143322-58-1

Usage

Uses

Used in Pharmaceutical Industry:
Eletriptan is used as a serotonin 5-HT1B/1D receptor agonist for the acute treatment of migraines. It is effective in relieving pain from mild to severe attacks of migraine and reduces time lost for ordinary activity for patients with migraine attacks when compared to placebo and sumatriptan. Eletriptan also provides relief from functional disability, nausea, photophobia, and phonophobia associated with migraines.
Eletriptan is metabolized primarily (>90%) by the CYP3A4 isozyme to its active metabolite, the N-desmethyleletriptan, which accounts for approximately 10% to 20% of the plasma concentration of that observed for the parent drug. Coadministration of eletriptan with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir may require dose reduction and closer monitoring for CNS side effects.
Furthermore, because eletriptan and its active metabolite, N-desmethyleletriptan, are also substrates for the P-glycoprotein efflux pumps responsible for their removal from the brain, coadministration of eletriptan with a known P-glycoprotein inhibitor and/or inducer such as digoxin, diltiazem, verapamil, or St. John’s Wort would result in higher brain levels of its active metabolite and thus a higher rate of the CNS side effects reported for this drug.
Eletriptan has a positive logD value, which could underlie its rapid and complete oral absorption and may be suggestive of good brain penetration. The oral bioavailability of Eletriptan is approximately 50% (14% for Sumatriptan) with a half-life of 5.7 hours (2 hours for Sumatriptan). Eletriptan is well tolerated with mild to moderate adverse events including asthenia, somnolence, dizziness, and nausea.

Originator

Pfizer (US)

Manufacturing Process

A mixture of the appropriate phenyl vinyl sulfone, tri-o-tolylphosphine, palladium (II) acetate, triethlamine and (R)-5-bromo-3-(Nmethylpyrrolidinylmethyl)-1H-indole in anhydrous acetonitrle was heated at reflux under nitrogen. The resultant reaction mixture was evaporated under reduced pressure, and the residue was column chromatographed using silica gel and elution with methylene chloride/absolute ethanol/ammonia to afford the (R )-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)- 1H-indole.A solution of (R)-5-trans-(2-phenylsulfonylethenyl)-3-(N-methylpyrrolidin-2- ylmethyl)-1H-indole and 10% Pd/C in ethanolic hydrogen chloride (prepared from absolute ethanol and acetyl chloride and N,N-dimethylformamide was shaken under a hydrogen atmosphere at room temperature). The resultant reaction mixture was filtered through diatomaceous earth (Celite trademark), washed with absolute ethanol, and the combined filtrates were evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, brine, dried(Na2SO4), and evaporated under reduced pressure to afford a oil product. Column chromatography of this product using silica gel and elution with methylene chloride/absolute ethanol/ammonia afforded the appropriate (R)-5- (2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.The salt eletriptan hydrobromide may be produced by reaction of the (R)-5- (2-phenylsulfonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with hydrobromic acid.

Therapeutic Function

Serotonin agonist

Clinical Use

5HT1 receptor agonist:Acute relief of migraine

Drug interactions

Potentially hazardous interactions with other drugsAntibacterials: concentration increased by clarithromycin and erythromycin - avoid.Antidepressants: increased risk of CNS toxicity with citalopram - avoid; possibly increased serotonergic effects with duloxetine and venlafaxine; increased serotonergic effects with St John’s wort - avoidAntifungals: concentration increased by itraconazole and ketoconazole - avoid.Antivirals: concentration increased by indinavir and ritonavir - avoid.Dapoxetine: possible increased risk of serotonergic effects - avoid for 2 weeks after stopping 5HT1 agonistsErgot alkaloids: increased risk of vasospasm - avoid.

Metabolism

In vitro studies indicate that eletriptan is primarily metabolised by hepatic cytochrome P-450 enzyme CYP3A4. This finding is substantiated by increased plasma concentrations of eletriptan followingknown selective and potent CYP3A4 inhibitors. In vitro studies also indicate a small involvement of CYP2D6 although clinical studies do not indicate any evidence of polymorphism with this enzyme.There are two major circulating metabolites identified that significantly contribute to plasma radioactivity following administration of 14C-labelled eletriptan. The metabolite formed by N-oxidation, has demonstrated no activity in animal in vitro models. The metabolite formed by N-demethylation, has been demonstrated to have similar activity to eletriptan in animal in vitro models. A third area of radioactivity in plasma has not been formally identified, but is most likely to be a mixture of hydroxylated metabolites which have also been observed excreted in urine and faeces.The plasma concentrations of the N-demethylated active metabolite are only 10-20% of those of parent, so would not be expected to significantly contribute to the therapeutic action of eletriptan. Non-renal clearance accounts for approximately 90% of the total clearance indicating that eletriptan is eliminated primarily by metabolism.

