WO2008058236A2

WO2008058236A2 - Methods for preparing cinacalcet hydrochloride

Info

Publication number: WO2008058236A2
Application number: PCT/US2007/084079
Authority: WO
Inventors: Pratap Reddy Padi; Surya Prabhakar Akundi; Sashi Kanth Suthrapu; Naveen Kumar Kolla; Vijaya Kumar Kotagiri; Uday Kumar Neelam; Sudhakar Reddy Baddam; Nagaraju Manne; Surya Narayana Devarakonda; Ram Thaimattam; Balaji Raghupati; Satish Kumar Vasamsetti
Original assignee: Dr. Reddy's Labortories, Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2006-11-08
Filing date: 2007-11-08
Publication date: 2008-05-15
Also published as: WO2008058236A3

Abstract

There is provided a process for making cinacalcet hydrochloride, said process including a) providing a solution of free base of cinacalcet in a solvent that is an alcohol or alkyl acetate; b) treating said solution with an amount of hydrochloric acid sufficient to convert said free base to said hydrochloride salt; c) adding an anti-solvent to said treated solution in the amount sufficient to precipitate said hydrochloride salt in the form of a solid; and d) isolating said precipitated solid thereby obtaining said cinacalcet hydrochloride. Other aspects, embodiments and variant related to cinacalcet are also provided.

Description

METHODS FOR PREPARING CINACALCET HYDROCHLORIDE

TECHNICAL FIELD

The present patent application relates to processes for the preparation of cinacalcet hydrochloride.

INTRODUCTION

Cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3- (trifluoromethyl) phenyl]-1-aminopropane and may be represented structurally by the formula I:

(I)

Cinacalcet belongs to the calcimimetics class of compounds. Calcimimetics are ionomimetics which effect one or more calcium receptor activities by binding to a calcium receptor. These compounds are useful in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease and hypocalcaemia in patients with parathyroid carcinoma. Cinacalcet hydrochloride is marketed as Sensipar™ in the USA and as Mimpara™ in Europe. It is available as 33, 66 and 99 mg tablets of cinacalcet hydrochloride equivalent to 30, 60 and 90 mg of cinacalcet free base respectively.

U.S. Patent No. 6,211 ,244 describes cinacalcet and its homologues along with their pharmaceutically acceptable salts.

PCT Publication No. WO2006/125026 describes an alternative process for the preparation of cinacalcet and its hydrochloride salt which may be easily scaled up. Other applications which describe processes for the preparation of cinacalcet hydrochloride, its polymorphs and intermediates include WO2006127941 , WO2006127933, WO2007/062147, WO2006/127932, and US Patent No. 6,342,636.

There still exists a need for a process for the preparation of cinacalcet, which may be scaled up for commercial production.

SUMMARY

In one aspect, there is provided a process for making cinacalcet hydrochloride, the process including: a) providing a solution of free base of cinacalcet in a solvent that is an alcohol or alkyl acetate; b) treating the solution of the free base with an amount of hydrochloric acid sufficient to convert the free base to the hydrochloride salt; c) adding an anti-solvent to the treated solution in the amount sufficient to precipitate the hydrochloride salt in the form of a solid; and d) isolating the precipitated solid thereby obtaining the cinacalcet hydrochloride.

Various embodiments and variants are provided.

In another aspect, there is provided a process for making cinacalcet hydrochloride, the process including: a) providing a solution of free base of cinacalcet in an alcoholic solvent; and b) treating the solution with an inorganic salt, which is a source of hydrochloric acid, to convert the free base of cinacalcet to the cinacalcet hydrochloride.

Various embodiments and variants are provided. In yet another aspect, there is provided a process for making cinacalcet hydrochloride, the process including: a) providing a solution of an acid addition salt of cinacalcet other than cinacalcet hydrochloride, wherein the salt is the salt of an acid weaker than hydrochloric acid; b) treating the solution with an amount of hydrochloric acid sufficient to convert said acid addition salt to said hydrochloride salt; and c) isolating the cinacalcet hydrochloride. Various embodiments and variants are provided.

In yet another aspect, there is provided a process for the purification of cinacalcet hydrochloride, the process including: a) providing a solution of cinacalcet hydrochloride in a nitrile solvent, b) adding an anti-solvent to the solution to precipitate a solid, and c) isolating the solid, which is the purified cinacalcet hydrochloride. Various embodiments and variants are provided.

In another aspect, there is provided a solid pharmaceutical composition that includes a molecular dispersion that consists essentially of cinacalcet hydrochloride in an amorphous form and polyvinylpyrollidone.

Various embodiments and variants are provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an XRPD pattern for crystalline cinacalcet hydrochloride obtained in Example 25.

DETAILED DESCRIPTION

The present patent application provides a process for making cinacalcet hydrochloride from free base of cinacalcet that includes the steps of: a) providing a solution of free base of cinacalcet in an alcohol or alkyl acetate; b) treating the solution of the free base with an hydrochloric acid to convert the free base to the hydrochloride salt; c) adding an anti-solvent to solution containing the hydrochloride salt to precipitate it in the form of a solid; and d) isolating the precipitated solid to obtain the cinacalcet hydrochloride.

In step a), the free base of cinacalcet is dissolved in a solvent. The desired solvents are alcohols, such as methanol, ethanol, and isopropanol, and alkyl acetate, sych as methyl acetate and ethyl acetate. Isopropanol and ethyl acetate are preferred. To affect the dissolution, cinacalcet may be placed into the solvent and heated. The concentration of cinacalcet in the solution may range from about 0.1 to about 10 g/ml in the solvent.

Step b) involves treating the solution of free base of cinacalcet with a source of hydrochloric acid, provided, optionally, in a suitable organic carrier. Hydrochloric acid gas, its aqueous solution, salts containing hydrochloric acid, or gas purged in organic solvents/carrier may be used.

The hydrochloric acid is provided in the amount sufficient to convert the free base. For example, the hydrochloric acid may be used in the amount of from about 0.5% w/w molar equivalents to about 5.0% w/w molar equivalents based on the weight of the free base of cinacalcet. The addition of hydrochloric acid may be carried out at a temperature lower than that used for preparing the solution in step a). Step c) involves adding an anti-solvent to the solution of the cinacalcet hydrochloride formed previously. Anti-solvent is added in the amount necessary to precipitate solid cinacalcet hydrochloride. Generally, examples of suitable anti- solvents which can be used for isolation of the solid include, but are not limited to, ethers, such as diisopropyl ether, diethyl ether, and dimethyl ether, and hydrocarbons, such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like, water or mixtures thereof. In one particular variant, the dissolution solvent is isopropanol. The preferred anti-solvent for isopropanol is water. In another particular variant, the dissolution solvent is ethyl acetate. The preferred anti-solvent for ethyl acetate is n-heptane. The temperatures in the range of about 10° C to about 25° C may be maintained for a period of time required for a more complete isolation of the solid. Optionally, small amounts of seeding crystals of cinacalcet hydrochloride may be added to cause the precipitation. Preferably, small amounts are about 1 to 20 weight %, more preferably about 5 weight %. Seeding crystals may be added before or after initiating the precipitation.

Step d) involves isolating precipitated solid of cinacalcet hydrochloride. Cinacalcet hydrochloride may be isolated using known techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor. If desired the crystals can be washed on the filter with a solvent. Optionally, the wet solid obtained can be dried. Drying can be carried out at reduced pressures, such as below 200 mm Hg or below 50 mm Hg, at temperatures of about 50° C to about 80° C. The drying can be carried out for any desired or required time periods, times about 1 to 20 hours being suitable for preparing some products.

