WO2008117299A1 - Process for preparing cinacalcet hydrochloride - Google Patents

Disclosed herein is a process for preparing Cinacalcet hydrochloride, (R)-α-methyl-N-[3-[3-(trifluoromethyl) phenyl] propyl]-1-naphthalene methane amine hydrochloride via N-[1-(R)-(1-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl] -1-propanamide(X), a novel intermediate.

PROCESS FORPREPARING CINACALCET HYDROCHLORIDE

Technical field

This invention relates to a process for preparing Cinacalcet Hydrochloride, (R)-α-methyl- N-[3-[3-(trifluoromethyl) phenyl] propyl] -1 -naphthalene methane amine hydrochloride.

Background and prior art

Cinacalcet Hydrochloride is a common name of the chemically known substance (R)-α- •methyl-N-[3-[3-(trifluoromethyl) phenyl] propyl] -1 -naphthalene methane amine hydrochloride), having a CAS number of 364782-34-3, a formula of C₂₂H₂₂F₃N-HCl and represented by the following structure.

Formula I

Cinacalcet Hydrochloride is marketed as Sensipar ^TM> and is the first drug in a class of compounds known as Calcimimetics. Calcimimetics are orally active molecules that decrease the secretion of parathyroid hormone by activating calcium receptors. These class of compounds are used to treat hyper para thyroidism, a condition characterized by the over secretion of parathyroid hormone. Cinacalcet hydrochloride is approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Chirnl LC

Scheme I

The desired Cinacalcet enantiomer may be produced by reacting ( R )-l-(l-naphthyl) ethyl amine with 3-[3-(trifluoromethyl) phenyl] propionaldehyde in the presence of titanium isopropoxide to produce the imine followed by treatment with ethanolic sodium cyano borohydride as disclosed in '244 patent and Drugs of the Future (2002), 27 (9) : 831 (Scheme II).

(R)-Cincalcet base

Scheme II

Another process in '244 patent describes treating 3-trifluoromethylcinnamonitrile with diisobutyl aluminium hydride, followed by treating the intermediate aluminium-imine complex with (R)-l-(l-naphthyl) ethyl amine, and reducing the resultant imine with ethanolic sodium cyanoborohydride (Scheme III).

Scheme III

The above three reported processes require reagents such as Titanium isopropoxide, DIBAL-H and Sodium cyanoborohydride. All the above reagents were toxic, hygroscopic, flammable and not environmental friendly, making the process difficult to apply on industrial scale.

The synthesis of 3-[3-(trifluoromethyl) phenyl] propionaldehyde is disclosed in the references and notes section as entry no 12 of Tetrahedron letters (2004) 45, 8355 (Scheme IV).

Scheme FV

The process for the synthesis of aldehyde involves the reduction of double bond of the cinnamic acid derivative followed by reduction of acid moiety to corresponding alcohol, which was subjected to Swern oxidation to get the aldehyde. The Swern-oxidation involves the use of reagents such as oxalyl Chloride and dimethyl sulfoxide, which are not environmental friendly and does not result in high yield, making the process uneconomical on industrial scale.

WO2006/125026 discloses another synthetic procedure for preparation of Cinacalcet. This procedure involves the Heck coupling of l-bromo-3-trifluoromethyl benzene with acrolein dialkyl acetal to get a mixture of unsaturated acetal (I) and saturated ester (II). The mixture of compounds was hydrolyzed to get a mixture of unsaturated aldehyde (III) and saturated ester (II). When the mixture of unsaturated aldehyde (III) and saturated ester (II) was subjected for double bond reduction it furnished a mixture of saturated aldehyde (IV) and saturated ester (II). Similarly when the mixture of unsaturated aldehyde (IV) and saturated ester (II) was subjected for carbonyl moiety reduction it furnished a mixture of unsaturated alcohol (V) and saturated alcohol (VI).The mixture of saturated aldehyde (IV) and saturated ester (II) was subjected to reduction of carbonyl moiety and the mixture of unsaturated alcohol (V) and saturated alcohol (VI) were subjected to reduction of double bond to get the saturated alcohol (VI) (Scheme V).

