180468-42-2

Basic information

• Product Name: Ethyl (S)-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate
• Synonyms: ETHYL (S)-1-PHENYL-1,2,3,4-TETRAHYDRO-2-ISOQUINOLINECARBOXYLATE;(S)-3,4-Dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid ethyl ester;(S)-ethyl 1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate;4-tetrahydro-2-isoquinolinecarboxylate;Ethyl (S)-1-phenyl-1;(1S)-Ethyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate;2(1H)-Isoquinolinecarboxylic acid,3,4-dihydro-1-phenyl-,ethyl ester,(1S)-;propyl (S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate
• CAS NO: 180468-42-2
• Molecular Formula: C₁₈H₁₉NO₂
• Molecular Weight: 281.35
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Isotope Labelled Compounds;Pharmaceuticals
• Mol File: 180468-42-2.mol
• Article Data: 23

Chemical Properties

• Boiling Point: 412.2 °C at 760 mmHg
• Flash Point: 203.1 °C
• Appearance: /
• Density: 1.145
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.582
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethanol (Slightly), Methanol (Slightly)
• PKA: -2.16±0.40(Predicted)
• CAS DataBase Reference: Ethyl (S)-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl (S)-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate(180468-42-2)
• EPA Substance Registry System: Ethyl (S)-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate(180468-42-2)

Safety Data

• Hazardous Substances Data: 180468-42-2(Hazardous Substances Data)

Usage

Uses

Solifenacin

InChI:InChI=1/C18H19NO2/c1-2-21-18(20)19-13-12-14-8-6-7-11-16(14)17(19)15-9-4-3-5-10-15/h3-11,17H,2,12-13H2,1H3

Synthetic route

chloroformic acid ethyl ester (541-41-3) + (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
With potassium carbonate In dichloromethane at 20℃;	100%
With triethylamine In dichloromethane at 20℃; for 5h;	99%
With potassium carbonate; 1-butyl-3-methylimidazolium Tetrafluoroborate at 20℃; for 2h; Reagent/catalyst; Concentration;	97.9%

ethyl bromide (74-96-4) + carbon dioxide (124-38-9) + (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
With sodium carbonate In 1,4-dioxane at 25℃; under 750.075 Torr; for 5h;	84%

ethyl (S)-((2-(2-hydroxyethyl)phenyl)(phenyl)methyl)carbamate → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; enantioselective reaction;	71%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Cooling with ice;	71%

1-phenyl-3,4-dihydroisoquinoline (52250-50-7) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4 / ethanol / 60 h / 20 °C 2: 100 percent / K2CO3 / CH2Cl2 / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: methanol; sodium tetrahydroborate / water / 5.42 h / 20 - 34 °C 2.1: D-tartaric acid / methanol; ethyl acetate / 2.08 h / 28 - 64 °C / Resolution of racemate 2.2: 1.17 h / pH 8 - 9 3.1: sodium carbonate / toluene / 2.17 h / 0 - 28 °C View Scheme

N-phenethylbenzamide (3278-14-6) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: P2O5; POCl3 / xylene / 2.5 h / Heating 2: NaBH4 / ethanol / 60 h / 20 °C 3: 100 percent / K2CO3 / CH2Cl2 / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: PPA / water / 4.25 h / 14.9 - 165 °C 1.2: 0.17 h / 28 - 42 °C / pH 2.1 - 7.12 2.1: methanol; sodium tetrahydroborate / water / 5.42 h / 20 - 34 °C 3.1: D-tartaric acid / methanol; ethyl acetate / 2.08 h / 28 - 64 °C / Resolution of racemate 3.2: 1.17 h / pH 8 - 9 4.1: sodium carbonate / toluene / 2.17 h / 0 - 28 °C View Scheme

(S)-1,2,3,4-tetrahydro-1-phenyl-isoquinoline-2-carboxylic acid (1035272-88-8) + chloroformic acid ethyl ester (541-41-3) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
With sodium carbonate In water; toluene at 14.9 - 34.8℃; for 3h;