The present patent application provides a process for making cinacalcet hydrochloride by a) providing a solution of free base of cinacalcet in an organic solvent; b) treating the solution with an inorganic salt, which is a source of hydrochloric acid, to convert the free base of cinacalcet to cinacalcet hydrochloride.

Examples of suitable solvents that may be used to dissolve the free base include, but are not limited to, alcoholic solvents such as CrC₄ alcohols; C₂-C₆ ketone, such as acetone, ethyl methyl ketone, and diethyl ketone; chlorinated solvents, such as Ci-C₆ straight chain, branched, or aromatic chlorohydrocarbons including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene; ethers such as THF, diethyl ether, methyl tertiary-butyl ether, and 1 ,4-dioxane; hydrocarbon solvents, such as toluene, xylene, and cyclohexane; esters, such as ethyl acetate, isopropyl acetate, tand ertiary-butyl acetate; nitriles, such as acetonitrile, and propionitrile; aprotic polar solvents, such as DMSO, DMF, DMAC, and NMP; and mixtures thereof or their combinations with water in various proportions. The preferred solvents are alcohol, particularly, methanol. The solution of the free base is treated with an inorganic salt which serves as a source of hydrochloric acid in situ. The preferred salt is ammonium chloride.

The present patent application also provides a process for making cinacalcet hydrochloride by a) providing a solution of an acid addition salt of cinacalcet other than cinacalcet hydrochloride, b) treating said solution with an amount of hydrochloric acid sufficient to convert the acid addition salt to said hydrochloride salt; and c) isolating said cinacalcet hydrochloride.

Step a) provides a solution of a cinacalcet salt other than hydrochloride in an organic solvent. Examples of suitable solvents that may be used to dissolve the salt of cinacalcet include, but are not limited to, alcoholic solvents such as d- C-₄ alcohols; C₂-C₆ ketone, such as acetone, ethyl methyl ketone, and diethyl ketone; chlorinated solvents, such as C-i-Cβ straight chain, branched, or aromatic chlorohydrocarbons including dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene; ethers such as THF, diethyl ether, methyl tertiary-butyl ether, and 1 ,4-dioxane; hydrocarbon solvents, such as toluene, xylene, and cyclohexane; esters, such as ethyl acetate, isopropyl acetate, tand ertiary-butyl acetate; nitriles, such as acetonitrile, and propionitrile; aprotic polar solvents, such as DMSO, DMF, DMAC, and NMP; and mixtures thereof or their combinations with water in various proportions.

The salt of cinacalcet provided in step a) is a salt of a weaker acid than hydrochloric acid to enable the salt exchange reaction of step b). Salts of inorganic acids, such as hydrobromide and sulfonate, and organic acids, such as acetate, succinate, oxalate, tartarate, formate, and maleate, may be used. Also, salts of cinacalcet with enantiomerically pure acids, such as tartaric acid, mandelic acid, and the like can also be used for the purpose. In step b), hydrochloric acid is added to the solution and displaces the salt of the weaker acid to provide cinacalcet hydrochloride. The isolation step may be carried out in any manner. Preferably, the isolating step includes adding an anti-solvent to the treated solution in the amount sufficient to precipitate the hydrochloride salt in the form of the solid, and filtering the solid.

The present patent application also provides a process for the purification of cinacalcet hydrochloride by a) providing a solution of cinacalcet hydrochloride in a nitrile solvent, b) adding an anti-solvent to precipitate a solid, and c) isolating the solid, purified cinacalcet hydrochloride.

Step a) involves providing a solution of cinacalcet hydrochloride in a nitrile solvent. Examples of suitable nitrile solvents include, but are not limited to, acetonitrile and propionitrile. The preferred solvent is acetonitrile Any form of starting cinacalcet hydrochloride (e.g., crystalline or amorphous forms, solvates and hydrates) may be utilized for preparing the solution. The dissolution temperature may range from about 20 to 120 °C. Concentration of cinacalcet hydrochloride may range from about 0.1 to about 1 g/ml in the solvent. After dissolution, the solution may be treated with materials such as carbon or with sodium sulfate for clarification.

Step b) involves adding an antisolvent to the solution obtained in the step a). Suitable antisolvents which can be used include, but are not limited to water, ethers, such as diisopropyl ether, diethyl ether, dimethyl ether, hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and mixtures thereof. The solid cinacalcet hydrochloride then precipitates. If desired, small amounts of seeding crystals of cinacalcet hydrochloride may be added to facilitate precipitation. Preferably, small amounts are about 1 to 20 weight %, more preferably about 5 weight %. Seeding crystals may be added before or after the step initiating the precipitation.

Step c) involves isolating solid, purified cinacalcet hydrochloride. Cinacalcet hydrochloride may be isolated using techniques such as filtration by gravity, or by suction, or centrifugation. The crystals so isolated will carry a small proportion of occluded mother liquor. If desired the crystals may be washed on the filter with a solvent. The wet solid obtained can be dried. Drying may be carried out at reduced pressures, such as below 200 mm Hg or below 50 mm Hg, at temperatures of about 50° C to about 80° C.

Cinacalcet hydrochloride prepared according to the processes described herein was characterized by its XRPD pattern. Figure 1 shows an example of XPRD of a sample of cinacalcet hydrochloride obtained. XRPD pattern has significant peaks at about 6.9, 13.8, 15.5, 15.9, 17.8, and 19.0 ± 0.2 degrees 2Θ. It is further characterized by additional XRPD peaks at about 20.8, 21.2, and 24.2, 25.4 ± 0.2 degrees 2Θ.

The cinacalcet hydrochloride was obtained by the processes described herein in a substantially pure form. The terms "substantially pure cinacalcet" is used to denote a solid that contains less than about 0.5%, or less than about 0.1 % of the corresponding impurities like 3-(3-trifluoromethyl-phenyl) propanoic acid of Formula III, desfluoro impurity, and the regio-isomer of Formula Ib as characterized by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture comprising the desired compound and one or more of the said impurities. The percentage here refers to the area-% of the peaks representing the said impurities. As used herein "desfluoro impurity" refers to [3-(3-Difluoromethy!-phenyl)-propyl]-(1 -naphthalen-1 -yl-ethyl)-amine represented by Formula Ia.

Formula Ia Formula Ib

"Regio-isomer" as used herein, refers to [3-(3-Difluoromethyl-phenyl)- propyl]-(2-naphthalen-1-yl-ethyl)-amine represented by Formula Ib. Cinacalcet prepared according to the process of the present invention is also free of an impurity at RRT 0.90 as measured by HPLC method disclosed in the present application. The desfluoro impurity is formed because of the corresponding desfluoro analougue in the starting 3-[3-(trifluoromethyl) phenyl] propenoic acid of Formula II, hence the corresponding desfluoro impurities may be present in all the intermediates starting from the compound of Formula III to the compound of Formula V. Cinacalcet and its salts obtained according to the process of the present invention have a chiral purity of more than about 99%, or more than about 99.5%. Cinacalcet hydrochloride obtained using the process of the present invention contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of individual residual organic solvents. In particular, it has less than about 1000 ppm, or less than about 500 ppm of the solvents selected from n-hexane, di-isopropyl ether, methanol, acetonitrile, toluene, ethyl acetate, and acetic acid.