.OH

F_*C

VI

Scheme V

The Heck reaction involves palladium catalyst which is a precious metal catalyst. The condensation of l-bromo-3-trifluoromethyl benzene with acrolein dialkyl acetal gave two products. The formation of multiple products during each conversion to get the alcohol (VI) makes the process unattractive from synthetic point of view.

WO2006/125026 discloses another strategy for the preparation of Cinacalcet. This procedure involves the Heck coupling of l-bromo-3-trifluoromethyl benzene with ethyl acrylate to get the unsaturated ester, which was subjected to reduction of double bond and reduction of carbonyl moiety to get the saturated alcohol, which was converted to a compound with leaving group and condensed with (R)-l-(l-naphthyl) ethyl amine to get Cinacalcet base (Scheme VI). ety

Scheme VI

The synthesis reported above (Scheme VI) also involves a Heck coupling reaction, which involves the use of palladium catalyst.

Therefore, there is need in the art to develop an alternate process for the synthesis of Cinacalcet free base and its hydrochloride salt, with high yield and purity and also suitable to industrial scale up. Thus the present invention provides such an alternate synthetic route to the preparation of Cinacalcet hydrochloride.

Summary of the invention:

In one preferred aspect, the invention provides a process for preparation of Cinacalcet hydrochloride as illustrated in scheme VII comprising the steps of: a) providing a suspension/solution of amide intermediate (X);

Formula X b) reducing the carbonyl moiety using suitable reducing agent at the reflux temperature of the solvent used to obtain Cinacalcet free base and c) providing a solution of Cinacalcet free base followed by treating with hydrochloric acid to obtain Cinacalcet hydrochloride salt.

Scheme VII

The process for reduction of amide intermediate (X) comprises providing a suspension of amide and suitable reducing agent in solvents selected from anhydrous organic solvents such as diethyl ether, tetrahydrofuran, alcohols (Cl - C4), toluene, dimethoxy ethane, etc and maintaining the reaction mixture at temperature of -2O⁰C to reflux temperature of the solvent used.

The suitable reducing agents are selected from the group comprising of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, AlH₃, diisobutyl aluminum hydride, NaAlEt₂ H₂ or sodium bis (2- methoxyethoxy) aluminum hydride. One preferred reducing agent is sodium borohydride/l2.

The process of isolation of Cinacalcet free base comprises destroying the excess borohydride solution using hydrochloric acid solution followed by basifying the reaction mass using suitable base and extracting the Cinacalcet free base by layer separation technique using suitable organic solvent.

The process of converting Cinacalcet free base into Cinacalcet hydrochloride salt comprises dissolving Cinacalcet free base in suitable organic solvent followed by treating with hydrochloric acid; maintaining the reaction mixture under stirring for sufficient time to obtain solids; and recrystallizing the hydrochloride salt from solvents selected from acetonitrile, alcohols (Cl - C4), n-hexane, n-heptane, cyclohexane, diethyl ether, n- pentane, acetone, water, isopropyl acetate, isobutyl acetate, toluene, methyl tert butyl ether, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, etc.

In another preferred embodiment the invention provides a process for the synthesis of a novel intermediate of compound of formula (X), as illustrated in Scheme VIII comprising: a) condensing 3-trifluoromethyl benzaldehyde (I) with malonic acid (VII) to obtain the unsaturated acid (VHI); b) reducing the unsaturated acid to obtain a saturated acid (IX); and c) converting the saturated acid to acid chloride followed by condensing with (R)-I-(I- naphthyl) ethyl amine to obtain amide (X).

