223673-36-7

Basic information

• Product Name: (N-tert-Butoxycarbonyl-N-[(1'R)-hydroxy-1-phenyl)ethyl])-4-aMinophenylethylaMine
• Synonyms: N-[2-(4-Aminophenyl)ethyl]-N-[(2R)-2-hydroxy-2-phenylethyl]carbamic acid tert-butyl ester;tert-butyl (R)-N-[2-(4-aminophenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate;(R)-tert-Butyl 4-aminophenethyl(2-hydroxy-2-phenylethyl)carbamate;(N-tert-Butoxycarbonyl-N-[(1'R)-hydroxy-1-phenyl)ethyl])-4-aMinophenylethylaMine;[2-(4-AMinophenyl)ethyl][(2R)-2-hydroxy-2-phenylethyl]carbaMic Acid 1,1-DiMethylethyl Ester
• CAS NO: 223673-36-7
• Molecular Formula: C₂₁H₂₈N₂O₃
• Molecular Weight: 356.45862
• EINECS: 1592732-453-0
• Product Categories: Amines;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 223673-36-7.mol
• Article Data: 9

Chemical Properties

• Appearance: /
• Density: 1.150
• Storage Temp.: Keep in dark place,Inert atmosphere,Room temperature
• Solubility: Chloroform
• CAS DataBase Reference: (N-tert-Butoxycarbonyl-N-[(1'R)-hydroxy-1-phenyl)ethyl])-4-aMinophenylethylaMine(CAS DataBase Reference)
• NIST Chemistry Reference: (N-tert-Butoxycarbonyl-N-[(1'R)-hydroxy-1-phenyl)ethyl])-4-aMinophenylethylaMine(223673-36-7)
• EPA Substance Registry System: (N-tert-Butoxycarbonyl-N-[(1'R)-hydroxy-1-phenyl)ethyl])-4-aMinophenylethylaMine(223673-36-7)

Safety Data

• Hazardous Substances Data: 223673-36-7(Hazardous Substances Data)

Usage

Chemical Properties

Brown Semi-Solid

Synthetic route

((2R)-2-hydroxy-2-phenylethyl)-[2-(4-nitrophenyl)ethyl]carbamic acid tert-butyl ester → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol for 2h;	95%
With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 75℃; for 4h;	93%
With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 75℃; for 4h;	93%

(2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide (521284-19-5) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: boron trifluoride diethyl etherate; sodium tetrahydroborate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 0.05 - 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 1.2: 11 h / 0 - 20 °C / Reflux 1.3: 20 - 25 °C 2.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 2.2: 16 h / 25 - 30 °C 3.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(R)-Mandelic Acid (611-71-2) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: boron trifluoride diethyl etherate; sodium tetrahydroborate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 0.05 - 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: Trimethyl borate; N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Reflux 2.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 2.2: 11 h / 0 - 20 °C / Reflux 2.3: 20 - 25 °C 3.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 3.2: 16 h / 25 - 30 °C 4.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(R)-2-(4-nitrophenylethylamino)-1-phenylethan-1-ol hydrochloride → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme

2-(4-nitrophenyl)ethylamine monohydrochloride (29968-78-3) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: Trimethyl borate; N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Reflux 2.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 2.2: 11 h / 0 - 20 °C / Reflux 2.3: 20 - 25 °C 3.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 3.2: 16 h / 25 - 30 °C 4.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(R)-2-[[2′-(4-nitrophenyl)ethyl]amino]-1-phenylethanol hydrochloride (521284-21-9) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 1.2: 16 h / 25 - 30 °C 2.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

di-tert-butyl dicarbonate (24424-99-5) + YM-208876 (391901-45-4) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
In tetrahydrofuran at 0℃;

p-Aminophenethylamine (13472-00-9) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / Heating 2: tetrahydrofuran / 0 °C View Scheme

(R)-Styrene oxide (20780-53-4) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / Heating 2: tetrahydrofuran / 0 °C View Scheme

