FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of N-[(1R)-1-(l-naphthyl)ethyl]-3-[3-(trif!uoromethyl)phenyl]propan-l-amine hydrochloride of Formula (I).

BACKGROUND OF THE INVENTION

N-[(lR)-l-(l-Naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l-amine hydrochloride is generically known as Cinacalcet.

Cinacalcet is a second generation calcimimetic agent, which decreases the secretion of parathyroid hormone (PTH) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH are an indicator of secondary hyperparathyroidism associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.

Cinacalcet is marketed under the name Sensipar® in the US and, in Europe, it is marketed under the name Mimpara® and Parareg®. It has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyrr.id carcinoma.

NPS Pharmaceuticals disclosed generically Cinacalcet and itS' pharmaceutically acceptable salts as calcium receptor-active molecules in US 6,011,068, US 6,313,146 and disclosed specifically in US 6,211,244. The above patents do not provide any examples for the preparation of Cinacalcet.

According to the generic process disclosed in US '244 Cinacalcet may be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylamine (V) with 1-acetylnaphthalene (VI) in the presence of titanium (IV) isopropoxide, to produce an imine (VII) , which is further reacted with ethanolic or methanolic sodium cyanoborohydride to produce racemic Cinacalcet (la), and resolution of the racemic Cinacalcet by chiral liquid chromatography to produce Cinacalcet (lb).

The process is as shown in Scheme -I below:

US '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethylcinnamonitrile (VHI) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (IX), which is flirther reacted with (R)~l-(l-naphthyl)ethylamine (X) to produce an imine (Vila), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyl-N-

((R)-l-(naphthaIen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) and reducing unsaturated Cinacalcet to produce Cinacalcet (lb).

Similarly, using the process disclosed in US '244, ^^ weli a& Drugs of th: Future 2002, 27(9), 831-836, Cinacalcet may be prepared by reacting (R)-l-(l-naphthyl)ethylamine (X) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) in the presence of titanium (IV) isopropoxide to produce intermediate compound imine (VII), which is further reduced using ethanolic sodium cyanoborohydride.


The above processes involve the use of flammable and highly toxic reagents, such as titanium (IV) isopropoxide, which is highly hygroscopic, expensive, toxic and ethanolic or methanolic sodium cyanoborohydride, which is highly toxic and flammable, and not environmentally friendly, making the process difficult on commercial scale.

US 7,250,533 discloses a process for the preparation of Cinacalcet, wherein 3-(3-(trifluoromethyl)phenyl]propanol (IV) is converted to a compound with a good leaving group (IVa), which is further condensed with (R)-l-(l-naphthyl)ethylamine (X) to produce Cinacalcet (lb). The reagents described in the patent, which have good leaving groups are thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide.


Us 7,393,967 discloses a process for the preparation of Cinacaicet, which comprises, condensing 3-bromotrifluorotoluene (XII) with allyl amine (XIII) to produce 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II), which is further reduced in presence of Pd/C to produce Cinacaicet (lb).


us 2007/0259964 Al discloses a process for the preparation of Cinacalcet (lb), wherein 3-(trifluoromethyl) cinnamic acid (XI) is reduced to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid (XIa) followed by converting to corresponding reactive derivative (XIV), which is further condensed with (R)-l-(l-naphthyl)ethylamine (X) in the presence of a base to produce N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoroniethyl)phenyl]propanamide (XV) and reducing the N-[(lS)-l-(l-naphthyl)ethy!]-3-[3-trifluoromethyl)phenyI propanamide (XV) to produce Cinacalcet (lb).


The major disadvantage with the above process is the formation of (- 2%) desfluoro Cinacalcet (Ic), due to the use of strong reducing agent such as BH3. The separation of undesired desfluoro Cinacalcet (Ic) from Cinacalcet (lb) is difficult and required repeated crystallization, resuhing in a significant loss of yield.

