120427-96-5

Basic information

• Product Name: 4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOLE-2-ONE
• Synonyms: 4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOLE-2-ONE;4-(2-Bromoethyl)-2-oxoindole;Ropinirole Intermediate 4;4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOL-2-ONE;4-(2-BROMOETHYL)OXINDOLE;4-(2-Bromoethyl)Oxyindole;4-(2-Bromoethyl)indolin-2-one;4-(2-broMoethyl)-2H-indol-2-one
• CAS NO: 120427-96-5
• Molecular Formula: C₁₀H₁₀BrNO
• Molecular Weight: 240.0965
• EINECS: 1308068-626-2
• Product Categories: Pharmaceutical material and intermeidates;Aromatics;Heterocycles;Indole Derivatives
• Mol File: 120427-96-5.mol
• Article Data: 7

Chemical Properties

• Melting Point: 153-155°C
• Boiling Point: 373.798 °C at 760 mmHg
• Flash Point: 179.867 °C
• Appearance: /
• Density: 1.528
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 14.05±0.20(Predicted)
• CAS DataBase Reference: 4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOLE-2-ONE(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOLE-2-ONE(120427-96-5)
• EPA Substance Registry System: 4-(2'-BROMOETHYL)-1,3-DIHYDRO-2H-INDOLE-2-ONE(120427-96-5)

Safety Data

• Hazardous Substances Data: 120427-96-5(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Solid

Uses

4-(2-BroMoethyl)-1,3-dihydro-2H-indolin-2-one can be used as a useful synthetic intermediate.

Synthetic route

4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indolin-2-one (120427-95-4) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
With sodium hypophosphite; palladium on activated charcoal In ethyl acetate for 0.583333h; Heating;	95%
With sodium hypophosphite monohydrate; palladium on activated charcoal In water; ethyl acetate Large scale;	95%
With sodium hypophosphite hydrate; palladium 10% on activated carbon In water; ethyl acetate for 1h; Heating / reflux;	88.97%
With phosphonic Acid; sodium iodide In ethanol at 70℃; for 5h; Reagent/catalyst;	86.7%

2-(2-bromoethyl)benzaldehyde (22901-09-3) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / MeONa / methanol / 1 h / 0 °C 2: 53 percent / AcCl, FeCl3 / CH2Cl2 / 3 h / 0 - 5 °C 3: 95 percent / aq. NaH2PO2 / 10percent Pd-C / ethyl acetate / 0.58 h / Heating View Scheme

2-(2-bromoethyl)-β-nitrostyrene → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 53 percent / AcCl, FeCl3 / CH2Cl2 / 3 h / 0 - 5 °C 2: 95 percent / aq. NaH2PO2 / 10percent Pd-C / ethyl acetate / 0.58 h / Heating View Scheme

sodium phosphinate hydrate + pyrographite (7440-44-0) + palladium (7440-05-3) + 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indolin-2-one (120427-95-4) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
In water

sodium phosphinate hydrate + 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indolin-2-one (120427-95-4) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
carbon palladium In water	17.0 g (82%)

isochromane (493-05-0) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: bromine / water / Irradiation 2: water; methanol / Acidic conditions; Large scale 3: iron(III) chloride / Acidic conditions; Large scale 4: palladium on activated charcoal; sodium hypophosphite monohydrate / water; ethyl acetate / Large scale View Scheme
Multi-step reaction with 7 steps 1: zinc(II) chloride / dichloromethane / Reflux 2: hexamethylenetetramine; acetic acid / ethanol; water 3: N-butylamine; acetic acid; nitromethane / methanol / 20 °C 4: iron(III) chloride / dichloromethane / 0 - 5 °C 5: hydrazine hydrate; palladium 10% on activated carbon / methanol 6: sodium hydroxide; water / methanol / Reflux 7: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

1-Bromoisochromane (50683-32-4) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: water; methanol / Acidic conditions; Large scale 2: iron(III) chloride / Acidic conditions; Large scale 3: palladium on activated charcoal; sodium hypophosphite monohydrate / water; ethyl acetate / Large scale View Scheme

2-(2-bromoethyl)-β-nitrostyrene → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: iron(III) chloride / Acidic conditions; Large scale 2: palladium on activated charcoal; sodium hypophosphite monohydrate / water; ethyl acetate / Large scale View Scheme

4-[2-(benzoyloxy)ethyl]-3-chloro-1,3-dihydro-2H-indolin-2-one (139122-17-1) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrazine hydrate; palladium 10% on activated carbon / methanol 2: sodium hydroxide; water / methanol / Reflux 3: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

4-(2-benzoyloxyethyl)-1,3-dihydro-2H-indolin-2-one (139122-18-2) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide; water / methanol / Reflux 2: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