Cinacalcet and its salts prepared as described herein exhibit defined micromeritic properties such as particle size distribution, bulk density, Carr index and Hausner ratio. Particle size distribution is often correlated with mean particle size. As used herein, the term "mean particle size" refers to the distribution of cinacalcet particles wherein about 50 volume percent of all particles measured have a particle size less than the defined mean particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined mean particle size value; this can be identified by the term "D₅₀." Similarly, a particle size distribution where 90 volume percent of the particles have sizes less than a specified size is referred to as "D₉₀" and a distribution where 10 volume percent of particles have sizes less than a specified size is referred to as "D₁₀."

In an embodiment, cinacalcet hydrochloride exhibits D₅₀ less than about 40 μm, or about 30 μm. Cinacalcet and its salts with desired D₅₀ can directly be obtained from a synthesis process, or alternatively, any known particle size reduction processes can be employed, such as but not limited to sifting, milling, micronization, fluid energy milling, ball milling, and the like to obtain the material with desired D_50. Upon such particle size reduction by these techniques, the material with desired D₅₀ may have values less than about 15 μm, or about 10 μm.

Bulk density as used herein is defined as the ratio of apparent volume to mass of the material taken, called untapped bulk density, and also the ratio of tapped volume to mass of material taken, called tapped bulk density. A useful procedure for measuring these bulk densities is described in United States Pharmacopeia 24, Test 616 (Bulk Density and Tapped Density), United States Pharmaceopeial Convention, Inc., 2000. In an embodiment, the bulk density of cinacalcet or its salts prepared in accordance with the present invention ranges between about 0.1 g/ml to about 0.5 g/ml, or from about 0.15 g/ml to about 0.35 g/ml.

Also provided are pharmaceutical compositions of cinacalcet or its pharmaceutically acceptable salts prepared according to the processes described herein, and one or more pharmaceutically acceptable carriers, excipients or diluents.

In a particular variant, the present patent application provides a solid pharmaceutical composition that includes a molecular dispersion consisting essentially of cinacalcet hydrochloride in an amorphous form and polyvinylpyrollidone. The molecular dispersion may be prepared by dissolving cinacalcet hydrochloride and polyvinylpyrollidone in a volatile organic solvent, and removing the solvent thus obtaining the molecular dispersion. In the molecular dispersion, cinacalcet hydrochloride and polyvinylpyrollidone may be present in the ratio ranging from about 1 :10 to 10:1 , or from about 1 :2 to 2:1. The molecular dispersions may be further formulated with additional excipients, as desired.

The pharmaceutical compositions may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the formulations include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. In an embodiment of the present invention, the compositions of cinacalcet or its pharmaceutically acceptable salts is a useful active ingredient in the range of 20 mg to 350 mg, or 40 mg to 320 mg. Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES

EXAMPLE 1 : PREPRATION OF 3-TRIFLUROMETHYL CINNAMIC ACID:

Trifluromethyl benzaldehyde (10 g) was taken into a round bottom flask containing acetic anhydride (3.8 g) and stirred for 15 minutes. The reaction mass was heated to about 175 ⁰C and stirred for about 5 hours. After completion of the reaction, the reaction mass was cooled to about 80 ⁰C followed by addition of water (40 ml) and again stirring for 15 minutes. pH of the reaction solution was adjusted to about 10 by addition of 100 ml of 10% sodium carbonate solution and stirring for about 15 minutes. The water was distilled at about 110 ⁰C under vacuum and the separated solid was filtered.

The obtained filtrate was charged into a fresh round bottom flask and cooled to about 0 ⁰C. pH of the solution was adjusted to about 2 by the addition of concentrated HCI (25 ml) and stirred for solid separation. The separated solid was filtered and washed with water (40 ml). The resultant solid was dried under vaccum at about 50 ⁰C to afford 2.4 g of the title compound.

Mass (m/z) : 215 a.m.u.

EXAMPLE 2: PREPARATION OF 3-[3-(TRIFLUROMETHYL) PHENYL] PROPANOIC ACID

A solution of 3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (100g) dissolved in methanol (600 ml) was taken into an autoclave vessel, and palladium-carbon (10% w/w) (25 g) was added to it. 4 kg/cm² of anhydrous hydrogen gas pressure was passed into the reaction suspension under agitation at about 25-35 ⁰C for about 3 hours. After the completion of the reaction, the reaction suspension was filtered on a celite bed and the celite bed was washed with methanol (100 ml). The filtrate was distilled completely at about 50 °C under a vacuum of about 650 mm/Hg to afford 95.5 g (%yield: 94.6) of the title compound.

Mass (m/z) : 218.16 a.m. u.

EXAMPLE 3: PREPRATION OF RACEMIC 1-(1-NAPTHYL) ETHYLAMINE:

1-acetonaphthone (200 g) and ammonium formate (370 g) were taken into a round bottom flask and Dean and stalk apparatus was arranged. The reaction mass was heated to about 165 °C and maintained for about 8-10 hrs, the collected water was discarded. Reaction completion was checked using thin layer chromatography, and after the reaction was completed, the reaction mass was allowed to cool to about 50 °C and HCI (200 ml) was added to it slowly, and stir for 10-15 min at 50 ⁰C. Add methanol (200 ml) slowly and then maintained for 15- 20 min.

The reaction mass was filtered through a hyflow bed and the bed was washed with methanol (400 ml). The filtrate was taken into another round bottom and add HCI (400 ml) slowly at 25-35°C, and the contents were heated to about 65 ⁰C. The reaction mass was maintained at about 65 ⁰C for about 3-4 hours and then cooled to about 25-35°C. Water (1000 ml) was added to it under stirring followed by addition of dichloromethane (1000 ml). The reaction mass was stirred for about 10 minutes, and then the organic layer was separated. The aqueous layer was washed with dichloromethane (1000 ml). The combined DCM washing layers were extracted with DM-Water (1000 ml). The combined aq. layer pH was then adjusted to about 10-12 using caustic lye and then extracted into dichloromethane (2000 ml) in two lots. The combined organic layer was washed with 2000 ml of water in two lots. The organic layer was distilled off completely under a vacuum of about 650 mm/Hg at 48⁰C to yield 120 g of the title compound.

Purity By GC: 98.41 %.

EXAMPLE 4: PREPARATION OF R-(-)-1-(1 -NAPTHYL) ETHYLAMINE (FORMULA IV) FROM RACEMIC 1-(1-NAPTHYL) ETHYLAMINE

Racemic 1-(1-napthyl) ethylamine (25 g) and dichloromethane (125 ml) were taken into a round bottom flask and stirred for about 10 minutes at about 28 ⁰C. Water (18.75 ml) was added to it and stirred for another 10 minutes. A solution of D (+) naproxen (33.6 g) in dichlormethane (250 ml) was added to the above mixture at about 28 ⁰C and stirred for about 4 hours at the same temperature. The separated solid was filtered and washed with dichloromethane (50 ml). The filtered solid was dried at about 60-70°C for 6 to 8 hours to yield 23 g D(+) Naproxen salt of 1-(1-napthyl) ethylamine.

The above solid was taken into another round bottom flask and toluene (250 ml) was added to it. The mixture was heated to about 110 ⁰C and maintained for about 30 minutes. The reaction mixture was then allowed to cool to about 40-45 °C and the separated solid was filtered and washed with toluene (50 ml). The wet solid was dried under suction and then taken into another round bottom flask and the process of recrystallization in toluene was repeated. The obtained solid was dried under suction and water (250 ml) was added to it followed by addition of caustic lye solution (10 ml). The mixture was stirred fro about 30 minutes and then dichloromethane (250 ml) was added to it and stirred for about 10 minutes. The organic layer was separated and the aqueous layer was extracted into dichloromethane (125 ml). The combined organic layer was washed with DM Water (250.0 ml) and dried over sodium sulfate and distilled off completely at about 45 ⁰C under a vacuum of about 650 mm/Hg to yield 7.6 g of the title compound. Chiral Purity: 99.66%. EXAMPLE 5: PREPARATION OF N- [(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3- TRIFLUROMETHYL) PHENYL] PROPANAMIDE:

3-[3-(trifluoromethyl) phenyl] propanoic acid (100 g) and dichloromethane (500 ml) were taken into a round bottom flask and stirred for about 5 minutes. To the reaction solution HOBT (77.76 g) was added followed by addition of DCC (118.65 g) dissolved in dichloromethane (500 ml) over a period of about 15 minutes. The resultant reaction mixture was stirred for about 1 hour.

