180272-45-1

Usage

Uses

Used in Pharmaceutical Industry:
(1R)-Phenyl-1,2,3,4-tetrahydroisoquinoline is used as a reagent for the preparation of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives. These derivatives act as muscarinic receptor antagonists, which have potential applications in the treatment of various conditions, such as overactive bladder, Alzheimer's disease, and other disorders related to the muscarinic system.
Additionally, (1R)-Phenyl-1,2,3,4-tetrahydroisoquinoline is considered for recycling to obtain the S enantiomer on a larger scale. This process could improve the efficiency of producing Solifenacin (S676700) and other related antimuscarinic agents, thereby contributing to the development of new treatments for various medical conditions.

Synthetic route

(R)-(+)-2-(4-methylphenylsulfonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (220936-57-2) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With samarium diiodide; water; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere;	99%
With ammonia; sodium In tetrahydrofuran at -78℃; for 0.75h;	68%

(R)-2-benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1443308-76-6) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In ethanol; ethyl acetate at 20℃; under 760.051 Torr; for 24h; Schlenk technique;	98%

C15H15N*C4H6O6 → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With water; sodium hydroxide In ethyl acetate at 20℃;	97.9%

1-phenylisoquinoline (3297-72-1) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; trichloroisocyanuric acid; hydrogen; (R)-segphos In tetrahydrofuran at 80℃; under 62059.4 Torr; for 48h; Catalytic behavior; Reagent/catalyst; Solvent; Autoclave; enantioselective reaction;	96%
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; trichloroisocyanuric acid; hydrogen; (R)-segphos In tetrahydrofuran at 80℃; under 62059.4 Torr; for 48h; Catalytic behavior; Reagent/catalyst; Solvent; Glovebox; Autoclave;	96%
Multi-step reaction with 3 steps 1: acetone / 24 h / 90 °C 2: bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (Rax,S,S)-C3-TunePhos / 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 View Scheme
Multi-step reaction with 3 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 View Scheme

1-phenyl-3,4-dihydroisoquinoline (52250-50-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Stage #1: 1-phenyl-3,4-dihydroisoquinoline With N-Bromosuccinimide; bis(1,5-cyclooctadiene)diiridium(I) dichloride; sodium carbonate; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In 1,2-dichloro-ethane at 20℃; for 0.166667h; Stage #2: With hydrogen In 1,2-dichloro-ethane at 30℃; under 25858.1 Torr; for 24h; enantioselective reaction;	94%
With N-Bromosuccinimide; bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; sodium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In 1,2-dichloro-ethane at 30℃; under 25858.1 Torr; for 24h; Glovebox; enantioselective reaction;	94%
With N-Bromosuccinimide; chloro(1,5-cyclooctadiene)rhodium(I) dimer; hydrogen; sodium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,2-dichloro-ethane at 30℃; under 25858.1 Torr; for 24h; Glovebox; enantioselective reaction;	94%

1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Stage #1: 1-phenyl-1,2,3,4-tetrahydroisoquinoline With N-Bromosuccinimide; bis(1,5-cyclooctadiene)diiridium(I) dichloride; sodium carbonate; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In 1,2-dichloro-ethane at 20℃; for 0.166667h; Stage #2: With hydrogen In 1,2-dichloro-ethane at 30℃; under 25858.1 Torr; for 24h; enantioselective reaction;	93%
With L-(-)-tartaric acid In methanol Resolution of racemate;
With potassium hydroxide In water; dimethyl sulfoxide for 11.8333h; Purification / work up; Heating / reflux;

1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8) → (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With borane-ammonia complex; 6-hydroxy-D-nicotine oxidase E350L/E352D mutant for 120h; Kinetics; Enzymatic reaction; enantioselective reaction;	A n/a B 86%
With D-tartaric acid Resolution of racemate;	A 79% B 2.78 g
Stage #1: 1-phenyl-1,2,3,4-tetrahydroisoquinoline With D-tartaric acid In water Resolution of racemate; Stage #2: With sodium hydroxide In water at 20℃; Purification / work up;	A n/a B n/a