InChI:InChI=1/C22H26N2O2S.BrH/c1-24-12-5-6-19(24)15-18-16-23-22-14-17(9-10-21(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

Upstream product

• 180637-89-2 (R)-5-[(2-phenylsulfonyl)ethenyl]-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole 
• 75-75-2 methanesulfonic acid 
• 144-62-7 oxalic acid 
• 5535-48-8 PVS 
• 143322-57-0 (R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole 
• 938-09-0 2-chloroethyl phenyl sulfone 
• 205369-12-6 (R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole 
• 180637-88-1 (R)-1-acetyl-5-[2-(phenylsulfonyl)ethyenyl]-3-(N-methylpyrrolidin-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 
• 873-55-2 sodium benzenesulfonate 
• 5339-26-4 (4-nitrophenyl)ethyl bromide 
• 868618-78-4 oxo(2-{4-[2-(phenylsulfonyl)ethyl]phenyl}hydrazino)acetic acid 

Downstream Products

• 273211-28-2 3-(N-methyl-2(R)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1H-indole hydrobromide monohydrate 
• 1408337-87-0 (1S,2R)-3-[(1-methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-N-oxide-1H-indole 
• 1408337-88-1 (1R,2R)-3-[(1-methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-N-oxide-1H-indole 
• 1217641-89-8 (R)-5-[2-(phenylsulfonyl)ethyl]-3-[(1-methyl-2-pyrrolidinyl-N-oxide)methyl]-1H-indole 
• 177834-92-3 eletriptan hydrobromide 

Relevant academic research and scientific papers

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.

A Low Rhodium Content Smart Catalyst for Hydrogenation and Hydroformylation Reactions

Abstract: This paper describes the preparation, broad characterization and study of activity in hydrogenation and hydroformylation reactions of an easily produced 0.18% Rh/Al2O3. Analytical studies on fresh and recycled samples shed light on the smart properties of such catalyst. Results showed high activity as well as fine/excellent chemoselectivity or regioselectivity, characteristics that may suggest a wide range of applicability. Graphic Abstract: The low metal content catalyst 0.18% Rh/Al2O3 was very active in both hydrogenation and hydroformylation reactions so providing intermediates for valuable APIs, as Nabumetone and Eletriptan, and a fragrance with a fresh, green-floral smell, that recalls scent of lily of the valley.[Figure not available: see fulltext.]

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.

A synthesis method according to sets up qu tan hydrobromide

The invention discloses a synthesis method of eletriptan hydrobromate, which comprises the following steps: reacting (R)-1-acetyl-3-(N-methylpyrrolidinyl-2-methy)-5-bromo-1H-indole and metal in an organic solvent to form a metal complex, reacting the metal complex with a boron reagent in an organic solvent to form aryl borane or aryl borate, carrying out acid-catalyzed hydrolysis to obtain aryl boric acid, and carrying out coupling and hydrolysis on the aryl boric acid and 2-chloroethylphenyl sulfone under the actions of a catalyst and an alkali to obtain eletriptan, or directly carrying out coupling and hydrolysis on the metal complex and 2-chloroethylphenyl sulfone to obtain eletriptan; and carrying out salification on the eletriptan and hydrobromic acid in an organic solvent to finally obtain the eletriptan hydrobromate. The method is simple to operate, has the advantages of high safety, high stability, low cost and higher yield, and is suitable for industrial production.

A NOVEL PROCESS FOR THE PREPARATION OF ELETRIPTAN

The present invention relates to a novel process for the preparation of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole and its intermediates thereof.

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.

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.

NOVEL PROCESS FOR THE PREPARATION OF ELETRIPTAN

The present invention relates to a novel process for the preparation of (R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indole and its intermediates thereof.

Second-generation process research towards eletriptan: A fischer indole approach

The development of a second-generation process for the synthesis of eletriptan via a Fischer indole cyclisation is described. The finalised process offers several potential advantages over the current route of manufacture including cost, throughput, and safety.

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.