WO2008058235A2

WO2008058235A2 - Processes for the preparation of cinacalcet

Info

Publication number: WO2008058235A2
Application number: PCT/US2007/084073
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
Original assignee: Dr. Reddy's Laboratories, Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2006-11-08
Filing date: 2007-11-08
Publication date: 2008-05-15
Also published as: WO2008058235A3

Abstract

There are described several processes for making a free base of cinacalcet. One of the described processes goes through an intermediate of the formula (II) where R1 and R2 are both hydrogen, or R1 and R2, together, form a double bond.

Description

PROCESSES FOR THE PREPARATION OF CINACALCET

TECHNICAL FIELD

The present patent application relates to processes for the preparation of cinacalcet and its salts. It also relates to intermediates for the preparation of cinacalcet.

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. They 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 can 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.

The prior art processes for preparation of analogues of cinacalcet require reagents which are not best for use on a large scale. 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 a free base of cinacalcet of the formula (I):

formula (I) which process includes treating a compound of the formula (II):

formula (II) where Ri and R₂ are both hydrogen, or R₁ and R₂, together, form a double bond, with a reducing agent effective to convert amides to secondary amines, whereby providing free base of cinacalcet.

Various embodiments and variants are provided.

In another aspect, there is provided a process for making a free base of cinacalcet, which process includes: a) providing a compound of the structure

b) converting the compound produced in step (a) to a compound of the structure

c) converting the compound produced in step (b) to a compound of the structure

wherein X is a leaving group; and d) without isolating, coupling the compound produced in step (c) with the compound of the structure

thereby producing free base of cinacalcet.

Various embodiments and variants are provided.

In yet another aspect, there is provided a process for making a free base of cinacalcet, the process including: a) providing a racemic compound of the formula (X)

formula (X), where Ri and R₂ are both hydrogen, or Ri and R₂, together, form a double bond;

b) reducing said compound of the formula (X) to produce a racemic compound of the structure

c) resolving said racemic compound produced in step b) thereby producing said free base of cinacalcet.

Various embodiments and variants are provided.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an XRPD pattern of a sample of crystalline N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide.

Fig. 2 is an XRPD pattern of a sample of crystalline N-(R)-(I -naphthalene- 1 -yl-ethyl)-3-(3-trifluromethyl-Phenyl) acrylamide.

Fig. 3 is an XRPD pattern of sample of crystalline N-[1-(1-napthyl)ethyl]-3- (3-trifluromethyl) phenyl] propanamide.

DETAILED DESCRIPTION

The term "cinacalcet" denotes R enantiomer and is used in this manner throughout the draft. The S-enantiomer and the racemic form, which is a mixture of the R and S enantiomers, will be referred to as S-cinacalcet and racemic cinacalcet for the purposes of differentiation.

The present patent application provides a process for making a free base of cinacalcet having the formula (I):

formula (I) by treating the compound of the formula (II):

formula (II) with a reducing agent effective to convert the amide of the compound of the formula (II) to the secondary amine of the compound of the formula (I). With reference to the formula (II), Ri and R₂ may be both hydrogen, or Ri and R₂, together, may form a double bond.

In one variant, Ri and R₂ are both hydrogen and thus the compound of the formula (II) has the structure MA:

(HA) In this embodiment, the reduction step involves only reduction of the amide.

In another embodiment, Ri and R₂, together, form a double bond and thus the compound of the formula (II) has the structure (NB):

(HB)

In this embodiment, the reduction step involves a reduction of both the amide and the double bond.

The compound of the formula (II) may be produced by a reaction between a compound of the formula (III):

formula (III) and a compound of the structure (IV):

(IV)

With reference to the formula (III), Ri and R₂ may be both hydrogen, or Ri and R₂, together, may form a double bond. R₃ is hydrogen, C₁-C₃ alkyl or -C(O)-CH₃.

In one embodiment, R-i and R₂, together, may form a double bond. If so, the reduction is sequential. The compound of the structure (NB):

(HB) Is converted to an intermediate of the structure (HA)

(HA) which is then further reduced to free base of cinacalcet (I).