(1R)-N-(8-menthyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (321670-05-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Stage #1: (1R)-N-(8-menthyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline With 3 A molecular sieve; sodium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 48h; Stage #2: With potassium hydroxide In tetrahydrofuran Further stages.;	82%

(1E)-4-hydroxy-1-mesityl-4-methylpent-1-en-3-one (1346681-71-7) + 1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8) → (1S)-2-(3-mesitylpropanoyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1346681-99-9) + (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With 2-(2,4,6-trimethyl-phenyl)-2,5,6,7-tetrahydro-pyrrolo[2,1-c] [1,2,4]triazol-4-ylium perchlorate; (4aR,9aS)-4-hydroxy-4,4a,9,9a-tetrahydroindeno[2,1-b][1,4]oxazin-3(2H)-one; 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 23℃; for 18h; Inert atmosphere; Resolution of racemate; optical yield given as %ee; enantioselective reaction;	A 49% B n/a C n/a

(1R,5S)-1,3,8,8-Tetramethyl-5-((R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-3-aza-bicyclo[3.2.1]octane-2,4-dione → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether at 0℃; for 48h;	42%
With lithium aluminium tetrahydride In diethyl ether at 0℃; for 48h; Yield given;

(1S,5R)-5,8,8-trimethyl-1-[(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl]-3-oxabicyclo[3.2.1]octan-2-one (660861-59-6) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With Li[AlH2(OCH3)2] In tetrahydrofuran at -50℃; for 72h;	35%

1-phenyl-3,4-dihydroisoquinoline (52250-50-7) → (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
With sodium tetrahydroborate In ethanol at 20℃; for 60h;
With hydrogen; bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine) In tetrahydrofuran; 1,1-dichloroethane at 20 - 50℃; under 22502.3 Torr; Product distribution / selectivity; Inert atmosphere;	A n/a B n/a
With 1,1'-bis-(diphenylphosphino)ferrocene; bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; iodine In dichloromethane at 20℃; under 38002.6 Torr; for 24h; Inert atmosphere; Autoclave; optical yield given as %ee; enantioselective reaction;

N-phenethylbenzamide (3278-14-6) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: P2O5; POCl3 / xylene / 2.5 h / Heating 2: NaBH4 / ethanol / 60 h / 20 °C View Scheme
Multi-step reaction with 3 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: potassium hydroxide / water; dimethyl sulfoxide / 11.83 h / Heating / reflux View Scheme

2-bromophenylacetaldehyde (96557-30-1) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 97 percent / CH2Cl2 / 20 °C 2.1: NaBH4; BF3*OEt2 / tetrahydrofuran / 2 h / 20 °C 2.2: 90 percent / NaOH / H2O / 1 h / Heating 3.1: 85 percent / 120 °C 4.1: t-BuLi / diethyl ether; pentane / 0.17 h / -90 °C 4.2: 78 percent / Et2AlCl / hexane / -90 - 20 °C 5.1: PCC; NaOAc; 3A molecular sieves / CH2Cl2 / 48 h / 20 °C 5.2: 82 percent / KOH / tetrahydrofuran View Scheme

ortho-bromobenzaldehyde (6630-33-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: potassium tert-butoxide / tetrahydrofuran / 0.5 h / 0 °C 1.2: tetrahydrofuran / 12 h / 20 °C 1.3: 95 percent / formic acid / CH2Cl2 / 72 h / 20 °C 2.1: 97 percent / CH2Cl2 / 20 °C 3.1: NaBH4; BF3*OEt2 / tetrahydrofuran / 2 h / 20 °C 3.2: 90 percent / NaOH / H2O / 1 h / Heating 4.1: 85 percent / 120 °C 5.1: t-BuLi / diethyl ether; pentane / 0.17 h / -90 °C 5.2: 78 percent / Et2AlCl / hexane / -90 - 20 °C 6.1: PCC; NaOAc; 3A molecular sieves / CH2Cl2 / 48 h / 20 °C 6.2: 82 percent / KOH / tetrahydrofuran View Scheme

