207679-81-0

Basic information

• Product Name: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol
• Synonyms: (R)-5-Hydroxymethyl tolterodine;3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol;R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol;5-hydroxyMethyl tolterodine (PNU 200577);Desfesoterodine;PNU 200577;PNU-200577;5-hydroxyMethyl Tolterodine (PNU 200577, 5-HMT, 5-HM)
• CAS NO: 207679-81-0
• Molecular Formula: C₂₂H₃₁NO₂
• Molecular Weight: 341.49
• Product Categories: Chiral Reagents;Inhibitors;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 207679-81-0.mol
• Article Data: 34

Chemical Properties

• Melting Point: 68-72°C
• Boiling Point: 490.721 °C at 760 mmHg
• Flash Point: 233.165 °C
• Appearance: /
• Density: 1.061 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.563
• Storage Temp.: -20?C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.61±0.48(Predicted)
• CAS DataBase Reference: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol(CAS DataBase Reference)
• NIST Chemistry Reference: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol(207679-81-0)
• EPA Substance Registry System: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol(207679-81-0)

Safety Data

• Hazardous Substances Data: 207679-81-0(Hazardous Substances Data)

Usage

Description

3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol, also known as (R)-5-HydroxyMethyl Tolterodine, is a metabolite of Tolterodine (T535800). It is a pale yellow solid with unique chemical properties that make it a valuable compound in the pharmaceutical industry.

Uses

Used in Pharmaceutical Applications:
3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol is used as an active metabolite for the treatment of urinary incontinence. As a muscarinic receptor antagonist, it helps to manage the involuntary loss of urine by blocking the action of acetylcholine on the bladder muscles, thereby reducing the frequency and intensity of urination.
Used in Urology:
In the field of urology, 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol is used as a therapeutic agent for patients suffering from overactive bladder syndrome. Its role in blocking muscarinic receptors helps to alleviate symptoms such as frequent urination, urgency, and incontinence, improving the quality of life for those affected.
Used in Drug Development:
3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol is also used in the development of new drugs targeting muscarinic receptors. Its unique chemical structure and properties make it a promising candidate for the creation of novel therapeutic agents with improved efficacy and reduced side effects.
Used in Research:
In the field of scientific research, 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxybenzenemethanol serves as a valuable compound for studying the mechanisms of action of muscarinic receptor antagonists. This knowledge can be applied to the development of more effective treatments for various conditions related to the autonomic nervous system.

InChI:InChI=1/C22H31NO2/c1-16(2)23(17(3)4)13-12-20(19-8-6-5-7-9-19)21-14-18(15-24)10-11-22(21)25/h5-11,14,16-17,20,24-25H,12-13,15H2,1-4H3/t20-/m1/s1

Synthetic route

(R)-2-[3-(N,N-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (R)-(-)-O-acetylmandelic acid salt → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With potassium carbonate In water; toluene at 50℃; for 6h;	85%
With potassium carbonate In water; toluene at 50℃; for 6h; Inert atmosphere;	85%
With potassium carbonate In water; toluene at 50℃; for 1h;	81%

(R)-(-)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: (R)-(-)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester With sodium hydroxide In methanol at 0 - 35℃; Inert atmosphere; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 5 - 25℃; for 4h; Stage #3: With water; sodium hydroxide In tetrahydrofuran at 0 - 5℃; for 3h;	98%
Stage #1: (R)-(-)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester With sodium hydroxide In methanol at 0 - 35℃; Inert atmosphere; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 5 - 25℃; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 3h;	98%
Stage #1: (R)-(-)-3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzoic acid methyl ester With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 3.5h; Stage #2: With ammonium chloride In tetrahydrofuran at -10℃;	95%
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at 0 - 5℃; for 2h; Inert atmosphere;

{4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]phenyl}methanol (156755-37-2) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With hydrogen; 5% Pd(II)/C(eggshell) In methanol at 50 - 55℃;	98%
With hydrogen; nickel In methanol at 20℃; for 4 - 5h;	96.5%
With hydrogen In methanol under 3000.3 - 3750.38 Torr;	72.5%

methyl (R)-(-)-3-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoate 2,3-dibenzoyl-D-tartaric acid salt (1294517-15-9) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: methyl (R)-(-)-3-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoate 2,3-dibenzoyl-D-tartaric acid salt With sodium hydrogencarbonate In ethyl acetate Inert atmosphere; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 3.5h; Stage #3: With ammonium chloride In tetrahydrofuran at -10 - 20℃; for 0.5h;	95%
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / ethyl acetate; water / Inert atmosphere 2.1: sodium hydroxide / methanol / 0 - 35 °C / Inert atmosphere 2.2: 5 - 25 °C 2.3: 3 h View Scheme

fesoterodine fumarate → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With ammonium hydroxide In methanol at 20℃; for 18h;	55%

