754159-68-7

Basic information

• Product Name: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid
• Synonyms: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid;(R)-4-(benzyloxy)-3-(3-(diisopropylamino)-1-phenylpropyl)benzoic acid
• CAS NO: 754159-68-7
• Molecular Formula: C₂₉H₃₅NO₃
• Molecular Weight: 445.59
• Mol File: 754159-68-7.mol
• Article Data: 4

Chemical Properties

• Appearance: /
• Density: 1.095
• CAS DataBase Reference: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid(754159-68-7)
• EPA Substance Registry System: 3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid(754159-68-7)

Safety Data

• Hazardous Substances Data: 754159-68-7(Hazardous Substances Data)

Usage

General Description

3-[(1R)-3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-(phenylmethoxy)benzoic acid, also known as IB-MECA, is a potent and selective agonist of the adenosine A3 receptor. It is a synthetic compound with therapeutic potential in the treatment of various inflammatory and autoimmune diseases. IB-MECA has been studied for its effects on inhibiting cell proliferation, reducing inflammation, and promoting apoptosis in cancer cells. It has also shown promise in treating conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Its chemical structure contains a benzene ring with a carboxylic acid group and various substituents, including a phenylmethoxy and bis(1-methylethyl)amino groups, that contribute to its biological activity.

Synthetic route

(E)-3-phenylacrylic acid (140-10-3) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions

Yield

Multi-step reaction with 8 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 View Scheme

R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine (950773-38-3) + carbon dioxide (124-38-9) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Stage #1: R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine With ethyl bromide; iodine; magnesium In tetrahydrofuran at 55℃; for 1h; Reflux; Stage #2: carbon dioxide In tetrahydrofuran at -65 - -60℃; for 1h;
Stage #1: R-(-)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]diisopropylamine With ethyl bromide; iodine; magnesium In tetrahydrofuran at 60 - 65℃; for 2h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran at -70 - -50℃; for 1h;

(+/-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropane-1-ol → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 6 steps 1.1: dmap; triethylamine / dichloromethane / 20 °C 2.1: potassium iodide / acetonitrile / 15 h / Reflux 3.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / Reflux 3.2: 1 h / -60 - -25 °C 3.3: 1 h / 0 - 20 °C 4.1: ammonia / ethyl acetate; water / pH 8 - 9 5.1: methanol / 50 - 65 °C 6.1: ammonia / water / pH 8 - 9 View Scheme
Multi-step reaction with 4 steps 1.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 5 °C 2.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 3.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 3.2: 1.5 h / -70 - -60 °C / Inert atmosphere 3.3: -10 - 25 °C 4.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 4.2: 10 - 15 °C View Scheme

(+/-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 4 steps 1.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / Reflux 1.2: 1 h / -60 - -25 °C 1.3: 1 h / 0 - 20 °C 2.1: ammonia / ethyl acetate; water / pH 8 - 9 3.1: methanol / 50 - 65 °C 4.1: ammonia / water / pH 8 - 9 View Scheme
Multi-step reaction with 2 steps 1.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 1.2: 1.5 h / -70 - -60 °C / Inert atmosphere 1.3: -10 - 25 °C 2.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 2.2: 10 - 15 °C View Scheme

4-bromo-phenol (106-41-2) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 8 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 View Scheme
Multi-step reaction with 7 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: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 6.2: 1.5 h / -70 - -60 °C / Inert atmosphere 6.3: -10 - 25 °C 7.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 7.2: 10 - 15 °C View Scheme

