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A PROCESS FOR PREPARING N-[1-(R)-(-)-(1-NAPHTHYL)ETHYL]-3-[3-(TRIFLUOROMETHYL)PHENYL]-1-AMINOPROPANE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

IP.com Disclosure Number: IPCOM000205315D
Publication Date: 2011-Mar-25
Document File: 9 page(s) / 109K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides a process for preparing N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane and pharmaceutically acceptable salts thereof.

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A PROCESS FOR PREPARING N-[1-(R)-(-)-(1-NAPHTHYL)ETHYL]-3-[3­(TRIFLUOROMETHYL)PHENYL]-1-AMINOPROPANE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

Abstract

The present disclosure provides a process for preparing N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane and pharmaceutically acceptable salts thereof.

Cinacalcet, chemically designated as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3­-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium.  It is disclosed in following patents U.S. Patent Nos. 6,211,244; 6,011,068; 6,313,146 and 6,031,003.

Reported processes require the use of titanium isopropoxide, diisobutylaluminium hydride (DIBAL), and sodium cyanoborohydride which are highly hygroscopic, expensive, toxic, inflammable and cause environmental hazards and thus not viable on industrial scale

We report a commercially viable process for preparing N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3­-(trifluoromethyl)phenyl]-1-aminopropane and pharmaceutically acceptable salts thereof such as cinacalcet which is operationally simple and employ non-expensive, easily available and environment friendly reagents.

The present disclosure provides process for preparing N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-­(trifluoromethyl)phenyl]-1-aminopropane and pharmaceutically acceptable salts thereof such as cinacalcet (Formula I) employing non-expensive, easily available and environment friendly reagents.

N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-­(trifluoromethyl)phenyl]-1-aminopropane and pharmaceutically acceptable salts thereof can be prepared by a process comprising the steps of:

(a)    converting a compound of Formula II

      wherein, R is hydrogen or a lower alkyl group,

      to a compound of Formula IV or pharmaceutically acceptable salt thereof;

(b)   reducing a compound of Formula IV or pharmaceutically acceptable salt thereof to N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-­(trifluoromethyl)phenyl]-1-aminopropane or pharmaceutically acceptable salt thereof.

Another process comprises the steps of: 

(a)    esterifying a compound of Formula II, wherein R is hydrogen

                  to a compound of formula II, wherein R is a lower alkyl group;

(b)   selectively reducing a compound of Formula II, wherein R is lower alkyl to a compound of Formula III,

wherein, X is a hydroxyl group;

(c)    replacing hydroxyl group of a compound of Formula III with a good leaving group;

(d)   condensing a compound of Formula III, wherein X is a good leaving group and (R)-1-(1-naphthyl)ethylamine to give a compound of Formula IV or pharmaceutically acceptable salt thereof;

(e)    reducing a compound of Formula IV or pharmaceutically acceptable salts thereof to N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-­(trifluoromethyl)phenyl]-1-aminopropane or pharmaceutically acceptable salts thereof.

3-[3-(trifluoromethyl)phenyl]prop-2-enoic acid of For...