetrafluoroborate; 4,12-bis(diphenylphosphino)-[2.2]-paracyclophane In ethanol at 0 - 25℃; under 15001.5 Torr; for 20h; Product distribution / selectivity;

2-(3-methoxybenzylidene)malononitrile (2972-72-7) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: tri-n-butyl-tin hydride / 2,2'-azobis(isobutyronitrile) / toluene / 10 h / Reflux 3.2: 20 °C 4.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 8.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 9.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 9.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 6.2: 0 - 5 °C 7.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 8.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 8.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: sulfuric acid / 5 h / 50 - 55 °C 7.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 8.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 9.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 9.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 7.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 7.2: 0 - 5 °C 8.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 9.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 9.2: 2 h / 50 - 55 °C View Scheme

3-methoxy-benzaldehyde (591-31-1) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 6 h / 50 - 60 °C 2.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 2.2: 0 - 5 °C 3.1: sodium hydride / toluene / 1 h / 20 °C / Inert atmosphere 3.2: 4 h / 45 - 50 °C 3.3: 0 - 5 °C / pH 1 4.1: lithium chloride / dimethyl sulfoxide / 15 h / 150 - 160 °C 5.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 5.2: pH 1 6.1: di-isopropyl ether / 6 h / 20 - 75 °C 7.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 8.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 9.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 10.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 10.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 6 h / 50 - 60 °C 2.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 2.2: 0 - 5 °C 3.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 3.2: 1 h / 25 °C 4.1: tri-n-butyl-tin hydride / 2,2'-azobis(isobutyronitrile) / toluene / 10 h / Reflux 4.2: 20 °C 5.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 5.2: pH 1 6.1: di-isopropyl ether / 6 h / 20 - 75 °C 7.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 8.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 9.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 10.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 10.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / -5 °C / Inert atmosphere 1.2: 0 °C 2.1: phosphorus tribromide / 0 - 25 °C 3.1: sodium hydride / dimethyl sulfoxide / 1 h / 25 °C 3.2: 5 h 4.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 7.2: 0 - 5 °C 8.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 9.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 9.2: 2 h / 50 - 55 °C View Scheme

2-cyano-3-(3-methoxyphenyl)acrylic acid ethyl ester (24393-44-0, 19098-69-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: tetrahydrofuran / -15 - 25 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: sodium hydride / toluene / 1 h / 20 °C / Inert atmosphere 2.2: 4 h / 45 - 50 °C 2.3: 0 - 5 °C / pH 1 3.1: lithium chloride / dimethyl sulfoxide / 15 h / 150 - 160 °C 4.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 8.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 9.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 9.2: 0.5 h / 0 - 5 °C View Scheme

2-[1-(3-methoxy-phenyl)-propyl]-malononitrile (1313429-15-0) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: tri-n-butyl-tin hydride / 2,2'-azobis(isobutyronitrile) / toluene / 10 h / Reflux 2.2: 20 °C 3.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 7.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 8.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 8.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 5.2: 0 - 5 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 6.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 6.2: 0 - 5 °C 7.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 8.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 8.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: sulfuric acid / 5 h / 50 - 55 °C 6.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 7.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 8.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 8.2: 2 h / 50 - 55 °C View Scheme

3-(1-bromopropyl)anisole (1313429-17-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 3 h / 25 °C 2.1: sodium hydride / toluene / 1 h / 20 °C / Inert atmosphere 2.2: 4 h / 45 - 50 °C 2.3: 0 - 5 °C / pH 1 3.1: lithium chloride / dimethyl sulfoxide / 15 h / 150 - 160 °C 4.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 8.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 9.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 9.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 10 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 3 h / 25 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: sodium amalgam / ethanol / 25 - 30 °C 4.1: sodium amide / toluene / 4 h / 20 °C / Reflux 4.2: Reflux 5.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 5.2: pH 1 6.1: di-isopropyl ether / 6 h / 20 - 75 °C 7.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 8.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 9.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 10.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 10.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 9 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 3 h / 25 °C 2.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 2.2: 1 h / 25 °C 3.1: sodium amalgam / methanol / 25 - 30 °C 4.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 8.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 9.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 9.2: 0.5 h / 0 - 5 °C View Scheme