6-bromo-4-phenyl-3,4-dihydro-2H-chromen-2-one (156755-23-6) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 7 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 View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate; sodium iodide / acetone / 25 - 30 °C 1.2: 5.5 h / 15 °C / Reflux 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 4 h / 5 - 10 °C / Inert atmosphere 3.1: dmap; triethylamine / dichloromethane / 2 h / 0 - 5 °C 4.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 5.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 5.2: 1.5 h / -70 - -60 °C / Inert atmosphere 5.3: -10 - 25 °C 6.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 6.2: 10 - 15 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / 60 - 65 °C 2.1: sodium hydroxide / water / 45 - 50 °C 3.1: ethanol / 5.83 h / 0 - 75 °C 4.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 5.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 6.1: toluene / 1 h / 0 - 35 °C 7.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 8.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 8.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / 60 - 65 °C 2.1: sodium hydroxide / water / 45 - 50 °C 3.1: ethanol / 5.83 h / 0 - 75 °C 4.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 5.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 6.1: toluene / 1 h / 0 - 35 °C 7.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 8.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 8.2: 1 h / -70 - -50 °C View Scheme

methyl 3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoate (156755-24-7) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 5 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: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 4.2: 1.5 h / -70 - -60 °C / Inert atmosphere 4.3: -10 - 25 °C 5.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 5.2: 10 - 15 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide / water / 45 - 50 °C 2.1: ethanol / 5.83 h / 0 - 75 °C 3.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 4.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 5.1: toluene / 1 h / 0 - 35 °C 6.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 7.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 7.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide / water / 45 - 50 °C 2.1: ethanol / 5.83 h / 0 - 75 °C 3.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 4.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 5.1: toluene / 1 h / 0 - 35 °C 6.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 7.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 7.2: 1 h / -70 - -50 °C View Scheme

(+/-)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester (250214-37-0) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 5 steps 1.1: potassium iodide / acetonitrile / 15 h / Reflux 2.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / Reflux 2.2: 1 h / -60 - -25 °C 2.3: 1 h / 0 - 20 °C 3.1: ammonia / ethyl acetate; water / pH 8 - 9 4.1: methanol / 50 - 65 °C 5.1: ammonia / water / pH 8 - 9 View Scheme
Multi-step reaction with 3 steps 1.1: acetonitrile / 32 h / 95 - 100 °C / autoclave; Inert atmosphere 2.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 2.2: 1.5 h / -70 - -60 °C / Inert atmosphere 2.3: -10 - 25 °C 3.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 3.2: 10 - 15 °C View Scheme

C20H18O8*C28H34BrNO (1135493-18-3) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water 2.1: ethyl bromide; iodine; magnesium / tetrahydrofuran / 1 h / 55 °C / Reflux 2.2: 1 h / -65 - -60 °C View Scheme

(-)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine hydrochloride → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: ammonia / ethyl acetate; water / pH 8 - 9 2: methanol / 50 - 65 °C 3: ammonia / water / pH 8 - 9 View Scheme

(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / 50 - 65 °C 2: ammonia / water / pH 8 - 9 View Scheme
Stage #1: (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine With D-tartaric acid In isopropyl alcohol at 30 - 35℃; for 16h; Stage #2: With water; sodium hydroxide In dichloromethane at 10 - 15℃;

(-)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine (-)-di-p-toluoyl-L-tartaric acid (1350477-43-8) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
With ammonia In water pH=8 - 9;

(+)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine (760147-33-9) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide / dimethyl sulfoxide / 5.5 h / 110 - 120 °C 2: methanol / 50 - 65 °C 3: ammonia / water / pH 8 - 9 View Scheme

Cinnamic acid (621-82-9) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions

Yield

Multi-step reaction with 7 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: ethyl bromide; iodine; magnesium / tetrahydrofuran / 4 h / 50 - 55 °C / Inert atmosphere 6.2: 1.5 h / -70 - -60 °C / Inert atmosphere 6.3: -10 - 25 °C 7.1: D-tartaric acid / isopropyl alcohol / 16 h / 30 - 35 °C 7.2: 10 - 15 °C View Scheme

R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (865889-33-4) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 2.1: toluene / 1 h / 0 - 35 °C 3.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 4.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 4.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 2.1: toluene / 1 h / 0 - 35 °C 3.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 4.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 4.2: 1 h / -70 - -50 °C View Scheme