In another embodiment, R-i, R₂, and R₃ are all hydrogen and the compound of the formula (III) has the structure (NIB):

(IHB)

The overall synthetic scheme is shown in the Scheme

As seen with reference to Scheme I, the compound of the structure (V) is typically produced as a transient intermediate for reductions of steps c) or f). The compound of the structure (V) is usually not isolated.

With reference to Scheme I, the steps a) or b) may be carried out with or without isolating intermediate compounds.

The reducing agents suitable for use in steps a), c) and f) are those capable of reducing an amide to a secondary amine. Non-limiting examples of suitable reducing agents include palladium on carbon, rhodium, Raney nickel, etc., lithium aluminum hydride, sodium borohydride in acidic conditions, sodium borohydride in pyridine, and sodium dihydro-bis- (2-methoxyethoxy) aluminate solution ("Vitride").

The condensation step b) or d) may be carried out in a number of ways. Thus, the condensation may be carried out in the presence of a coupling agent, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), in the presence of a catalytic auxiliary nucleophiles, such as 1-hydroxybenzotriazole (HOBt), N- hydroxysuccinimide (HOSu), and N-hydroxy-5-norbene-endo-2, 3-dicarboxamide (HONB), or dehydrating agents, such as carbonyldiimidazole, boric acid, phosphorus pentoxide, acetic anhydride, and sulfuric acid. The condensation may be also carried out by treating the carboxylic acid with a chlorinating agent to produce an acid chloride, followed by a reaction with the amine of the formula (IV) in the presence of a base. Non-limiting examples of chlorinating agents include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride.

Steps a), b), c) and f) may be carried out in an organic solvent. Examples of suitable solvents include, but are not limited to, hydrocarbon solvents, such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; alcoholic solvents, such as C₁-C₄ alcohols; C₂-C₆ ketone solvents, 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 tetrahydrofuran (THF), diethylether, methyl tertiary-butyl ether, and 1 ,4- dioxane; hydrocarbon solvents, such as toluene, xylene, and cyclohexane; esters, such as ethyl acetate, isopropyl acetate, and tertiary-butyl acetate; nitriles, such as acetonitrile, and propionitrile; and aprotic polar solvents, such as dimethylsulfoxide (DMSO), N,N-dimethyl-formamide (DMF), dimethylacetamide (DMAC), and N-methylpyrrolidinone (NMP); and mixtures thereof or their combinations with water in various proportions.

The reactions shown in Scheme I may be carried out at temperatures ranging from about -10 to about 200 ⁰C, or from about 10 ⁰C to about 100 ⁰C.

3-[3-(trifluoromethyl) phenyl] propanoic acid formed in step a) may be used without being isolated, and proceeded to the next step. N- [(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide obtained in step b) may be further purified by recrystallization, or slurry in a suitable solvent. Suitable solvents which may be used for recrystallization or slurry include, but are not limited to, hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as tetrahydrofuran, diethyl ether; halogenated solvents such as dichloromethane, and chloroform; or mixtures thereof.

After it is obtained, the free base of cinacalcet of the formula (I) may be converted to a desired pharmaceutically acceptable salt. An example of the process for making cinacalcet hydrochloride is shown in U.S. Patent No. 6,211 ,244, particularly, Examples 1 and 2, which is incorporated herein by reference in its entirety and for the purpose stated. In one particular valiant, the present application provides a process in which the free base of cinacalcet is not isolated after its prepared from the compound of the formula (MA) or (MB), and is converted to the hydrochloride salt directly.

With reference to the Scheme I, the starting acid of the structure (IIIA) (3- [3-(trifluoromethyl) phenyl] propenoic acid ):

(IIIA) may be obtained by a reaction of trifluoromethyl benzaldehyde:

with an aliphatic carboxylic acid, such as acetic acid, propanoic acid, butanoic acid, and malonic acid, or with dicarboxylic anhydride, such as acetic, maleic, succinic, and phthalic anhydrides. Preferably, the reaction is conducted in the absence of additional solvent at temperatures that range from about 20 °C to about 200 ⁰C.