D-(+)-menthyl 3-(3-N,N'-diisopropylamino-1(R)-phenyl-propyl)-4-hydroxy-benzoate hydrochloride (1449220-60-3) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: D-(+)-menthyl 3-(3-N,N'-diisopropylamino-1(R)-phenyl-propyl)-4-hydroxy-benzoate hydrochloride With water; sodium hydroxide In dichloromethane pH=7 - 8; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃;	83%
Stage #1: D-(+)-menthyl 3-(3-N,N'-diisopropylamino-1(R)-phenyl-propyl)-4-hydroxy-benzoate hydrochloride With sodium hydroxide In dichloromethane; water pH=7 - 8; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃;	83%

(R)-6-hydroxymethyl-4-phenylchroman-2-(R)-ol (960373-33-5) + diisopropylamine (108-18-9) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: (R)-6-hydroxymethyl-4-phenylchroman-2-(R)-ol; diisopropylamine With hydrogen; palladium on activated charcoal In methanol at 20℃; under 3000.3 Torr; for 18h; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran Stage #3: With water In tetrahydrofuran

(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol (R)-2-acetoxy(phenyl)acetate (1333234-72-2) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With potassium carbonate In toluene at 50℃; for 2h;	70%

(R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol fumarate → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)-phenyl]-methanol fumarate With sodium carbonate; sodium hydroxide In dichloromethane; water Stage #2: With hydrogen; Raney nickel In methanol	59%

RS-N,N-diisopropyl-3-(2-hydroxy-5-(hydroxymethyl)phenyl)-3-phenylpropylamine (200801-70-3) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: RS-N,N-diisopropyl-3-(2-hydroxy-5-(hydroxymethyl)phenyl)-3-phenylpropylamine With D-Malic acid In di-isopropyl ether; isopropyl alcohol at 20 - 80℃; Stage #2: With sodium hydrogencarbonate In water pH=10; Product distribution / selectivity;	40.2%
Multi-step reaction with 2 steps 1: tert-Amyl alcohol / 25 - 70 °C 2: potassium carbonate / toluene; water / 1 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: tetrahydrofuran / 10 - 55 °C 2: potassium carbonate / toluene; water / 50 - 55 °C View Scheme

(R)-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol (R)-(-)-acetoxymandelic acid salt → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With potassium carbonate In water; toluene at 50 - 55℃;

(R)-3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxybenzyl acetate (1390644-47-9) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With water; lithium hydroxide In methanol at 25 - 35℃; for 4h;

(R)-(4-(allyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)phenyl)methanol → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With sodium tetrahydroborate; tetrakis(triphenylphosphine) palladium(0) In methanol at 25 - 30℃; for 2h;

(R)-N,N-diisopropyl-3-phenyl-3-(5-formyl-2-hydroxyphenyl)propyl-1-amine (214601-12-4) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With sodium tetrahydroborate In methanol Product distribution / selectivity;	74%
Stage #1: (R)-N,N-diisopropyl-3-phenyl-3-(5-formyl-2-hydroxyphenyl)propyl-1-amine With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran at 0℃; Product distribution / selectivity;	73%

C34H59NO2Si2 → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	92%

methyl 4-hydroxylbenzoate (99-76-3) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 20 - 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate / Inert atmosphere 3.2: 3.5 h / 20 °C 3.3: 0.5 h / -10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / water / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate / Inert atmosphere 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 20 °C 4.2: -10 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 20 - 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / Inert atmosphere 4.1: sodium hydroxide / methanol / 0 - 35 °C / Inert atmosphere 4.2: 4 h / 5 - 25 °C 4.3: 3 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / Inert atmosphere 4.1: sodium hydroxide / methanol / 0 - 35 °C / Inert atmosphere 4.2: 5 - 25 °C 4.3: 3 h View Scheme
Multi-step reaction with 4 steps 1.1: 1-methyl-piperazine / toluene / 25 - 110 °C 1.2: 5 h / 60 - 65 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 25 - 50 °C / 10343.2 Torr / Autoclave 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0 - 30 °C / Inert atmosphere 4.1: D-Malic acid / isopropyl alcohol; di-isopropyl ether / 20 - 80 °C 4.2: pH 10 View Scheme

