239463-85-5

Basic information

• Product Name: 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate
• Synonyms: 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate;5-[(2R)-2-aMinopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate (1:1);R)-5-(2-aMinopropyl)-1-(3-benzyloxypropyl) indoline-7-carbonitrile tartrate;(R)-3-(5-(2-aMinopropyl)-7-cyanoindolin-1-yl)propyl benzoate (2R,3R)-2,3-dihydroxysuccinate;5-[(2R)-2-AMinopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dih;5-[(2R)-2-AMinopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioa;5-[(2R)-2-aMinopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-carbonitrile-1H-indole(2R,3R)-2,3-dihydroxybutanedioat;5-((2R)-2-AMINOPROPLY)-1-(3-(BENZYLOXY)PROPYL)-2,3-DIHYDRO-7-CARBONOTRILE-1H-INDOLE-(2R,3R)-2,3-DIHYDROBUTANEDIOATE (ACI
• CAS NO: 239463-85-5
• Molecular Formula: C₄H₆O₆*C₂₂H₂₅N₃O₂
• Molecular Weight: 513.53964
• EINECS: 1308068-626-2
• Product Categories: Intermediates
• Mol File: 239463-85-5.mol

Chemical Properties

• Appearance: /
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: DMSO (Slightly, Sonicated), Ethanol (Slightly, Heated, Sonicated), Methanol (Sli
• Stability: Hygroscopic
• CAS DataBase Reference: 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate(CAS DataBase Reference)
• NIST Chemistry Reference: 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate(239463-85-5)
• EPA Substance Registry System: 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate(239463-85-5)

Safety Data

• Hazardous Substances Data: 239463-85-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate is used as an intermediate in the synthesis of Silodosin (S465000), an α1a-adrenoceptor antagonist. 5-[(2R)-2-Aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indole-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate plays a vital role in the development of medications for the treatment of benign prostatic hyperplasia (BPH), a common condition in aging men that affects the prostate gland and can cause urinary problems.
As an intermediate in the pharmaceutical industry, this compound contributes to the production of drugs that help alleviate the symptoms of BPH, such as difficulty in starting urination, weak urine flow, and frequent urination. The α1a-adrenoceptor antagonist activity of Silodosin helps relax the muscles in the prostate and bladder neck, improving urine flow and reducing the discomfort associated with BPH.

Synthetic route

L-Tartaric acid (87-69-4) + C38H39N3O4 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Stage #1: C38H39N3O4 With palladium on activated charcoal; hydrogen Stage #2: L-Tartaric acid Inert atmosphere;	33.3%

L-Tartaric acid (87-69-4) + C42H41N3O4 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Stage #1: C42H41N3O4 With palladium on activated charcoal; hydrogen Stage #2: L-Tartaric acid Inert atmosphere;	30.9%

L-Tartaric acid (87-69-4) + 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propylbenzoate → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Stage #1: 3-(5-(2-((tert-butoxycarbonyl)amino)propyl)-7-cyanoindolin-1-yl)propylbenzoate With hydrogenchloride In chloroform; water at 25 - 30℃; for 5h; Stage #2: L-Tartaric acid In water; acetone at 20 - 25℃; for 12h;	23.5%

L-Tartaric acid (87-69-4) + 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole (1338365-54-0) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
In tetrahydrofuran; water at 20 - 65℃; Product distribution / selectivity;
In water; acetone at 20℃; for 49h;	2.05 g

1-(3-benzoyloxypropyl)-7-cyano-5-(2-nitropropyl)-2,3-dihydroindole (350797-56-7) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; zinc / water; methanol / 20 h / 60 - 65 °C 2: water; tetrahydrofuran / 20 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 2: water; acetone / 49 h / 20 °C View Scheme

1-(3-benzoyloxypropyl)-5-(2-nitro-1-propenyl)-2,3-dihydroindole (350797-53-4) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; potassium hydroxide / tetrahydrofuran; water / -10 - 20 °C 2.1: trichlorophosphate / 0 - 50 °C 2.2: Cooling with ice 3.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 3.2: 2 h / 80 °C 4.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 5.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-(3-benzoyloxypropyl)-5-(2-nitropropyl)-2,3-dihydroindole (350797-54-5) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 0 - 50 °C 1.2: Cooling with ice 2.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 2.2: 2 h / 80 °C 3.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 4.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-(3-benzoyloxypropyl)-7-formyl-5-(2-nitropropyl)-2,3-dihydroindole (350797-55-6) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 1.2: 2 h / 80 °C 2.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 3.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-(3-benzoyloxypropyl)-7-cyano-5-(2-nitropropyl)-2,3-dihydroindole (350797-56-7) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions	Yield
Multi-step reaction with 2 steps 1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 2: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