The chiral amine of the structure (IV):

(IV) may be produced by a resolution of the racemic amine:

The resolution may be accomplished by treating the racemic amine with a resolution agent (e.g., an enantiomerically pure acid). Suitable enantiomerically pure acids include, but are not limited to, naproxen, tartaric acid, mandelic acid, 2,3: 4,6-Di-O-isopropylidene-2-keto-gluconic acid. The preferred resolution agent is naproxen. Non-limiting examples of suitable solvents for the resolution include C_rC₄ alcohols; C₂-C₆ ketone solvents 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, dichlorobenzene and the like; ethers such as tetrahydrofuran (THF), diethylether, methyl tertiary-butyl ether, 1 ,4-dioxane and the like; and mixtures thereof or their combinations with water in various proportions. Suitable temperatures for conducting the reactions range from about 10 °C to about 75 °C, or from about 20 °C to about 40 ⁰C.

After treatment with the acid, the adduct of the racemate and the enantiomeric acid is separated and the desired diastereomeric adduct is converted to free amine by a treatment with a base. Aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base may be used. Suitable bases include, but are not limited to, alkali metal hydrides, such as lithium hydride, and sodium hydride; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; carbonates of alkali metals such as sodium carbonate and potassium carbonate; bicarbonates of alkali metals, such as sodium bicarbonate and potassium bicarbonate; ammonia; and mixtures thereof.

The product of the resolution may be subjected to further resolutions and/or recrystallizations to achieve the desired chiral purity of the amine of the structure (IV). Suitable solvents that may be used for recrystallization or slurry include, but are not limited to, alcoholic solvents such as Ci-C₄ alcohols; C₂-C₆ ketone solvents such as acetone, ethyl methyl ketone, and diethyl ketone; hydrocarbon solvents such as toluene, xylene, cyclohexane and the like; and mixtures thereof. The desired chiral purity is more than 99%, preferably, more than 99.5%.

Racemic 1-(1-naphthyl)ethylamine) may be prepared by treating 1- acetonapthone:

with a base in an organic solvent. Suitable bases which may be used include but are not limited to, ammonium formate, ammonia, carbonates of alkali metals such as sodium carbonate, and potassium carbonate; bicarbonates of alkali metals, such as sodium bicarbonate, and potassium bicarbonate; and mixtures thereof. Aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base may be used. The reaction may be carried out in the presence of a solvent, non-limiting examples of which include hydrocarbon solvents, such as toluene, xylene, and cyclohexane at a temperature of about 20 °C to about 200 ⁰C.

The intermediate of the structure (HA) (N-[(1 R)-1-(1-napthyl) ethyl]-3-(3- trifluromethyl) phenyl] propanamide):

(HA) is separately contemplated. In particular, N-[(1 R)-1-(1-napthyl) ethyl]-3-(3- trifluromethyl) phenyl] propanamide of the structure (NA) was obtained in a crystalline form. An example of XPRD spectra for a sample of N-[(1 R)-1-(1- napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide is shown in Figure 1. The XRPD data reported herein were obtained using Cu Kα-1 radiation, having the wavelength 1.541 A, and were obtained on a Bruker Axe D8 Advance Powder X-ray Diffractometer.

The crystalline form of the compound of the structure (NA) is characterized by an XRPD pattern having significant peaks at about 9.9, 14.9, 15.2, 15.9, 17.6, 18.2, 19.6, and 21.7 ± 0.2 degrees 2Θ. It may be further characterized by the additional XRPD peaks at about 22.4, 24.8, and 25.3 ± 0.2 degrees 2Θ.

N-[(1 R)-1-(1-napthyl) ethyl]-3-(3-trifluromethyl) phenyl] propanamide was obtained in a highly pure form. A solid with purity of more than about 95%, or more than about 98%, was obtained. The solid of the compound of the structure (MA) contains individual impurities in the amount of less than about 1 %, or less than about 0.5% by weight. In particular, -[(1 R)-1-(1-napthyl) ethyl]-3-(3- trifluromethyl) phenyl] propanamide obtained by the processes described herein contains less than about 1 %, preferably, less than about 0.5% of impurities of the structures:

where R represents Ci to C₅ alkyl, aryl, cyclo-alkyl, or substituted aryl group.