2α-(2'-bromophenylmethyl)-4,4,7α-trimethyl-trans-octahydro-1,3-benzoxazine (321669-61-8) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: NaBH4; BF3*OEt2 / tetrahydrofuran / 2 h / 20 °C 1.2: 90 percent / NaOH / H2O / 1 h / Heating 2.1: 85 percent / 120 °C 3.1: t-BuLi / diethyl ether; pentane / 0.17 h / -90 °C 3.2: 78 percent / Et2AlCl / hexane / -90 - 20 °C 4.1: PCC; NaOAc; 3A molecular sieves / CH2Cl2 / 48 h / 20 °C 4.2: 82 percent / KOH / tetrahydrofuran View Scheme

N-[(2'-bromophenyl)ethyl]-8-aminomenthol (321669-65-2) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 85 percent / 120 °C 2.1: t-BuLi / diethyl ether; pentane / 0.17 h / -90 °C 2.2: 78 percent / Et2AlCl / hexane / -90 - 20 °C 3.1: PCC; NaOAc; 3A molecular sieves / CH2Cl2 / 48 h / 20 °C 3.2: 82 percent / KOH / tetrahydrofuran View Scheme

3-[(2'-bromophenyl)ethyl]-2α-phenyl-4,4,7α-trimethyl-trans-octahydro-1,3-benzoxazine (321669-82-3) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: t-BuLi / diethyl ether; pentane / 0.17 h / -90 °C 1.2: 78 percent / Et2AlCl / hexane / -90 - 20 °C 2.1: PCC; NaOAc; 3A molecular sieves / CH2Cl2 / 48 h / 20 °C 2.2: 82 percent / KOH / tetrahydrofuran View Scheme

phenyl N-tosyl imine (51608-60-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) n-butyllithium / 1.) hexane, THF, -100 deg C, 15 min, 2.) THF, -85 to -100 deg C, 6 h 2: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 3: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 4: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

(4R,5R)-2-(2-Bromo-benzyl)-4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3]dioxolane (172794-67-1) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) n-butyllithium / 1.) hexane, THF, -100 deg C, 15 min, 2.) THF, -85 to -100 deg C, 6 h 2: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 3: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 4: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme
Multi-step reaction with 6 steps 1: 1.) n-butyllithium / 1.) hexane, THF, -100 deg, 2 h, 2.) THF, 0 deg C, 2 h 2: 53 percent / ammonium cerium(IV) nitrate / methanol; H2O / 3 h / Ambient temperature 3: 81 percent / Et3N / tetrahydrofuran / 8 h / Ambient temperature 4: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 5: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 6: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

4-methoxy-N-[(E)-phenylmethylidene]aniline (1613-90-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1.) n-butyllithium / 1.) hexane, THF, -100 deg, 2 h, 2.) THF, 0 deg C, 2 h 2: 53 percent / ammonium cerium(IV) nitrate / methanol; H2O / 3 h / Ambient temperature 3: 81 percent / Et3N / tetrahydrofuran / 8 h / Ambient temperature 4: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 5: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 6: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

N-<(αR and αS)-2-<<(4R,5R)-4,5-bis(2-methoxypropan-2-yl)-1,3-dioxolan-2-yl>methyl>benzhydryl>-4-methoxyaniline → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 53 percent / ammonium cerium(IV) nitrate / methanol; H2O / 3 h / Ambient temperature 2: 81 percent / Et3N / tetrahydrofuran / 8 h / Ambient temperature 3: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 4: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 5: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

(-)-N-<(αR)-2-<<(4R,5R)-4,5-bis(2-methoxypropan-2-yl)-1,3-dioxolan-2-yl>methyl>benzhydryl>-4-methylbenzenesulfonamide (213595-50-7) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 2: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 3: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

(R)-(+)-2-(4-methylphenylsulfonyl)-1-phenyl-1,2-dihydroisoquinoline (220936-55-0) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 2: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

C-{2-[4,5-bis-(1-methoxy-1-methyl-ethyl)-[1,3]dioxolan-2-ylmethyl]-phenyl}-C-phenyl-methylamine → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 81 percent / Et3N / tetrahydrofuran / 8 h / Ambient temperature 2: 48 percent / p-TsOH, conc. HCl / methanol; H2O / 96 h / Heating 3: 90 percent / LiAlH4 / tetrahydrofuran / 16 h / Heating 4: 68 percent / Na, liquid ammonia / tetrahydrofuran / 0.75 h / -78 °C View Scheme