After the completion of the reaction, the reaction mass was cooled to about 5 ⁰C followed by stirring for about 40 minutes. The by-product dicyclohexyl urea (DCU) was filtered through celite and the filtrate was distilled completely at about 39 ⁰C under vacuum. The complex residue obtained was dissolved in dichloromethane (800 ml) and stirred for about 5 minutes. Potassium carbonate (66.24 g) was charged followed by addition of R -(+)-1-(1-naphthyl) ethylamine of Formula IV (82.08 g) dissolved in dichloromethane (200 ml) over about 15 minutes.

The resultant reaction solution was stirred at about 25 ⁰C for about 15 minutes. After the completion of the reaction, the reaction mixture was cooled to about 5 ⁰C followed by stirring for about 40 minutes. Solid separated was filtered and the filtrate was distilled completely at about 39 ⁰C under vacuum. To the residue 500 ml of n-hexane was charged followed by raising the temperature to about 45 ⁰C. The resultant reaction solution was stirred for about 40 minutes. The separated solid was filtered and washed with n-hexane (200 ml). The wet solid was dried at about 75 ⁰C under vacuum for about 9 hrs to afford 141.5 g of title compound. Mass (m/z): 371 amu. EXAMPLE 6: ALTERNATE PROCESS FOR THE PREPARATION OF N-[(1 R)-1- (1 -NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE WITHOUT USING HOBT:

3-[3-(trifluoromethyl) phenyl] propanoic acid (2 g) and dichloromethane (10 ml) were charged into a round bottom flask and stirred for about 5 minutes. To the reaction solution, DCC (2.3 g) dissolved in dichloromethane (500 ml) was added over a period of about 15 minutes. Potassium carbonate (1.24 g) was charged followed by addition of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (1.5 g) dissolved in dichloromethane (10 ml) over about 15 minutes. The resultant reaction mixture was stirred for about 2 hours.

After the completion of the reaction the by-product DCU was filtered through celite and washed with dichloromethane (5 ml) and the filtrate was distilled completely at about 39 ⁰C under vacuum. To the residue 16 ml of n- hexane was charged followed by raising the temperature to about 70 ⁰C. The resultant reaction solution was stirred for about 10-15 minutes and then cooled to 25 to 35 ⁰C. The separated solid was filtered and washed with n-hexane (4 ml). The solid obtained was dried at about 75 ⁰C under vacuum for about 9 hrs to afford 2.5 g of the title compound. Mass (m/z) : 371 amu.

Purity By HPLC: 83.77%

EXAMPLE 7: PREPARATION OF N-[(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3- TRIFLUROMETHYL) PHENYL] PROPANAMIDE OF FORMULA V STARTING FROM 3-[3-(TRIFLUROMETHYL) PHENYL] PROPENOIC ACID

3-[3-(trifluromethyl) phenyl] propenoic acid (50 g) and toluene (500 ml were taken into an autoclave vessel and 5% Pd/C (5 g) was added to it. The reaction mass was heated to about 42 ⁰C and a pressure of 5 Kg/cm² was applied and maintained for about 4 hours. After the reaction was completed, the reaction mass was filtered over a celite bed and the bed was washed with 200 ml of toluene. The filtrate was distilled at a temperature of about 60 °C under vacuum to get a residue. To the residue obtained dichloromethane (250 ml) was added and stirred at 28 ⁰C. HoBt (37.45 g) was added to the above mixture followed by addition of a solution of DCC (57.25 g) in dichloromethane (450 ml). The reaction mass was maintained at about 28 ⁰C for about 3 hours and then cooled to about 5 ⁰C and maintained for about 30 minutes. The reaction mass was then filtered over a celite bed and the bed was washed with dichloromethane (100 ml). The filtrate was taken into a fresh round bottom flask and stirred at about 27 ⁰C for about 30 minutes. K₂CO₃ (31.9 g) was added to the filtrate followed by the addition of a solution of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (39.5 g) in dichloromethane (100 ml). The reaction mass was maintained at about 27 ⁰C for about 3 hours.

After the reaction was completed, water (400 ml) was added to the reaction mass and cooled to about 5⁰C. The reaction mass was maintained at about 5 ⁰C for about 30 minutes, and then filtered over a hyflow bed. The bed was washed with dichloromethane (100 ml). The organic layer was separated from the filtrate and washed with water (2X200 ml). The organic layer was then distilled and ethyl acetate (800 ml) was added to it and cooled to about 10 °C. The reaction mass was maintained at about 10 ⁰C for about 30 minutes and then filtered over a celite bed. The bed was washed with ethyl acetate (50 ml). The combined organic layer was distilled off completely at about 60 °C, and then n-hexane (100 ml) was added to it at the same temperature. Another 350 ml of n-hexane was added to the crude obtained and heated to about 40 °C. The reaction mass was maintained at the same temperature for about 30 minutes followed by addition of another 150 ml of n-hexane. The reaction mass was then cooled to about 30 ⁰C and maintained for about 30 minutes. The separated solid was filtered and washed with n-hexane (150 ml). The wet solid was dried at about 42 ⁰C for about 6 hours to yield 68.7 g of the title compound. Purity By HPLC: 97.7% EXAMPLE 8: PROCESS FOR THE PREPARATION OF CINACALCET:

Tetrahydrofuran (50 ml) and N-[(1 R)-1-(1-napthyl) ethyl]-3-(3- trifluoromethyl) phenyl] propanamide (10 g) were taken into a round bottom flask followed by stirring for about 5 minutes under nitrogen atmosphere. Lithium aluminium hydride (1.73 g) was added over a period of 20 minutes followed by heating to about 64 ⁰C. The resultant reaction solution was stirred for about 3 hours followed by cooling to about 10 ⁰C. The reaction solution was quenched by the addition of ethyl acetate (150 ml) followed by addition of water (150 ml) over a period of about 15 minutes. The organic layer was separated, and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layer was washed with saturated sodium chloride solution (2*50 ml). The organic layer was separated followed by drying over anhydrous sodium sulphate (10 g). The solvent was distilled completely at about 40 ⁰C under vacuum to afford 7.5 g of the title compound.

Purity by HPLC: 90.33%.

Specific optical rotation (SOR) : [α]_D ²⁵ = + 9.62°. (C =1% Methanol). Mass (m/z) : 357 amu.

