177834-92-3

Basic information

• Product Name: Eletriptan hydrobromide
• Synonyms: Unii-m41W832ta3;Relpax Also see: E505000;(R)-5-[2-(Benzenesulfonyl)ethyl]-3-[(N-Methylpyrrolidin-2-yl)Methyl]-1H-indole hydrobroMide;Relert;(R)-3-((1-Methylpyrrolidin-2-yl)Methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole hydrobroMide;Eletriptan HCl;1H-Indole,3-[[(2R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]-,hydrobromide;eletriptan hydrobromide
• CAS NO: 177834-92-3
• Molecular Formula: BrH*C₂₂H₂₆N₂O₂S
• Molecular Weight: 382.51904
• EINECS: 1312995-182-4
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pfizer compounds;Pharmaceuticals
• Mol File: 177834-92-3.mol

Chemical Properties

• Melting Point: 169-171?C
• Boiling Point: 633.9 °C at 760 mmHg
• Flash Point: 337.2 °C
• Appearance: off-white to light tan/
• Vapor Pressure: 1.58E-16mmHg at 25°C
• Storage Temp.: Desiccate at RT
• Solubility: DMSO: >10mg/mL
• CAS DataBase Reference: Eletriptan hydrobromide(CAS DataBase Reference)
• NIST Chemistry Reference: Eletriptan hydrobromide(177834-92-3)
• EPA Substance Registry System: Eletriptan hydrobromide(177834-92-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 177834-92-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Eletriptan hydrobromide is used as an active pharmaceutical ingredient for the treatment of migraine headaches. It is particularly effective due to its ability to target serotonin receptors, which play a role in the onset of migraines, and provides relief from the symptoms.
Used in Antimigraine Applications:
Eletriptan hydrobromide is used as an antimigraine agent for the treatment of migraine headaches. It helps to alleviate the symptoms by targeting serotonin receptors, which are involved in the onset of migraines, and provides relief to patients suffering from this condition.
Used in Antibiotic Applications:
Although not explicitly mentioned in the provided materials, Eletriptan hydrobromide may also have potential applications in the development of new antibiotics or as a component in combination therapies for bacterial infections. Further research would be required to explore this possibility.

Originator

Relpax,Pfizer

Biological Activity

Orally active, selective 5-HT 1B/1D receptor agonist. Produces a dose-dependent reduction in carotid artery blood flow in vivo . Displays antimigraine activity.

InChI:InChI=1/C22H26N2O2S.BrH/c1-24-12-5-6-19(24)15-18-16-23-22-10-9-17(14-21(18)22)11-13-27(25,26)20-7-3-2-4-8-20;/h2-4,7-10,14,16,19,23H,5-6,11-13,15H2,1H3;1H/t19-;/m1./s1

Synthetic route

eletriptan (143322-58-1) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
With hydrogen bromide In acetone at 20℃; for 0.25h; Product distribution / selectivity;	98.34%
With hydrogen bromide In water; butanone Industry scale;	96.3%
With hydrogen bromide In water; acetone at -45 - 15℃; Product distribution / selectivity;	90%

(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole hydrobromide (143577-60-0) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Stage #1: (R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole hydrobromide With hydrogen; palladium 10% on activated carbon In methanol at 40℃; under 3677.86 Torr; Stage #2: With hydrogen bromide In isopropyl alcohol at 25 - 70℃; for 5h; Product distribution / selectivity;	88.33%

3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide monohydrate (273211-28-2) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
In water; acetone at 20℃; for 120h; Product distribution / selectivity;
In ethanol; ethyl acetate at 20 - 80℃; for 17.5h; Product distribution / selectivity;
In water; ethyl acetate at 10 - 80℃; for 3.5h; Product distribution / selectivity;