L-Tartaric acid (87-69-4) + 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole (1338365-54-0) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions	Yield
In water; acetone at 25 - 65℃; Resolution of racemate;	A n/a B n/a

benzoic acid (65-85-0) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions

Yield

Multi-step reaction with 8 steps 1.1: triethylamine / N,N-dimethyl-formamide / 20 °C 1.2: 3 h / 100 °C 2.1: trichlorophosphate / 2 h / 20 °C 2.2: Cooling with ice 3.1: ammonium acetate / 20 - 100 °C 4.1: sodium tetrahydroborate; potassium hydroxide / tetrahydrofuran; water / -10 - 20 °C 5.1: trichlorophosphate / 0 - 50 °C 5.2: Cooling with ice 6.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 6.2: 2 h / 80 °C 7.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 8.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-indoline (496-15-1) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions

Yield

Multi-step reaction with 8 steps 1.1: triethylamine / N,N-dimethyl-formamide / 20 °C 1.2: 3 h / 100 °C 2.1: trichlorophosphate / 2 h / 20 °C 2.2: Cooling with ice 3.1: ammonium acetate / 20 - 100 °C 4.1: sodium tetrahydroborate; potassium hydroxide / tetrahydrofuran; water / -10 - 20 °C 5.1: trichlorophosphate / 0 - 50 °C 5.2: Cooling with ice 6.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 6.2: 2 h / 80 °C 7.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 8.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-(3-benzoyloxypropyl)-2,3-dihydroindole hydrochloride (350797-51-2) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions

Yield

Multi-step reaction with 7 steps 1.1: trichlorophosphate / 2 h / 20 °C 1.2: Cooling with ice 2.1: ammonium acetate / 20 - 100 °C 3.1: sodium tetrahydroborate; potassium hydroxide / tetrahydrofuran; water / -10 - 20 °C 4.1: trichlorophosphate / 0 - 50 °C 4.2: Cooling with ice 5.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 5.2: 2 h / 80 °C 6.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 7.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

1-(3-benzoyloxypropyl)-5-formyl-2,3-dihydroindole (350797-52-3) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 5-[(2S)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate

Conditions

Yield

Multi-step reaction with 6 steps 1.1: ammonium acetate / 20 - 100 °C 2.1: sodium tetrahydroborate; potassium hydroxide / tetrahydrofuran; water / -10 - 20 °C 3.1: trichlorophosphate / 0 - 50 °C 3.2: Cooling with ice 4.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 2 h / 50 °C 4.2: 2 h / 80 °C 5.1: platinum on carbon; hydrogen / ethyl acetate / 25 - 30 °C / 6000.6 - 7500.75 Torr / Autoclave 6.1: acetone; water / 25 - 65 °C / Resolution of racemate View Scheme

C22H25N3O5 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 2: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 3: water; acetone / 49 h / 20 °C View Scheme

3-(indolin-1-yl)propan-1-ol → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: triethylamine / dichloromethane / 8 h / 0 - 25 °C / Inert atmosphere 2.1: trichlorophosphate / 1,2-dichloro-ethane / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 80 °C / Inert atmosphere 3.1: ammonium acetate; acetic acid / 4 h / 80 °C 4.1: sodium tetrahydroborate / dichloromethane; methanol / 1 h / 0 - 25 °C 5.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 5.2: 2 h / 0 - 80 °C / Inert atmosphere 6.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 7.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 8.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 9.1: water; acetone / 49 h / 20 °C View Scheme

3-(indolin-1-yl)propyl benzoate → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 1 h / 0 °C / Inert atmosphere 1.2: 2 h / 0 - 80 °C / Inert atmosphere 2.1: ammonium acetate; acetic acid / 4 h / 80 °C 3.1: sodium tetrahydroborate / dichloromethane; methanol / 1 h / 0 - 25 °C 4.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 4.2: 2 h / 0 - 80 °C / Inert atmosphere 5.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 6.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 7.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 8.1: water; acetone / 49 h / 20 °C View Scheme

1-(3-benzoyloxypropyl)-5-formyl-2,3-dihydroindole (350797-52-3) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: ammonium acetate; acetic acid / 4 h / 80 °C 2.1: sodium tetrahydroborate / dichloromethane; methanol / 1 h / 0 - 25 °C 3.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 3.2: 2 h / 0 - 80 °C / Inert atmosphere 4.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 5.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 6.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 7.1: water; acetone / 49 h / 20 °C View Scheme

