WO2014178068A2

WO2014178068A2 - An improved process for preparation of n-[1-(1-naphthyl)ethyl] -3- [3-(trifluoromethyl)phenyl]propan-1-amine and pharmaceutically acceptable salts thereof

Info

Publication number: WO2014178068A2
Application number: PCT/IN2014/000219
Authority: WO
Inventors: Shri Prakash Dhar Dwivedi; Ashok Prasad; Jitesh Amratlal DESAI; Ankur Vinodbhai NAIK
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2013-04-08
Filing date: 2014-04-08
Publication date: 2014-11-06
Anticipated expiration: 2015-10-08
Also published as: WO2014178068A3

Abstract

The present invention relates to an improved process for preparation of N- [1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine and pharmaceutically acceptable salts thereof. In particular, the present invention relates to an improved process for preparation cinacalcet or pharmaceutically acceptable salts and intermediates thereof.

Description

AN IMPROVED PROCESS FOR PREPARATION OF N-[l-(l- N APHTH YL)ETH YL] -3- [3-(TRIFLUOROMETH YL)PHEN YL] PROP AN- 1 -AMINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of N- [ 1 -( 1 -naphthyl)ethyl] -3 - [3 -(trifluoromethyl)phenyl]propan- 1 -amine and pharmaceutically acceptable salts thereof. In particular, the present invention relates to an improved process for preparation cinacalcet or pharmaceutically acceptable salts and intermediates thereof.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Cinacalcet (approved as its HCl salt) is known to be useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed as Sensipar™ in the USA and as Mimpara™ in Europe. Chemically cinacalcet hydrochloride is (R)-N- [ 1 -( 1 -naphthyl)ethyl] -3 - [3 -(trifluoromethyl)phenyl]propan- 1 -amine,

hydrochloride which is represented as Formula-la.

Formula (la)

U.S. Patent No. 6,21 1,244 and 6,01 1,068 describe cinacalcet and its homologues along with their pharmaceutically acceptable salts. The patents disclose synthetic route for the preparation of cinacalcet and pharmaceutically acceptable salts thereof as illustrated in Scheme- 1

Scheme-1

The above depicted Scheme-1 involves titanium tetraisopropoxide and sodium cyanoborohydride catalyst, which are not commercially viable.

U.S. PG-Pub. No. 2012/0053362 Al discloses the preparation of salt of (R)- or (S)-isomer of 1 -naphthylethylamine with mandelic acid and its use in the preparation of cinacalcet.

U.S. Patent Nos. 6,342,636 and 7,250,533, U.S. PG-Pub. No. 2011/0295037 Al, International (PCT) Publication Nos. WO 2007/127445, WO 2007/127449, WO 2008/035381, WO 2008/058235, WO 2006/127932 discloses various other methods for preparation of cinacalcet or its pharmaceutically acceptable salt.

There still exists a need for a process for the preparation of cinacalcet or pharmaceutically acceptable salts thereof, which involves less reaction steps and may be scaled up for commercial production

SUMMARY OF THE INVENTION

In one general aspect, there is provided an improved process for preparing cinacalcet of Formula I or pharmaceutically acceptable salts thereof

(I)

comprising the steps of:

(a) reacting (R)- l-(naphthalen-l-yl)ethanamine compound of Formula (A)

(A)

with 3-(3-(trifluoromethyl)phenyl)propanal compound of Formula (B)

(B)

in a suitable solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl] propan-1 -amine (cinacalcet) compound of Formula (I); and

(b) optionally, converting cinacalcet of Formula (I) into pharmaceutically acceptable salts thereof.

In another general aspect, there is provided a "one pot" process for preparing cinacalcet of Formula (I

(I)

comprising reacting (R)-l-(naphthalen-l-yl)ethanamine compound of Formula (A)

(A) with 3-(3-(trifluoromethyl)phenyl)propanal compound of Formula (B)

(B)

in a suitable solvent and Raney Nickel as a reducing agent under hydrogen pressure.

In another general aspect, there is provided a R-(+)-l-(l -naphthyl) ethylamine tartrate of Formula (II) in a solid state form.

(II)

In another general aspect, there is provided solid state form of R-(+)-l-(l- naphthyl) ethylamine tartrate of Formula (II) which is characterized by XRD and IR.