3-[[(R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenyl-sulfonyl)ethyl]indole para-toluenesulfonate (1162655-06-2) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Stage #1: 3-[[(R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenyl-sulfonyl)ethyl]indole para-toluenesulfonate With ammonia In tert-butyl methyl ether; water pH=10.5 - 11.0; Stage #2: With sodium carbonate In tert-butyl methyl ether; water Stage #3: With hydrogen bromide In ipa; acetone pH=6.6 - 7.5; Product distribution / selectivity;
Stage #1: 3-[[(R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenyl-sulfonyl)ethyl]indole para-toluenesulfonate With ammonia In tert-butyl methyl ether; water pH=10.5 - 11.0; Stage #2: With sodium carbonate In tert-butyl methyl ether; water Stage #3: With hydrogen bromide In ipa pH=6.6 - 7.5; Product distribution / selectivity;

(R)-5-[2-(phenylsulfonyl)ethyl]-3-[(1-methyl-2-pyrrolidinyl)methyl]-1H-indole hemioxalate → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
With hydrogen bromide In water; isopropyl alcohol at 25 - 30℃; for 2.5 - 3h; pH=6 - 7; Product distribution / selectivity;
With hydrogen bromide In water; ethyl acetate at 25 - 30℃; for 2.5 - 3h; Product distribution / selectivity;
With hydrogen bromide In water; acetone at 25 - 30℃; for 2.5h; pH=6 - 7; Product distribution / selectivity;

3-{[(2R)-1-methylpyrrolidin-2-yl] methyl}-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole hydrobromide → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
With hydrogen; 5% Pd(II)/C(eggshell) In methanol; water at 20 - 25℃; under 3800.26 Torr; Product distribution / selectivity;
With hydrogen; 5% Pd(II)/C(eggshell) In water at 20 - 50℃; Product distribution / selectivity; Autoclave;

5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylamine / acetonitrile / 25 - 83 °C 2.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 25 - 35 °C 2.2: 25 - 83 °C 3.1: potassium carbonate; methanol / 25 - 35 °C 3.2: 25 - 30 °C 4.1: hydrogen / 5% Pd(II)/C(eggshell) / water; acetone / 25 - 35 °C / Inert atmosphere 5.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 5.2: 10.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / acetonitrile / 25 - 83 °C 2.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 25 - 35 °C 2.2: 25 - 83 °C 3.1: potassium carbonate; methanol / 25 - 35 °C 3.2: 25 - 35 °C / Inert atmosphere 4.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 4.2: 10.5 h / 20 - 25 °C View Scheme

(R)-1-acetyl-5-[2-(phenylsulfonyl)ethyenyl]-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (180637-88-1) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate; methanol / 25 - 35 °C 1.2: 25 - 30 °C 2.1: hydrogen / 5% Pd(II)/C(eggshell) / water; acetone / 25 - 35 °C / Inert atmosphere 3.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 3.2: 10.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate; methanol / 25 - 35 °C 1.2: 25 - 35 °C / Inert atmosphere 2.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 2.2: 10.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 2.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 2.2: 0.5 h / 25 - 30 °C 3.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme

C16H19BrN2O → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 25 - 35 °C 1.2: 25 - 83 °C 2.1: potassium carbonate; methanol / 25 - 35 °C 2.2: 25 - 30 °C 3.1: hydrogen / 5% Pd(II)/C(eggshell) / water; acetone / 25 - 35 °C / Inert atmosphere 4.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 4.2: 10.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 25 - 35 °C 1.2: 25 - 83 °C 2.1: potassium carbonate; methanol / 25 - 35 °C 2.2: 25 - 35 °C / Inert atmosphere 3.1: sodium hydroxide / ethyl acetate; water / 0.33 h / 25 - 30 °C / pH 7 - 10 3.2: 10.5 h / 20 - 25 °C View Scheme

(R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole methanesulphonate (1261286-61-6) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Stage #1: (R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole methanesulphonate With sodium hydroxide In water; ethyl acetate at 25 - 30℃; for 0.333333h; pH=7 - 10; Stage #2: With hydrogen bromide In water; acetone at 20 - 25℃; for 10.5h; Product distribution / selectivity;