Scheme VIII

The process of condensation of 3-trifluoromethyl benzaldehyde with malonic acid is carried out in solvents, such as pyridine, lutidines, triethyl amine, 4-(dimethylamino) pyridine, diisopropyl ethyl amine, dimethyl amine, diethyl amine in presence of base selected from inorganic base such as alkali metal carbonates, bicarbonates, hydroxides like sodium carbonate or potassium carbonate or sodium hydroxide or potassium hydroxide or organic base such as primary, secondary or tertiary amines, or cyclic amine such as piperidine. The reaction is carried out preferably at the reflux temperature of the solvent for 4 to 6 hrs. After completion of the reaction, the reaction mixture is cooled to room temperature and pH is adjusted to 2 to 3 using mineral acid solution. The solid is isolated by conventional means such as filtration, and washed with water to get unsaturated acid.

The process of reducing the unsaturated acid is carried out using hydrogenation catalysts such as platinum, Raney Nickel or palladium. The reduction is preferably carried out using palladium on carbon (5 - 10 %) under a hydrogen pressure of 4 to 6 kg at a temperature of 20-25⁰C. The progress of the reaction is monitored by TLC. After the completion of the reaction the product is isolated by distilling the reaction mixture under reduced pressure. This reaction is carried out in solvents such as Cl to C4 alcohols, dimethoxy ethane, ethyl acetate, or mixture thereof.

The process of converting the acid chloride to acid amide using conventional chlorinating agents such as PC15, POC13, thionyl chloride, oxalyl chloride and the like in solvents selected from such as dimethylformamide, toluene, methylene dichloride, ethylene dichloride or mixtures thereof. The reaction is accomplished by heating the reaction mixture at a temperature of 60 to 8O⁰C for 2 to 4 hrs to obtain acid chloride. The acid chloride can be isolated by any conventional methods such as distilling the solvent.

Further the condensation reaction of acid chloride with ( IR)-I (1-naphthyl) ethane amine is carried in solvents selected from chlorinated organic solvents such as methylene chloride, ethylene dichloride etc, in presence of organic base selected from primary amines such as methylamine, ethanolamine, trisamine; secondary amines such as dimethylamine, dimethyl ethanolamine, cyclic amines such as piperidine, pyrrolidine or tertiary amines such as trimethyl amine, dimethyl ethanolamine at a temperature of 0- 10⁰C for upto 2 hrs. After the completion of the reaction, water is added and the product, N-[l-(R-( 1-naphthyl) ethyl]-3-[3-trifluromethyl) phenyl]- 1-propanamide is isolated using layer separation technique.

The above amide is recrystallised using a suitable solvent or solvent mixture. Detailed description of the invention

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides an improved process for synthesis of Cinacalcet hydrochloride via a novel intermediate compound of formula (X) as illustrated in Scheme (VTII) comprising: a) condensing 3-trifluoromethyl benzaldehyde (I) with malonic acid(VII) to obtain the unsaturated acid (VIII); b) reducing the unsaturated acid to obtain a saturated acid (IX); c) converting the acid to acid chloride followed by condensing with (R)-l-(l-naphthyl) ethyl amine to get the amide(X); d) providing a suspension/solution of amide intermediate (X) and suitable reducing agent to obtain reaction mixture; e) reducing the carbonyl moiety using suitable reducing agent at reflux temperature to obtain Cinacalcet free base and f) providing a solution of Cinacalcet free base followed by treating with hydrochloric acid to obtain Cinacalcet hydrochloride salt.

Scheme VIII

The term, unsaturated acid of fonnula (VIII) refers to the following structure.

The term saturated acid refers to the following structure

The novel intermediate of the compound of formula (X) is characterized as having melting range of 108-111°C.

IR (KBr) Ow cm^"1): 3298.38, 3082.35, 2970.48, 2357.09, 1643.41, 1554.68, 1450.52,

1330.93, 1122.61, 1072.48, 798.56, 775.41, 705.97.

¹H NMR (CDCl₃-DMSO-^) (δ ppm): 7.26 - 8.03 (HH, m), 5.91 (IH, m), 5.58 (IH, bd),

3.03 (2H, in), 2.46 (2H, m), 1.60 (3H, d).

MS (m/~)\ 372 [M+l].

The compound of formula (X) is used in the preparation of Cinacalcet or its pharmaceutically acceptable salts thereof. In one preferred embodiment, the invention provides a process for preparation of Cinacalcet hydrochloride as illustrated in scheme VII.