In another general aspect, there is provided a solid state form of R-(+)-l-(l - naphthyl) ethylamine tartrate of Formula (II) having water content of about 4.5%.

In another general aspect, there is provided a solid state form of R-(+)-l-(l- naphthyl) ethylamine tartrate of Formula (II) is having chiral purity greater than about 99.8% as measured by HPLC.

In another general aspect, there is provided a process for preparing R-(+)-l-

(l-naphthyl)ethylamine tartrate of Formula (II) in a solid state form

(II)

comprising the steps of:

(a) reacting racemic 1-(1 -Naphthyl) ethylamine with D-(-)-tartaric acid in a suitable organic solvent at a suitable temperature range; and

(b) isolating R-(+)-l-(l -naphthyl) ethylamine tartrate of Formula (II) in a solid state form. In another general aspect, there is provided use of the solid state form of R- (+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) in the preparation of cinacalcet of Formula I or pharmaceutically acceptable salts thereof.

In another general aspect, there is provided an improved process for preparing cinacalcet of Formula I or pharmaceutically acceptable salts thereof of;

(I)

comprising the steps of:

(a) converting R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) into R- (+)-l-(l-naphthyl) ethylamine of Formula (A);

(b) reacting R-(+)-l-(l-naphthyl)ethylamine of Formula (A) with 3-(3-(trifluoro methyl)phenyl)propanal of Formula (B) in a suitable organic solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain cinacalcet of Formula (I);

(c) optionally, converting cinacalcet of Formula (I) into pharmaceutically acceptable, salts thereof.

In another general aspect, there is provided a process for preparing (R)-(+)- (l-naphthyl)ethylamine of Formula

(A)

comprising the steps of:

(a) reacting racemic l-(l-naphthyl)ethylamine with D-(-)-tartaric acid in a suitable organic solvent to obtain (R)-(+)-(l-naphthyl)ethylamine tartrate of Formula (II); and

(b) converting (R)-(+)-(l-naphthyl) ethylamine tartrate of Formula (II) into (R)- (+)-(! -naphthyl) ethylamine of Formula (A). In another general aspect, there is provided an improved process for preparing cinacalcet of table salts thereof

comprising the steps of:

(a) reacting racemic l-(l-Naphthyl) ethylamine with D-(-)-tartaric acid in a suitable organic solvent to obtain R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II);

(b) converting R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) into R- (+)- 1 -( 1 -naphthy 1) ethylamine of Formula (A) ;

(c) reacting R-(+)-l-(l-naphthyl) ethylamine of Formula (A) with 3-(3- (trifiuoromethyl)phenyl) propanal of Formula (B) in a suitable organic solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain cinacalcet of Formula (I); and

(d) optionally, converting cinacalcet of Formula (I) into pharmaceutically acceptable salts thereof.

In another general aspect, there is provided process for preparing crystalline Form-I of cinacalcet hydrochloride of Formula (la)

(la)

comprising the steps of:

(a) treating cinacalcet hydrochloride of Formula (la) in a suitable organic solvent; and

(b) isolating crystalline Form-I of cinacalcet hydrochloride of Formula (la).

In another general aspect, there is provided a process of racemization and recycling of undesired isomer (S)-(-)-l-(l-naphthyl) ethylamine of Formula (Al)

(Al)

comprising the steps of:

(a) reacting S-(-)-l-(l-naphthyl)ethylamine with a base in a suitable solvent to obtain racemic l -(l-naphthyl)ethylamine; and

(b) converting racemic l-(l-naphthyl)ethylamine into desired R-(+)-l-(l- naphthyl) ethylamine and recycling the undesired S-(-)-l-(l-naphthyl) ethylamine as in step (a).

In another general aspect, there is provided process for the purification of cinacalcet hydrochloride of Formula (la) using ester solvent.

In another general aspect, there is provided cinacalcet hydrochloride of Formula (la) having purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.98% and having all other impurities less than 0.1% as measured by HPLC.

In another general aspect there is provided commercially viable eco-friendly process for cinacalcet hydrochloride of Formula (la) which is free from use of hazardous and toxic reagents . BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIGURE-1: Illustrated X-ray diffractogram (XRD) of cinacalcet hydrochloride Form-I.

FIGURE-2: Illustrated X-Ray diffraction (XRD) pattern of R-(+)-l-(l-naphthyl) ethyl amine tartrate of Formula (II) in solid state form.