(R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (143322-57-0) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: isopropyl alcohol; water / 4 h / 20 - 35 °C 2.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 2.2: 4 h / 100 °C 3.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 4.1: potassium carbonate; water / methanol 5.1: hydrogen bromide / water / pH 1.5 6.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide / 95 - 100 °C 1.2: 0 - 5 °C / pH 8 - 9 2.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 3.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 4.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 4.2: 0.5 h / 25 - 30 °C 5.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 1.2: 3 h / Reflux 2.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 3.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 3.3: 0.5 h / 20 °C View Scheme

(R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]-5-bromo-1H-indole (143322-56-9) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 60 °C / Reflux 2.1: isopropyl alcohol; water / 4 h / 20 - 35 °C 3.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 3.2: 4 h / 100 °C 4.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 5.1: potassium carbonate; water / methanol 6.1: hydrogen bromide / water / pH 1.5 7.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 3 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 39 h / 25 °C / 760.05 Torr / Inert atmosphere; Reflux 2.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 75 - 80 °C 3.1: hydrogen / palladium 10% on activated carbon / methanol / 40 °C / 3677.86 Torr 3.2: 5 h / 25 - 70 °C View Scheme

(R,E)-1-(3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1H-indol-1-yl)ethan-1-one → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate; water / methanol 2: hydrogen bromide / water / pH 1.5 3: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme

Z-D-proline (6404-31-5) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; toluene / 2.5 h / 20 - 25 °C 2.1: methylmagnesium chloride / tert-butyl methyl ether; tetrahydrofuran / 0.75 h / 20 °C 2.2: 0.5 h / 3 - 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 60 °C / Reflux 4.1: isopropyl alcohol; water / 4 h / 20 - 35 °C 5.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 5.2: 4 h / 100 °C 6.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 7.1: potassium carbonate; water / methanol 8.1: hydrogen bromide / water / pH 1.5 9.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 25 - 30 °C 2.1: ethylmagnesium bromide / diethyl ether / 2.25 h / 25 °C / 760.05 Torr / Reflux 2.2: 1 h / -30 °C 2.3: 0.17 h / -30 - 30 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 39 h / 25 °C / 760.05 Torr / Inert atmosphere; Reflux 4.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 75 - 80 °C 5.1: hydrogen / palladium 10% on activated carbon / methanol / 40 °C / 3677.86 Torr 5.2: 5 h / 25 - 70 °C View Scheme

N-benzyloxycarbonyl-D-proline acid chloride (61350-62-7) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: methylmagnesium chloride / tert-butyl methyl ether; tetrahydrofuran / 0.75 h / 20 °C 1.2: 0.5 h / 3 - 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 60 °C / Reflux 3.1: isopropyl alcohol; water / 4 h / 20 - 35 °C 4.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 4.2: 4 h / 100 °C 5.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 6.1: potassium carbonate; water / methanol 7.1: hydrogen bromide / water / pH 1.5 8.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 4 steps 1.1: ethylmagnesium bromide / diethyl ether / 2.25 h / 25 °C / 760.05 Torr / Reflux 1.2: 1 h / -30 °C 1.3: 0.17 h / -30 - 30 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 39 h / 25 °C / 760.05 Torr / Inert atmosphere; Reflux 3.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 75 - 80 °C 4.1: hydrogen / palladium 10% on activated carbon / methanol / 40 °C / 3677.86 Torr 4.2: 5 h / 25 - 70 °C View Scheme

(R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (205369-12-6) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 2: potassium carbonate; water / methanol 3: hydrogen bromide / water / pH 1.5 4: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 2.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 3.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 3.2: 0.5 h / 25 - 30 °C 4.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 2.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 3.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 3.3: 0.5 h / 20 °C View Scheme

5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole ethanedioate (1196663-29-2) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 1.2: 4 h / 100 °C 2.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 3.1: potassium carbonate; water / methanol 4.1: hydrogen bromide / water / pH 1.5 5.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme

(R)-5-(2-Benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Stage #1: (R)-5-(2-Benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole With hydrogen; Raney nickel In methanol under 517.162 - 775.743 Torr; for 5h; Industry scale; Stage #2: With hydrogen bromide In water; ethyl acetate for 0.5h; Industry scale; Stage #3: In toluene Reflux; Industry scale;
Multi-step reaction with 2 steps 1: hydrogen bromide / water / pH 1.5 2: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: methanesulfonic acid / acetone; water / 0.08 h 1.2: 6 h / 30 °C / 2250.23 Torr 2.1: hydrogen bromide / water; ethanol / 6 h / 20 °C View Scheme

(R)-5-[(2-phenylsulfonyl)ethenyl]-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (180637-89-2) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Stage #1: (R)-5-[(2-phenylsulfonyl)ethenyl]-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole With methanesulfonic acid; hydrogen; 5%-palladium/activated carbon In acetone Stage #2: With ammonia In dichloromethane; water Stage #3: With hydrogen bromide In dichloromethane; water at 20℃; for 0.5h;
Multi-step reaction with 2 steps 1.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 1.2: 0.5 h / 25 - 30 °C 2.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
With 10% Pd/C; hydrogen bromide In water; acetone at 25 - 30℃;
Multi-step reaction with 2 steps 1: methanesulfonic acid; 5%-palladium/activated carbon; hydrogen / water; acetone / 0.08 h / 25 - 35 °C / 3800.26 - 4560.31 Torr 2: hydrogen bromide / water; isopropyl alcohol / 4 - 5 h / 25 - 35 °C View Scheme

PVS (5535-48-8) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 1.2: 3 h / Reflux 2.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 3.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 3.2: 0.5 h / 25 - 30 °C 4.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 1.2: 3 h / Reflux 2.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 3.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 3.3: 0.5 h / 20 °C View Scheme

(R)-pyrrolidine-1,2-dicarboxylic acid 1-phenyl ester (105370-80-7) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 3 h / Reflux 2.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 2.2: -10 - 25 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 3.2: 0 - 35 °C / pH 12 - 13 4.1: N,N-dimethyl-formamide / 95 - 100 °C 4.2: 0 - 5 °C / pH 8 - 9 5.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 6.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 7.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 7.2: 0.5 h / 25 - 30 °C 8.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 3 h / Reflux 2.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 2.2: -10 - 25 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 3.2: 0 - 35 °C / pH 12 - 13 4.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 4.2: 3 h / Reflux 5.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 6.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 6.3: 0.5 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 3 h / Reflux 2.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 2.2: -10 - 25 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 3.2: 0 - 35 °C / pH 12 - 13 4.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 4.2: 3 h / Reflux 5.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 6.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 6.2: 0.5 h / 25 - 30 °C 7.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 3 h / Reflux 2.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 2.2: -10 - 25 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 3.2: 0 - 35 °C / pH 12 - 13 4.1: N,N-dimethyl-formamide / 95 - 100 °C 4.2: 0 - 5 °C / pH 8 - 9 5.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 6.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 7.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 7.3: 0.5 h / 20 °C View Scheme

(R)-2-chlorocarbonylpyrrolidine-1-carboxylic acid phenyl ester (1353991-67-9) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 1.2: -10 - 25 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 2.2: 0 - 35 °C / pH 12 - 13 3.1: N,N-dimethyl-formamide / 95 - 100 °C 3.2: 0 - 5 °C / pH 8 - 9 4.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 5.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 6.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 6.2: 0.5 h / 25 - 30 °C 7.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 1.2: -10 - 25 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 2.2: 0 - 35 °C / pH 12 - 13 3.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 3.2: 3 h / Reflux 4.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 5.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 5.3: 0.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 1.2: -10 - 25 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 2.2: 0 - 35 °C / pH 12 - 13 3.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 3.2: 3 h / Reflux 4.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 5.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 5.2: 0.5 h / 25 - 30 °C 6.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: ethylmagnesium bromide; zinc(II) chloride / dichloromethane; tetrahydrofuran / 5 - 30 °C 1.2: -10 - 25 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 2.2: 0 - 35 °C / pH 12 - 13 3.1: N,N-dimethyl-formamide / 95 - 100 °C 3.2: 0 - 5 °C / pH 8 - 9 4.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 5.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 6.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 6.3: 0.5 h / 20 °C View Scheme