3-(3-methoxy-phenyl)-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester (1313429-18-3) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: sodium amalgam / ethanol / 25 - 30 °C 3.1: sodium amide / toluene / 4 h / 20 °C / Reflux 3.2: Reflux 4.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 4.2: pH 1 5.1: di-isopropyl ether / 6 h / 20 - 75 °C 6.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 7.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 8.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 9.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 9.2: 0.5 h / 0 - 5 °C View Scheme

3-(3-methoxy-phenyl)-2-(toluene-4-sulfonyl)-pentanenitrile (1313429-19-4) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: potassium carbonate / dimethyl sulfoxide / 0.25 h / 25 °C 1.2: 1 h / 25 °C 2.1: sodium amalgam / methanol / 25 - 30 °C 3.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 7.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 8.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 8.2: 0.5 h / 0 - 5 °C View Scheme

2-[1-(3-methoxy-phenyl)-propyl]-2-methyl-malononitrile (1313429-21-8) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: tri-n-butyl-tin hydride / 2,2'-azobis(isobutyronitrile) / toluene / 10 h / Reflux 1.2: 20 °C 2.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 6.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 7.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 7.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 4.2: 0 - 5 °C 5.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 6.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 6.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: sulfuric acid / 5 h / 50 - 55 °C 5.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 5.2: 0 - 5 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme

3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester (1313429-22-9) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sodium amalgam / ethanol / 25 - 30 °C 2.1: sodium amide / toluene / 4 h / 20 °C / Reflux 2.2: Reflux 3.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 3.2: pH 1 4.1: di-isopropyl ether / 6 h / 20 - 75 °C 5.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 6.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 7.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 8.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 8.2: 0.5 h / 0 - 5 °C View Scheme

3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanenitrile (1313429-23-0) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium amalgam / methanol / 25 - 30 °C 2.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 6.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 7.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 7.2: 0.5 h / 0 - 5 °C View Scheme

2-methyl-3-(3-methoxyphenyl)pentanenitrile (1313429-24-1) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 5.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 6.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 4.2: 0 - 5 °C 5.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 6.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 6.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: sulfuric acid / 5 h / 50 - 55 °C 5.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 5.2: 0 - 5 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme

2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (1313429-25-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: lithium chloride / dimethyl sulfoxide / 15 h / 150 - 160 °C 2.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 2.2: pH 1 3.1: di-isopropyl ether / 6 h / 20 - 75 °C 4.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 5.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 6.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 7.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 7.2: 0.5 h / 0 - 5 °C View Scheme

2-methyl-3-(3-methoxyphenyl)valeric acid (1616-70-2) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: di-isopropyl ether / 6 h / 20 - 75 °C 2.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 3.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 4.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 5.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 5.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 5 steps 1.1: di-isopropyl ether / 6 h / 20 - 75 °C 2.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 3.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 3.2: 0 - 5 °C 4.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 5.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 5.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 6 steps 1.1: di-isopropyl ether / 6 h / 20 - 75 °C 2.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 3.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 4.2: 0 - 5 °C 5.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 6.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 6.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 6 steps 1.1: di-isopropyl ether / 6 h / 20 - 75 °C 2.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 3.1: sulfuric acid / 5 h / 50 - 55 °C 4.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 5.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 6.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 6.2: 2 h / 50 - 55 °C View Scheme

diethyl 1-(3-methoxyphenyl)propylmethylmalonate (1313429-26-3) → (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydroxide / ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 5.1: sodium carbonate / toluene; water / 1 h / 0 - 5 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 20 - 80 °C / Inert atmosphere 6.2: 0.5 h / 0 - 5 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: borane-dimethyl sulfide complex / tetrahydrofuran / 1 h / 50 - 55 °C / Inert atmosphere 4.2: 0 - 5 °C 5.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 6.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 6.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: sulfuric acid / 5 h / 50 - 55 °C 5.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 4 h / 50 - 55 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; ethylene glycol / 4 h / 170 - 180 °C 1.2: pH 1 2.1: di-isopropyl ether / 6 h / 20 - 75 °C 3.1: hydrogenchloride / water; tert-butyl methyl ether / 0.5 h / 20 - 25 °C 4.1: thionyl chloride / toluene / 3 h / 75 - 80 °C 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 0 - 55 °C 5.2: 0 - 5 °C 6.1: triethylamine / dmap / dichloromethane / 6 h / 25 - 30 °C 7.1: sodium hydroxide / dimethyl sulfoxide / 0.17 h / 20 - 25 °C 7.2: 2 h / 50 - 55 °C View Scheme

(βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) → tapentadol (175591-23-8)