FIGURE-3: Illustrated infra-red (IR) spectrum of R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) in solid state form. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l -amine (cinacalcet) of Formula (I), which is commercially available as (R)-cinacalcet hydrochloride (la)

(la)

The term "pharmaceutically acceptable salt" is selected from a hydrochloride salt, a hydrobromide salt, an oxalate salt, a maleate salt, a fumarate salt, a besylate salt, a tosylate salt or a tartrate salt.

In one general aspect, there is provided an improved process for preparing cinacalcet of Formula I s thereof

(I)

comprising the steps of:

(a) reacting (R)-l-(naphthalen-l-yl)ethanamine compound of Formula (A)

(A)

with 3-(3-(trifludromethyl)phenyl)propanal compound of Formula (B)

(B) in a suitable solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl] propan-1 -amine (cinacalcet) compound of Formula (I); and

The suitable solvent for step (a) is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohol, ketones, ester and the like. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes. Particularly, the solvent may be methanol.

The suitable metal catalyst as a reducing agent under hydrogen pressure in step (a) may be selected from Raney-Ni, Pd/C, Pt/C and Rh/C. The preferred metal catalyst may be Raney-Ni.

The suitable salt of step (b) is selected from hydrochloride, hydrobromide, oxalate, maleate, fumarate, tartrate. Particularly, the salt may be hydrochloride.

The suitable organic solvent for step (b) is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohol, ketones, ester and the like. In particular, the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, Ci- C₄ straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes. Particularly, the solvent may be methanol.

(I)

comprising reacting (R)-l-(naphthalen-l-yl)ethanamine compound of Formula (A) with 3-(3-(trifiuoromethyl ound of Formula (B)

(B)

The suitable solvent for condensation of compound of Formula (A) and Formula (B) is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohol, ketones, ester and the like. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, Q-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes. Particularly, the solvent may be methanol.

(la)

comprising the steps of:

(b) isolating crystalline Form-I of cinacalcet hydrochloride of Formula (la)

The suitable organic solvent for step (a) is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohol, ketones, ester and the like. In particular, the suitable solvent comprises ester solvents selected form ethyl acetate, isopropyl acetate, ethyl butyrate etc. Particularly, the solvent may be ethyl acetate. .

In another general aspect, there is provided a X-Ray diffraction pattern of crystalline Form-I of cinacalcet hydrochloride substantially as depicted in Fig. 1.

In another general aspect, there is provided a solid state form of R-(+)-l-(l- naphthyl) ethylamine tartrate of Formula (II) in a solid state form

(Π)

The solid state form of R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) is characterized by at least one or more of the following properties:

i. a X-Ray diffraction pattern having peaks at about 6.8, 11.4, 13.8, 15.7, 17.4, 20.7, 22.8, 25.5, 26.5, 31.9 and 34.9 ±0.2 degrees 2-theta substantially as depicted in Fig. 2;

ii. having additional peaks at about 11.4, 13.1, 17.0, 21.2, 23.4, 28.1, 29.8, 32.5, 37.1 and 38.8 ± 0.2 degrees 2-theta;

iii. an IR spectrum substantially in accordance with Fig. 3; or

iv. an IR spectrum having absorption bands at about 3653, 3396, 3319, 2997, 2721, 2509, 1708, 1597, 1525, 1442, 1400, 1303, 1263, 1120, 1066, 991, 894, 869, 842, 806, 788, 680, 615, 570, 520, 478, 441 and 414±2 cm^"1.

The solid state form of R-(+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) having water content of about 4.0% to 5.5% which corresponds to monohydrate.

In another embodiment, there is provided a solid state form of R-(+)-l-(l- naphthyl) ethylamine tartrate of Formula (II) is having chiral purity greater than about 99.8% as measured by HPLC.

In another embodiment, there is provided a process for preparing R-(+)-l-(l- naphthyl)ethylamine tartrate of Formula (II) in a solid state form

comprising the steps of:

(a) reacting racemic l-(l-naphthyl)ethylamine with D-(-)-tartaric acid in a suitable organic solvent at a suitable temperature range; and

(b) isolating R-(+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) in a solid state form.

The suitable organic solvent for step (a) comprises one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be mixture of methanol-water.