(R)-2-(5-bromo-1H-indole-3-carbonyl)pyrrolidine-1-carboxylic acid phenyl ester (1353991-68-0) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 1.2: 0 - 35 °C / pH 12 - 13 2.1: N,N-dimethyl-formamide / 95 - 100 °C 2.2: 0 - 5 °C / pH 8 - 9 3.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 4.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 5.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 5.2: 0.5 h / 25 - 30 °C 6.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 1.2: 0 - 35 °C / pH 12 - 13 2.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 2.2: 3 h / Reflux 3.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 4.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 4.3: 0.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 1.2: 0 - 35 °C / pH 12 - 13 2.1: N,N-dimethyl-formamide / 95 - 100 °C 2.2: 0 - 5 °C / pH 8 - 9 3.1: N-ethyl-N,N-diisopropylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 90 - 95 °C / Inert atmosphere 4.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 5.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone 5.3: 0.5 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 10 - 50 °C / Inert atmosphere; Darkness 1.2: 0 - 35 °C / pH 12 - 13 2.1: triethylamine / N,N-dimethyl-formamide / 2 h / 90 - 100 °C 2.2: 3 h / Reflux 3.1: water; sodium carbonate; methanol / 2 h / 25 - 30 °C 4.1: hydrogen; methanesulfonic acid / 5%-palladium/activated carbon / acetone / 20 °C / 2585.81 Torr 4.2: 0.5 h / 25 - 30 °C 5.1: hydrogen bromide / dichloromethane; water; ethylene glycol / 0.5 h / 5 - 10 °C / Inert atmosphere View Scheme

PVS (5535-48-8) + (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (143322-57-0) → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 75 - 80 °C 2.1: hydrogen / palladium 10% on activated carbon / methanol / 40 °C / 3677.86 Torr 2.2: 5 h / 25 - 70 °C View Scheme

tert-butyl (R,E)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1H-indole-1-carboxylate hydrobromide → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 2.1: methanesulfonic acid / acetone; water / 0.08 h 2.2: 6 h / 30 °C / 2250.23 Torr 3.1: hydrogen bromide / water; ethanol / 6 h / 20 °C View Scheme

tert-butyl (R)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole-1-carboxylate → eletriptan hydrobromide (177834-92-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tris-(o-tolyl)phosphine; triethylamine; palladium diacetate / acetonitrile / 15 h / Inert atmosphere; Reflux 2.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 3.1: methanesulfonic acid / acetone; water / 0.08 h 3.2: 6 h / 30 °C / 2250.23 Torr 4.1: hydrogen bromide / water; ethanol / 6 h / 20 °C View Scheme

eletriptan hydrobromide (177834-92-3) → 4-methyl-8-[2-(phenylsulfonyl)ethyl]-1,2,3,5,10,10a-hexahydropyrrolidino[3,2-b]indol-4-ium (1408337-90-5)

Conditions	Yield
With dihydrogen peroxide In water; acetonitrile at 80 - 85℃; for 0.75h;	60%

eletriptan hydrobromide (177834-92-3) → 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide monohydrate (273211-28-2)

Conditions	Yield
With water at 60℃; under 20 Torr; for 16h; Product distribution / selectivity;