WO 2008/068625 A2 discloses condensation of 3-[3 (trifluoromethyl)phenyl]propionaldehyde (III) with (R)-l-(l-naphthyl)ethyIam!ne (X) in the absence of titanium isopropoxide to produce Cinacalcet (lb).

us 7,247,751 B2 discloses a process for the preparation of crystalline Form I of Cinacalcet HCI by providing a solution of Cinacalcet base in a solvent, acidifying the solution with hydrochloric acid to obtain a reaction mixture and maintaining the reaction mixture to obtain Cinacalcet hydrochloride crystalline Form I.

WO 2009/039241 discloses a process for the preparation of Cinacalcet hydrochloride (1) by treating Cinacalcet base with carboxylic acid to produce carboxylate salt of Cinacalcet, which is further treating with anion exchange to produce Cinacalcet hydrochloride.

US 7,294,735 discloses a process for the purification of Cinacalcet hydrochloride by treating Cinacalcet base having 3 to 6% of 3-(3-(triiiuoromethyl)phenyJ[>propyl-(R)-l-(naphthalen-l-yl)ethyl carbamate (Cinacalcet carbamate) (XVI) in a solvent selected from acetone, C2.8 ethers and water with hydrochloric acid.

Cinacalcet (lb) prepared by the above processes contains 3-(3-(trifluoromethyl)phenyl)propyl-(R)-l-(naphthaien-l-yl)ethyl carbamate (Cinacalcet carbamate) (XVI) as an impurity in various amounts using different reaction conditions. Removal of Cinacalcet carbamate (XVI) in Cinacalcet hydrochloride (1) is often proved to be difficult and requires repeated crystallizations. Additionally, a second and third crystallization reduces yield as some Cinacalcet hydrochloride (I) remains uncrystallized and is not recovered from the liquid phase.

Hence, there is a need to develop a process, which provides Cinacalcet hydrochloride (I) with high chemical purity and optical purity.

The present invention is specifically directed towards the purification of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yi,iethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) by making its hydrochloride salt (Ila) and can be used as such to produce Cinacalcet hydrochloride (I) of high purity and yield.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and effective process for the preparation of Cinacalcet hydrochloride (I) with high purity and good yields on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of N-[(lR)-I-(]-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]p^opan-l-amine hydrochloride of Formula (I), reducing 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen^l-yl)ethyl)prop-2-en-1-amine hydrochloride (Ila), to produce N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-propan-1-amine hydrochloride of Formula (1), without isolating free base of N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-i-amine (lb).

According to an embodiment, the present invention also provides hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet hydrochloride) of Formula (Ila).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of N-[(iR)-l- (1 -naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1 -amine hydrochloride (Cinacalcet hydrochloride) of Formula I.

The process comprises, reducing 3-(3-(trifluoromethyl)phenyl-N-((R)--l-(naphthaIen-l-yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) (Ila), preferably, by catalytic hydrogenation (i.e., with hydrogen in %^ presence of catalyst) to produce Cinacalcet hydrochloride (I). The hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet hydrochloride) (Ila) may be dissolved in a lower alcohol selected from C1-C4 aliphatic, straight chain or branched alcohol, and exposed to H2 pressure in the presence of a catalyst such as Pd/C or Pt02 or Raney nickel. Preferably, hydrogen is present at a pressure of about 1 atmosphere to about 1000 psi. Typically, the hydrogenation is carried out over a period of about 1 to about 6 hours to produce Cinacalcet hydrochloride. The reaction mixture containing Cinacalcet hydrochloride is cooled and filtered. The filtered cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce Cinacalcet hydrochloride, which is isolated by the addition of organic solvent selected from acetonitrile, ether, heptane, methyl isobutyl ketone (MIBK).

It has been observed that Cinacalcet hydrochloride produced by the process having Cinacalcet carbamate, 3-(3-(trifluoromethy l)pheny l)propyl(R)-1 -(naphthalen-1 -yl)ethyl carbamate (XVI) less than 0.01% by HPLC and desfluoro Cinacalcet (Ic) less than 0.05% by HPLC without further purification. Further, the process of the present invention does not involve isolation of Cinacalcet freebase and the resulting finished product has high chemical and optical purity according to high performance liquid chromatography (HPLC).

