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
• Article Data: 23

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

Chemical Properties

Eletriptan hydrobromide is Tan Solid

Originator

Relpax,Pfizer

Uses

Different sources of media describe the Uses of 177834-92-3 differently. You can refer to the following data:
1. Relpax is a second generation triptan drug used in the treatment of migraine headaches.
2. antibiotic
3. Eletriptan hydrobromide is a second generation triptan drug used in the treatment of migraine headaches.

Brand name

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

• 143322-58-1 eletriptan 
• 273211-28-2 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide monohydrate 
• 1162655-06-2 3-[[(R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenyl-sulfonyl)ethyl]indole para-toluenesulfonate 
• 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 

Downstream Products

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

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.

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.

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.