EXAMPLE 9: PREPARATION OF CINACALCET HYDROCHLORIDE STARTING FROM N-[(1 R)-1-(1 -NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE WITHOUT ISOLATING CINACALCET FREE BASE:

N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide (200 g) was taken into a round bottom flask and toluene (2000 ml) was added to it. The contents were heated to about 50 to 60⁰C and checked for clear dissolution. Vitride (670 ml) was added to the above reaction mass between 50⁰C to 60⁰C. The reaction mass was stirred at about 50 to 60⁰C for 25-30 min. Reaction completion was checked using thin layer chromatography. After the rection was completed, the reaction mass was cooled to 0-5⁰C. A solution of 10% sodium potassium tartarate (4000 ml) precooled to 5-10⁰C was added slowly to the above reaction mass below 15°C. The reaction mass was stirred at 25-35°C for 15-30 min. The organic layer was separated and the aqueous layer was extracted into toluene (1000 ml). The combined organic layer was washed with 1 % acetic acid solution (2 x 1000ml) at 50-60⁰C followed by washing with water (2 x 1000 ml) at 50-60⁰C. The organic layer was distilled off completely at below 6O⁰C under vacuum. The residue obtained was cooled to 25-35°C and ethyl acetate (200 ml) was added to it. The solution was stirred for 5-10 minutes and then filtered through Hyflow bed, and the bed was washed with ethyl acetate (400 ml). The filtrate was distilled off completely under vaccum at 50-60°C.

20 g of the crude obtained above and ethyl acetate (20 ml) were taken into another round bottom flask and stirred for 10 minutes at 25 to 35 ⁰C. The mixture was heated to 50 to 60 ⁰C and HCI dissolved in ethyl acetate (20 ml) was added at the same temperature slowly. The reaction mass was stirred for about 20 minutes at 50 to 60 °C and then 300 ml of di-idopropyl ether was added to it. The reaction mass was maintained at the same temperature for another 20 minutes and then 200 ml of water was added to it. The reaction contents were stirred for another 20 minutes and then cooled to 25 to 35 °C. The reaction mass was maintained at 25 to 35 °C for about 60 minutes and then filtered. The filtered solid was washed with di-idopropyl ether (40 ml) and the wet solid was dried at about 70 °C for 6 to 8 hours to yield 16.9 g of the title compound. Purity By HPLC: 99.5%. Impurity 1 : (Desfluro impurity): 0.04%. Impurity 2: (at RRT 0.90): 0.17%. Impurity 3: (amide of Formula V): 0.05%.

EXAMPLE 10: ALTERNATIVE PROCESS FOR THE PREPARATION OF CINACALCET HYDROCHLORIDE:

A solution of N- [(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluoromethyl) phenyl] propanamide (40 g) in tetrahydrofuran was stirred for about 10 minutes under nitrogen atmosphere at about 30 ⁰C. Lithium aluminium hydride (7.91 g) was slowly added over about 30 minutes. The resultant reaction mixture was heated to about 65 ⁰C followed by stirring for about 5 hours. After the completion of the reaction, reaction mass was cooled to about 0 ⁰C followed by quenching the reaction mass with 10% aqueous hydrochloric acid (400 ml) slowly over about 15 minutes. The reaction mass was extracted with dichloromethane (400 ml) followed by separation of organic and aqueous layers. The aqueous layer was extracted with dichloromethane (200 ml) followed by separation of organic and aqueous layers.

The combined organic layers were washed with saturated sodium chloride solution (2x200 ml). The organic layer was dried over 40 g of anhydrous sodium sulphate. The solvent was distilled off completely at about 40 °C under vacuum to afford a residue. To the residue ethyl acetate (200 ml) was added and stirred at about 40 ⁰C for about 15 minutes. To this solution n-heptane (320 ml) was added followed by cooling to about 25 ⁰C. The resultant suspension was stirred for about 45 minutes. The separated solid was filtered and washed with n-heptane (80 ml). The wet solid was dried at about 75 ⁰C for about 4 hours to afford 25.8 g of the title compound.

EXAMPLE 11 : PROCESS FOR THE PREPARATION OF N-(R)-(I- NAPHTHALENE-1-YL- ETHYL)-3-(3 0 TRIFLUROMETHYL-PHENEYL) ACRYL AMIDE

3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (5 g) and dichloromethane (50 ml) were taken into a round bottom flask followed by stirring for about 5 minutes. To the reaction solution HOBT (3.72 g) was charged followed by addition of a solution of DCC (5.68 g) in dichloromethane (25 ml) over a period of about 15 minutes. The resultant reaction mixture was stirred for about 3-4 hours. After the completion of the reaction, bi product DCU was filtered through celite and washed with dichloromethane (5 ml). The filtrate was charged into a round bottom flask. Potassium carbonate (3.174) was charged followed by addition of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (3.93 g) dissolved in dichloromethane (10 ml) over about 15 minutes. The resultant reaction solution was stirred at about 25 to 35 ⁰C for about 90 minutes. The separated solid was filtered and the filtrate was distilled completely at about 39 ⁰C under vacuum. To the residue n-hexane (40 ml) was charged followed by raising the temperature to about 45 ⁰C. The resultant reaction solution was stirred for about 40 minutes. The solid separated was filtered and washed with n-hexane (10 ml). The solid obtained was dried at about 75 ⁰C under vacuum for about 5 hrs to afford 5.8 g of title compound. Purity By HPLC: 98.2%. Mass (m/z): 371 amu.

EXAMPLE 12: ALTERNATE PROCESS FOR THE PREPARATION OF N-(1- NAPHTHALENE-I -YL-ETHYL)-S-(S-TRIFLUROMETHYL-PHENYL) ACRYL

AMIDE WITHOUT USING HOBT:

3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (2 g) and dichloromethane (10 ml) were taken into a round bottom flask and stirred for about 5 minutes. DCC (2.3 g) dissolved in 10 ml of dichloromethane was added over a period of about 15 minutes, and then potassium carbonate (1.24 g) was added followed by addition of a solution of R-(+)-1-(1-naphthyl) ethylamine of Formula IV (1.5 g) dissolved in dichloromethane (10 ml) over about 15 minutes.

The resultant reaction mixture was stirred for about 1 to 2 hours. After the completion of the reaction the by-product DCU was filtered through celite, and the celite bed was washed with dichloromethane (4 ml). The filtrate was distilled completely at about 39 ⁰C under vacuum. To the residue obtained, 20 ml of n- heptane was added followed by raising the temperature to about 70 to 75 ⁰C. The resultant reaction solution was stirred for about 10 to 15 minutes and cooled to about 25 to 35 ⁰C. The separated solid was filtered and washed with n-heptane (5 ml). The wet solid was dried at about 75 °C under vacuum for about 9 hours to afford 2.6 g of title compound. Purity By HPLC: 96.73%. Mass (m/z) : 371 amu.

EXAMPLE 13: PREPARATION OF R-(-)-N-(1-NAPHTHALEN-1-YL-ETHYL)-3-(3- TRIFLUOROMETHYL-PHENYL)-ACRYLAMIDE USING BORIC ACID:

3-(trifluoromethyl) cinnamic acid (3Og) was taken into a round bottom flask containing toluene (300 ml) and stirred for about 10 minutes. R-(-)-1-(1-napthyl) ethylamine of Formula IV (0.79 g) was added to the mixture followed by addition of boric acid (1.69 g). The reaction mass was heated to about 110 ⁰C and maintained until completion of the reaction. The separated solid was filtered and washed with toluene 960 ml). The obtained filtrate was distilled completely at about 75 ⁰C under vacuum to afford the title compound as a residue.

The obtained solid was charged into a round bottom flask containing n- heptane (90 ml). The mass was heated to about 45 ⁰C and stirred for about 60 minutes. The separated solid was filtered and washed with n-hexane (300 ml) and suction dried for about 15 minutes. The obtained solid was filtered and dried under vacuum at about 50 ⁰C to afford 17 g of the title compound.