According to an embodiment, the present invention also provides a process for the preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-1-amine hydrochloride of Formula (Ila), to produce 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthaIen-l- yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II),

(ii) treating 3-(3-(trifluoromethyI)phenyl-N-((R)-l-(naphthalen-l- yI)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) witli hydrochloric acid. 3-(3-(Trifluoromethy l)pheny 1-N-((R)-1 -(naphthalen-1 -y l)ethy l)prop-2-en-1 –amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ila) can be prepared by reductive amination of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia) with (R)-l-(l-naphthyl)ethylamine (X), in the presence.of a reducing agent selected from sodium triacetoxyborohydride, sodium cyanoborohydride (NaBHaCN) in a solvent selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, acetonitrile to produce 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l- amine (unsaturated Cinacalcet) (11). The reaction may be performed at a temperature ranging from about 0°C to about 50°C based on the solvents used for the reaction. The above reaction is conducted in presence of an acid selected from acetic acid. The reaction mixture containing the 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prGp-2-en-l-amine (unsaturated Cinacalcet) (II) is cooled and residual salts and reagents are filtered from the reaction mixture. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce crude 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II).

Alternatively, 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen-l-yl)ethyI)prop-2-en-1-amine (unsaturated Cinacalcet) (II) thus obtained may be recovered from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C4.8 ethers, chlorinated solvents, €3^ esters, C5-8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.

3-(3-(Trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-I-amine (unsaturated Cinacalcet) (II) produced by any of the above methods is treated with hydrochloric acid in a solvent selected from acetonitrile, THF, ethers, ethylacetate, methyl isobutyl ketone (MIBK), acetone, toluene to produce hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-I-amine (unsaturated Cinacalcet hydrochloride) (Ila), which is isolated by evaporating the solvent or precipitation of compound from the reaction mixture, by cooling the reaction mixture, followed by addition of an organic solvent.

According to an embodiment, the present invention provides an alternative process for the preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-I-(naphthalen-I-yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ila), which comprises:

(i) reacting 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb), with a reagent containing the leaving group to produce a compound of Formula IVc,


Treating 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IV) with a reagent containing the leaving group, which is selected from thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide to produce 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen-I-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II). More preferably, the thionyl halide is either thionyl bromide or thionyl chloride, while the preferred aliphatic sulfonyl halide is methanesulfony! chloride and the preferred aromatic sulfonyl halide is benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or p-toiuenesulfonyl chloride.

The above reaction is carried out in presence of suitable solvent, which is selected from inert organic solvent. The suitable inert organic solvents for the above reaction include but are not limited to halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform; ether, toluene like. The reaction may be performed at a temperature ranging from 0°C to about 35°C based on the solvent or mixture of solvents used for the reaction. The reagent containing the leaving group is added to the solution of 3-[3-(trifluoromethyl)phenyl]-2-propen-l--ot (IVb) in the organic solvent. More preferably, the reagent is added slowly in a drop-wise manner. Most preferably, this addition is carried out while maintaining the reaction mixture at a temperature of about 0°C to about 10°C.

The reaction is carried out in presence or absence of a base. When the leaving group is sulfonyl chloride, the reaction is carried out in presence of a base. Preferably, the organic base is an amine, more preferably, triethyiaminCj diisopropylethylamine, and pyridine. The sufficient period of time necessary for obtaining compound (IVc) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 4 to about 24 hours. More preferably, the reaction mixture is maintained for about 8 hour to about 15 hours.

The compound (IVc) obtained by the above process can be isolated by precipitation of compound from the reaction mixture or by removing the solvent from the reaction mixture.