(R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / -10 - 20 °C 2.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 2.2: 20 °C / pH 9 - 10 3.1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 4.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / dichloromethane / 0 - 25 °C 2.1: sodium hydroxide / ethanol / 75 - 80 °C 2.2: Cooling 3.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / -10 - 20 °C 2.1: hydrogenchloride; water; phosphoric acid / 32 h / 95 - 100 °C 2.2: 20 °C / pH 9 - 10 3.1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 4.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / -10 - 20 °C 2.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 2.2: 20 °C / pH 9 - 10 3.1: D-tartaric acid / water / Resolution of racemate 3.2: 20 °C 4.1: acetone / 5 °C / Reflux View Scheme

4-nitrophenyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (881834-78-2) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydroxide / ethanol / 75 - 80 °C 1.2: Cooling 2.1: triethylamine / dichloromethane / -10 - 20 °C 3.1: hydrogenchloride; water; phosphoric acid / 32 h / 95 - 100 °C 3.2: 20 °C / pH 9 - 10 4.1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 5.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide / ethanol / 75 - 80 °C 1.2: Cooling 2.1: acetone / 5 °C / Reflux View Scheme

1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 2: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: D-tartaric acid / water / Resolution of racemate 1.2: 20 °C 2.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: D-tartaric acid / water / Resolution of racemate 1.2: 20 °C 2.1: potassium carbonate / dichloromethane / 0 - 25 °C 3.1: sodium hydroxide / ethanol / 75 - 80 °C 3.2: Cooling 4.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: D-tartaric acid / methanol; ethyl acetate / 2.08 h / 28 - 64 °C / Resolution of racemate 1.2: 1.17 h / pH 8 - 9 2.1: sodium carbonate / toluene / 2.17 h / 0 - 28 °C View Scheme

N-acetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline (1300713-32-9) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water; phosphoric acid / 32 h / 95 - 100 °C 1.2: 20 °C / pH 9 - 10 2.1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 3.1: acetone / 5 °C / Reflux View Scheme

N-chloroacetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline (1085541-60-1) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 1.2: 20 °C / pH 9 - 10 2.1: D-tartaric acid / water / 1.5 h / 65 - 95 °C / Resolution of racemate 3.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 1.2: 20 °C / pH 9 - 10 2.1: D-tartaric acid / water / Resolution of racemate 2.2: 20 °C 3.1: acetone / 5 °C / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 1.2: 20 °C / pH 9 - 10 2.1: D-tartaric acid / water / Resolution of racemate 2.2: 20 °C 3.1: potassium carbonate / dichloromethane / 0 - 25 °C 4.1: sodium hydroxide / ethanol / 75 - 80 °C 4.2: Cooling 5.1: acetone / 5 °C / Reflux View Scheme

1-phenyl-3,4-dihydroisoquinoline (52250-50-7) + diethyl dicarbonate (1609-47-8) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + ethyl (R)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (180468-41-1)

Conditions	Yield
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (R)-3,5-diMe-Synphos; hydrogen In 1,4-dioxane at 40℃; under 22502.3 Torr; for 18h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;

N-benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1443308-90-4) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; hydrogenchloride; 5%-palladium/activated carbon / ethanol; ethyl acetate / 24 h / 20 °C / 760.05 Torr / Schlenk technique 2: triethylamine / dichloromethane / 5 h / 20 °C View Scheme

C22H18N(1+)*Br(1-) (1443308-91-5) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 3 steps 1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) / dichloromethane; tetrahydrofuran / 20 h / 30 °C / 31029.7 Torr / Autoclave; Glovebox 2: hydrogen; hydrogenchloride; 5%-palladium/activated carbon / ethanol; ethyl acetate / 24 h / 20 °C / 760.05 Torr / Schlenk technique 3: triethylamine / dichloromethane / 5 h / 20 °C View Scheme

1-phenylisoquinoline (3297-72-1) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 4 steps 1: acetone / 24 h / 90 °C 2: bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) / dichloromethane; tetrahydrofuran / 20 h / 30 °C / 31029.7 Torr / Autoclave; Glovebox 3: hydrogen; hydrogenchloride; 5%-palladium/activated carbon / ethanol; ethyl acetate / 24 h / 20 °C / 760.05 Torr / Schlenk technique 4: triethylamine / dichloromethane / 5 h / 20 °C View Scheme