EXAMPLE 14: PREPARATION OF CINACALCET STARTING FROM N-(1-

NAPHTHALENE-I -YL-ETHYL)-S-(S-TRIFLUROMETHYL-PHENYL)-

ACRYLAMIDE:

Tetrahydrofuran (20 ml) and N-(1-naphthalene-1-yl-ethyl)-3-(3- trifluromethyl-phenyl)acryl amide (1.7 g) were taken into a round bottom flask and stirred for about 5 minutes under nitrogen atmosphere. Lithium aluminum hydride (LAH) (0.51 g) was added over about 20 minutes followed by heating to about 64 ⁰C. The resultant reaction solution was stirred at about 64 ⁰C for about 23 hours followed by cooling to about 0 to 10 ⁰C. The reaction solution was quenched by adding ethyl acetate (25 ml) followed by water (25 ml) over about 15 minutes. The organic layer was separated and washed with saturated sodium chloride solution (2^χ15 ml). The organic layer was separated and dried over 1.7 g of anhydrous sodium sulphate. The solvent was distilled completely at about 40 ⁰C under vacuum. The crude compound was purified by column chromatography using silica glass column and using n-hexane and ethyl acetate in the ratio of 9:1 as eluent to afford 0.8 g of the title compound.

Purity By HPLC: 98.78%.

EXAMPLE 15: PREPARATION OF Cl NACALCET ACETATE FROM R-(-)-N-(1- NAPHTHALEN-I -YL-ETHYL)-S-(S-TRIFLUOROMETHYL-PHENYL)- ACRYLAMIDE USING VITRIDE AS THE REDUCING AGENT:

R-(-)-N-(1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide (150 g) was taken into a 4 neck round bottom flask containing toluene (450 ml) and stirred for about 10 minutes. 377 ml of vitride was added slowly at about 30 ⁰C over about 3 hours. The resultant reaction mixture was heated to about 55 ⁰C and stirred for about 5 hours. The reaction mass was cooled to about 5 ⁰C and the reaction mass was quenched by the addition of 10% sodium potassium tartrate solution (1500 ml) and stirred for about 45 minutes. The organic and aqueous layers were separated and the aqueous layer was extracted with toluene (2^χ350 ml). The organic layer was then washed with water (2^χ350 ml). The organic layer was distilled completely at about 75 ⁰C under vacuum to afford 136 g of residue.

The obtained residue was cooled to about 30° C and toluene (450 ml) was charged followed by stirring for about 5 minutes. 5% acetic acid solution (450 ml) was added slowly over about 30 minutes followed by stirring for about 3 hours. The organic and aqueous layers were separated and the organic layer was dried over anhydrous sodium sulfate. Organic layer was distilled completely at about 75 ⁰C under vacuum to afford the 66g of the title compound. EXAMPLE 16: PARTIAL REDUCTION OF N-(I -NAPHTHALENE-I -YL-ETHYL)-S -(3-TRIFLUROMETHYL-PHENYL) ACRYLAMIDE TO GIVE N- [(1 R)-1-(1- NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE:

A solution of N-(1-naphthalene-1-yl-ethyl)-3-(3-trifluromethyl-phenyl) acryl amide (2 g) dissolved in methanol (150 ml)was taken into an autoclave vessel followed by addition of Raney nickel (2 g) and 5 kg/cm² of anhydrous hydrogen gas pressure was passed into the reaction suspension under agitation at about 45 -50 ⁰C for about 3 hours. After the completion of the reaction, the reaction suspension was filtered on celite and the celite bed was washed with methanol (10 ml). The filtrate was distilled completely at about 50 ⁰C under vacuum. N- hexane (16 ml) was added followed by raising the temperature to about 45 ⁰C. The resultant reaction solution was stirred for about 40 minutes. The separated solid was filtered and washed with n-hexane (4 ml). The wet solid was dried at about 75 ⁰C under vacuum for about 5 hrs to afford 1.6 g of title compound. Purity By HPLC: 96.88% Mass (m/z) : 371 amu.

EXAMPLE 17: PROCESS FOR THE PREPARATION OF 3-(3- TRIFLUOROMETHYL-PHENYL)-PROPAN-1-OL.

3-[3-(trifluromethyl) phenyl] propanoic acid (2.94 g) and tetrahydrofuran (30 ml) were taken into a round bottom flask followed by stirring for about 10 minutes under nitrogen atmosphere. Lithium aluminium hydride (0.5 g) was added slowly over about 5 minutes. The resultant reaction solution was stirred for about 35 minutes. The reaction solution was cooled to about 5 ⁰C followed by quenching by the addition of 10% HCI (30 ml) slowly over about 15 minutes. The reaction mass was extracted with dichloromethane (30 ml) followed by separation of organic and aqueous layers. The organic layer was distilled completely at about 39 ⁰C under high vacuum to afford 2.7 g of the title compound. Mass (m/z): 204 amu. EXAMPLE 18: PROCESS FOR THE PREPARATION OF 1-(3-BROMO- PROPYL)-3-TRIFLUOROMETHYL-BENZENE.

3-(3-Trifluoromethyl-phenyl)-propan-1-ol (2 g) and 48% aqueous hydrobromic acid (0.8 g) were charged into a round bottom flask followed by stirring for about 10 minutes. The resultant reaction mass was cooled to about 5 ⁰C followed by addition of concentrated sulfuric acid (1.92 g) slowly over about 10 minutes. The reaction mixture was heated to about 110 ⁰C and stirred for about 2 hours. The reaction solution was then cooled to about 30 ⁰C followed by quenching by addition of precooled water (50 ml). The reaction solution was extracted with dichloromethane (2*50 ml) followed by separation of organic and aqueous layers. The organic layer was washed with saturated sodium chloride solution (2^χ25 ml). The organic layer was dried over anhydrous sodium sulfate (2 g) followed by distillation of solvent completely at about 40 °C under vacuum to afford 2.1 g of the title compound.

EXAMPLE 19: PROCESS FOR THE PREPARATION OF CINACALCET FROM THE COMPOUND:

1-(3-bromo-propyl)-3-trifluoromethyl-benzene (2 g) and dichloromethane (10 ml) were taken into a round bottom flask followed by stirring for about 10 minutes. To the reaction solution R-(+)-1-(1-naphthyl) ethylamine of Formula IV (1.3 g) and potassium carbonate (0.75 g) were charged. The resultant reaction mixture was heated to about 38 ⁰C followed by stirring for about 1 hour, 15 minutes. After the completion of the reaction, the solvent was distilled completely at about 40 ⁰C under vacuum. To the residue methyl isobutyl ketone (10 ml) was charged followed by heating to about 78 ⁰C and stirring for about 1 hour, 15 minutes.

Potassium iodide (0.2 g) was charged followed by heating to about 78 ⁰C and stirring for about 8 hours. The reaction mass was cooled to about 26 ⁰C followed by addition of 10% hydrochloric acid solution (100 ml). The resultant reaction suspension was stirred for about 10 minutes. The organic layer was separated and distilled completely at about 39 ⁰C, to afford a solid. Ethyl acetate (30 ml) and n-heptane (100 ml) were added followed by stirring at about 45 ⁰C for about 20 minutes. The separated solid was filtered and washed with n-heptane (20 ml). The wet solid was dried at about 70 ^CC under vacuum for about 3 hours to afford 0.9 g of the title compound.