The compound (IVc) is condensed with (R)-l-(l-naphthyl)ethylamine (X) in the presence of suitable base in a solvent to produce 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II). The suitable base used in the reaction is selected from an inorganic base such as alkali carbonate, more preferably, K2CO3, Na2C03, CS2CO3, NaHC03 or KHCO3. The^ most preferred base is K2CO3. The solvent is an organic solvent selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone, more preferably acetonitrile. The reaction may be performed at a temperature ranging from about 25°C to about reflux temperature of the solvent or mixture of solvents used for the reaction. The reaction time is about 5 to about 24 hours, more preferably about 10 to about 20 hours. After completion of the reaction, filtering off the salts obtained in the reaction and evaporating to obtain a residue. The residue containing 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) in a solvent selected from toluene, methyl isobutyl ketone (MIBK) is washed with acidic solution, followed by washing with sodium chloride solution and isolated 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) by removing the solvent.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLES:

EXAMPLE 1

Stage-1:

Preparation of 3-(3-(trifluoromethyI)phenyl-N-((R)-l-(naphthalen-l- yI)ethyI)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCI) (Ila): 3-[3-(Trifluoromethyi)phenyI]-2-propenai (10 g, 50 mmol) was added to a solution of (R)-l-(l-naphthyl)ethylamine (8.46 g, 49 mmol) in tetrahydrofuran (250 ml). The resulting clear solution was stirred for 15 min, and acetic acid (4 g) and sodium triacetoxyborohydride (prepared separately by treating 2.6 g of sodium borohydride and 12.5 g of acetic acid in 50 ml of tetrahydrofuran) were added at 10-15°C. After stirring for 2 hr at room temperature, the reaction mass was concentrated. The resulting residue was dissolved in methylene chloride (150 ml) and washed with IN HCI solution to remove unreacted amine. Separated organic layer was washed with sodium carbonate solution. The organic layer was concentrated to produce unsaturated Cinacalcet base (16.2 g). The residue containing unsaturated Cinacalcet base was dissolved in acetonitrile (20 ml) and acidified with HCI. The resulting mass was concentrated and product was isolated from acetonitrile to produce unsaturated Cinacalcet HCI as white solid (10.7 g, 55%). 'H NMR (CDCI3) (5 ppm): - 10.82 (br.s, IH), 10.34 (br.s, IH), 7.27-8.30 (m, IIH), 6.47 (m, iH), 6.16 (d, IH), 5.25 (m, iH), 3.71 (m, IH), 3.39(m, IH), 1.97 (d, 3H); MS (m/z): 356.1 [M+1].

Stage-2:

Preparation of Cinacaicet HCI

A mixture of unsaturated Cinacaicet hydrochloride (9g, 23 mmol) and 5% Pd/C (0.9g) in methanol (90 ml) was hydrogenated at 3 Kg/cm^ for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. Acetonitrile (36 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr, filtered and dried to produce Cinacaicet hydrochloride (7.6 g, 84%). HPLC purity: 99.7% Desfluro impurity: 0.02%

Example 2:

Stage-1:

Preparation of l-(3-chloro-l-propenyl)-3-(trifluoromethyI)benzene Thionyl chloride (17.7 g, 148 mmol) was added to a mixture of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (20, 99 mmol), toluene (20 ml) and few drops of DMF and refluxed for 4 hrs. Concentrated the reaction mass to produce 1 -(3-ch]oro-l-propenyl)-3-(trifluoromethyl)benzene (21.4 g, 98%).

Stage-2:

Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l- yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacaicet HCI) (Ila) l-(3-Chloro-l-propenyl)-3-(trifluoromethyi)benzene (20 g, 91 mmol) was added to a mixture of (R)-l-(l-naphthyOethylamine (15.19g, 89 mmol), K2CO3 (25 g, 181 mmol), potassium iodide (0.08 g) and methyl isobutyl ketone (MIBK) (10 ml). After refluxing for 13 hrs, the salts were removed by filtration. Organic layer was washed with IN HCI followed by aqueous sodium bicarbonate soiutJon. 2N HCI (60 ml) was added to this organic layer and concentrated. Acetonitrile (60 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to produce unsaturated Cinacaicet hydrochloride (10.2 g, 28.8%).