Scheme VII

The process for reduction of novel amide intermediate (X) comprises providing a suspension of amide and suitable reducing agent in solvents selected from anhydrous organic solvents such as diethyl ether, tetrahydrofuran, alcohols (Cl - C4), toluene, dimethoxy ethane, etc and maintaining the reaction mixture at temperature of -20⁰C to reflux temperature of the solvent used.

The suitable reducing agents are selected from the group comprising of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, AlH₃, diisobutyl aluminum hydride, NaAlEt₂ H₂ or sodium bis (2- methoxyethoxy) aluminum hydride. One preferred reducing agent is sodium borohydride/I₂.

The process of isolation of Cinacalcet free base comprises destroying the excess borohydride solution using hydrochloric acid solution followed by basifying the reaction mass using suitable base such as sodium or potassium hydroxides and extracting the Cinacalcet free base by layer separation technique using suitable organic solvent.

The solvent used for the extraction of Cinacalcet is such that the compound should be completely dissolved in that solvent. The solvent used for extracting Cinacalcet is chlorinated solvents such as methylene dichloride, ethylene dichloride, or aliphatic esters such as ethyl acetate.

The process of converting Cinacalcet free base into Cinacalcet hydrochloride salt comprises dissolving Cinacalcet free base in suitable organic solvent followed by treating with hydrochloric acid solution; maintaining the reaction mixture under stirring for sufficient time to obtain solids; and recrystallizing the hydrochloride salt from solvents selected from acetonitrile, alcohols (Cl - C4), n-hexane, n-heptane, cyclohexane, diethyl ether, n-pentane, acetone, water, isopropyl acetate, isobutyl acetate, toluene, methyl tert butyl ether, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, etc.

The solvent used for conversion of Cinacalcet free base to hydrochloride salt is preferably hydrocarbon solvent such as acetonitrile, alcohols (Cl - C4), n-hexane, n-heptane, cyclohexane, diethyl ether, n-pentane, acetone, water, isopropyl acetate, isobutyl acetate, toluene, methyl tert butyl ether, dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, hexanes, etc.

In another preferred embodiment the invention provides a process for the synthesis of a novel intermediate of compound of formula (X), as illustrated in Scheme VIII.

Scheme VIII

«

The condensation of 3-trifluoromethyl benzaldehyde with malonic acid is carried out in solvents, such as pyridine, lutidines, triethyl amine, 4-(dimethylamino) pyridine, diisopropyl ethyl amine, dimethyl amine or diethyl amine in presence of base selected from inorganic base such as alkali metal carbonates, bicarbonates, hydroxides like sodium carbonate or potassium carbonate or sodium hydroxide or potassium hydroxide or organic base such as primary, secondary or tertiary amines, or piperidine. The reaction is carried out preferably at the reflux temperature of the solvent for 4 to 6 hrs. After the completion of the reaction, the reaction mixture is cooled to room temperature and pH is adjusted to 2 to 3 using mineral acid solution. The solid is isolated by conventional means such as filtration, and washed with water to get unsaturated acid of foπnula (VIII).

The mineral acid used in pH adjustment is selected from dilute sulfuric acid, hydrochloric acid, preferably hydrochloric acid solution.

The reduction of the unsaturated acid is carried out using reducing agents such as platinum, Raney Nickel or palladium. The reduction is preferably carried out using palladium on carbon (5 - 10 %) under a hydrogen pressure of 4 to 6 kg at a temperature of 20-25⁰C. The progress of the reaction is monitored by TLC. After the completion of the reaction the product is isolated by distilling the reaction mixture under reduced pressure. This reaction is carried out in solvents such as Cl to C4 alcohols, dimethoxy ethane, ethyl acetate etc.

The conversion of the acid chloride to acid amide is carried out using conventional chlorinating agents such as PC15, POCB, thionyl chloride, oxalyl chloride, and the like in solvents selected from solvents such as dimethylformamide, toluene, methylene dichloride, ethylene dichloride or mixtures thereof. The reaction is accomplished by heating the reaction mixture at a temperature of 60 to 80⁰C for 2 to 4 hrs to obtain acid chloride.