((2R)-2-hydroxy-2-phenylethyl)-[2-(4-nitrophenyl)ethyl]carbamic acid tert-butyl ester → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol for 2h;	95%
With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 75℃; for 4h;	93%
With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 75℃; for 4h;	93%

di-tert-butyl dicarbonate (24424-99-5) + YM-208876 (391901-45-4) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
In tetrahydrofuran at 0℃;

p-Aminophenethylamine (13472-00-9) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / Heating 2: tetrahydrofuran / 0 °C View Scheme

(R)-Styrene oxide (20780-53-4) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / Heating 2: tetrahydrofuran / 0 °C View Scheme

(2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide (521284-19-5) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: boron trifluoride diethyl etherate; sodium tetrahydroborate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 0.05 - 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 2: triethylamine / tetrahydrofuran / 1 h / 20 °C 3: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 1.2: 11 h / 0 - 20 °C / Reflux 1.3: 20 - 25 °C 2.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 2.2: 16 h / 25 - 30 °C 3.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(R)-2-(4-nitrophenylethylamino)-1-phenylethan-1-ol hydrochloride → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 20 °C 2: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme

(R)-Mandelic Acid (611-71-2) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: boron trifluoride diethyl etherate; sodium tetrahydroborate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 0.05 - 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / tetrahydrofuran; ethanol; water / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: Trimethyl borate; N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Reflux 2.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 2.2: 11 h / 0 - 20 °C / Reflux 2.3: 20 - 25 °C 3.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 3.2: 16 h / 25 - 30 °C 4.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

2-(4-nitrophenyl)ethylamine monohydrochloride (29968-78-3) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C 2: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 24 h / 70 °C / Cooling with ice 3: triethylamine / tetrahydrofuran / 1 h / 20 °C 4: ammonium chloride; iron / water; tetrahydrofuran; ethanol / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: Trimethyl borate; N-ethyl-N,N-diisopropylamine / acetonitrile / 8 h / Reflux 2.1: sodium tetrahydroborate / tetrahydrofuran / 25 °C 2.2: 11 h / 0 - 20 °C / Reflux 2.3: 20 - 25 °C 3.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 3.2: 16 h / 25 - 30 °C 4.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(R)-2-[[2′-(4-nitrophenyl)ethyl]amino]-1-phenylethanol hydrochloride (521284-21-9) → (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonia / water; dichloromethane / 0.17 h / pH 9 - 10 1.2: 16 h / 25 - 30 °C 2.1: hydrogen / methanol / 4.5 h / 25 - 30 °C / 3750.38 - 6000.6 Torr / Autoclave View Scheme

(1H-tetrazol-5-yl)-acetic acid (21743-75-9) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-tetrazol-5-yl)acetyl]amino}phenyl)ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	99%

α-(2-methyl-4-thiazolyl)acetic acid (13797-62-1) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-{[2-(2-methylthiazol-4-yl)acetyl]amino}phenyl)ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	99%

N-Benzyloxycarbonyl-L-proline (1148-11-4) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (S)-2-((4-(2-((tert-butoxycarbonyl)((R)-2-hydroxy2-phenylethyl)amino)ethyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester

Conditions	Yield
Stage #1: N-Benzyloxycarbonyl-L-proline With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at -20℃; for 1h; Stage #2: (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester In dichloromethane at 20℃; for 3h;	99%
Stage #1: N-Benzyloxycarbonyl-L-proline With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at -20℃; for 1h; Stage #2: (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester In dichloromethane at -20 - 20℃; for 4h;	99%
Stage #1: N-Benzyloxycarbonyl-L-proline With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at -20℃; for 1h; Stage #2: (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester In dichloromethane at 20℃; for 4h;	99%

Z-D-proline (6404-31-5) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-2-((4-(2-((tert-butoxycarbonyl)((R)-2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester

Conditions	Yield
Stage #1: Z-D-proline With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at -20℃; for 1h; Stage #2: (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester In dichloromethane at -20 - 20℃; for 4h;	94%
Stage #1: Z-D-proline With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at -20℃; for 1h; Stage #2: (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester In dichloromethane at 20℃; for 4h;	94%