3-(N,N-diisopropylamino)-1-phenylpropan-1-ol (906532-26-1) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 20 - 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate / Inert atmosphere 3.2: 3.5 h / 20 °C 3.3: 0.5 h / -10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / water / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate / Inert atmosphere 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 20 °C 4.2: -10 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 20 - 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / Inert atmosphere 4.1: sodium hydroxide / methanol / 0 - 35 °C / Inert atmosphere 4.2: 4 h / 5 - 25 °C 4.3: 3 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: methanesulfonic acid / 50 - 55 °C / Inert atmosphere 2.1: ethanol / 60 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / ethyl acetate; water / Inert atmosphere 4.1: sodium hydroxide / methanol / 0 - 35 °C / Inert atmosphere 4.2: 5 - 25 °C 4.3: 3 h View Scheme
Multi-step reaction with 4 steps 1: perchloric acid / dichloromethane; water / 13 h / 40 °C / Inert atmosphere 2: sodium tetrahydroborate; calcium chloride / ethanol / 3 h / -10 - 20 °C / Inert atmosphere 3: tert-Amyl alcohol / 17 h / 20 - 70 °C / Inert atmosphere 4: potassium carbonate / water; toluene / 6 h / 50 °C / Inert atmosphere View Scheme

methyl 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoate (156755-35-0) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 2: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere 2: hydrogen / Raney nickel / methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 5 h / 0 - 20 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 2 h / 25 - 35 °C / Autoclave 2.2: 25 - 35 °C View Scheme

(+/-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropane-1-ol → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: triethylamine / dichloromethane / 12 h / 25 - 30 °C 2.1: acetonitrile / 30 h / 95 - 100 °C / autoclave; Sealed tube 3.1: isopropyl alcohol / 15 h / 25 - 86 °C 4.1: sodium hydroxide / water 5.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 5.2: 1 h / -65 - -60 °C 6.1: thionyl chloride / 10 °C / Reflux 7.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 8.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: pyridine / dichloromethane / 5 - 30 °C / Industry scale 2.1: water / 75 - 78 °C / Industry scale 3.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 50 - 60 °C 3.2: -70 - -60 °C 3.3: -50 °C 4.1: borane-dimethyl sulfide complex / tetrahydrofuran / 25 - 50 °C 4.2: 0.5 h / 10 - 15 °C / Industry scale 5.1: raney nickel / methanol / 30 - 35 °C / Autoclave 6.1: tetrahydrofuran / 10 - 55 °C 7.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 7 steps 1.1: pyridine / dichloromethane / 5 - 30 °C / Industry scale 1.2: 5 - 30 °C / Industry scale 2.1: water / 75 - 78 °C / Industry scale 3.1: ethyl bromide; magnesium / iodine / tetrahydrofuran / 50 - 60 °C 3.2: -70 - -60 °C 4.1: dimethylsulfide borane complex / tetrahydrofuran / 25 - 50 °C 5.1: methanol / 30 - 35 °C 6.1: tetrahydrofuran / 10 - 55 °C 7.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme

(+/-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: isopropyl alcohol / 15 h / 25 - 86 °C 2.1: sodium hydroxide / water 3.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 3.2: 1 h / -65 - -60 °C 4.1: thionyl chloride / 10 °C / Reflux 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 6.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 5 steps 1.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 50 - 60 °C 1.2: -70 - -60 °C 1.3: -50 °C 2.1: borane-dimethyl sulfide complex / tetrahydrofuran / 25 - 50 °C 2.2: 0.5 h / 10 - 15 °C / Industry scale 3.1: raney nickel / methanol / 30 - 35 °C / Autoclave 4.1: tetrahydrofuran / 10 - 55 °C 5.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 5 steps 1.1: ethyl bromide; magnesium / iodine / tetrahydrofuran / 50 - 60 °C 1.2: -70 - -60 °C 2.1: dimethylsulfide borane complex / tetrahydrofuran / 25 - 50 °C 3.1: methanol / 30 - 35 °C 4.1: tetrahydrofuran / 10 - 55 °C 5.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme

6-bromo-4-phenyl-3,4-dihydro-2H-chromen-2-one (156755-23-6) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: potassium carbonate; sodium iodide / acetone / Reflux 2.1: sodium tetrahydroborate / 1,2-dimethoxyethane / 0.17 h 2.2: 3 h / 10 °C 3.1: triethylamine / dichloromethane / 12 h / 25 - 30 °C 4.1: acetonitrile / 30 h / 95 - 100 °C / autoclave; Sealed tube 5.1: isopropyl alcohol / 15 h / 25 - 86 °C 6.1: sodium hydroxide / water 7.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 7.2: 1 h / -65 - -60 °C 8.1: thionyl chloride / 10 °C / Reflux 9.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 10.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 9 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 35 °C / Industry scale 1.2: 5 - 30 °C / pH 1 - 2 / Industry scale 2.1: potassium carbonate / acetone / 20 - 25 °C / Industry scale 2.2: 50 - 60 °C 3.1: pyridine / dichloromethane / 5 - 30 °C / Industry scale 4.1: water / 75 - 78 °C / Industry scale 5.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 50 - 60 °C 5.2: -70 - -60 °C 5.3: -50 °C 6.1: borane-dimethyl sulfide complex / tetrahydrofuran / 25 - 50 °C 6.2: 0.5 h / 10 - 15 °C / Industry scale 7.1: raney nickel / methanol / 30 - 35 °C / Autoclave 8.1: tetrahydrofuran / 10 - 55 °C 9.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 9 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 35 °C / Industry scale 1.2: 0 - 5 °C / Industry scale; Reflux 1.3: 0.5 h / 25 - 30 °C / pH 1 - 2 / Industry scale 2.1: potassium carbonate / acetone / 20 - 25 °C / Industry scale 2.2: 50 - 60 °C / Industry scale 3.1: pyridine / dichloromethane / 5 - 30 °C / Industry scale 3.2: 5 - 30 °C / Industry scale 4.1: water / 75 - 78 °C / Industry scale 5.1: ethyl bromide; magnesium / iodine / tetrahydrofuran / 50 - 60 °C 5.2: -70 - -60 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 25 - 50 °C 7.1: methanol / 30 - 35 °C 8.1: tetrahydrofuran / 10 - 55 °C 9.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme

(+/-)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester (250214-37-0) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: acetonitrile / 30 h / 95 - 100 °C / autoclave; Sealed tube 2.1: isopropyl alcohol / 15 h / 25 - 86 °C 3.1: sodium hydroxide / water 4.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 4.2: 1 h / -65 - -60 °C 5.1: thionyl chloride / 10 °C / Reflux 6.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 7.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 6 steps 1.1: water / 75 - 78 °C / Industry scale 2.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 50 - 60 °C 2.2: -70 - -60 °C 2.3: -50 °C 3.1: borane-dimethyl sulfide complex / tetrahydrofuran / 25 - 50 °C 3.2: 0.5 h / 10 - 15 °C / Industry scale 4.1: raney nickel / methanol / 30 - 35 °C / Autoclave 5.1: tetrahydrofuran / 10 - 55 °C 6.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 6 steps 1.1: water / 75 - 78 °C / Industry scale 2.1: ethyl bromide; magnesium / iodine / tetrahydrofuran / 50 - 60 °C 2.2: -70 - -60 °C 3.1: dimethylsulfide borane complex / tetrahydrofuran / 25 - 50 °C 4.1: methanol / 30 - 35 °C 5.1: tetrahydrofuran / 10 - 55 °C 6.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme

methyl 3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoate (156755-24-7) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: sodium tetrahydroborate / 1,2-dimethoxyethane / 0.17 h 1.2: 3 h / 10 °C 2.1: triethylamine / dichloromethane / 12 h / 25 - 30 °C 3.1: acetonitrile / 30 h / 95 - 100 °C / autoclave; Sealed tube 4.1: isopropyl alcohol / 15 h / 25 - 86 °C 5.1: sodium hydroxide / water 6.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 6.2: 1 h / -65 - -60 °C 7.1: thionyl chloride / 10 °C / Reflux 8.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 9.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 8 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / 1,2-dimethoxyethane / 3.5 h / 0 - 10 °C 1.2: 0 - 5 °C 2.1: triethylamine / dichloromethane / 0.5 h / 20 - 30 °C 3.1: 25 - 112 °C / Autoclave 4.1: isopropyl alcohol / 14 h / 25 - 80 °C 5.1: sodium hydroxide / water / 0 - 35 °C / pH 9 6.1: magnesium / iodine / tetrahydrofuran / 1 h / -70 - 70 °C 6.2: -5 - 35 °C 6.3: pH 1 - 2 7.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 0 - 5 °C 8.1: hydrogen / 5%-palladium/activated carbon / methanol / 2 h / 25 - 35 °C / Autoclave 8.2: 25 - 35 °C View Scheme
Multi-step reaction with 8 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 5 - 10 °C / Inert atmosphere 2.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 5 °C 3.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 4.1: isopropyl alcohol / 30 - 55 °C 5.1: sodium hydroxide; water / dichloromethane / 0.25 h / 10 - 20 °C / pH 11.5 5.2: 4 h / 25 - 55 °C / Inert atmosphere 5.3: -70 - -10 °C / Inert atmosphere 6.1: thionyl chloride / 5 h / 40 - 45 °C 7.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 0 - 5 °C / Inert atmosphere 8.1: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 25 - 30 °C / 2206.72 - 2942.29 Torr View Scheme

diisopropylamine (108-18-9) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate; potassium iodide / toluene; methanol / 20 h / Reflux 2.1: methanesulfonic acid / 3 h / 100 °C 3.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 3.2: 0.08 h 3.3: pH 8 4.1: tert-Amyl alcohol / 25 - 70 °C 5.1: potassium carbonate / toluene; water / 1 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; potassium iodide / toluene; methanol / 20 h / Reflux 2.1: methanesulfonic acid / 20 h / 120 °C 2.2: pH 7 2.3: 21 h / 100 °C 3.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 3.2: 0.08 h 3.3: pH 8 4.1: tert-Amyl alcohol / 25 - 70 °C 5.1: potassium carbonate / toluene; water / 1 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; potassium iodide / toluene; methanol / 20 h / Reflux 2.1: methanesulfonic acid / 23 h / 130 °C 2.2: pH 7 2.3: 4 h / 78 °C 3.1: sodium tetrahydroborate / methanol / 2 h / 0 °C 3.2: 0.08 h 3.3: pH 8 4.1: tert-Amyl alcohol / 25 - 70 °C 5.1: potassium carbonate / toluene; water / 1 h / 50 °C View Scheme

(-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine hydrochloride → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: borane-dimethyl sulfide complex / tetrahydrofuran / 25 - 50 °C 1.2: 0.5 h / 10 - 15 °C / Industry scale 2.1: raney nickel / methanol / 30 - 35 °C / Autoclave 3.1: tetrahydrofuran / 10 - 55 °C 4.1: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 4 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 25 - 50 °C 2: methanol / 30 - 35 °C 3: tetrahydrofuran / 10 - 55 °C 4: potassium carbonate / toluene; water / 50 - 55 °C View Scheme
Multi-step reaction with 6 steps 1: ammonia / ethyl acetate; water / pH 8 - 9 2: methanol / 50 - 65 °C 3: ammonia / water / pH 8 - 9 4: sulfuric acid / 20 °C / Reflux 5: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere 6: hydrogen / Raney nickel / methanol / 20 °C View Scheme

Tolterodine acid (194482-44-5) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Stage #1: Tolterodine acid With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran at 0℃; Product distribution / selectivity;

