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PROCESS FOR THE PREPARATION OF LORCASERIN HYDROCHLORIDE

IP.com Disclosure Number: IPCOM000238331D
Publication Date: 2014-Aug-18
Document File: 4 page(s) / 73K

Publishing Venue

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Abstract

Reported herein is a process for the preparation of lorcaserin hydrochloride of Formula I.

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PROCESS FOR THE PREPARATION OF LORCASERIN HYDROCHLORIDE

Abstract

Reported herein is a process for the preparation of lorcaserin hydrochloride of Formula I.

The reported process is for the preparation of lorcaserin hydrochloride of Formula I.

Formula I

The process comprises:

i)              reaction of 2-(4-chlorophenyl)ethanol of Formula II

Formula II

with a halogenating, phosphorylating, carboxylating, sulfonating, or silylating reagent to obtain an intermediate of Formula III;

Formula III (X = Leaving group)

ii)            reaction of the intermediate of Formula III with 1-amino-2-propanol to obtain 1-{[2-(4-chlorophenyl)ethyl]amino}propan-2-ol of Formula IV, or a salt thereof;

Formula IV

iii)          reaction of the 1-{[2-(4-chlorophenyl)ethyl]amino}propan-2-ol of Formula IV or a salt thereof with a cyclizing agent to obtain lorcaserin free base;

iv)          treating lorcaserin free base with a chiral resolving agent to obtain the (R)-isomer; and

v)            conversion of the (R)-isomer into lorcaserin hydrochloride of Formula I

wherein the reaction of 1-{[2-(4-chlorophenyl)ethyl]amino}propan-2-ol of Formula IV, or a salt thereof, with the cyclizing agent is carried out without converting the hydroxyl group of the intermediate of Formula IV or a salt thereof into a halogen derivative.

Examples of leaving groups include halogens, phosphate esters, alkoxy, carboxyl, sulfonyl, and silyl groups.

The reaction of 2-(4-chlorophenyl)ethanol of Formula II with the halogenating, phosphorylating, carboxylating, sulfonating, or silylating reagent is carried out in a solvent selected from the group comprising amides, substituted or unsubstituted hydrocarbons, ethers, nitriles, esters, ketones, sulfoxides, sulfolane, l,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, and tetramethylurea.  The reaction is carried out at a temperature of about 0°C to about 100°C.

The reaction of the intermediate of Formula III with 1-amino-2-propanol is carried out in the presence of a solvent selected from the group comprising amides, substituted or unsubstituted hydrocarbons, ethers, nitriles, esters, ketones, sulfoxides, sulfolane, l,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, and tetramethylurea.  The reaction is carried out at a temperature of about 0°C to about 200°C for about 1 hour to about 10 hours.

The cyclization of 1-{[2-(4-chlorophenyl)ethyl]amino}propan-2-ol of Formula IV or a salt thereof is carried out in the presence of a Lewis acid cyclizing agent.  Examples of Lewis acids include aluminum halides, boron trihalides, iron (III) halides, zinc halides, hydrogen fluoride, sulphuric acid, phosphorus pentoxide, polyphophoric acid, antimony (V) halides, stannic (IV) halides, titanium (IV) halides, tellurium (II) halides, tellurium (IV) halides, and bismuth (III) halides.  The cyclizing agent is admixed with a salt of an alkali metal, a salt of an alkaline earth metal, or an ammonium halide.  The cyclization is carried out in the presence of a solvent selected from nitromethane, nitrobenz...