1-(3-benzoyloxypropyl)-5-(2-nitro-1-propenyl)-2,3-dihydroindole (350797-53-4) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium tetrahydroborate / dichloromethane; methanol / 1 h / 0 - 25 °C 2.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 80 °C / Inert atmosphere 3.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 4.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 5.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 6.1: water; acetone / 49 h / 20 °C View Scheme

1-indoline (496-15-1) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: potassium carbonate / acetonitrile / 12 h / 90 °C 2.1: triethylamine / dichloromethane / 8 h / 0 - 25 °C / Inert atmosphere 3.1: trichlorophosphate / 1,2-dichloro-ethane / 1 h / 0 °C / Inert atmosphere 3.2: 2 h / 0 - 80 °C / Inert atmosphere 4.1: ammonium acetate; acetic acid / 4 h / 80 °C 5.1: sodium tetrahydroborate / dichloromethane; methanol / 1 h / 0 - 25 °C 6.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 6.2: 2 h / 0 - 80 °C / Inert atmosphere 7.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 8.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 9.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 10.1: water; acetone / 49 h / 20 °C View Scheme

1-(3-benzoyloxypropyl)-5-(2-nitropropyl)-2,3-dihydroindole (350797-54-5) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trichlorophosphate / 1 h / 0 °C / Inert atmosphere 1.2: 2 h / 0 - 80 °C / Inert atmosphere 2.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 3.1: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 4.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 5.1: water; acetone / 49 h / 20 °C View Scheme

1-(3-benzoyloxypropyl)-7-formyl-5-(2-nitropropyl)-2,3-dihydroindole (350797-55-6) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 12 h / 70 °C 2: acetic anhydride / tetrahydrofuran / 24 h / 70 °C 3: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 48 h / 40 °C 4: water; acetone / 49 h / 20 °C View Scheme

C24H28N2O4 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 1 h / 50 °C / Inert atmosphere 1.2: 3.5 h / 50 °C 2.1: hydrogenchloride / water / 12 h / Inert atmosphere; Reflux 3.1: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

C24H27N3O3 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water / 12 h / Inert atmosphere; Reflux 2: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile (239463-72-0) + L-Tartaric acid (87-69-4) → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
In methanol; water for 0.5h; Inert atmosphere; Reflux;

C24H28N2O5 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; triethylsilane / toluene / 18 h / 45 °C / Inert atmosphere 2.1: trichlorophosphate / 0.5 h / Cooling with ice; Inert atmosphere 2.2: 3 h / 50 °C 3.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 1 h / 50 °C / Inert atmosphere 3.2: 3.5 h / 50 °C 4.1: hydrogenchloride / water / 10 h / Inert atmosphere; Reflux 5.1: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

C24H30N2O4 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 0.5 h / Cooling with ice; Inert atmosphere 1.2: 3 h / 50 °C 2.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 1 h / 50 °C / Inert atmosphere 2.2: 3.5 h / 50 °C 3.1: hydrogenchloride / water / 10 h / Inert atmosphere; Reflux 4.1: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

C25H30N2O5 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 1 h / 50 °C / Inert atmosphere 1.2: 3.5 h / 50 °C 2.1: hydrogenchloride / water / 10 h / Inert atmosphere; Reflux 3.1: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

C25H29N3O4 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water / 10 h / Inert atmosphere; Reflux 2: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

C26H32N2O5 → 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; triethylsilane / toluene / 22 h / 45 °C / Inert atmosphere 2.1: trichlorophosphate / 0.5 h / Cooling with ice; Inert atmosphere 2.2: 3 h / 50 °C 3.1: hydroxylamine hydrochloride; pyridine / tetrahydrofuran / 1 h / 50 °C / Inert atmosphere 3.2: 3.5 h / 50 °C 4.1: hydrogenchloride / water / 12 h / Inert atmosphere; Reflux 5.1: water; methanol / 0.5 h / Inert atmosphere; Reflux View Scheme

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) → (R)-5-(2-aminopropyl)-1-(3-hydroxypropyl)indoline-7-carbonitrile (1401991-17-0)

Conditions	Yield
With potassium hydroxide In methanol for 2h; Reflux;	100%
With water; potassium hydroxide In methanol at 20℃;

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) → 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile (239463-72-0)

Conditions	Yield
With sodium carbonate In water; ethyl acetate for 2h; Large scale;	99%
With sodium hydroxide In dichloromethane; water at 10℃; pH=11;	97.5%
With sodium carbonate In water pH=10;	1.25 g
With potassium carbonate In water pH=10;