The acid chloride can be isolated by any conventional methods such as distilling the solvent.

Further the reaction of acid chloride with (IR)-I (1-naphthyl) ethane amine is carried in solvents selected from chlorinated organic solvents such as methylene chloride, ethylene dichloride etc., in presence of organic base selected from primary amines such as methylamine, ethanolamine, trisamine; secondary amines such as dimethylamine, dimethyl ethanolamine, cyclic amines such as piperidine, pyrrolidine or tertiary amines such as trimethyl amine, dimethyl ethanolamine at a temperature of 0 - 10⁰C for upto 2 hrs. After the completion of the reaction, product, N-[l-(R-(l-naphthyl) ethyl]-3-[3- trifluromethyl) phenyl]-l-propanamide is isolated using layer separation technique.

The above amide is recrystallised using a suitable solvent or solvent mixture such as hexane, heptane, n-hexane, n-heptane, ethyl acetate, isopropyl acetate, cyclohexane, methyl formate, ethyl formate, propyl acetate, toluene, propyl formate, methyl acetate, isobutyl acetate or their mixture thereof.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Example 1 :

Preparation of 3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (VIIl) 3-Trifluoromethylbenzaldehyde (50.0 gm, 0.287 moles), malonic acid (32.90 gm, 0.315 moles) and piperidine (3.66 gm, 0.043 moles) in dry pyridine (80 ml) was heated at 110- 115 ⁰C for 4-5 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the mixture was cooled to room temperature and chilled water (400 ml, 0-5 ⁰C) was added to the reaction mass and stirred for 1 hour. pH of the reaction mass was adjusted to 2-3 with 2 N HCl solution (200 ml) at 5 - 10 ⁰C and stirred for 1 hour. The resulting solid was filtered, washed with chilled water (400 ml, 0-5⁰C) and dried at 50 - 55 ⁰C to get title compound. (45 gm, 72.52 %).

Melting point: 131 - 133°C.

IR (KBr) (υm_ax_jcm^'1): 1689.53, 1631.67, 1442.66, 1261.36, 1176.50, 1072.35, 937.34,

871.76, 806.19, 694.33, 655.75.

¹H NMR (CDCl₃) (δ ppm): 7.53 - 7.84 (5H, m), 6.53 (IH, d).

MS (m/z): 215 [M-I] Example 2:

Preparation of 3-[3-(trifluoromethyl) phenyl]-2-propanoic acid (IX) 3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (50 gm, 0.231 moles), methanol (250 ml) and 10 % palladium on carbon (2.5 gm, 5%) was autoclaved for 2.5-3.0 h under hydrogen pressure of 4 kg at 20-25 ⁰C. The progress of the reaction was monitored by TLC. Upon completion of reaction, the reaction solution was filtered through celite and the reaction mixture was distilled under reduced pressure at 40 - 45 ⁰C to give title compound. (48 gm, 95.20 %).

Melting point: 30 - 35 ⁰C.

IR (KBr) (υ_raax cm^'1): 2966.62, 2947.33, 2889.46, 1712.85, 1454.38, 1330.93, 1168.90,

1134.18, 1076.32, 802.41, 702.1 1.

¹H NMR (CDCl₃) (δ ppm): 10.59 (IH, bs), 7.39 - 7.47 (4H, m), 3.03 (IH, t), 2.68 (IH, m).

