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PROCESS FOR THE PREPARATION OF PURE AMOROLFINE HYDROCHLORIDE

IP.com Disclosure Number: IPCOM000200536D
Publication Date: 2010-Oct-18
Document File: 7 page(s) / 72K

Publishing Venue

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Abstract

The present disclosure relates to a process for the preparation of pure amorolfine hydrochloride.

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PROCESS FOR THE PREPARATION OF PURE amorolfine HYDROCHLORIDE

Abstract

The present disclosure relates to a process for the preparation of pure amorolfine hydrochloride.

             Amorolfine hydrochloride is chemically the hydrochloride salt of (±)-cis-2,6-Dimethyl-4-[3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropyl]morpholine of Formula I.

Formula I

Amorolfine hydrochloride is used topically as an antifungal agent.  It has a broad spectrum of activity against dermatophytes, various filamentous and dematiaceous fungi, yeasts and dimorphic fungi.

Processes for preparing amorolfine or its salts are provided in U.S. Patent No. 4,202,894, GB Patent No. 1,589,253, European Patent Nos. EP. 0,024,334, EP 0,008,686, PCT Publication No. WO 2007/000628, Indian Application No. 2667/

DEL

/2007 and ES Patent No. 0,549,250.

ES Patent No. 0,549,250 describes a method of hydrogenating 3-(2,6-dimethylmorpholin-4-yl)-2-methyl-1-[4-(2-methylbutan-2-yl)phenyl]propan-1-one of Formula II using palladium-carbon in the presence of glacial acetic acid. 

Formula II

The resultant product is isolated as oil, which crystallizes in the refrigerator, and is further converted into the hydrochloride salt in acetone using isopropanolic hydrochloride.  However, ES Patent No. 0,549,250 does not mention the geometry of the compound of Formula II or the resultant product.

Indian Application No. 2667/DEL/2007 provides a similar process for the preparation of amorolfine using the cis-isomer of the compound of Formula II.  However, in order to achieve better purity and yield, amorolfine is isolated in the above process as an oxalate salt and converted into hydrochloride salt.

The present authors have developed an advantageous process wherein amorolfine can be isolated as hydrochloride salt directly obtained from the reaction mixture with purity of about 99% or above.  The present process does not require the preparation of any intermediate salt preparation and at the same time the present process is capable of providing pure amorolfine hydrochloride with better yield.

A first aspect of the present disclosure provides a process for the preparation of amorolfine hydrochloride having a purity of about 99% or above, wherein the process comprises:

a)       hydrogenation of 3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-methyl-1-[4-(2-methylbutan-2-yl)phenyl]propan-1-one of Formula IIA or its salt in the presence of an organic acid;

Formula IIA

b)            treating the reaction mixture obtained in step a) with a water immiscible organic solvent, water and a base;

c)             treating the reaction mixture obtained in step b) with hydrochloric acid to obtain amorolfine hydrochloride; and

d)            isolating amorolfine hydrochloride from the reaction mixture thereof.

3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-methyl-1-[4-(2-methylbutan-2-yl) phenyl]propan-1-one of Formula IIA or its salt, for example, hydrochloride salt, may be prepared according to the method provided in Indian Application No. 2667/DEL/2007.  Th...