EXAMPLE 20: PREPARATION OF RACEMIC CINACALCET

N-[1-(1-napthyl)ethyl]-3-(3-trifluoromethyl)phenyl propanamide (93 g) and tetrahydrofuran (930 ml) was charged into a round bottom flask and stirred for about 10 minutes at about 30 ⁰C under nitrogen atmosphere. Lithium aluminum hydride (16.23 g) was added slowly over about 20 minutes followed by heating to about 60 to 65 ⁰C and maintained for about 3 hours. The reaction mass was cooled to about 10 ⁰C and quenched by addition of ethyl acetate (930 ml) and water (930 ml) for about 10 to 15 minutes at about 5 ⁰C. The organic layer was separated and aqueous layer extracted with ethyl acetate (465 ml). The organic layer was washed with saturated sodium chloride solution. The organic layer was then dried over anhydrous sodium sulphate and distilled completely under vacuum to afford 93.59 g of the title compound.

EXAMPLE 21 : PREPARATION OF CINACALCET FROM RACEMIC CINACALCET:

N-[1 -(1 -naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1 -amino propane (25 g), acetone (125 ml) and water (15 ml) were taken into a round bottom flask and stirred for about 10 minutes at about 3O⁰C. (-)-di-p-toluoyl-D-tartaric acid (75 g) dissolved in acetone (75 ml) was added followed by stirring at about 30 ⁰C for about 3 hours. The separated solid was filtered and washed with acetone (50 ml) followed by drying at about 75 ⁰C for about 2 hours. 1.5 g of the obtained solid was taken into a round bottom flask and ethyl acetate (15 ml) was added to it and heated to reflux and maintained for about 30 minutes. The solution was cooled to about 30 ⁰C and the separated solid filtered and dried at about 75°C for about 3 hours to obtain the diasteromeric salt.

The obtained dried solid was taken into another round bottom flask containing ethyl acetate (90 ml). The mixture was heated to reflux for about 30 minutes followed by cooling to 30 ⁰C and stirring for about 30 minutes. The separated solid was filtered and washed with ethyl acetate and dried at about 75⁰C for about 3 hours.

The obtained solid was charged into a round bottom flask containing water (75 ml). Caustic lye (8.5 ml) was added to the solution and stirred for 5-10 minutes. Dichloromethane (110 ml) was added to the solution and stirred for 10 minutes at about 30 ⁰C. The organic layer was separated and washed with water (75 ml). The combined organic layers were dried over anhydrous sodium sulphate followed by complete distillation of the organic layer at about 35 ⁰C under vacuum to afford 3.23 g of title compound.

Chiral Purity By HPLC: 99.45%.

EXAMPLE 22: PREPARATION OF CINACALCET HYDROCHLORIDE IN ISOPROPYL ALCHOL AND WATER:

Cinacalcet free base (7.5 g) and isopropyl alcohol (37.5 ml) were taken into a round bottom flask and heated to about 70 ⁰C. To the resultant reaction solution, a 30% aqueous hydrochloric acid was added over about 15 minutes followed by stirring for about 15 minutes. The resultant reaction suspension was cooled to about 40 ⁰C followed by charging the reaction suspension into another round bottom flask containing precooled demineralised water (375 ml). The reaction mass was stirred at about 25 ⁰C for about 45 minutes. The separated solid was filtered and washed with demineralised water (187.5 ml). The wet solid was dried at about 75 ⁰C for about 6 hours to afford 8 g of the title compound. Purity by HPLC: 92.9%.

EXAMPLE 23: PURIFICATION OF CINACALCET HYDROCHLORIDE IN A COMBINATION OF ACETONITRILE AND WATER:

Cinacalcet hydrochloride (10.0 g) was taken into a round bottom flask. A solution of acetonitrile (16 ml) and water (84 ml) was added to it and the mixture heated to 70-80⁰C. The mixture was stirred at 70-80⁰C for 10-20min and checked for clear dissolution. The reaction mass was then cooled to 5-10⁰C and stirred at 5-10 °C for 1-2 hours. The separated solid was filtered and washed with water (30 ml). The wet material was suck dried for 30-45min followed by drying at 65-75°C under vacuum for 6-8 hrs.

To the dry solid a solution of acetonitrile (14.4 ml) and water (75.6 ml) was added and the mixture heated to 70-80⁰C. The mixture was maintained at 70- 80⁰C for 10-20min and checked for clear dissolution. The solution was then filtered through paper cloth, and the cloth was washed with water (30 ml). The filtrate was cooled to 5-10⁰C, and stirred for 1-2 hours. The separated solid was filtered and washed with water (30 ml). The wet material was suck dried for 30- 45 minutes under vacuum, followed by drying at 65-75°C under vacuum for 6-8 hours to yield 8.2 g of the title compound. Purity By HPLC: 99.8% Chiral Purity By HPLC: 99.93%

EXAMPLE 24: PURIFICATION OF CINACALCET HYDROCHLORIDE IN A COMBINATION OF ETHYL ACETATE AND N-HEPTANE FOLLOWED BY PURIFICATION IN ACETONITRILE:

8 g of cinacalcet hydrochloride obtained in above example and acetonitrile (36 ml) were taken into a round bottom flask followed by heating to about 70 °C. The resultant reaction solution was stirred for about 30 minutes followed by cooling to about 25 ⁰C. The reaction solution was stirred at about 25 ⁰C for 30 minutes. The solvent was distilled completely at about 50 ⁰C under vacuum to afford a residue. To the residue 45 ml of ethyl acetate was charged followed by stirring at about 50 ⁰C for about 15 minutes to obtain a homogenous solution. To the resultant reaction solution 72 ml of n-heptane was charged followed by stirring at about 25 ⁰C for about 45 minutes. The solid separated was filtered and the solid was washed with 18 ml of n-heptane.

The solid obtained was dried at about 75 ⁰C for about 3 hours to afford 9 g of the title compound. To the solid obtained 36 ml of acetonitrile was charged followed by heating to about 70 ⁰C. The reaction solution was stirred at about 70 ⁰C for about 15 minutes followed by cooling to about 30 ⁰C. The resultant reaction suspension was stirred at about 30 ⁰C for about 45 minutes. The separated solid was filtered and the solid was washed with 18 ml of acetonitrile. The solid obtained was dried at about 75 ⁰C for about 6 hours to afford 3.2 g of the title compound in pure form. Purity by HPLC: 99.38%.

EXAMPLE 25: PURIFICATION OF CINACALCET HYDROCHLORIDE IN ACETONITRILE:

Cinacalcet hydrochloride (65 g) and acetonitrile (325 ml) were taken into a round bottom flask and heated to about 70 °C for about 15 minutes. The resultant reaction solution was cooled to about 40 °C followed by stirring for about 30 minutes. The separated solid was filtered and washed with acetonitrile (65 ml). The wet solid was dried at about 70 ⁰C for about 6 hours to afford 49 g of the title compound in pure form. Purity by HPLC: 99.46%.

DSC: Shows endotherm at 179.43. EXAMPLE 26: PREPARATION OF CINACALCET HYDROCHLORIDE FROM CINACALCET ACETATE SALT

Cinacalcet acetate (5 g) was taken into a 4 neck round bottom flask containing 25 ml of toluene and stirred for about 10 minutes. Activated charcoal carbon (2.5 g) was added to it and heated to about 65° C for about 45 minutes. The suspension was filtered through celite and the celite bed was washed with methanol (10 ml). The filtrate was distilled completely at about 65 ⁰C under vacuum to give 26 g of residue.

The obtained residue was taken into a 4 neck round bottom flask containing 25 ml of dichloromethane and stirred for about 15 minutes. 10% aqueous hydrochloric acid (25 ml) was added to the reaction solution and stirred for about 15 minutes. The aqueous layer was separated, and the organic layer was distilled completely at about 35 ⁰C under vacuum to afford a residue of the title compound. To the obtained residue ethyl acetate (10 ml) was added and stirred for about 2 hours. The separated solid was filtered and the solid was washed with n-heptane (10 ml) to afford 2.01 g of the title compound.