MS (jn/∑): 217 [M-I]

Example 3:

Preparation of N-[I -(R)-(I -naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- propanamide(X)

Thionyl chloride (6.69 ml, 0.0917 moles) was added dropwise to a solution of 3-[3- (trifluoromethyl) phenyl]-2-propanoic acid (10 gm, 0.045 moles), dimethylformamide (0.5 ml) and dry toluene (100 ml) at 25 - 30 ⁰C under nitrogen atmosphere. The reaction mixture was heated to 70 - 75 ⁰C for 2.0 h. After 2.0 h the toluene was distilled under reduced pressure at 50 - 55 ⁰C. Fresh toluene (100 ml) was further added to reaction mixture to get clear solution. This solution was added dropwise to a solution of ( 1 R)- 1(1- naphthyl)ethane amine (4.88 gm, 0.0285 moles), triethylamine (1 1.53 gm, 0.1 14 moles) in methylene chloride (200 ml) at 0 - 5 ⁰C for 1.5 - 2.0 h under nitrogen atmosphere. After completion of the reaction (by TLC)₅ water (50 ml) was added in the reaction mixture and the layers were separated, the organic layer was washed again with water (50 ml). The organic layer was evaporated under reduced pressure to get a crude solid, which was then dissolved in a mixture of hexane (25 ml) and ethyl acetate (30 ml) at reflux and the cooled to O - 5 ⁰C to get solids which was filtered and dried at 50-55⁰C to get the title compound (10 gm, 70.87 %).

Melting point: 108-111⁰C.

IR (KBr) (iw cm^"1): 3298.38, 3082.35, 2970.48, 2357.09, 1643.41, 1554.68, 1450.52,

1330.93, 1122.61, 1072.48, 798.56, 775.41, 705.97.

¹H NMR (CDCl₃-DMSO-^) (δ ppm): 7.26 - 8.03 (HH, m), 5.91 (IH, m), 5.58 (IH, bd),

3.03 (2H, m), 2.46 (2H, m), 1.60 (3H, d).

MS (m/s): 372 [M+l].

Example 4:

Preparation of (R)-α-methyl-N- [3-[3-(trifluoromethyl) phenyl] propyl]- 1- naphthalene methane amine hydrochloride

To a suspension of N-[l-(R)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- propanamide (50 gm, 0.134 moles) and NaBH₄ (50 gm, 1.313 moles) in dry THF (600 ml) under nitrogen atmosphere was added a solution of iodine (167.5 gm, 0.66 moles) in dry THF (800 ml) at 0 - 5 ⁰C for 2.5 hours. The reaction mixture was then brought to room temperature and then refluxed (70 - 75 ⁰C) for 4.0 h. The reaction mass was cooled to 0-5⁰C and the excess borohydride destroyed by careful addition of 3 N HCl (150 ml). The reaction mixture was basified using 3 N NaOH (225 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 100 ml). The combined organic extracts were washed with water (100 ml) and dried over Na₂SO₄ The organic layer was evaporated to dryness under vacuum at 40 - 45 ⁰C to get a residue, which was dissolved in hexane (300 ml) and 10 % HCl solution (300 ml) was added at room temperature and stirred for 1 h. The solids separated were filtered and washed with hexane (5 x 25 ml) and dried to get the crude product. The crude product was dissolved in acetonitrile (450 ml) at reflux temperature and then cooled to room temperature, filtered the solids and dried at 50 - 55 ⁰C for 8 h to get Cinacalcet HCl (51.0 gm, 96.22 %).

Melting point: 180-184⁰C.

IR (KBr) (υ_max cm^"1) 3437.26, 3363.97, 2962.76, 2796.88, 2750.58, 2712.01, 2511.40,

1585.54, 1450.52, 1327.07, 1168.90, 1130.32, 1072.46, 798.56, 775.41, 702.11. ¹H NMR (CDCb-DMSO-cfe) (δ ppm): 10.62 (IH, bs), 10.07 (IH, bs), 7.16 - 8.5 (1 IH, m), 5.19 (IH₅ q), 2.75 (2H, t), 2.52 (2H, m), 2.28 (2H₅ m), 1.98 (3H, d). MS (m/z): 358 [M+l].

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim,

1. Novel process for preparation of Cinacalcet hydrochloride comprising:

a) providing a suspension/solution of amide intermediate (X)

b) reducing the carbonyl moiety in using suitable reducing agent at the reflux temperature of the solvent used to obtain Cinacalcet free base and c) providing a solution of Cinacalcet free base followed by treating with hydrochloric acid to obtain Cinacalcet hydrochloride salt.