(3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoyl chloride (1429299-07-9) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene / 1 h / 0 - 35 °C 2.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 3.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 3.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 1 h / 0 - 35 °C 2.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 3.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 3.2: 1 h / -70 - -50 °C View Scheme

R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide (1429299-08-0) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 2.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 2.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 2.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 2.2: 1 h / -70 - -50 °C View Scheme

benzyl chloride (100-44-7) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: potassium carbonate / 60 - 65 °C 2.1: sodium hydroxide / water / 45 - 50 °C 3.1: ethanol / 5.83 h / 0 - 75 °C 4.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 5.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 6.1: toluene / 1 h / 0 - 35 °C 7.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 8.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 8.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate / 60 - 65 °C 2.1: sodium hydroxide / water / 45 - 50 °C 3.1: ethanol / 5.83 h / 0 - 75 °C 4.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 5.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 6.1: toluene / 1 h / 0 - 35 °C 7.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 8.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 8.2: 1 h / -70 - -50 °C View Scheme

(+/-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1185739-54-1) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: ethanol / 5.83 h / 0 - 75 °C 2.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 3.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 4.1: toluene / 1 h / 0 - 35 °C 5.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 6.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 6.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 6 steps 1.1: ethanol / 5.83 h / 0 - 75 °C 2.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 3.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 4.1: toluene / 1 h / 0 - 35 °C 5.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 6.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 6.2: 1 h / -70 - -50 °C View Scheme

R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1S,2R)-ephedrine salt (1429299-06-8) → 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 3.1: toluene / 1 h / 0 - 35 °C 4.1: tetrahydrofuran / 4.5 h / 60 - 65 °C 5.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 5.2: 1 h / -70 - -50 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; toluene / 1 h / 20 - 25 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 50 - 55 °C 3.1: toluene / 1 h / 0 - 35 °C 4.1: iodine; lithium aluminium tetrahydride / tetrahydrofuran / 2.25 h / 0 - 65 °C 5.1: iodine; magnesium; ethyl bromide / tetrahydrofuran / 2 h / 60 - 65 °C / Inert atmosphere 5.2: 1 h / -70 - -50 °C View Scheme

methanol (67-56-1) + 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → methyl 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoate (156755-35-0)

Conditions	Yield
With sulfuric acid at 20℃; Product distribution / selectivity; Reflux;
With thionyl chloride at 0 - 65℃;	64 g

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol (207679-81-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 20 °C / Reflux 2: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere 3: hydrogen / Raney nickel / methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 30 - 55 °C 1.2: 0.33 h / 0 - 5 °C 2.1: hydrogen / Raney nickel / methanol / 20 °C View Scheme
Multi-step reaction with 3 steps 1: thionyl chloride / 0 - 65 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 30 °C 3: hydrogen; palladium 10% on activated carbon / isopropyl alcohol / 25 - 30 °C / 2068.65 - 2585.81 Torr / Autoclave View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → fesoterodine (286930-02-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 20 °C / Reflux 2: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere 3: hydrogen / Raney nickel / methanol / 20 °C 4: triethylamine / acetonitrile / -10 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 30 - 55 °C 1.2: 0.33 h / 0 - 5 °C 2.1: hydrogen / Raney nickel / methanol / 20 °C 3.1: triethylamine / acetonitrile / -10 °C View Scheme
Multi-step reaction with 4 steps 1: thionyl chloride / 0 - 65 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 30 °C 3: hydrogen; palladium 10% on activated carbon / isopropyl alcohol / 25 - 30 °C / 2068.65 - 2585.81 Torr / Autoclave 4: sodium hydrogencarbonate / dichloromethane / 3 h / -2 - 3 °C View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → {4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]phenyl}methanol (156755-37-2)

Conditions	Yield
Stage #1: 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at 30 - 55℃; Stage #2: With water; sodium hydroxide In toluene at 0 - 5℃; for 0.333333h;
Multi-step reaction with 2 steps 1: sulfuric acid / 20 °C / Reflux 2: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → fesoterodine fumarate