4-bromo-phenol (106-41-2) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 11 steps 1.1: sulfuric acid / 120 - 125 °C 2.1: potassium carbonate; sodium iodide / acetone / Reflux 3.1: sodium tetrahydroborate / 1,2-dimethoxyethane / 0.17 h 3.2: 3 h / 10 °C 4.1: triethylamine / dichloromethane / 12 h / 25 - 30 °C 5.1: acetonitrile / 30 h / 95 - 100 °C / autoclave; Sealed tube 6.1: isopropyl alcohol / 15 h / 25 - 86 °C 7.1: sodium hydroxide / water 8.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 8.2: 1 h / -65 - -60 °C 9.1: thionyl chloride / 10 °C / Reflux 10.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 11.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 10 steps 1.1: sulfuric acid / 4 h / 25 - 125 °C 2.1: potassium carbonate; sodium iodide / acetone / 2 h / 25 - 60 °C 3.1: aluminum (III) chloride; sodium tetrahydroborate / 1,2-dimethoxyethane / 3.5 h / 0 - 10 °C 3.2: 0 - 5 °C 4.1: triethylamine / dichloromethane / 0.5 h / 20 - 30 °C 5.1: 25 - 112 °C / Autoclave 6.1: isopropyl alcohol / 14 h / 25 - 80 °C 7.1: sodium hydroxide / water / 0 - 35 °C / pH 9 8.1: magnesium / iodine / tetrahydrofuran / 1 h / -70 - 70 °C 8.2: -5 - 35 °C 8.3: pH 1 - 2 9.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 0 - 5 °C 10.1: hydrogen / 5%-palladium/activated carbon / methanol / 2 h / 25 - 35 °C / Autoclave 10.2: 25 - 35 °C View Scheme
Multi-step reaction with 10 steps 1.1: sulfuric acid / 12 h / 120 - 125 °C 2.1: potassium carbonate; sodium iodide / acetone / 25 - 30 °C 2.2: 5.5 h / 15 °C / Reflux 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 5 - 10 °C / Inert atmosphere 4.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 5 °C 5.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 6.1: isopropyl alcohol / 30 - 55 °C 7.1: sodium hydroxide; water / dichloromethane / 0.25 h / 10 - 20 °C / pH 11.5 7.2: 4 h / 25 - 55 °C / Inert atmosphere 7.3: -70 - -10 °C / Inert atmosphere 8.1: thionyl chloride / 5 h / 40 - 45 °C 9.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 0 - 5 °C / Inert atmosphere 10.1: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 25 - 30 °C / 2206.72 - 2942.29 Torr View Scheme
Multi-step reaction with 10 steps 1.1: sulfuric acid / 12 h / 120 - 125 °C 2.1: potassium carbonate; sodium iodide / acetone / 25 - 30 °C 2.2: 5.5 h / 15 °C / Reflux 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 5 - 10 °C / Inert atmosphere 4.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 5 °C 5.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 6.1: isopropyl alcohol / 30 - 55 °C 7.1: sodium hydroxide; water / dichloromethane / 0.25 h / 10 - 20 °C / pH 11.5 7.2: 4 h / 25 - 55 °C / Inert atmosphere 7.3: -70 - -10 °C / Inert atmosphere 8.1: thionyl chloride / 5 h / 40 - 45 °C 9.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 18 h / 25 - 30 °C / 2206.72 - 2942.29 Torr / autoclave 10.1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran / 2 h / 0 - 5 °C / Inert atmosphere View Scheme

(R)-4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid hydrochloride (156755-33-8) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: thionyl chloride / 10 °C / Reflux 2: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 3: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 0 - 5 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 2 h / 25 - 35 °C / Autoclave 2.2: 25 - 35 °C View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 5 h / 40 - 45 °C 2: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 0 - 5 °C / Inert atmosphere 3: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 25 - 30 °C / 2206.72 - 2942.29 Torr View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 5 h / 40 - 45 °C 2: hydrogen / 5%-palladium/activated carbon / ethyl acetate / 18 h / 25 - 30 °C / 2206.72 - 2942.29 Torr / autoclave 3: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran / 2 h / 0 - 5 °C / Inert atmosphere View Scheme

R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine (950773-38-3) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 1.2: 1 h / -65 - -60 °C 2.1: thionyl chloride / 10 °C / Reflux 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / 25 - 30 °C 4.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol / 50 - 55 °C View Scheme
Multi-step reaction with 3 steps 1.1: magnesium / iodine / tetrahydrofuran / 1 h / -70 - 70 °C 1.2: -5 - 35 °C 1.3: pH 1 - 2 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 0 - 5 °C 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 2 h / 25 - 35 °C / Autoclave 3.2: 25 - 35 °C View Scheme
Multi-step reaction with 4 steps 1.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 1.2: 1 h / -70 - -50 °C 2.1: thionyl chloride / 0 - 65 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 30 °C 4.1: hydrogen; palladium 10% on activated carbon / isopropyl alcohol / 25 - 30 °C / 2068.65 - 2585.81 Torr / Autoclave View Scheme