Upstream product

• 143577-60-0 (R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole hydrobromide 
• 5535-48-8 PVS 
• 143322-57-0 (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole 
• 1353991-68-0 (R)-2-(5-bromo-1H-indole-3-carbonyl)pyrrolidine-1-carboxylic acid phenyl ester 
• 1353991-67-9 (R)-2-chlorocarbonylpyrrolidine-1-carboxylic acid phenyl ester 
• 105370-80-7 (R)-pyrrolidine-1,2-dicarboxylic acid 1-phenyl ester 
• 180637-89-2 (R)-5-[(2-phenylsulfonyl)ethenyl]-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole 
• 1196663-29-2 5-bromo-3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-1H-indole ethanedioate 
• 205369-12-6 (R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole 
• 61350-62-7 N-benzyloxycarbonyl-D-proline acid chloride 
• 6404-31-5 Z-D-proline 
• 143322-56-9 (R)-3-[(N-benzyloxycarbonylpyrrolidin-2-yl)carbonyl]-5-bromo-1H-indole 
• 1261286-61-6 (R)-5-(2-phenylsulphonylethyl)-3-(N-methylpyrrolidine-2-yl-methyl)-1H-indole methanesulphonate 
• 180637-88-1 (R)-1-acetyl-5-[2-(phenylsulfonyl)ethyenyl]-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole 

Downstream Products

• 1408337-90-5 4-methyl-8-[2-(phenylsulfonyl)ethyl]-1,2,3,5,10,10a-hexahydropyrrolidino[3,2-b]indol-4-ium 
• 273211-28-2 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide monohydrate 

Relevant articles and documents

PROCESS FOR PREPARING (( R)-3-[(-1-METHYLPYRROLIDIN-2-YL)METHYL]-5-(2-PHENYLSULFONYLETHYL)-1H-INDOLE

The present invention provides an efficient and environmentally friendly process for the preparation of (R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)-1H- indole (eletriptan) and pharmaceutically acceptable salts thereof, in good yield and high purity, which is also suitable for industrial scale applications. The present invention also provides new acid addition salts of (R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2- phenylsulfonylethyl)-1H-indole, which are also suitable for preparing (R)-3-[(-1- methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)-1H-indole and pharmaceutically acceptable salts thereof, in good yield and high purity. The present invention additionally provides tert-butylcarbonyl protected precursors to the compound eletriptan.

PROCESS FOR THE PREPARATION OF 5-SUBSTSITUTED INDOLE DERIVATIVE

The present invention relates to an improved and industrially advantageous process for preparation of eletri tan of formula I,or pharmaceutically acceptable salts thereof from bromo indole intermediate of formula II, through isolation of N-acetylated bromo indole intermediate of formula III, to elude carrying forward of impurities to next stage. The present invention relates to process for the preparation of 5-bromo-3-[(R)-l-methyl-pyrrolidin-2- lmeth l -lH-indol of formula II, a key intermediate for the synthesis of eletriptan or pharmaceutically acceptable salts thereof, through novel keto carbamate intermediate. The present invention also relates to novel process for the preparation of a-form of eletriptan hydrobromide.

Synthesis of compounds related to the anti-migraine drug eletriptan hydrobromide

Eletriptan hydrobromide (1) is a selective serotonin (5-HT1) agonist, used for the acute treatment of the headache phase of migraine attacks. During the manufacture of eletriptan hydrobromide the formation of various impurities were observed and identified by LC-MS. To control the formation of these impurities during the preparation of active pharmaceutical ingredients, the structure of the impurities must be known. Major impurities of the eletriptan hydrobromide synthesis were prepared and characterized by using various spectroscopic techniques, i.e., mass spectroscopy, FTIR , 1H NMR, 13C NMR/DEPT, and further confirmed by co-injection in HPLC. The present study will be of great help in the synthesis of highly pure eletriptan hydrobromide related compounds.

Investigational study into the formation of methoxy derivative and other impurities during the optimization of eletriptan hydrobromide

During the process development of eletriptan hydrobromide, we have observed formation of an unknown impurity in the final product at enhanced levels which was identified as a methoxy substituted derivative on the side chain of the product. The present work involves detailed optimization studies directed toward the development of an efficient process for the commercial production of eletriptan hydrobromide substantially free from the methoxy impurity and other impurities.