(1R,5S)-1,3,8,8-Tetramethyl-5-(1-phenyl-1H-isoquinoline-2-carbonyl)-3-aza-bicyclo[3.2.1]octane-2,4-dione → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 13 percent / H2 / Pd/C / ethanol / 48 h 2: 42 percent / LiAlH4 / diethyl ether / 48 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: H2 / Pd/C / ethanol / 48 h / Ambient temperature 2: LiAlH4 / diethyl ether / 48 h / 0 °C View Scheme

4-nitrophenyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (881834-78-2) → (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Stage #1: 4-nitrophenyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate With sodium hydroxide In ethanol at 75 - 80℃; Stage #2: With water Cooling;

N-chloroacetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline (1085541-60-1) → (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

N-phenethylbenzamide (3278-14-6) → (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2-chloropyridine; trifluoromethylsulfonic anhydride / dichloromethane / -78 - 20 °C / Inert atmosphere 2: 1,1'-bis-(diphenylphosphino)ferrocene; bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; iodine / dichloromethane / 24 h / 20 °C / 38002.6 Torr / Inert atmosphere; Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: phosphorus pentoxide; trichlorophosphate / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / 140 °C 1.2: 1 h 2.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; phosphoric acid; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; potassium iodide / tetrahydrofuran / 16 h / 50 °C / 22502.3 Torr View Scheme
Multi-step reaction with 3 steps 1.1: phosphorus pentoxide; trichlorophosphate / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / 140 °C 1.2: 1 h 2.1: palladium on activated charcoal; hydrogen / 30 °C / 3750.38 Torr 3.1: trifluoroacetic acid / methanol; ethanol; hexane / 25 °C / Resolution of racemate View Scheme

benzoyl chloride (98-88-4) → (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8, 96719-89-0, 118864-75-8) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: 2-chloropyridine; trifluoromethylsulfonic anhydride / dichloromethane / -78 - 20 °C / Inert atmosphere 3: 1,1'-bis-(diphenylphosphino)ferrocene; bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; iodine / dichloromethane / 24 h / 20 °C / 38002.6 Torr / Inert atmosphere; Autoclave View Scheme
Multi-step reaction with 3 steps 1.1: dichloromethane / 2 h / 0 - 5 °C 1.2: 6 h / 0 °C / Reflux 2.1: phosphorus pentoxide; trichlorophosphate / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / 140 °C 2.2: 1 h 3.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; phosphoric acid; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; potassium iodide / tetrahydrofuran / 16 h / 50 °C / 22502.3 Torr View Scheme
Multi-step reaction with 4 steps 1.1: dichloromethane / 2 h / 0 - 5 °C 1.2: 6 h / 0 °C / Reflux 2.1: phosphorus pentoxide; trichlorophosphate / 5,5-dimethyl-1,3-cyclohexadiene / 5 h / 140 °C 2.2: 1 h 3.1: palladium on activated charcoal; hydrogen / 30 °C / 3750.38 Torr 4.1: trifluoroacetic acid / methanol; ethanol; hexane / 25 °C / Resolution of racemate View Scheme

(R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → 1-phenyl-1,2,3,4-tetrahydroisoquinoline (22990-19-8)

Conditions	Yield
With water; potassium hydroxide In dimethyl sulfoxide at 120℃; for 10h;	92.1%
With potassium hydroxide; water In dimethyl sulfoxide at 160℃; for 15h;
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / -10 - 20 °C 2.1: hydrogenchloride; water; phosphoric acid / 95 - 100 °C 2.2: 20 °C / pH 9 - 10 View Scheme

(R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → 1-phenyl-3,4-dihydroisoquinoline (52250-50-7)