In general, racemic l-(l-naphthyl) ethylamine with D-(-)-tartaric acid may be reacted at a mole ratio in the range from 1 :05 to 1 :2. Particularly the molar ratio may be 1 : 1.

The suitable temperature range for the reaction in step (a) may be 25°C to 90°C. The preferred temperature range may be 55 to 65°C.

In general, R-(+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) in a solid state form may be isolated from a suitable solvent selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the solvent may be methanol.

In another embodiment, there is provided use of soild state form of R-(+)-l- (1 -naphthyl)ethylamine tartrate of Formula (II) for the preparation of cinacalcet of Formula I or pharmaceutically acceptable salts thereof.

In another embodiment, there is provided an improved process for preparing cinacalcet of Formula I or pharmaceutically acceptable salts thereof;

comprising the steps of:

(a) reacting racemic l-(l-Naphthyl) ethylamine with D-(-)-tartaric acid in a suitable organic solvent to obtain (R)-(+)-l-(l-naphthyl) ethylamine tartrate of

Formula (II);

(b) converting R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) into R- (+)-l-(l-naphthyl)ethylamine of Formula (A) in presence of base in suitable organic solvent;

(c) reacting R-(+)-l-(l-naphthyl)ethylamine of Formula (A) with 3-(3-(trifluoro methyl)phenyl)propanal of Formula (B) in a suitable organic solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain cinacalcet of Formula (I); and

In general, R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) may be converted to R-(+)-l-(l-naphthyl)ethylamine of Formula (A) in a suitable organic solvent selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C C₄ straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be water and toluene.

In general, R-(+)-l -(l-naphthyl)ethylamine tartrate of Formula (II) may be converted to R-(+)-l-(l-naphthyl)ethylamine of Formula (A) using a suitable base selected from alkali and alkaline metal hydroxides and carbonates, preferably sodium hydroxide. R-(+)-l -(l-naphthyl) ethylamine of Formula (A) obtained in step (i) may be isolated or in-situ treated with 3-(3-(trifluoromethyl) phenyl) propanal of Formula (B) for the formation of cinacalcet of Formula I or pharmaceutically acceptable salts thereof.

The suitable organic solvent for step (b) may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. Particularly, the solvent may be methanol.

The metal catalyst as a reducing agent under hydrogen pressure in step (b) may be selected from Raney-Ni, Pd/C, Pt/C, Rh C. The preferred metal catalyst may be Raney-Nickel.

The suitable organic solvent for converting cinacalcet into its pharmaceutically acceptable salts in step (c) may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. Particularly, the solvent may be methanol.

In another embodiment, there is provided a process for preparing (R)-(+)-l-

( 1 -naphthyl) ethylamine of Formula

(A)

comprising the steps of:

(a) reacting racemic 1-(1 -naphthyl) ethylamine with D-(-)-tartaric acid in a suitable organic solvent to obtain (R)-(+)-(l-naphthyl)ethylamine tartrate of Formula (II); and

(b) converting (R)-(+)-(l -naphthyl)ethylamine tartrate of Formula (II) into (R)- (+)-(l -naphthyl) ethylamine of Formula (A).

The suitable organic solvent for step (a) may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be mixture of methanol-water.

In general, R-(+)-l -(l-naphthyl)ethylamine tartrate of Formula (II) in a solid state may be isolated from a suitable solvent selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. Particularly, the solvent may be methanol.

In general, (R)-(+)-(l-naphthyl)ethylamine tartrate of Formula (II) may be converted into (R)-(+)-(l-naphthyl)ethylamine of Formula (A) in a suitable organic solvent selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be water and toluene.

In general, (R)-(+)-(l-naphthyl)ethylamine tartrate of Formula (II) may be converted into (R)-(+)-(l -naphthyl)ethylamine of Formula (A) using a suitable base selected from alkali and alkaline metal hydroxides and carbonates, preferably sodium hydroxide.