(E)-3-phenylpropenal (14371-10-9) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 1-methyl-piperazine / toluene / 25 - 110 °C 1.2: 5 h / 60 - 65 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 25 - 50 °C / 10343.2 Torr / Autoclave 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0 - 30 °C / Inert atmosphere 4.1: D-Malic acid / isopropyl alcohol; di-isopropyl ether / 20 - 80 °C 4.2: pH 10 View Scheme
Multi-step reaction with 4 steps 1.1: 1-methyl-piperazine / toluene / Heating 1.2: 5 h / Reflux 2.1: methanol / 1.25 h / 40 °C / Inert atmosphere 2.2: 20 h / 40 °C / 5948.09 Torr / Inert atmosphere 3.1: tert-Amyl alcohol / 70 °C / Resolution of racemate; Large scale reaction 4.1: potassium carbonate / water; toluene / 6 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: 1-methyl-piperazine / toluene / Heating 1.2: 5 h / Reflux 2.1: 5%-palladium/activated carbon; hydrogen / tert-Amyl alcohol / 80 °C / 5171.62 Torr 3.1: tert-Amyl alcohol / 70 °C / Resolution of racemate; Large scale reaction 4.1: potassium carbonate / water; toluene / 6 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: 1-methyl-piperazine / toluene / Heating 1.2: 5 h / Reflux 2.1: titanium(IV)isopropoxide / tetrahydrofuran / 1 h / Reflux 2.2: 20 °C 3.1: tert-Amyl alcohol / 70 °C / Resolution of racemate; Large scale reaction 4.1: potassium carbonate / water; toluene / 6 h / 50 °C View Scheme

formic acid (64-18-6) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → (R)-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol formate (380636-49-7)

Conditions	Yield
In acetonitrile at 20℃;	100%

(2E)-but-2-enedioic acid (110-17-8) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → (R)-5-hydroxymethyl tolterodine fumarate salt (380636-50-0)

Conditions	Yield
In acetone at 20℃; for 0.5h;	100%
In acetone at 25 - 30℃; for 1h;	2.4 g

isobutyryl chloride (79-30-1) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → fesoterodine (286930-02-7)

Conditions	Yield
With sodium hydroxide In water; toluene at 20℃; Product distribution / selectivity; Inert atmosphere;	98%
With sodium hydroxide In water; toluene at 20℃; for 0.166667h; Product distribution / selectivity; Inert atmosphere;	98%
With sodium hydroxide In water; toluene at 20℃; Inert atmosphere;	98%

isobutyryl chloride (79-30-1) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → (R)-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethyl-phenyl isobutyrate

Conditions	Yield
With sodium hydroxide In water; toluene at 20℃; for 0.166667h; Inert atmosphere;	98%

isobutyryl chloride (79-30-1) + (2E)-but-2-enedioic acid (110-17-8) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → [2-[(1R)-3-(di(propan-2-yl)amino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl]-2-methylpropanoate fumarate

Conditions	Yield
Stage #1: isobutyryl chloride; (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol With triethylamine In dichloromethane at 0 - 30℃; for 0.75h; Stage #2: (2E)-but-2-enedioic acid In cyclohexane; butanone at 0 - 20℃;	71%

isobutyryl chloride (79-30-1) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → fesoterodine (286930-02-7) + C30H43NO4 (1208313-13-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - -5℃; for 2.5h; Product distribution / selectivity;
With triethylamine In dichloromethane at -10 - -5℃; for 2.5h; Product distribution / selectivity;
Stage #1: isobutyryl chloride; (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol In dichloromethane at -10 - -5℃; for 2.5h; Stage #2: With sodium carbonate In dichloromethane; water Product distribution / selectivity;

(R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → (3R)-3-[2-hydroxy-5-(hydroxymethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropane-1-aminium iodide

(S)-Mandelic acid (17199-29-0) + isobutyryl chloride (79-30-1) + (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0) → 2-[(1R)-3-[bis(1-methylethyl)amino]-1-phenylpropyl]-4-hydroxy-methylphenyl isobutyrate mandelate (1206695-46-6)

Conditions	Yield
Stage #1: isobutyryl chloride; (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol In dichloromethane at -10 - 0℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water for 0.25h; Stage #3: (S)-Mandelic acid In isopropyl alcohol at 10 - 55℃; for 7.5h;