4-(2'-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (139122-19-3) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃;

2-(2-methyl-3-nitrophenyl)acetic acid (23876-15-5) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: borane-THF / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C / Inert atmosphere 2.2: 8 h / 20 °C / Inert atmosphere 3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.33 h / 0 °C / Inert atmosphere 3.2: 8 h / 20 °C / Inert atmosphere 4.1: sodium hydroxide / tetrahydrofuran / 0.17 h / 0 °C 4.2: 1 h / 20 °C / pH 1.5 5.1: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 20 °C 6.1: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

2-[2-(chloromethyl)phenyl]ethylbenzoate (168476-58-2) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions

Yield

Multi-step reaction with 6 steps 1: hexamethylenetetramine; acetic acid / ethanol; water 2: N-butylamine; acetic acid; nitromethane / methanol / 20 °C 3: iron(III) chloride / dichloromethane / 0 - 5 °C 4: hydrazine hydrate; palladium 10% on activated carbon / methanol 5: sodium hydroxide; water / methanol / Reflux 6: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

2-(2-methyl-3-nitrophenyl)ethyl alcohol (855382-76-2) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 8 h / 20 °C / Inert atmosphere 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.33 h / 0 °C / Inert atmosphere 2.2: 8 h / 20 °C / Inert atmosphere 3.1: sodium hydroxide / tetrahydrofuran / 0.17 h / 0 °C 3.2: 1 h / 20 °C / pH 1.5 4.1: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 20 °C 5.1: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

1-[(2-methyl-3-nitrophenethyloxy)methyl]benzene (1426679-26-6) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.33 h / 0 °C / Inert atmosphere 1.2: 8 h / 20 °C / Inert atmosphere 2.1: sodium hydroxide / tetrahydrofuran / 0.17 h / 0 °C 2.2: 1 h / 20 °C / pH 1.5 3.1: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 20 °C 4.1: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

ethyl 3-[2-[2-(benzyloxy)ethyl]-6-nitrophenyl]-2-oxopropanoate (1441070-77-4) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / tetrahydrofuran / 0.17 h / 0 °C 1.2: 1 h / 20 °C / pH 1.5 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 20 °C 3.1: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

2-[2-[2-(benzyloxy)ethyl]-6-nitrophenyl]acetic acid (1426679-27-7) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 5 h / 20 °C 2: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

benzoic acid (2-formyl)phenethyl ester (139122-15-9) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: N-butylamine; acetic acid; nitromethane / methanol / 20 °C 2: iron(III) chloride / dichloromethane / 0 - 5 °C 3: hydrazine hydrate; palladium 10% on activated carbon / methanol 4: sodium hydroxide; water / methanol / Reflux 5: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

benzoic acid (2-(2-nitroethenyl))phenethyl ester (139122-16-0) → 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: iron(III) chloride / dichloromethane / 0 - 5 °C 2: hydrazine hydrate; palladium 10% on activated carbon / methanol 3: sodium hydroxide; water / methanol / Reflux 4: carbon tetrabromide; triphenylphosphine / dichloromethane / 0 - 20 °C View Scheme

sodium acetate (127-09-3) + 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 4-(2-acetoxyethyl)-1,3-dihydro-2H-indolin-2-one (168476-61-7)

Conditions	Yield
In ethanol; water for 24h; Heating;	89%

di-n-propylamine (142-84-7) + 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → ropinirole hydrochloride (91374-20-8) + 4-ethylenyl-1,3-dihydro-2H-indol-2-one

Conditions	Yield
With hydrogenchloride In water Large scale;	A 57% B 38%

di-n-propylamine (142-84-7) + 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → ropinirole hydrochloride (91374-20-8)

Conditions	Yield
Stage #1: di-n-propylamine; 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one In water; acetonitrile at 65 - 70℃; for 1.25h; Stage #2: With hydrogenchloride In water pH=2;	50%

propylamine (107-10-8) + 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 4-ethylenyl-1,3-dihydro-2H-indol-2-one + N-Despropylropinirole

Conditions	Yield
Reflux;	A 35% B 45%

di-n-propylamine (142-84-7) + 4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → Ropinirole (91374-21-9) + 4-ethylenyl-1,3-dihydro-2H-indol-2-one

Conditions	Yield
In water for 2.5h; Heating;	A n/a B 38%

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → Ropinirole (91374-21-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 87 percent / pyridine / CH2Cl2 / 4 h / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 4-ethylenyl-1,3-dihydro-2H-indol-2-one

Conditions	Yield
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 87 percent / pyridine / CH2Cl2 / 4 h / 5 - 10 °C 4: H2O / 2 h / Heating View Scheme

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 4-(2'-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (139122-19-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating View Scheme

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl methanesulfonate (139122-21-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C View Scheme