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 2,3-dihydro-1-[3-(benzoyloxy)propyl]-5-[(2R)-2-[[2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile (885340-11-4)

Conditions	Yield
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In water; ethyl acetate at 20℃; for 1h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With tetrabutylammomium bromide; sodium carbonate In acetonitrile at 75 - 85℃; for 30h; Reagent/catalyst; Solvent;	85%
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In water; ethyl acetate at 20℃; for 1h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With sodium carbonate In isopropyl alcohol at 80℃; Product distribution / selectivity;
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In N,N-dimethyl acetamide; acetonitrile at 80℃; for 0.5h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With potassium iodide at 80℃; for 10h;
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In N,N-dimethyl acetamide; acetonitrile at 80℃; for 0.5h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With potassium iodide In N,N-dimethyl acetamide; acetonitrile at 80℃; for 10h;
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In water; ethyl acetate for 2h; Reflux; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With sodium carbonate In toluene Reflux;

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + di-tert-butyl dicarbonate (24424-99-5) → 5-[(2R)-2-(tert-butoxycarbonyl)aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h;	84.48%
With potassium carbonate In dichloromethane; water at 15 - 25℃; for 5h;	457 g

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + oxalic acid (144-62-7) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 1-(3-hydroxypropyl)-5-(2R)-2-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aminopropyl-2,3-dihydro-1H-indole-7-carbonitrile oxalic acid

Conditions

Yield

Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In N,N-dimethyl acetamide; acetonitrile at 80℃; for 0.5h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With potassium iodide In N,N-dimethyl acetamide; acetonitrile at 80℃; for 10h; Stage #3: oxalic acid at 50℃; for 0.5h; Solvent;

82%

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + succinic acid (110-15-6) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 1-(3-hydroxypropyl)-5-(2R)-2-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aminopropyl-2,3-dihydro-1H-indole-7-carbonitrile succinic acid

Conditions

Yield

Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In N,N-dimethyl acetamide; acetonitrile at 80℃; for 0.5h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With potassium iodide In N,N-dimethyl acetamide; acetonitrile at 80℃; for 10h; Stage #3: succinic acid at 50℃; for 0.5h;

81%

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + (2E)-but-2-enedioic acid (110-17-8) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 1-(3-hydroxypropyl)-5-(2R)-2-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aminopropyl-2,3-dihydro-1H-indole-7-carbonitrile fumaric acid

Conditions

Yield

Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In N,N-dimethyl acetamide; acetonitrile at 80℃; for 0.5h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With potassium iodide In N,N-dimethyl acetamide; acetonitrile at 80℃; for 10h; Stage #3: (2E)-but-2-enedioic acid at 50℃; for 0.5h;

81%

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + L-Tartaric acid (87-69-4) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 3-(7-cyano-5-[(2R)-2-(2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino)propyl]-2,3-dihydro-1H-indol-1-yl)propylbenzoate (2R,3R)-tartrate salt

Conditions	Yield
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt; 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With sodium carbonate In acetonitrile for 24h; Reflux; Stage #2: L-Tartaric acid In ethanol at 20℃; for 5h;	79.3%
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In acetic acid butyl ester; water at 45℃; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene In acetic acid butyl ester; water for 18h; Reflux; Stage #3: L-Tartaric acid In acetic acid butyl ester at 80℃;	4.6 g

5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt (239463-85-5) + 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene (160969-03-9) → 2,3-dihydro-1-[3-(benzoyloxy)propyl]-5-[(2R)-2-[[2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile (885340-11-4) + C40H41F6N3O7

Conditions	Yield
Stage #1: 5-[(2R)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate salt With potassium carbonate In water; ethyl acetate at 20℃; for 2h; Stage #2: 1-(2-methanesulfonyloxyethoxy)-2-(2,2,2-trifluoroethoxy)benzene With sodium carbonate In tert-butyl alcohol for 24h; Heating / reflux;

Upstream product

• 350797-53-4 1-(3-benzoyloxypropyl)-5-(2-nitro-1-propenyl)-2,3-dihydroindole 
• 350797-54-5 1-(3-benzoyloxypropyl)-5-(2-nitropropyl)-2,3-dihydroindole 
• 350797-55-6 1-(3-benzoyloxypropyl)-7-formyl-5-(2-nitropropyl)-2,3-dihydroindole 
• 350797-56-7 1-(3-benzoyloxypropyl)-7-cyano-5-(2-nitropropyl)-2,3-dihydroindole 
• 87-69-4 L-Tartaric acid 
• 1338365-54-0 5-(2-aminopropyl)-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole 
• 65-85-0 benzoic acid 
• 496-15-1 1-indoline 
• 350797-51-2 1-(3-benzoyloxypropyl)-2,3-dihydroindole hydrochloride 
• 350797-52-3 1-(3-benzoyloxypropyl)-5-formyl-2,3-dihydroindole 
• 239463-72-0 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile 
• 1402161-28-7 5-[2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile L-(+)-tartrate 