Conditions	Yield
With dimethyl sulfoxide at 100℃; for 24h; Solvent; Temperature; Schlenk technique; Green chemistry; chemoselective reaction;	87%
Multi-step reaction with 2 steps 1: trichloroisocyanuric acid / dichloromethane / 1.5 h / 3 - 5 °C 2: potassium hydroxide / methanol / 1 h / 20 °C View Scheme
With hydrogenchloride; oxygen In aq. phosphate buffer at 37℃; pH=7.8;
With air In N,N-dimethyl-formamide at 100℃; for 24h; Schlenk technique; Green chemistry;

chloroformic acid ethyl ester (541-41-3) + (R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → ethyl (R)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (180468-41-1)

Conditions	Yield
With potassium carbonate In dichloromethane at 20℃;

(R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → (3S)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (774517-20-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / CH2Cl2 / 20 °C 2: NaH / toluene / Heating View Scheme

(R)-(-)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (180272-45-1) → (3R)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (740780-79-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / CH2Cl2 / 20 °C 2: NaH / toluene / Heating View Scheme

Upstream product

• 52250-50-7 1-phenyl-3,4-dihydroisoquinoline 
• 3278-14-6 N-phenethylbenzamide 
• 98-88-4 benzoyl chloride 
• 98-56-6 4-chlorobenzotrifluoride 
• 22990-19-8 1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 220936-57-2 (R)-(+)-2-(4-methylphenylsulfonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 64-04-0 phenethylamine 
• 104598-38-1 1-phenyl-3,4-dihydroisoquinoline hydrobromide 
• 1196-38-9 3,4-dihydroisoquinolin-1(2H)-one 
• 100-58-3 phenylmagnesium bromide 
• 3297-72-1 1-phenylisoquinoline 
• 1443308-91-5 C₂₂H₁₈N⁽¹⁺⁾*Br^(1-) 
• 1443308-76-6 (R)-2-benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 52250-51-8 1-phenyl-3,4-dihydroisoquinoline hydrochloride 

Downstream Products

• 1300713-32-9 N-acetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 881834-78-2 4-nitrophenyl-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 
• 242478-37-1 solifenacin 
• 22990-19-8 (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 180468-42-2 (S)-N-carboxylic acid ethyl ester-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 1085541-60-1 N-chloroacetyl-(1R)-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 740780-79-4 (3R)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate 
• 774517-20-3 (3S)-1-azabicyclo[2.2.2]oct-3-yl (1R)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate 
• 3297-72-1 1-phenylisoquinoline 
• 126114-66-7 (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride 
• 126114-98-5 2-benzyl-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline 
• 52250-50-7 1-phenyl-3,4-dihydroisoquinoline 
• 180272-31-5 1(S)-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ethyl ester 
• 22990-19-8 1-phenyl-1,2,3,4-tetrahydroisoquinoline 

Relevant academic research and scientific papers

Low-Temperature Nickel-Catalyzed C?N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand

The transition-metal-catalyzed C?N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as ?50 °C), enantioselective Ni-catalyzed C?N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.

Asymmetric Transfer Hydrogenation of Unhindered and Non-Electron-Rich 1-Aryl Dihydroisoquinolines with High Enantioselectivity

The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for imine ATH.

Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines

Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.

A through halogen bond activation isoquinoline asymmetric hydrogenation method

A through halogen bond activation isoquinoline asymmetric hydrogenation method, the catalyzing system is [...] complex, the activator is a halide. The reaction can be carried out under the following conditions, temperature: 25 - 100 °C; solvent: tetrahydr

Asymmetric Transfer Hydrogenation in Thermomorphic Microemulsions Based on Ionic Liquids

A thermomorphic ionic-liquid-based microemulsion system was successfully applied for the Ru-catalyzed asymmetric transfer hydrogenation of ketones. On the basis of the temperature-dependent multiphase behavior of the targeted microemulsion, simple product separation as well as catalyst recycling could be realized. The use of water-soluble ligands improved the immobilization of the catalyst in the microemulsion phase and significantly decreased the catalyst leaching into the organic layer upon extraction of the product. Eventually, the optimized microemulsion system could be applied to a wide range of aromatic ketones that were reduced with good isolated yields (up to 98%) and enantioselectivities (up to 97%), while aliphatic ketones were less successful.