The intermediate of the structure (MB) (N-(1-naphthalene-1-yl-ethyl)-3-(3- trifluromethyl-Phenyl) acrylamide):

(HB) is also separately contemplated. In particular, N-(1-naphthalene-1-yl-ethyl)-3-(3- trifluromethyl-Phenyl) acrylamide of the structure (HB) was obtained in a crystalline form. An example of XPRD spectra for a sample of N-(1-naphthalene- 1-yl-ethyl)-3-(3-trifluromethyl-Phenyl) acrylamide is shown in Figure 2.

The XRPD data reported herein were obtained using Cu Kα-1 radiation, having the wavelength 1.541 A, and were obtained on a Bruker Axe D8 Advance Powder X-ray Diffractometer.

The crystalline form of the compound of the structure (HB) is characterized by an XRPD pattern having significant peaks at about 7.7, 13.7, 14.1 , 17.7, 19.0, 19.8, and 20.2 ± 0.2 degrees 2Θ. It is further characterized by additional XRPD peaks at about 21.4, 22.5, 22.9, and 23.7 ± 0.2 degrees 2Θ.

N-(1-naphthalene-1-yl-ethyl)-3-(3-trifluromethyl-Phenyl) acrylamide of the structure (HB) was obtained in highly pure form. A solid with purity of more than about 95%, or more than about 98%, was obtained. The solid of the compound of the structure (HA) contains individual impurities in the amount of less than about 1%, or less than about 0.5% by weight.

The present patent application also provides another process for making a free base of cinacalcet. While the scope of the invention should be evaluated with reference to the appended claims, Scheme Il contains an illustration of this embodiment:

Scheme Il

With reference to Scheme II, step a) involves a reduction of carboxylic acid to a primary alcohol. Examples of suitable reduction conditions and/or reducing agents include, but are not limited to, catalytic reduction using hydrogen and metals like palladium on carbon, rhodium, Raney nickel, lithium aluminum hydride, sodium borohydride in acidic conditions, sodium borohydride in pyridine, and sodium dihydro-bis- (2-methoxyethoxy) aluminate solution ("Vitride").

Step b) involves a halogenation reaction to provide a transient intermediate (VIII). 1-(3-bromo-propyl)-3-trifluoromethyl-benzene of the structure VIII is difficult to handle because of its irritant nature. Hence, an in-situ process which proceeds without isolating the bromo intermediate of Formula VIII is advantageous. Examples of suitable brominating agents which may be used in step b) include, but are not limited to, hydrogen bromide, bromine gas, and N-bromo succinamide.

Step c) involves condensation between the primary halide and the amine of the structure (IV). The condensation may be affected in several ways. Examples of suitable reagents/reaction conditions which may be used to affect the condensation of step c) include, but are not limited to, conducting the reaction in the presence of a coupling agent, such as EDCI, DCC, DIPCDI in the presence of catalytic auxiliary nucleophiles like HOBt, HOSu, and N-hydroxy-5-norbene-endo- 2, HONB, dehydrating agents like carbonyldiimidazole, boric acid, phosphorus pentoxide, acetic anhydride, and sulfuric acid.

One or more of the steps a) or b) may be carried out without isolating intermediate compounds. The reactions set forth in Scheme Il may be carried at temperatures ranging from about -10 ⁰C to about 200 ⁰C, or from about 20 °C to about 100 °C.

The present patent application also provides a process for making a free base of cinacalcet having the formula (I):

formula (I) by treating the racemic compound of the formula (X):

formula (X) with a reducing agent effective to convert an amide of the compound of the formula (X) to a secondary amine of the compound of the formula (I), and then resolving the racemic cinacalcet of the formula (XII):

formula (XII) to give the free base of cinacalcet of the formula (I).

With reference to the formula (X), Ri and R₂ may be both hydrogen, or R1 and R2, together, may form a double bond.

In one variant, R-i and R₂ are both hydrogen and thus the compound of the formula (II) has the structure XA:

(XA) In this embodiment, the reduction step involves only reduction of the amide.

In another embodiment, Ri and R₂, together, form a double bond and thus the compound of the formula (X) has the structure (XB):

(XB)

The compound of the formula (X) may be produced by a reaction between a compound of the formula (III):

formula (III) with a compound of the structure (Xl):

(Xl)

With reference to the formula (III), Ri and R₂ may be both hydrogen, or R₁ and R₂, together, may form a double bond. R₃ is hydrogen, C₁-C₃ alkyl or -C(O)-CH₃.