Downstream Products

• 885340-11-4 2,3-dihydro-1-[3-(benzoyloxy)propyl]-5-[(2R)-2-[[2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile 
• 239463-72-0 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indole-7-carbonitrile 
• 160970-54-7 silodosin 
• 1426173-86-5 C₂₅H₂₈⁽²⁾H₄F₃N₃O₄ 
• 885340-12-5 (2R)-3-(7-cyano-5-(2-((2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)-2,3-dihydro-1H-indol-1-yl)propyl benzoate oxalate 

Relevant articles and documents

THE MANUFACTURING METHOD OF INTERMEDIATE FOR SYNTHESIS OF SILODOSIN AND THE MANUFACTURING METHOD OF SILODOSIN

The present invention relates to a method for producing an intermediate for the synthesis, of a cilodosin, and a method for producing, a cilodosin using the, same, which can be used in a method for producing a cilodosin, which can increase the price competitiveness and can reduce. risk factors in the production process, facilitate mass production, and obtain a high purity of xylodosin. (by machine translation)

Preparation method of silodosin intermediate

The invention discloses a preparation method of a silodosin intermediate and relates to the technical field of medical synthesis, aiming at solving the problem in an existing preparation method that the yield of the silodosin intermediate is low. The preparation method of the silodosin intermediate comprises the following steps: carrying out chirally-induced reductive amination on an alpha-substituted acetone compound to obtain an initial intermediate; carrying out amino protection on the initial intermediate to obtain an amino protected intermediate; carrying out hydroformylation on the aminoprotected intermediate to obtain a hydroformylated intermediate; carrying out oximation on the hydroformylated intermediate to obtain an oximated intermediate; carrying out cyaniding on the oximatedintermediate to obtain a cyanated intermediate; carrying out amino deprotection on the cyanated intermediate to obtain free alkali of the silodosin intermediate; carrying out salt forming treatment onthe free alkali of the silodosin intermediate to obtain the silodosin intermediate. The preparation method of the silodosin intermediate, provided by the invention, is used for preparing silodosin.

Method for preparing silodosin intermediate

The invention discloses a method for preparing silodosin intermediate 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indolyl-7-nitrily-L-(+)-tartrate. The method specifically comprisesthe steps of recovering waste filter liquor in a resolution reaction, subjecting the filter liquor to catalyzed racemation by a palladium catalyst so as to prepare a raw material, i.e., 5-[2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indolyl-7-nitrile, and then, at least repeating resolution once, thereby increasing the yield of the resolution product, i.e., a key intermediate of silodosin, i.e., 5-[(2R)-2-aminopropyl]-2,3-dihydro-1-[3-(benzoyloxy)propyl]-1H-indolyl-7-nitrily-L-(+)-tartrate. The target product prepared by the method disclosed by the invention is high in yield and low in cost, preconceptions in the prior art are overcome, and thus, the method is more applicable to industrial production.

Process for Production of Optically Active Indoline Derivatives or Salts Thereof

The present invention relates to a synthesis method of optically active indoline derivatives or salts thereof, which are represented by general formula I and useful as a starting material for the production of drugs. By introducing terephthaloyl chloride as a starting material and using the same as a link in the synthesis of indoline derivatives or salts thereof, the present invention increases efficiency, greatly facilitates confirmation of intermediates, purification, and processes, and also increases the efficiency of reaction due to excellent stability. By using inexpensive and easy-to-handle zinc instead of expensive platinum catalyst, the present invention improves the yield thereof. By introducing a benzyl group into an amine group (general formula III, preferably chemical formula 23) to ensure optical purity in the final process, the present invention can produce, merely by means of recrystallization, optically pure indoline derivatives or salts thereof, represented by the general formula I.COPYRIGHT KIPO 2016

Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists

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Method for preparing silodosin midbody

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METHOD FOR PREPARING SILODOSIN

The present invention relates to a process for preparing silodosin with high optical purity up to 99.9% enantiomeric excess (e.e.) or above. The process makes use of a method step, in which the enantiomers contained in a racemic mixture of a compound represented by the general formula V: wherein * denotes the asymmetric center, R1 is a protecting group, and R2 is cyano or carbamoyl, are separated.

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