In another embodiment, there is provided a process of racemization arid recycling of undesired isomer (S)-(-)- 1 -( 1 -naphthyl) ethylamine of Formula ( A 1 )

(Al)

comprising the steps of:

(a) reacting S^"-(-)-l-(l-naphthyl)ethylamine with a base in a suitable solvent to obtain racemic l-(l-naphthyl)ethylamine; and

(b) converting racemic l-(l-naphthyl)ethylamine into desired R-(+)-l-(l- naphthyl) ethylamine and recycling the undesired S-(-)-l-(l - naphthyl)ethylamine as in step (a). In general, the suitable solvent for step (a) comprises one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters, ethers or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, dimethyl formamide, ethylene glycol, diethylene glycol, polyethylene glycol (PEG), dimethyl acetamide, dimethyl sulfoxide (DMSO), methylene dichloride, acetonitrile, Cj-C₄ straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. In particular, the solvent may be dimethyl sulfoxide (DMSO).

The base for step (a) may be selected from alkali and alkaline metal hydroxides and carbonates, preferably sodium hydroxide.

The suitable organic solvent for converting racemic l-(l-naphthyl) ethylamine in to R-(+)-l-(l-naphthyl) ethylamine in step (b) may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C(-C straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be mixture of methanol-water.

In another general aspect, there is provided an improved process for preparing cinacalcet of le salts thereof

comprising the steps of:

(b) converting R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) into R- (+)-l-(l-naphthyl) ethylamine of Formula (A); (c) reacting R-(+)-l-(l-naphthyl) ethylamine of Formula (A) with 3-(3- (trifluoromethyl)phenyl) propanal of Formula (B) in a suitable organic solvent and a metal catalyst as a reducing agent under hydrogen pressure to obtain cinacalcet of Formula (I); and

The suitable organic solvent for step (a) may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, d-C₄ straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be mixture of methanol-water.

In general, R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) may be converted in to into R-(+)-l-(l-naphthyl) ethylamine of Formula (A) in a suitable organic solvent selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. In particular, the suitable solvent comprises toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, Q-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like. Particularly, solvent may be water and toluene.

In general, R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) may be converted in to into R-(+)-l -(l-naphthyl) ethylamine of Formula (A) using a suitable base selected from alkali and alkaline metal hydroxides and carbonates, preferably sodium hydroxide.

The suitable organic solvent for step (c) may be selected from may be selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof. Particularly, the solvent may be methanol. The metal catalyst as a reducing agent under hydrogen pressure in step (c) may be selected from Raney-Ni, Pd/C, Pt/C, Rh/C. The preferred metal catalyst may be Raney-Nickel.

The process for preparing cinacalcet of Formula I or pharmaceutically acceptable salts thereof as per present invention may be represented as shown in Scheme-2

Cinacalcet Hydrochloride (la when HX is HCI)

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES OF THE INVENTION:

Example 1: Preparation of R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) - Water (500 ml) and methanol (400 ml) were added in a RBF at 25°C to 35°C followed by addition of D-(-)-tartaric acid (87.60 g). The reaction mass was heated at 60°C to 65 °C and racemic l-(l-Naphthyl) ethyl amine (100 g) and methanol (100 ml) was added. The reaction mass was maintained for 10 hours. The reaction mass was filtered at 60-65°C and washed with 50% aq. methanol (100 mL). The dry solid was treated with methanol (250 ml) at 25°C to 35°C. The reaction mass was heated at 60°C to 65°C and maintained for 40 minutes. The reaction mass was cooled to 42°C to 45°C and filtered and washed with methanol (25 ml) afforded R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II). (Chiral Purity >99.8% and water content= 4.59%)

XRD & IR substantially as depicted in Fig. 2 and Fig. 3 respectively.

Example 2: Preparation of R-(+)-l-(l-naphthyI) ethylamine tartrate of Formula (II) - Water (500 ml) and methanol (400 ml) were added in a RBF at 25°C to 35°C followed by addition of D-(-)-tartaric acid (83.26 g). The reaction mass was heated at 60°C to 65 °C and racemic l-(l-Naphthyl) ethyl amine (100 g) in methanol (100 ml) was added. The reaction mass was maintained for 10 hours. The reaction mass was filtered at 60°C to 65°C and washed with 50% aq. methanol (100 mL). The dry solid was treated with methanol (250 ml) at 25°C to 35°C. The reaction mass was heated at 60°C to 65°C and maintained for 40 minutes. The reaction mass was cooled to 42°C to 45°C, filtered and washed with methanol (25 ml) afforded R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II). (Chiral Purity >99.8% and water content^ 5.0%)

XRD & IR substantially as depicted in Fig.2 and Fig. 3 respectively.