6-tert-butoxycarbonylamino-2-pyridylacetic acid (408367-22-6) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-[2-(4-{[2-(6-tert-butoxycarbonylamino-2-pyridyl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate (1256096-35-1)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	89%

(5-amino-1,2,4-thiadiazol-3-yl)acetic acid hydrochloride (1256096-44-2) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-[2-(4-{[2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	86%

2-Bromoacetyl bromide (598-21-0) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-{4-[(2-bromoacetyl)amino]phenyl}ethyl)-N-(2-hydroxy-2-phenylethyl)carbamate (1256096-30-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In chloroform at 0℃;	85%

2-(6-oxopyridazin-1(6H)-yl)acetic acid (95209-84-0) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-(2-hydroxy-2-phenylethyl)(4-(2-(6-oxopyridazin-1(6H)-yl)acetylamino)phenethyl)carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 50℃; for 12h;	79%

(1-(4-nitrobenzyl)imidazol-2-yl)acetic acid hydrochloride (211103-05-8) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-{2-[4-({2-[1-(4-nitrobenzyl)imidazol-2-yl]acetyl}amino)phenyl]ethyl}carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	77%

2-(6-chloropyridin-2-yl)acetic acid (885267-14-1) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-[2-(4-{[2-(6-chloro-2-pyridyl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	75%

(2-amino-5-methylthiazol-4-yl)acetic acid hydrochloride (1256096-43-1) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-[2-(4-{[2-(2-amino-5-methylthiazol-4-yl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	73%

2-(2-oxopyrazine-1(2H)-yl)acetic acid (42352-55-6) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-(2-hydroxy-2-phenylethyl)(4-(2-(2-oxopyrazin-1(2H)-yl)acetylamino)phenethyl)carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 50℃; for 12h;	70%

2-(6-oxopyrimidin-1(6H)-yl)acetic acid (1190392-07-4) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-(2-hydroxy-2-phenylethyl)(4-(2-(6-oxopyrimidin-1(6H)-yl)acetylamino)phenethyl)carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 50℃; for 12h;	69%

(2-oxo-2H-pyridin-1-yl)-acetic acid (56546-36-2) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-(2-hydroxy-2-phenylethyl)(4-(2-(2-oxopyridine-1(2H)-yl)acetylamino)phenethyl)carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 50℃; for 12h;	64%

(6-benzyloxy-2-pyridyl)acetic acid (1000569-02-7) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-[2-(4-{[2-(6-benzyloxy-2-pyridyl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	56%

2-(2-oxopyrimidin-1(2H)-yl)acetic acid (95209-83-9) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → (R)-(2-hydroxy-2-phenylethyl)(4-(2-(2-oxopyrimidin-1(2H)-yl)acetylamino)phenethyl)carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 50℃; for 12h;	40%

1,2,4-triazol-3-ylacetic acid hydrochloride (1087714-25-7) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-{[2-(1H-1,2,4-triazol-3-yl)acetyl]amino}phenyl)ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 13h;	36%

5-bromo-thiazolidine-2,4-dione (125518-48-1) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl 4-[(2,4-dioxo-1,3-thiazolidin-5-yl)amino]phenethyl[(2 R)-2-hydroxy-2-phenylethyl]carbamate (391901-46-5)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;

(R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → 5-[4-(2-{[(2 R)-2-Hydroxy-2-phenylethyl]amino}ethyl)anilino]-1,3-thiazolidine-2,4-dione

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / dimethylformamide / 20 °C 2: CF3COOH / CH2Cl2 / 20 °C View Scheme

8-carboxyquinoline (86-59-9) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(8-quinolinecarbonyl)amino]phenyl]ethyl]carbamate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 18.5h;

pyridine-2-carbonyl chloride (29745-44-6) + (R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-[4-[(2-pyridinecarbonyl)amino]phenyl]ethyl]carbamate