(S)-2-[(R)-tert-butylsulfinyl]-1-phenyl-1,2,3,4-tetrahydroisoquinoline → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 0 - 20 °C 2.1: triethylamine / dichloromethane / 0.17 h / 0 °C 2.2: 1 h / 20 °C View Scheme

2-(2-bromoethyl)benzaldehyde (22901-09-3) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper(II) sulfate / dichloromethane / 20 h / 23 °C 2.1: toluene; diethyl ether / 3 h / -40 - 25 °C / Inert atmosphere 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 20 °C 4.1: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 0 - 20 °C 5.1: triethylamine / dichloromethane / 0.17 h / 0 °C 5.2: 1 h / 20 °C View Scheme

(R)-N-{(E)-[2-(2-bromoethyl)phenylmethylidene]}-2-methylpropane-2-sulfinamide → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene; diethyl ether / 3 h / -40 - 25 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 20 °C 3.1: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 0 - 20 °C 4.1: triethylamine / dichloromethane / 0.17 h / 0 °C 4.2: 1 h / 20 °C View Scheme

(R)-N-{(S)-[2-(2-bromoethyl)phenyl](phenyl)methyl}-2-methylpropane-2-sulfinamide → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 20 °C 2.1: hydrogenchloride / methanol; 1,4-dioxane / 1 h / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.17 h / 0 °C 3.2: 1 h / 20 °C View Scheme

triphenylboroxine (3262-89-3) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: (R)-N-(4,4-dimethyl-2-methylenepentyl)-2-methylpropane-2-sulfinamide; chlorobis(cyclooctene)rhodium(I) dimer / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 6 h / 60 °C / Inert atmosphere 2.1: Trimethylenediamine / 0.5 h / 20 °C / Microwave irradiation 3.1: triethylamine / dichloromethane / 6 h / 20 °C 3.2: 6 h / 20 °C 4.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C View Scheme

(S)-N-(dimethylsulfamoyl)-C-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)-C-phenylmethyleneamine → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: Trimethylenediamine / 0.5 h / 20 °C / Microwave irradiation 2.1: triethylamine / dichloromethane / 6 h / 20 °C 2.2: 6 h / 20 °C 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: Trimethylenediamine / 2.5 h / 120 °C / Microwave irradiation 2: triethylamine / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme

C17H30N2O3SSi → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: (R)-N-(4,4-dimethyl-2-methylenepentyl)-2-methylpropane-2-sulfinamide; chlorobis(cyclooctene)rhodium(I) dimer / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 6 h / 60 °C / Inert atmosphere 2.1: Trimethylenediamine / 0.5 h / 20 °C / Microwave irradiation 3.1: triethylamine / dichloromethane / 6 h / 20 °C 3.2: 6 h / 20 °C 4.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: C18H31NOS; [RhCl(cis-cyclooctene)2]2 / toluene / 0.5 h / 20 °C / Inert atmosphere; Schlenk technique 1.2: 6 h / 60 °C 2.1: Trimethylenediamine / 2.5 h / 120 °C / Microwave irradiation 3.1: triethylamine / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice 5.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme

C21H31NOSi → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 6 h / 20 °C 1.2: 6 h / 20 °C 2.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme

C24H35NO3Si → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme

2-<2-(t-Butyldimethylsilyloxy)ethyl>benzaldehyde (81168-10-7) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: titanium(IV) tetraethanolate / tetrahydrofuran / 12 h / Reflux 2.1: C18H31NOS; [RhCl(cis-cyclooctene)2]2 / toluene / 0.5 h / 20 °C / Inert atmosphere; Schlenk technique 2.2: 6 h / 60 °C 3.1: Trimethylenediamine / 2.5 h / 120 °C / Microwave irradiation 4.1: triethylamine / dichloromethane / 12 h / 20 °C / Inert atmosphere; Cooling with ice 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice View Scheme