EXAMPLE 27: PREPRATION OF CINACALCET HYDROCHLORIDE FROM CINACALCET FREE BASE USING AMMONIUM CHLORIDE:

Cinacalcet of Formula I (5 g) and methanol (45 ml) were taken into a round bottom flask and stirred for about 10 minutes. Ammonium chloride (0.8) was taken into the reaction solution and cooled to about 20 ⁰C and stirred for 2 hours. The reaction solution was distilled completely at about 45 ⁰C under vacuum and dichloromethane (50 ml) and water (10 ml) were added and stirred for about 15 minutes at about 30 ⁰C. The organic layer was separated and washed with water (10 ml) and then dried over anhydrous sodium sulfate. The obtained neat organic layer was treated with carbon (0.5 g) and stirred for about 15 minutes. The resultant mixture was passed through celite and the celite bed was washed with dichloromethane (10 ml). The obtained filtrate was distilled completely under vacuum to give the title compound as a residue.

The obtained residue was dissolved in acetone and stirred at about 30 ⁰C for about 45 minutes. The separated solid was filtered and the solid was washed with acetone (5 ml). The obtained solid was dried at about 75°C under vacuum to give 1.8 g of the title compound.

Purity By HPLC: 98.27%.

EXAMPLE 28: PREPARATION OF CINACALCET HYDROCHLORIDE FROM CINACALCET OXALATE SALT:

Cinacalcet free base (2 g) was taken into a round bottom flask, ethyl acetate (20 ml) and oxalic acid (0.5 g) were added to it. The mixture was stirred and heated to about 55 °C and checked for clear dissolution. After a clear dissolution was obtained, the reaction mass was distilled at about 55 °C atmospherically. To the residue obtained, diisopropyl ether (16 ml) was added, and transferred to another round bottom flask. Di-isopropyl ether (16 ml) and water (20 ml) were then added to it and heated to about 50 °C. A 11.5% solution of hydrochloric acid in ethyl acetate (0.23 ml) was then added to the solution obtained above and maintained at about 53 °C for about 30 minutes. The reaction mass was then allowed to cool to about 25 °C and maintained for about 2 hours. The separated solid was filtered and washed with di-isopropyl ether (4 ml). The wet solid as dried at about 75 °C for about 5 hours to yield 1.5 g of the title compound.

Purity By HPLC: 98.9%.

Impurity 1 (Desfluoro impurity): 0.14%.

Impurity 2 (RRT impurity): 0.83%. EXAMPLE 29: PREPARATION OF [3-(3-DIFLUOROMETHYL-PHENYL)- PROPYL]-(I -NAPHTHALEN-I -YL-ETHYL)-AMINE FROM N- [(1 R)-1-(1- NAPTHYL) ETHYL]-3-(3-TRIFLUROMETHYL) PHENYL] PROPANAMIDE:

N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide (75 g) and tetrahydrofuran (750 ml) were taken into a round bottom flask and heated to about 40 ⁰C. lithium aluminium hydride (59.82 g) was added to it slowly at the same temperature. The reaction mass was further heated to about 65 ⁰C and maintained for about 50 hours. The reaction mass was then cooled to about 5 °C. The cooled reaction mass was slowly added to ethyl acetate (750 ml) cooloed to a temperature of about 5 ⁰C. and stirred for about 30 minutes. Water (750 ml) was then added to the above reaction mass and stirred at about 28 °C for 30 minutes. The reaction mass was fltered over a celite bed and the organic layer was separated. The organic layer was distilled off completely at about 45 °C under a vacuum of about 650 tnm/Hg to yield 72.0 g of the title compound in crude form.

Mass (m/z): 339.

EXAMPLE 30: DETERMINATION OF IMPURITIES IN CINACALCET AND ITS

SALTS:

Determining the level of impurities in cinacalcet and its salts using HPLC. The

HPLC analysis conditions are as described in Table 1.

Table 1 : HPLC method for detecting the level of the impurities.

Column and Hypersil Gold C-18 150 X 4.6 X 3.0 μ. or equivalent Packing:

Buffer: 0.02 M of NaH₂PO₄-H₂O was taken in 1000 mL of MQ water

And, 1 ml triethylamine was added and mixed well. pH was adjusted to 6.0 with dilute phosphoric acid.

Mobile Phase Mixed buffer and acetonitrile in the ratio 80:20 v/v. A:

Mobile Phase Mixed acetonitrile and buffer in the ratio 80: 20 v/v.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

We claim:

1. A process for making cinacalcet hydrochloride, said process comprising: a) providing a solution of free base of cinacalcet in a solvent that is an alcohol or alkyl acetate; b) treating said solution with an amount of hydrochloric acid sufficient to convert said free base to said hydrochloride salt; c) adding an anti-solvent to said treated solution in the amount sufficient to precipitate said hydrochloride salt in the form of a solid; and d) isolating said precipitated solid thereby obtaining said cinacalcet hydrochloride.

2. The process of claim 1 , wherein said solvent is selected from the group consisting of isopropanol and ethyl acetate

3. The process of claim 2, wherein said solvent is isopropanol.

4. The process of claim 3, wherein said anti-solvent is water.

5. The process of claim 2, wherein said solvent is ethyl acetate.

6. The process of claim 5, wherein said anti-solvent is n-heptane.

7. A process for making cinacalcet hydrochloride, said process comprising: a) providing a solution of free base of cinacalcet in an organic solvent; b) treating said solution with an inorganic salt, which is a source of hydrochloric acid, to convert said free base of cinacalcet to said cinacalcet hydrochloride.

8. The process of claim 7, wherein said solvent is an alcohol

9. The process of claim 8, wherein said alcohol is methanol.

10. The process of claim 7, wherein said inorganic salt is ammonium chloride.

11. A process for making cinacalcet hydrochloride, said process comprising: a) providing a solution of an acid addition salt of cinacalcet other than cinacalcet hydrochloride, wherein said salt is the salt of an acid weaker than hydrochloric acid; b) treating said solution with an amount of hydrochloric acid sufficient to convert said acid addition salt to said hydrochloride salt; and c) isolating said cinacalcet hydrochloride.

12. The process of claim 11 , wherein said isolating step comprises adding an anti-solvent to said treated solution in the amount sufficient to precipitate said hydrochloride salt in the form of the solid, and filtering said solid.

13. A solid pharmaceutical composition comprising a molecular dispersion that consists essentially of cinacalcet hydrochloride in an amorphous form and polyvinylpyrollidone.

14. The solid pharmaceutical composition of claim 13, which is prepared by a process comprising providing a solution of said cinacalcet hydrochloride and said polyvinylpyrollidone in a volatile organic solvent, and removing solvent thereby obtaining said molecular dispersion.

15. The solid pharmaceutical composition of claim 13, wherein said cinacalcet hydrochloride and said polyvinylpyrollidone are present in the ratio ranging from about 1 :10 to 10:1.

16. The solid pharmaceutical composition of claim 13, wherein said cinacalcet hydrochloride and said polyvinylpyrollidone are present in the ratio ranging from about 1 :2 to 2:1.

17. A process for the purification of cinacalcet hydrochloride, said process comprising: a) providing a solution of cinacalcet hydrochloride in a nitrile solvent, b) adding an anti-solvent to said solution to precipitate a solid, c) isolating said solid, which is the purified cinacalcet hydrochloride.

18. The process of claim 17, wherein said nitrile solvent is acetonitrile.