Breaking Symmetry: Engineering Single-Chain Dimeric Streptavidin as Host for Artificial Metalloenzymes

The biotin-streptavidin technology has been extensively exploited to engineer artificial metalloenzymes (ArMs) that catalyze a dozen different reactions. Despite its versatility, the homotetrameric nature of streptavidin (Sav) and the noncooperative binding of biotinylated cofactors impose two limitations on the genetic optimization of ArMs: (i) point mutations are reflected in all four subunits of Sav, and (ii) the noncooperative binding of biotinylated cofactors to Sav may lead to an erosion in the catalytic performance, depending on the cofactor:biotin-binding site ratio. To address these challenges, we report on our efforts to engineer a (monovalent) single-chain dimeric streptavidin (scdSav) as scaffold for Sav-based ArMs. The versatility of scdSav as host protein is highlighted for the asymmetric transfer hydrogenation of prochiral imines using [Cp*Ir(biot-p-L)Cl] as cofactor. By capitalizing on a more precise genetic fine-tuning of the biotin-binding vestibule, unrivaled levels of activity and selectivity were achieved for the reduction of challenging prochiral imines. Comparison of the saturation kinetic data and X-ray structures of [Cp*Ir(biot-p-L)Cl]·scdSav with a structurally related [Cp*Ir(biot-p-L)Cl]·monovalent scdSav highlights the advantages of the presence of a single biotinylated cofactor precisely localized within the biotin-binding vestibule of the monovalent scdSav. The practicality of scdSav-based ArMs was illustrated for the reduction of the salsolidine precursor (500 mM) to afford (R)-salsolidine in 90% ee and >17 ?000 TONs. Monovalent scdSav thus provides a versatile scaffold to evolve more efficient ArMs for in vivo catalysis and large-scale applications.

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C?H Functionalization

Reported is an achiral CpxRhIII/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary

Solifenacin succinate raw medicine synthesis process

The invention discloses a solifenacin succinate raw medicine synthesis process. 2-phenylethylamine and 3-quinuclidinone hydrochloride are respectively used as starting raw materials for synthesizing afragment A and a fragment B; then, condensation reaction occurs to generate solifenacin; through salt formation, the solifenacin succinate is obtained. The process is characterized in that straight-chain paraffin and water are used as reaction solvents; alkali metal hydroxides or carbonate and bicarbonates of the alkali metal hydroxides are used as acid-binding agents; phenylethylamine and benzoyl chloride take acylation reaction to generate midbodies 1 of solid precipitation fragments A insoluble in reaction solvents; in the post treatment process, filtering is directly performed; isomers ofthe fragment A are subjected to catalytic racemization through alkali metal hydroxides by using dimethylsulfoxide as a solvent, so that the byproduct isomers can be recovered and utilized; in the second-step reaction post treatment of the fragment B, a conventional pressure reduced distillation method is used for obtaining high-purity and high-yield 3-acetoxyquinine acetate. The invention provides a novel synthesis process with the advantages of high yield and economic and environment-friendly effects, and is suitable for industrial mass production.

Dual Stereocontrol for Enantioselective Hydrogenation of Dihydroisoquinolines Induced by Tuning the Amount of N-Bromosuccinimide

An efficient dual stereocontrol in iridium-catalyzed hydrogenation of 1-substituted 3,4-dihydroisoquinolines was realized by tuning the amount of N-bromosuccinimide using chiral ligand of single configuration, providing both enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 89% ee (S) and 98% ee (R), respectively. Dual activation role of N-bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity under two hydrogenation conditions.

A one-pot process for the enantioselective synthesis of tetrahydroquinolines and tetrahydroisoquinolines: Via asymmetric reductive amination (ARA)

Asymmetric reductive amination for the synthesis of both chiral tetrahydroquinolines (THQs) and tetrahydroisoquinolines (THIQs) has been realized with an Ir/ZhaoPhos catalytic system via a one-pot N-Boc deprotection/intramolecular asymmetric reductive amination (ARA) sequence. Control experiments reveal that HCl plays a vital role to the success of this transformation. The HCl acid assists the removal of the N-Boc protecting group and also provides chloride ions to interact with the thiourea moiety in ZhaoPhos, thus leading to excellent reaction enantiocontrol.