benzoyl chloride (98-88-4) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium carbonate / water / 0.25 h / 29.8 °C 1.2: 4.33 h / 17.5 - 26.6 °C 2.1: PPA / water / 4.25 h / 14.9 - 165 °C 2.2: 0.17 h / 28 - 42 °C / pH 2.1 - 7.12 3.1: methanol; sodium tetrahydroborate / water / 5.42 h / 20 - 34 °C 4.1: D-tartaric acid / methanol; ethyl acetate / 2.08 h / 28 - 64 °C / Resolution of racemate 4.2: 1.17 h / pH 8 - 9 5.1: sodium carbonate / toluene / 2.17 h / 0 - 28 °C View Scheme

phenethylamine (64-04-0) → (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium carbonate / water / 0.25 h / 29.8 °C 1.2: 4.33 h / 17.5 - 26.6 °C 2.1: PPA / water / 4.25 h / 14.9 - 165 °C 2.2: 0.17 h / 28 - 42 °C / pH 2.1 - 7.12 3.1: methanol; sodium tetrahydroborate / water / 5.42 h / 20 - 34 °C 4.1: D-tartaric acid / methanol; ethyl acetate / 2.08 h / 28 - 64 °C / Resolution of racemate 4.2: 1.17 h / pH 8 - 9 5.1: sodium carbonate / toluene / 2.17 h / 0 - 28 °C View Scheme

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + (R)-quinuclidin-3-ol (25333-42-0) → solifenacin (242478-37-1)

Conditions	Yield
With sodium hydride; 1-butyl-3-methylimidazolium Tetrafluoroborate In N,N-dimethyl-formamide at 100℃; for 6h; Temperature; Concentration;	95.1%
With sodium hydride In toluene for 3h; Heating;	89%
Stage #1: (R)-quinuclidin-3-ol With sodium hydride In toluene; mineral oil at 0℃; for 0.25h; Inert atmosphere; Stage #2: (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline In toluene; mineral oil at 130℃; for 8h; Inert atmosphere; Dean-Stark;	88%

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + diphenylamine (122-39-4) → (S)-N,N,1-triphenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	84%
With sodium hydride In toluene at 103 - 135℃; Temperature;	82%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 4-chloro-aniline (106-47-8) → (S)-N-(p-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	81%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 4-fluoroaniline (371-40-4) → (S)-N-(p-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	78.3%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 2,6-Dichloroaniline (608-31-1) → (S)-N-(2,6-dichlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	77.5%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 3-bromoaniline (591-19-5) → (S)-N-(m-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	77.5%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 4-methoxy-aniline (104-94-9) → (S)-N-(p-methoxyphenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	77%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 2-bromoaniline (615-36-1) → (S)-N-(o-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	74.5%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + benzylamine (100-46-9) → (S)-N-benzyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	73%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + phenyl sulfamate (19792-91-7) → C24H24N2O5S

Conditions	Yield
Stage #1: (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline; phenyl sulfamate With aluminum oxide; bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]} at 20℃; for 0.0833333h; Stage #2: With bis(tertbutylcarbonyloxy)iodobenzene at 20℃; for 6h; enantioselective reaction;	73%

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 1-amino-3-methylbenzene (108-44-1) → (S)-1-phenyl-N-m-tolyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	70%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 2-Chloroaniline (95-51-2) → (S)-N-(o-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	69.6%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 2-methoxy-phenylamine (90-04-0) → (S)-N-(o-methoxyphenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	68%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 3-chloro-aniline (108-42-9) → (S)-N-(m-chlorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	66%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + meta-fluoroaniline (372-19-0) → (S)-N-(m-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	65.7%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + aniline (62-53-3) → (S)-N,1-diphenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	65%
With sodium hydride In toluene at 110 - 120℃;	64.7%