Upstream product

• 156755-37-2 {4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]phenyl}methanol 
• 1000377-72-9 C₃₁H₄₈N₂OSi 
• 1000377-73-0 (R)-N,N-diisopropyl-3-phenyl-3-(5-formyl-2-triisopropylsilyloxyphenyl)propyl-1-amine 
• 124937-52-6 tolterodine tartrate 
• 286930-03-8 fesoterodine fumarate 
• 1055330-27-2 3-hydroxy-3-phenylpropyl 4-nitrobenzene sulfonate 
• 4850-49-1 1-phenyl-1,3-propanediol 
• 290362-27-5 3-hydroxy-3-phenylpropyl methanesulfonate 
• 94-02-0 ethyl 3-oxo-3-phenylpropionate 
• 209747-05-7 (S)-2-[3-[bis-(1-methylethyl)-amino]-1-phenylpropyl]-4-methylphenol tartrate 
• 1402604-30-1 benzyl desfesoterodine fumarate 
• 848768-06-9 (R)-3-[2-(benzyloxy)-5-methylphenyl]-N,N-diisopropyl-3-phenylpropan-1-amine 
• 1449220-62-5 racemic 3-(3-N,N'-diisopropylamino-1-phenyl-propyl)-4-hydroxy-benzoyl chloride hydrochloride 

Downstream Products

• 286930-03-8 fesoterodine fumarate 
• 156755-20-3 PNU 200577 l-mandelate salt 
• 1350462-15-5 lithium (R)-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol 
• 1390644-37-7 (R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxylmethyl)phenyl methacrylate 
• 286930-02-7 fesoterodine 
• 1390644-34-4 isobutyric acid 2-((R)-3-diisopropylammonium-1-phenyIpropyl)-4-(hydroxymethyl)phenyl ester (R)-acetoxy(phenyl)acetate 
• 1390644-38-8 (R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxylmethyl)phenylmethacrylate mandelate 
• 1390644-50-4 (R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenyl-2-bromo-2-methyl propanoate 
• 1390644-52-6 2-((R)-3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyi)phenyl-3-bromo-2-methyl propanoate 
• 286930-03-8 2-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl 2-methylpropanoate fumarate 
• 286930-03-8 fesoterodine fumarate 
• 1539221-44-7 (R)-2-(3-N,N-diisopropylamino-1-phenylpropyl)-4-trityloxymethylphenol 
• 1539220-58-0 (R)-2-(3-N,N-diisopropylamino-1-phenylpropyl)-4-trityloxymethylphenoxyisobutyrate 

Relevant articles and documents

Electrochemical oxidation of 5-hydroxymethyl tolterodine and identification of its oxidation products using liquid chromatography and mass spectrometry

The electrochemical behavior of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of antimuscarinic drugs tolterodine and fesoterodine used to treat urge incontinence and overactive bladder, was investigated using cyclic and differential pulse voltammetry at glassy carbon electrode. Electrooxidation of 5-HMT proceeds as a complex pH-dependent process. Controlled potential electrolysis of 5-HMT solutions was performed at platinum gauze electrode in aqueous-methanolic media. Electrolyzed solutions were analyzed using ultra performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry. Two main oxidation centers of the studied molecule were located: the p-hydroxybenzyl alcohol group and the tertiary amino group. Oxidation of the first center proceeds in several steps leading to the formation of 5-formyl tolterodine, p-benzoquinone derivative and several dimeric, hydroxylated and methoxylated products depending on pH of the solution and electrode potential. The second center is oxidized preferentially in alkaline media at higher potentials under the hydrolytic cleavage of diisopropylamine and formation of corresponding aldehydes. Mechanism of the electrochemical oxidation of 5-HMT has been proposed.

Formal synthesis of fesoterodine by acid-facilitated aromatic alkylation

The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzaldehyde from ethyl benzoylacetate by Friedel-Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the reduction of the ketoester to a 1,3-diol, diisopropylamine substitution, and Friedel-Crafts alkylation, followed by reduction and chiral resolution.

PROCESS FOR THE PREPARATION OF OPTICALLY PURE FESOTERODINE DERIVATIVES

3,3-diphenylpropylamines of general formula (I), particularly Fesoterodine, as well as their enantiomers, solvates and salts, can be produced by treating a compound of formula (II) with a chiral alcohol to yield the diastereomeric esters of formula (IV) and (IV′), which can be further transformed into a compound of formula (I), or an enantiomer, solvate or salt thereof, wherein R1 is C1-C8 alkyl; and R2 and R3, independently of one another, represent H or C1-C6 alkyl, or together form a ring of 3 to 7 members with the nitrogen to which they are bound.