Conditions	Yield
With triethylamine In chloroform at 20℃; for 2h;

(R)-(4-aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester (223673-36-7) → tert-butyl ((R)-2-hydroxy-2-phenylethyl)(4-((S)-pyrrolidine-2-carboxamido)phenethyl)carbamate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / -20 °C 1.2: 3 h / 20 °C 2.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 1 h / -20 °C 1.2: 4 h / -20 - 20 °C 2.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 4 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / -20 °C 1.2: 4 h / 20 °C 2.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 4 h / 20 °C View Scheme

Upstream product

• 521284-21-9 (R)-2-[[2′-(4-nitrophenyl)ethyl]amino]-1-phenylethanol hydrochloride 
• 29968-78-3 2-(4-nitrophenyl)ethylamine monohydrochloride 
• 611-71-2 (R)-Mandelic Acid 
• 223673-34-5 (R)-2-(4-nitrophenylethylamino)-1-phenylethan-1-ol hydrochloride 
• 521284-19-5 (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide 
• 223673-35-6 ((2R)-2-hydroxy-2-phenylethyl)-[2-(4-nitrophenyl)ethyl]carbamic acid tert-butyl ester 
• 20780-53-4 (R)-Styrene oxide 
• 13472-00-9 p-Aminophenethylamine 
• 24424-99-5 di-tert-butyl dicarbonate 
• 391901-45-4 YM-208876 

Downstream Products

• 1256096-30-6 tert-butyl (R)-N-(2-{4-[(2-bromoacetyl)amino]phenyl}ethyl)-N-(2-hydroxy-2-phenylethyl)carbamate 
• 1256096-35-1 tert-butyl (R)-N-[2-(4-{[2-(6-tert-butoxycarbonylamino-2-pyridyl)acetyl]amino}phenyl)ethyl]-N-(2-hydroxy-2-phenylethyl)carbamate 

Relevant articles and documents

Systematic Investigation into the Formation of Significant Amounts of Unknown Impurity during Scale-up of NaBH4-I2 Mediated Reduction of Nitro-Amide Intermediate of Mirabegron No.

After successful development of a manufacturing process for the Mirabegron (1) at the laboratory scale, a muddled situation was aroused during the scale-up batches, wherein sodium borohydride-iodine (NaBH4-I2) mediated reduction of nitro-amide 4 ended up with substantial amounts (～10%) of unspecified impurity in the nitro-amine intermediate 5. On the basis of the structure elucidation and meticulous investigation, a reaction path for its genesis during the process was identified and an efficient mechanism proposed to arrest its formation. In-situ generated nickel boride (Ni2B) due to reaction of NiI2 (corrosion product) with NaBH4 followed by electrophilic attack of THF (solvent) was found to be the reason for the formation of impurity (8a). Execution of subsequent batches with proper controls arrested this impurity and successfully provided the Mirabegron with the desired quality.

Amide substituted pyrrolidine amide derivatives and use thereof (by machine translation)

The invention discloses amide substituted pyrrolidine amide derivatives and their use, in particular, the invention relates to a novel class of amide substituted pyrrolidine amide derivatives containing such compounds and pharmaceutical composition, can be used to activate β 3 - adrenergic receptor. The invention also relates to processes for preparing such compounds and pharmaceutical compositions, and in the preparation of the treatment by the β 3 - adrenergic receptor activation mediated diseases or conditions, in particular the overactive bladder of the use of the medicament. (by machine translation)

Nitrogen heterocyclic ring group substituted amide derivative and application thereof

The invention discloses a nitrogen heterocyclic ring group substituted amide derivative and application thereof, particularly relates to a novel nitrogen heterocyclic ring group substituted amide derivative and a drug composition comprising the compound, and further relates to methods for preparing the compound and the drug composition, and application of the compound and the drug composition to preparation of drugs for treating diseases or symptoms, particularly overactive bladder, excited and mediated by beta 3-adrenergic receptors. The compound and the drug composition can be used for activating the beta 3-adrenergic receptors.