Example 3: Preparation of R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) - Water (500 ml) and methanol (400 ml) were added in a RBF at 25°C to 35°C followed by addition of D-(-)-tartaric acid (87 g). The reaction mass was heated at 60°C to 65°C and racemic l-(l-Naphthyl) ethyl amine (100 g) in methanol (100 ml) was added. The reaction mass was maintained for 15 hours. The reaction mass was cooled to 55°C to 60°C and washed with 50% aq. methanol (100 ml) afforded R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II). (Chiral Purity >82%).

R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) (Chiral Purity = 82%) (15 g) was treated methanol (150 ml). The reaction mass was heated at 60°C to 65°C and maintained for 30 minutes. The reaction mass was filtered and washed with methanol (15 ml) afforded R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II). (Chiral Purity >99.5% and water content= 4.59%)

XRD & IR substantially as depicted in Fig.2 and Fig. 3 respectively.

Example 4: Preparation of cinacalcet hydrochloride of Formula (la) - Water (90 ml), R-(+)-l-(l-Naphthyl)ethylamine tartrate of Formula (II) (30 g) and toluene (90 ml) were added in a RBF at 25°C to 35°C. The pH of reaction mass was adjusted to 12.5 to 13.5 by adding 10% NaOH solution and stirred for 30 minutes. Toluene layer was separated and toluene was distilled out under vacuum below 70°C to afford R-(+)-l-(l-naphthyl) ethylamine. Residue was cooled to 25°C to 35°C and methanol (200) was added and reaction mass was transferred in to autoclave (2 L). The reaction mass was stirred for 30 minutes. Raney-Ni (2 g) was added under Nitrogen. Nitrogen pressure of 2-3 Kg/cm² was applied and released and was repeated. The reaction mass was hydrogenated at 50°C to 55°C and maintained for 6 to 8 hours. Pressure was released and reaction mass was filtered through Hyflow bed and washed with methanol (20 ml). The pH of reaction mass was adjusted between 1 to 2 with cone. HC1 (10-15 ml) and methanol was distilled out under vacuum below 50°C. The residue was cooled to 25°C to 35°C and methanol (60 ml) and reaction mass was heated to 35°C to 45°C and further cooled to 25°C to 35°C. The reaction mass was filtered and washed with 50 % aqueous methanol (2x10 ml) and treated with water (100 ml) and maintained for 45 minutes. The reaction mass was filtered and washed with water (2 x 10 ml) afforded cinacalcet hydrochloride of Formula (la) which was treated with ethyl acetate (1200 mL) at 25°C to 35°C. The reaction mass was heated at 70°C to 80°C and maintained for 30 minutes and treated with activated charcoal (3 g). The reaction mass was filtered and washed with ethyl acetate (50 ml). The reaction mass_, was concentrated till 700 mL ethyl acetate remained. The reaction mass was cooled to 15°C to 20°C and stirred for 90 mintues. The reaction mass was filtered and washed with ethyl acetate afforded cinacalcet hydrochloride of Formula (la). (Purity> 99.9% by HPLC).

Example-5: Preparation of N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl) phenyl]propan-l-amine hydrochloride (cinacalcet hydrochloride) of Formula-(Ia) - 17 g of (R)-l-(naphthalen-l-yl)ethanamine of Formula (A) is charged in a Autoclave containing methanol (200 ml). To the same 20 g 3-(3- (trifluoromethyl)phenyl) propanal of Formula (B) was added at temperature ranging from 25°C to 35°C. 2 g of Raney- nickel was charged into the reaction mass and applied 2-4 Kg/cm² of Hydrogen pressure. Temperature increased to 35°C to 40°C: The reaction mass was filtered through hyflow bed and washed the bed with methanol. Adjusted the pH of reaction mass between 1.0 to 2.0 with Cone. HC1 (approx. 10.0-15.0 mL) solvent was evaporated and crude residue was treated with water afforded cinacalcet hydrochloride of Formula (la).

Example-6: Purification of cinacalcet hydrochloride of Formula-(Ia) - lOg of Cinacalcet hydrochloride was charged in a RBF containing 70 mL of acetone at temperature ranging from 25°C to 35°C. Reaction mass was heated to 50°C to 55°C and stirred for one hour. The reaction mass was cooled and product was filtered off. The solid was washed and dried to yield 70 % to 90% of the pure title compound.

