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Process for the preparation of (S)-Methyl-2-Methoxy-5-((1-(4-phenyl-1H-imidazol-2-yl)ethylamino)methyl)benzoate oxalate

IP.com Disclosure Number: IPCOM000247658D
Publication Date: 2016-Sep-24
Document File: 3 page(s) / 646K

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Abstract

Process for the preparation of (S)-Methyl-2-Methoxy-5-((1-(4-phenyl-1H-imidazol-2-yl)ethylamino)methyl)benzoate oxalate, by treating (S)-Methyl-2-Methoxy-5-((1-(4-phenyl-1H-imidazol-2-yl)ethylamino)methyl)benzoate with an oxalic acid and thereafter converting into Eluxodoline.

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Process for the preparation of (S)-Methyl-2-Methoxy-5-((1-(4-phenyl-1H-imidazol-2- yl)ethylamino)methyl)benzoate oxalate

Eluxadoline is chemically known as Methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-
((S)-1-(4-phenyl-1Himidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoate (referred to as Compound A) and has the following structure:

Eluxadoline is a mu-opioid receptor agonist and has been approved in USA under the trade name VIBERZ® as a tablet having dosage strengths 75MG and 100MG for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

Eluxadoline as well as its pharmaceutically acceptable salts were disclosed in US 7,741,356 B2. US '356 discloses the synthesis of Eluxadoline dihydrochloride, which is as shown below:

IPCOM000242564D discloses the crystalline (S)-Methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2- yl)ethyl)amino)methyl)benzoate hydrochloride salt and its synthesis, which is an intermediate in the synthesis of Eluxadoline. The synthesis is as shown below:

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(S)-Methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl)benzoate can be prepared as its organic acid salt, and can be used in the preparation of Eluxadoline.

The organic acids of (S)-Methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2- yl)ethyl)amino)methyl)benzoate are selected from the group comprising of Formic acid, Acetic acid, Citric acid, Oxalic acid, Succinic acid, Fumaric acid, Malic acid and the like.

The (S)-Methyl-2-methoxy-5-(((1-(4-phenyl-1H-imidazol-2-yl)ethyl)amino)methyl)benzoate organic acid salt (referred to as Compound 1) is prepared by treating (S)-Methyl-2-methoxy-5-(((1-(4-phenyl- 1H-imidazol-2-yl)ethyl)amino)methyl)benzoate with an organic acid and an organic solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters and hydrocarbons or mixtures thereof.

The halogenated solvents are selected from the group comprising of dichloromethane, ethylene dichloride, chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, isopropanol, butanol and the like; ketones are selected from the group comprising of acetone, methyl isobutyl ketone and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether, dioxane and the like; esters are selected from the gro...