Conditions	Yield
With hydrogen bromide In water at 100 - 110℃; for 3h;	98%
Stage #1: (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine With dimethylsulfide In methanesulfonic acid at 5 - 60℃; for 2.16667h; Stage #2: With sodium hydroxide In water at 5℃; pH=9 - 10;	88.62%
With methanesulfonic acid; DL-methionine at 80℃; for 16h;	81%

(βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) → tapentadol hydrochloride

Conditions	Yield
Stage #1: (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine With boron tribromide In dichloromethane at 20℃; for 15h; Cooling with ice; Stage #2: With hydrogenchloride In water	90%
Stage #1: (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine With boron tribromide In dichloromethane at 20℃; for 15h; Cooling with ice; Stage #2: With methanol In dichloromethane Cooling with ice; Stage #3: With hydrogenchloride In water	90%
Stage #1: (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine With methanesulfonic acid; DL-methionine at 80℃; for 12h; Stage #2: With hydrogenchloride In ethyl acetate at 0℃;	88%

(βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) → (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentane-1-amine hydrochloride

Conditions	Yield
With hydrogenchloride In di-isopropyl ether at 25 - 30℃; for 2h;	87%
With hydrogenchloride In isopropyl alcohol at 0 - 20℃; for 4.08333h;

(βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine (175591-22-7) → (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-1-amine hydrochloride

Conditions	Yield
Stage #1: (βR,γR)-γ-ethyl-N,N,β-trimethyl-3-methoxybenzenepropanamine With methanesulfonic acid; dimethylsulfide at 0 - 45℃; for 7h; Stage #2: With hydrogenchloride In water; butanone at 20 - 25℃; for 2h; pH=6.5 - 7; Temperature;	54%

Upstream product

• 197144-97-1 (E)-(RS)-[3-(3-methoxy-phenyl)-2-methyl-pent-3-enyl]-dimethylamine hydrochloride 
• 4988-34-5 tetrahydro-2H-thiopyran-1-oxide 
• 41533-19-1 3-(N,N-Dimethylaminomethyl)-tetrahydro-4H-thiopyran-4-on 
• 54961-39-6 4-(3-methoxyphenyl)-3-methyl-4-oxobutanoic acid 
• 37951-49-8 1-(3-methoxyphenyl)propan-1-one 
• 50-00-0 formaldehyd 
• 117843-11-5 R-4-(3-methoxyphenyl)-3-methyl-4-oxobutanoate 
• 1322723-50-1 (βR,γR)-γ-ethyl-3-methoxy-β-methylbenzenepropanol 
• 506-59-2 N,N-dimethylammonium chloride 
• 10365-98-7 3-methoxyphenylboronic acid 
• 623-36-9 (E)-2-methylpent-2-enal 
• 56030-38-7 3-methoxycinnamoyl chloride 
• 6099-04-3 3-methoxycinnamic acid 

Downstream Products

• 175591-23-8 tapentadol 
• 175591-09-0 tapentadol hydrochloride 
• 1314003-88-7 (R,R)-tapentadol-(PABA tert-butyl ester) carbamate 
• 1314003-30-9 (R,R)-tapentadol-PABA carbamate trifluoroacetate 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF TAPENTADOL AND ANALOGS THEREOF

The present invention relates to a process for the preparation of tapentadol and analogs or compounds or stereoisomers of formula (I), Formula I wherein, A is aryl, heteroaryl, and cycloalkyl; R is H, OH, OR1, halogen, C1-C12 alkyl, cycloalkyl, aryl or heteroaryl; R1 is C1-C12 alkyl, cycloalkyl, aryl or heteroaryl, wherein each of these groups may further be substituted with one or more substituent selected from H, OH, halogen, CN, NO2, C1-C4 alkyl or phenyl. Further, the multi-step process involves no column chromatography purification until the very last step. This makes this process highly commercially viable and industrially useful.

NEW SYNTHESIS OF TAPENTADOL-HCl INTERMEDIATES

The present invention relates to a process for the synthesis of tapentadol intermediates comprising the following route of synthesis: (I) → (II) → (III) → (IV) → (V).

PROCESS FOR PREPARING SUBSTITUTED PHENYLALKANES

The invention provides methods for preparing substituted phenylalkanes. In particular, the processes comprise reacting a phenyl boronic compound with an α-β unsaturated carbonyl-containing compound via an asymmetric 1,4-addition reaction. The processes may be useful in the synthesis of tapentadol.