Stage-3:

Preparation of Cinaealcet HCI

A mixture of unsaturated Cinaealcet hydrochloride (9 g, 23 mmol) and 5% Pd/C (0.9g) in methanol (90 ml) was hydrogenated at 3 Kg/cm^ for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. Acetonitrile (36 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr., filtered and dried to produce Cinaealcet hydrochloride (7.3 g, 81%). HPLC purity: 99.6% Desfluro impurity: 0.02%

Example 3:

Stage-1:

Preparation of 3-(trifluoromethyl)cinnamyl methanesulfonate

Methanesulfonyl chloride (12.47 g, 109 mmol) was added to a mixture of 3-[3-(trifluoromethyl)phenyl]-2-propen-I-ol (20 g, 99 mmol), diisopropylethylamine (16.6 g, 128 mmol) and methylene chloride (300 ml) at 0-5°C. After stirring the reaction mass at 25-30°C for 18 hrs, pre cooled IN HCI (30 ml) was added.' The organic layer was separated and washed with sodium chloride solution. The organic layer was concentrated under reduced pressure to produce 3 (trifluoromethyl)cinnamyl methanesulfonate (21.4 g, 77%).

Stage-2:

Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthaIen-l- yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinaealcet HCI) (Ila) Method a: 3-(Trifluoromethyl)cinnamyl methanesulfonate (10 g, 36 mmol) was added to a mixture of (R)-l-(I-naphthyl)ethylamine (5.98 g, 35 mmol), K2CO3 (9.87 g, 71 mmol) and acetonitrile (30 ml). After refluxing for 15 hrs, the salts were removed by filtration. The filtrate was concentrated. Toluene (50 ml) was added to the residue and washed with IN HCI followed by aqueous sodium bicarbonate solution. 2N HCI (30 ml) was added to this organic layer and concentrated. Acetonitrile (30 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to produce unsaturated Cinacalcet hydrochloride (7.7 g, 55%).

Method b:

3-(Trifluoromethyl)cinnamyl methanesulfonate (10 g, 36 mmol) was added to a mixture of (R)-l-(l-naphthyl)ethylamine (5.98 g, 35 mmol), CS2CO3 (13.96 g, 43 mmol) and acetonitrile (30 ml). After refluxing for 15 hrs, the salts were removed by filtration. The filtrate was concentrated. Toluene (50 mj) was added to the residue and washed with IN HCI followed by aqueous sodium bicarbonate solution. 2N HCI (30 ml) was added to the organic layer and concentrated. Acetonitrile (30 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to get unsaturated Cinacalcet hydrochloride (5.6 g, 40%).

Stage-3:

Preparation of Cinacalcet HCI:

A mixture of unsaturated Cinacalcet hydrochloride (10 g, 25 mmol) and 5% Pd/C (I g) in methanol (90 ml) was hydrogenated at 3 Kg/crr^ for 2 hr. The reaption mass was filtered and concentrated under reduced pressure. Acetonitrile (40 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr., filtered and dried to produce Cinacalcet hydrochloride (8.3 g, 83%). HPLC purity: 99.9% Desfluro impurity: 0.01% Carbamate impurity: 0.01%

WE CLAIM

1. A process for the preparation of N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyI]propan-1 -amine hydrochloride of Formula (I),

which comprises:

reducing 3-(3-(trifluoromethyl)phenyl-N-((R)-!-(naphthalan-l-yl)ethyl)prop-2- en-1 - amine hydrochloride (Ila), to produce N-[( 1R)-1 -(1 -naphthy l)ethyl]-3-[3-(trifluoromethy l)pheny 1]-propan-1-amine hydrochloride of Formula (I), without isolating free base of N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoioinethyl)phenyl]propan-I-amine (lb).

2. The process according to claim 1, wherein reduction is carried out with hydrogen in the presence of catalyst.

3. The process according to claim 2, wherein catalyst is selected from Pd/C or PtOi or Raney nickel.

4. The process according to claim 1, wherein reduction is carried out in presence of solvent.

5. The process according to claim 4, wherein solvent is selected from lower alcohol selected from C1-C4 aliphatic, straight chain or branched alcohol.

6. The process according to claim 2, wherein hydrogen is present at a pressure of about 1 atmosphere to about 1000 psi.

7. The process according to claim 1, wherein N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l-amine hydrochloride of Formula (1) is directly isolated from the reaction mass.

8. 3-(3-(Trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l- amine hydrochloride of Formula (11).