Example-7: Preparation of crystalline Form-I of cinacalcet hydrochloride of Formula-(Ia) - lOg of Cinacalcet hydrochloride was charged in a RBF containing 120 ml of ethyl acetate at temperature ranging from 25°C to 35°C. Reaction mass was heated to 70°C to 80°C and stirred. The reaction was filter at the same temperature. The reaction mass was cooled and product was filtered off. The solid was washed with ethyl acetate and dried to yield 80 % to 98% of the pure title compound.

XRD substantially as depicted in Fig.1.

Claims

We claim:

1. An improved process for preparing cinacalcet of Formula

pharmaceutically acceptable salts thereof

comprising the steps of:

(a) reacting racemic l-(l-naphthyl)ethylamine with D-(-)-tartaric acid in a suitable organic solvent to obtain (R)^(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II);

(b) converting (R)-(+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) into (R)-(+)-l-(l-naphthyl)ethyl amine of Formula (A) in the presence of a base in a suitable organic solvent;

(c) reacting R-(+)-l-(l-naphthyl)ethylamine of Formula (A) with 3-(3- (trifluoro- methyl)phenyl)propanal of Formula (B) in a suitable solvent and a reducing agent under hydrogen pressure to obtain cinacalcet of Formula (I); and

2. The process according to claim 1 (a), wherein organic solvent is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohols, ketones, esters or a mixture thereof.

3. The process according to in claim 1, wherein base is selected from alkali and alkaline metal hydroxides and carbonates.

4. The process according to claim 1 (a), wherein reducing agent under hydrogen pressure is selected from Raney-Ni, Pd/C, Pt/C and Rh/C.

5. R-(+)-l-(l-naphthyl)ethylamine tartrate of Formula (II) according to claim 1 in solid form.

characterized by at least one or more of the following properties:

i) a X-Ray diffraction pattern having peaks at about 6.8, 11.4, 13.8, 15.7,

17.4, 20.7, 22.8, 25.5, 26.5, 31.9 and 34.9 ±0.2 degrees 2-theta substantially as depicted in FIG.2;

ii) having additional peaks at about 11.4, 13.1, 17.0, 21.2, 23.4, 28.1, 29.8,

32.5, 37.1 and 38.8 ± 0.2 degrees 2-theta;

iii) an IR spectrum substantially in accordance with FIG.3; or

iv) an IR spectrum having absorption bands at about 3653, 3396, 3319, 2997, 2721, 2509, 1708, 1597, 1525, 1442, 1400, 1303, 1263, 1120, 1066, 991, 894, 869, 842, 806, 788, 680, 615, 570, 520, 478, 441 and 414±2 cm^"1.

6. The solid state form according to claim 5 is having water content of about 4.0% to 5.5%.

7. A one pot process for preparing 7Y-[1 -(1 -naphthyl)ethyl]-3-[3-(trifluoromethyl) phenyljpropan- 1 -amine (cinacalcet) of Formula (I)

(I)

reacting (R)-l-(naphthalen-l-yl)ethanamine compound of Formula (A)

(A)

with 3-(3-(trifluoromethyl)phenyl)propanal compound of Formula (B)

(B) in a suitable solvent and Raney-Nickel as a reducing agent under hydrogen pressure to obtain N-[l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl] propan-1 -amine (cinacalcet) of Formula (I).

8. The process according to claim 6, wherein solvent is selected from one or more of hydrocarbons, halogenated solvents, nitriles, amides, alcohol, ketones and esters.

9. Use of solid state form of R-(+)-l-(l-naphthyl) ethylamine tartrate of Formula (II) in the preparation of cinacalcet hydrochloride of Formula (I).

10. A process for preparing R-(+)-l-(l-naphthyl)ethyl amine tartrate of Formula (II) in a solid state of:

(a) reacting racemic l-(l-naphthyl)ethylamine with D-(-)-tartaric acid in a suitable organic solvent at 55°C to 65°C; and

1 1. The process according to claim 10, wherein suitable organic solvent comprises one or more of toluene, xylene, ethyl benzene dimethyl formamide, dimethyl acetamide, methylene dichloride, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the like.

12. Cinacalcet hydrochloride prepared according to claim 1, wherein cinacalcet hydrochloride of Formula (la) is having purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.98% and having all other impurities less than 0.1 % as measured by HPLC.