2. The process as claimed in claim 1, wherein the solvent used to provide suspension or solution is selected from dry THF, diethyl ether, alcohols (Cl - C4), toluene, or dimethoxy ethane.

3. The process as claimed in claim 1, wherein said reducing agent is selected from sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, AlH₃, diisobutyl aluminum hydride, NaAlEt₂ H₂ or sodium bis(2-methoxyethoxy)aluminum hydride.

4. The process as claimed in claim 1, wherein the amide intermediate is prepared by a process comprising the steps of: a) condensing 3-trifluoromethyl benzaldehyde (I) with malonic acid (VIl) in a solvent to obtain the unsaturated acid (VIII); b) reducing the unsaturated acid to obtain a saturated acid (IX) using hydrogenation catalyst; and c) converting the saturated acid to acid chloride using chlorinating agent followed by condensing with (R)-I-(I - naphthyl) ethyl amine to obtain amide(X).

5. The process as claimed in claim 4, wherein said condensation is carried in presence of solvent selected such as lutidines, triethyl amine, 4-(dimethylamino) pyridine, diisopropyl ethyl amine, dimethyl amine, or diethyl amine.

6. The process as claimed in claim 4, wherein said base is selected from a group alkali metal carbonates, bicarbonates, hydroxides consisting of sodium carbonate or potassium carbonate or sodium hydroxide or potassium hydroxide or organic base such as primary, secondary or tertiary amines, or cyclic amine such as piperidine.

7. The process as claimed in claim 6, wherein said base is piperidine.

8. The process as claimed in claim 4, wherein said solvent used in condensation reaction is selected from a group consisting of pyridine, lutidines, triethyl amine, 4-(dimethylamino) pyridine, diisopropyl ethyl amine, dimethyl amine, diethyl amine, or mixture thereof.

9. The process as claimed in claimed in claim 4, wherein the hydrogenation catalyst used to reduce unsaturated acid to saturated acid is selected from platinum, Raney Nickel or palladium.

10. The process as claimed in claim 9, wherein said hydrogenation agent is (5 - 10 %)palladium on carbon.

11. The process as claimed in claim 4, wherein said reduction reaction is carried out under a hydrogen pressure of 4 to 6 Kg at a temperature of 20-25⁰C.

12. The process as claimed in claim 4, wherein the reduction of unsaturated acid is carried in a solvent selected from Cl to C4 alcohols or dimethoxy ethane or ethyl acetate.

^ 13. The process as claimed in claim 4, wherein the conversion of acid to acid chloride carried out in a solvent selected from dimethylformamide, toluene, methylene dichloride, ethylene dichloride, or mixtures thereof.

14. The process as claimed in claim 4, wherein the preparation of amide compound is carried out in chlorinated solvent in presence of an organic base at a temperature of O to lO°C.

15. The process as claimed in claim 12, wherein said organic base is selected from the group consisting of primary amines such as methylamine, ethanolamine, trisamine; secondary amines such as dimethylamine, dimethyl ethanolamine, cyclic amines such as piperidine, pyrrolidine or tertiary amines such as trimethyl amine, dimethyl ethanolamine.

16. The process as claimed in claim 1, wherein the amide compound is recrystallised from solvents hexane, heptane, n-hexane, n-heptane, ethyl acetate, isopropyl acetate, cyclohexane, methyl formate, ethyl formate, propyl acetate, toluene, propyl formate, methyl acetate, isobutyl acetate or their mixture thereof.

17. A compound represented by Formula (X) according to claim 1 or a pharmaceutically acceptable salt thereof, and inclusive of enantiomers, and racemic mixtures thereof.

18. Use of the compound of formula (X) in the preparation of Cinacalcet or its pharmaceutical salts thereof.

19. The process for preparation of Cinacalcet hydrochloride using novel intermediate and the intermediate thereof as substantially described herein with reference to the examples 1 to 4 and preceding claims 1 to 18.