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PROCESS FOR THE PREPARATION OF LORCASERIN HYDROCHLORIDE

IP.com Disclosure Number: IPCOM000237115D
Publication Date: 2014-Jun-03
Document File: 4 page(s) / 38K

Publishing Venue

The IP.com Prior Art Database

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.

Formula I

The reported process involves the preparation of lorcaserin hydrochloride of Formula I by the conversion of 2-(4-chlorophenyl)ethanol of Formula II into an intermediate of Formula III (wherein X is a leaving group selected from halogens, phosphate esters, alkoxy, carboxyl, sulfonyl, and silyl groups); reacting the intermediate of Formula III with allyl amine to obtain N-[2-(4-chlorophenyl)ethyl]prop-2-en-1-amine of Formula IV or a salt thereof; cyclization of N-[2-(4-chlorophenyl)ethyl]prop-2-en-1-amine of Formula IV or a salt thereof to obtain lorcaserin; treating lorcaserin with a chiral resolving agent; and conversion of the (R)-isomer of lorcaserin into lorcaserin hydrochloride of Formula I.

  

           Formula II                        Formula III                                       Formula IV

The conversion of 2-(4-chlorophenyl)ethanol of Formula II into the intermediate of Formula III is carried out by reacting 2-(4-chlorophenyl)ethanol of Formula II with a halogenating, phosphorylating, carboxylating, sulfonating, or silylating reagent in the presence of a solvent.  Examples of solvents include 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 allyl amine is carried out in the presence of an organic or inorganic base in a solvent at about 0°C to the reflux temperature of the solvent.  Examples of organic bases include triethylamine, N,N-diisopropylethylamine, tributylamine, and pyridine.  Examples of inorganic bases include hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of solvents include amides, substituted or unsubstituted hydrocarbons, ethers, nitriles, esters, ketones, sulfoxides, sulfolane, l,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, and tetramethylurea.

The cyclization of the intermediate of Formula IV or a salt thereof is carried out in the presence of a Lewis acid at a temperature of about 40°C to 150°C in a solvent.  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.  Examples of solvents include nitromethane, nitrobenzene, dichloromethane, chloroform, and 1,2-dichlorobenzene.

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