Conditions	Yield
Multi-step reaction with 5 steps 1: sulfuric acid / 20 °C / Reflux 2: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 3 h / Inert atmosphere 3: hydrogen / Raney nickel / methanol / 20 °C 4: triethylamine / acetonitrile / -10 °C 5: butanone / -5 °C / Heating View Scheme
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 30 - 55 °C 1.2: 0.33 h / 0 - 5 °C 2.1: hydrogen / Raney nickel / methanol / 20 °C 3.1: triethylamine / acetonitrile / -10 °C 4.1: butanone / -5 °C / Heating View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → Tolterodine acid (194482-44-5)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In methanol at 25 - 30℃; under 2206.72 - 2942.29 Torr; for 8h; autoclave;

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxyl-methyl)phenyl isobutyrate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 25 - 30 °C / 2206.72 - 2942.29 Torr / autoclave 2.1: chloroform / 0.75 h / -45 - -35 °C 3.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 6 h / 25 - 30 °C / 2206.72 - 2942.29 Torr / autoclave 3.2: 1 h / 0 - 5 °C 3.3: 7.5 h / 0 - 30 °C View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → (R)-3-(3-(diisopropylamino)-1-phenylpropyl)-4-(methacryloyloxy)benzoic acid (1390644-41-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 25 - 30 °C / 2206.72 - 2942.29 Torr / autoclave 2: chloroform / 0.75 h / -45 - -35 °C View Scheme

4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoic acid (754159-68-7) → 2-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl 2-methylpropanoate fumarate

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / 0 - 65 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 30 °C 3: hydrogen; palladium 10% on activated carbon / isopropyl alcohol / 25 - 30 °C / 2068.65 - 2585.81 Torr / Autoclave 4: sodium hydrogencarbonate / dichloromethane / 3 h / -2 - 3 °C 5: butanone; cyclohexane / 20 - 36 °C View Scheme

Upstream product

• 1429299-06-8 R-(-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1S,2R)-ephedrine salt 
• 1185739-54-1 (+/-)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid 
• 100-44-7 benzyl chloride 
• 1429299-08-0 R-(-)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide 
• 1429299-07-9 (3R)-3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoyl chloride 
• 865889-33-4 R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid 
• 621-82-9 Cinnamic acid 
• 760147-33-9 (+)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine 
• 1350477-43-8 (-)-N,N-diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine (-)-di-p-toluoyl-L-tartaric acid 
• 701906-29-8 (+)-N,N-Diisopropyl-3-(2-benzyloxy-5-carboxyphenyl)-3-phenylpropylamine 
• 1135493-18-3 C₂₀H₁₈O₈*C₂₈H₃₄BrNO 
• 250214-37-0 (+/-)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester 
• 156755-24-7 methyl 3-[2-(benzyloxy)-5-bromophenyl]-3-phenylpropanoate 
• 156755-23-6 6-bromo-4-phenyl-3,4-dihydro-2H-chromen-2-one 

Downstream Products

• 156755-35-0 methyl 4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]benzoate 
• 207679-81-0 (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)-phenol 
• 286930-02-7 fesoterodine 
• 156755-37-2 {4-(benzyloxy)-3-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]phenyl}methanol 
• 286930-03-8 fesoterodine fumarate 
• 286930-03-8 2-[(1R)-3-(dipropan-2-ylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl 2-methylpropanoate fumarate 
• 1390644-41-3 (R)-3-(3-(diisopropylamino)-1-phenylpropyl)-4-(methacryloyloxy)benzoic acid 
• 250214-44-9 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxyl-methyl)phenyl isobutyrate 
• 194482-44-5 Tolterodine acid 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF FESOTERODINE OR ITS SALTS

The present invention relates to a process for the preparation of fesoterodine or its salts.

SOLID STATE FORMS OF FESOTERODINE INTERMEDIATES

Provided herein are novel solid state forms of fesoterodine intermediates, (R)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid and (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol, and processes for their preparation thereof. The solid state intermediates are useful for preparing fesoterodine or a pharmaceutically acceptable salt thereof in high purity.