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + m-Anisidine (536-90-3) → (S)-N-(m-methoxyphenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	63.5%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 2-Fluoroaniline (348-54-9) → (S)-N-(o-fluorophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	63%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + 4-bromo-aniline (106-40-1) → (S)-N-(p-bromophenyl)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	61.6%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + o-toluidine (95-53-4) → (S)-1-phenyl-N-o-tolyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	59.5%
With sodium hydride In toluene at 110 - 120℃;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + p-toluidine (106-49-0) → (S)-1-phenyl-N-p-tolyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

Conditions	Yield
With sodium hydride In toluene at 110 - 120℃;	53%
With sodium hydride In toluene at 110 - 120℃;

(3R)-1-azabicyclo[2.2.2]octan-3-ol hydrochloride + (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) → solifenacin (242478-37-1)

Conditions	Yield
Stage #1: (3R)-1-azabicyclo[2.2.2]octan-3-ol hydrochloride With sodium methylate at 5 - 30℃; Inert atmosphere; Stage #2: (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline In N,N-dimethyl-formamide; toluene at 60℃; Reflux;	51%

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + sodium (R)-quinuclidin-3-ol → solifenacin (242478-37-1)

Conditions	Yield
Stage #1: sodium (R)-quinuclidin-3-ol With sodium methylate In N,N-dimethyl-formamide; toluene at 25℃; Inert atmosphere; Reflux; Stage #2: (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline In N,N-dimethyl-formamide; toluene at 70℃; Reflux;	50%

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + (R)-quinuclidin-3-ol (25333-42-0) → (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3S)-1-azabicyclo[2.2.2]oct-3-yl ester (732228-02-3) + (3R)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (740780-79-4) + (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + solifenacin (242478-37-1)

Conditions	Yield
With potassium 2-methylbutan-2-olate In toluene at 90℃; for 3h; Product distribution / selectivity;	A 1.1% B 3.2% C 6% D n/a

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) + (S)-quinuclidin-3-ol (3684-26-2, 25333-42-0, 34583-34-1, 1619-34-7) → (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3S)-1-azabicyclo[2.2.2]oct-3-yl ester (732228-02-3)

Conditions	Yield
With sodium hydride In toluene Heating;

(S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180468-42-2) → (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3S)-1-azabicyclo[2.2.2]oct-3-yl ester (732228-02-3) + (3R)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (740780-79-4) + solifenacin (242478-37-1)

Conditions	Yield
Stage #1: (R)-quinuclidin-3-ol With sodium hydride In toluene for 0.166667h; Stage #2: (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline In toluene at 26 - 110℃; for 4.33333h; Product distribution / selectivity;

Upstream product

• 541-41-3 chloroformic acid ethyl ester 
• 22990-19-8 (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 180272-45-1 (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 881834-78-2 4-nitrophenyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 
• 22990-19-8 1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 1300713-32-9 N-acetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 1085541-60-1 N-chloroacetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 52250-50-7 1-phenyl-3,4-dihydroisoquinoline 
• 1609-47-8 diethyl dicarbonate 
• 1443308-91-5 C₂₂H₁₈N⁽¹⁺⁾*Br^(1-) 
• 3297-72-1 1-phenylisoquinoline 
• 3262-89-3 triphenylboroxine 
• 64-04-0 phenethylamine 
• 98-88-4 benzoyl chloride 

Downstream Products

• 242478-37-1 solifenacin 
• 1262506-09-1 solifenacin succinate 
• 862207-71-4 (1S)-3,4-dihydro-1-phenyl-2-(1H)-isoquinolinecarboxylic acid (3S)-1-azabicyclo[2.2.2]oct-3-yl ester succinate 

Relevant articles and documents

Study on synthesis and biological effects of a series of 3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives

In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents. Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action.

Preparation method and application of solifenacin derivative

The invention relates to a preparation method of a solifenacin derivative. The preparation method includes the steps of: (a) using a solifenacin EP impurity A shown as formula 1, adding chlorine dioxide shown as formula 2 in the presence of potassium carb

Highly Enantioselective Arylation of N,N-Dimethylsulfamoyl-Protected Aldimines Using Simple Sulfur-Olefin Ligands: Access to Solifenacin and (S)-(+)-Cryptostyline II

With the use of a simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed addition of arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.