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 2-(2'-oxo-2,3-dihydro-4-indolyl)ethyl benzenesulphonate (139122-22-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 80 percent / pyridine / CH2Cl2 / 5 - 10 °C View Scheme

4-(2'-bromoethyl)-1,3-dihydro-2H-indol-2-one (120427-96-5) → 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl-4-methylbenzene-1-sulfonate (139122-20-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / ethanol; H2O / 24 h / Heating 2: 70 percent / aq. HCl / 2.5 h / Heating 3: 87 percent / pyridine / CH2Cl2 / 4 h / 5 - 10 °C View Scheme

Upstream product

• 7440-44-0 pyrographite 
• 7440-05-3 palladium 
• 120427-95-4 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indolin-2-one 
• 139122-16-0 benzoic acid (2-(2-nitroethenyl))phenethyl ester 
• 139122-15-9 benzoic acid (2-formyl)phenethyl ester 
• 1426679-27-7 2-[2-[2-(benzyloxy)ethyl]-6-nitrophenyl]acetic acid 
• 1441070-77-4 ethyl 3-[2-[2-(benzyloxy)ethyl]-6-nitrophenyl]-2-oxopropanoate 
• 1426679-26-6 1-[(2-methyl-3-nitrophenethyloxy)methyl]benzene 
• 855382-76-2 2-(2-methyl-3-nitrophenyl)ethyl alcohol 
• 168476-58-2 2-[2-(chloromethyl)phenyl]ethylbenzoate 
• 23876-15-5 2-(3-nitro-2-methylphenyl)acetic acid 
• 139122-19-3 4-(2'-hydroxyethyl)-1,3-dihydro-2H-indol-2-one 
• 139122-18-2 4-(2-benzoyloxyethyl)-1,3-dihydro-2H-indolin-2-one 
• 139122-17-1 4-[2-(benzoyloxy)ethyl]-3-chloro-1,3-dihydro-2H-indolin-2-one 

Downstream Products

• 91374-21-9 Ropinirole 
• 120427-93-2 4-ethylenyl-1,3-dihydro-2H-indol-2-one 
• 139122-19-3 4-(2'-hydroxyethyl)-1,3-dihydro-2H-indol-2-one 
• 139122-22-8 2-(2'-oxo-2,3-dihydro-4-indolyl)ethyl benzenesulphonate 
• 139122-20-6 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl-4-methylbenzene-1-sulfonate 
• 91374-20-8 ropinirole hydrochloride 

Relevant articles and documents

Preparation method of 4-(2-bromoethyl)-1, 3-dihydro-2H-indole-2-ketone

The invention provides a preparation method of 4-(2-bromoethyl)-1, 3-dihydro-2H-indole-2-ketone, and the preparation method of the 4-(2-bromoethyl)-1, 3-dihydro-2H-indole-2-ketone is characterized in that the 4-(2-bromoethyl)-1, 3-dihydro-2H-indole-2-ketone is prepared by taking o-bromoethyl benzaldehyde as an initial raw material and carrying out a series of reactions. The raw materials are cheap and easy to obtain, the product yield and purity are high, and the method has excellent economic and environment-friendly benefits.

PROCESS FOR PURIFICATION OF ROPINIROLE

The invention discloses an improved process for the purification of ropinirole hydrochloride by dissolving or suspending crude ropinirole base or its pharmaceutically acceptable salt in a suitable solvent, reacting with a nitrogenous base to form an imine derivative, optionally treating the reaction mixture with a base to adjust the pH, and isolating purified ropinirole hydrochloride. The invention also provides for a pharmaceutical composition comprising pure ropinirole hydrochloride as active ingredient.

Development of large-scale syntheses of ropinirole in the pursuit of a manufacturing process

Two plant syntheses of ropinirole {4-[2-(di-n-propyIamino)-ethyl]-1,3-dihydro-2H-indolin-2-one hydrochloride, SK&F-101468-A} using the ferric chloride mediated cyclisation of β-nitrostyrenes to form 3-chlorooxindoles as the key step are described. The first synthesis suffered the severe limitation of the final-step chemistry being nonselective in the reaction between di-n-propylamine and the bromide precursor to ropinirole as both substitution and elimination pathways were promoted and by-product formation at a level of 40% resulted. This problem was rectified in the latter synthesis by the more selective reaction between di-n-propylamine and the sulfonate ester precursor promoting ropinirole formation to a level of 88%. This second synthesis is now used as the commercial route, and problems (and their solutions) identified during the development of this route are now described. The identification of novel by-products which enabled the Sommelet oxidation step to be optimised is also reported. A unimolecular decomposition mechanism during hydrolysis of the hexaminium salt to form the key benzaldehyde intermediate is proposed and substantiated with experimental data.