PROCESS FOR PREPARATION OF ELETRIPTAN AND SALT THEREOF

The present invention relates to an improved process for the preparation of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethyl]-1H-indole or pharmaceutically acceptable salts thereof, particularly 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethyl]-1H-indole hydrobromide (Eletriptan hydrobromide). The present invention further relates to novel polymorphs of 3-(N-methyl-2(R)-pyrrolidinyl methyl)-5-[2-(phenyl sulfonyl)ethenyl]-1H-indole hydrobromide and process for preparation thereof.

HIGHLY PURE ELETRIPTAN OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF SUBSTANTIALLY FREE OF ELETRIPTAN N-OXIDE IMPURITY

Provided herein is an impurity of eletriptan, eletriptan N-oxide, (R)-5-[2- (phenylsulfonypethyl]-3-[(1-methyl-2-pyrrolidinyl-N-oxide)methyl]-1H-indole, and a process for the preparation and isolation thereof. Provided further herein is a highly pure eletriptan or a pharmaceutically acceptable salt thereof substantially free of eletriptan N-oxide impurity, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure eletriptan or a pharmaceutically acceptable salt thereof substantially free of eletriptan N-oxide impurity.

PROCESS FOR PREPARING ELETRIPTAN HYDROBROMIDE HAVING α-FORM

A process for preparation of eletriptan hydrobromide having α-form of formula (I) is described that includes reducing 3-((R)-1-methylpyrrolidin-2-yl)methyl)-5-((E)-2-(phenylsulfonyl)vinyl)-1H-indole of formula (II) in presence of a metal catalyst to the product of formula (III) and then converting to hydrobromide salt having α-form of formula (I).

SYNTHESIS OF 3--5-[2-(PHENYLSULFONYL)ETHYL]-1H-INDOLE

The present invention refers to the synthesis of 3-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-5-[2-(phenylsulfonyl)ethyl]-1H-indole, a drug known by the name Eletriptan, or of its salts. In particular, the present invention regards a process for the synthesis of Eletriptan or of its salt, comprising the following steps: a) Salifying the intermediate of Formula (6), using a dicarboxylic acid to obtain a derived salt; b) Optionally, purifying said raw salt obtained according to step a) by solvent crystallization to obtain a purified salt of the intermediate of Formula (6); c) Converting said salt of the intermediate of formula (6) according to step a) or said purified salt according to step b) into an intermediate of formula (10); d) Converting the intermediate of Formula (10) into Eletriptan or its salt.

AN IMPROVED PROCESS FOR THE PREPARATION OF ELETRIPTAN AND ITS SALT THEREOF

The present invention relates to an improved process for the preparation of Eletriptan hydrobromide by hydrolyzing (R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N- methylpyrrolidin-2-ylmethyl)-1 H-indole, followed by reduction in the presence of a metal catalyst, methanesulphonicacid in a solvent, to get the Eletriptan methanesulphonate. Setting free of the methanesulphonate salt with a base and the compound is extracted into an organic solvent, optionally passed the organic layer through silica gel column, the solvent is evaporated to get residue. The residue is dissolved in another solvent followed by addition of aqueous hydrobromic acid to get Eletriptan hydrobromide.

SYNTHESIS OF 3-{[(2R)-1-METHYLPYRROLIDIN-2-YL]METHYL}-5-[2-(PHENYLSULFONYL)ETHYL]-1H-INDOLE

The present invention refers to the synthesis of 3-{[(2R)-l-methylpyrrolidin-2-yl]methyl}-5-[2-(phenylsulfonyl)ethyl]-lH-indole, a drug known by the name Eletriptan, or of its salts. In particular, the present invention regards a process for the synthesis of Eletriptan or of its salt, comprising the following steps: a) Salifying the intermediate of Formula (6), using a dicarboxylic acid to obtain a derived salt; b) Optionally, purifying said raw salt obtained according to step a) by solvent crystallization to obtain a purified salt of the intermediate of Formula (6); c) Converting said salt of the intermediate of formula (6) according to step a) or said purified salt according to step b) into an intermediate of formula (10); d) Converting the intermediate of Formula (10) into Eletriptan or its salt.