In one embodiment, Ri and R₂, together, may form a double bond. If so, the reduction is sequential. The compound of the structure (XB):

(XB) Is converted to an intermediate of the structure

which is then further reduced to racemic cinacalcet (XII).

In another embodiment, R-i, R₂ and R₃ are all hydrogen and the compound of the formula (III) has the structure (IIIB):

Scheme III illustrates the process described above:

Scheme III

With reference to Scheme III, the steps a) or b) may be carried out with or without isolating intermediate compounds.

The condensation step b) or d) may be carried out in a number of ways. Thus, the condensation may be carried out in the presence of a coupling agent, such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIPCDI), in the presence of a catalytic auxiliary nucleophiles, such as 1-hydroxybenzotriazole (HOBt), N- hydroxysuccinimide (HOSu), and N-hydroxy-5-norbene-endo-2, 3-dicarboxamide (HONB), or dehydrating agents, such as carbonyldiimidazole, boric acid, phosphorus pentoxide, acetic anhydride, and sulfuric acid. The condensation may be also carried out by treating the carboxylic acid with a chlorinating agent to produce acid chloride, followed by a reaction with the amine of the formula (IV) in the presence of a base. Non-limiting examples of chlorinating agents include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride.

Steps a), b), c) and f) may be carried out in an organic solvent. Examples of suitable solvents include, but are not limited to, hydrocarbon solvents, such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; alcoholic solvents, such as Ci-C₄ alcohols; C₂-C₆ ketone solvents, 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 tetrahydrofuran (THF), diethylether, methyl tertiary-butyl ether, and 1 ,4- dioxane; hydrocarbon solvents, such as toluene, xylene, and cyclohexane; esters, such as ethyl acetate, isopropyl acetate, and tertiary-butyl acetate; nitriles, such as acetonitrile, and propionitrile; and aprotic polar solvents, such as dimethylsulfoxide (DMSO), N,N-dimethyl-formamide (DMF), dimethylacetamide (DMAC), and N-methylpyrrolidinone (NMP); and mixtures thereof or their combinations with water in various proportions.

The reactions shown in Scheme III may be carried out at temperatures ranging from about -10 to about 200 ⁰C, or from about 10 ⁰C to about 100 ⁰C.

The racemic cinacalcet (XII) obtained via the process of Scheme III may be subjected to a chiral resolution to obtain R-cinacalcet. The resolution may be accomplished by treating the racemic cinacalcet with a resolution agent (e.g., an enantiomerically pure acid). Suitable enantiomerically pure acids include, but are not limited to, naproxen, tartaric acid, mandelic acid, 2,3: 4,6-Di-O-isopropylidene- 2-keto-gluconic acid. The preferred resolution agent is naproxen. Non-limiting examples of suitable solvents for the resolution include CrC₄ alcohols; C₂-C₆ ketone solvents 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, dichlorobenzene and the like; ethers such as tetrahydrofuran (THF), diethylether, methyl tertiary-butyl ether, 1 ,4-dioxane and the like; and mixtures thereof or their combinations with water in various proportions. Suitable temperatures for conducting the reactions range from about 10 ⁰C to about 75 °C, or from about 20 ⁰C to about 40 °C.

The product of the resolution may be subjected to further resolutions and/or recrystallizations to achieve the desired chiral purity. Suitable solvents that may be used for recrystallization or slurry include, but are not limited to, alcoholic solvents such as CrC₄ alcohols; C₂-C₆ ketone solvents such as acetone, ethyl methyl ketone, and diethyl ketone; hydrocarbon solvents such as toluene, xylene, cyclohexane and the like; and mixtures thereof. The desired chiral purity is more than 99%, preferably, more than 99.5%. N-[1-(1-napthyl)ethyl]-3-(3-trifluromethyl) phenyl] propanamide of Formula XA is separately contemplated. Figure 3 illustrates an example of XPRD of a sample of the compound (XA). It is characterized by an XRPD pattern having significant peaks at about 7.6, 13.4, 13.9, 17.3, 18.1 , 18.7, 19.6, and 20.1 , 21.3, 22.6, 23.7, 24.6 ± 0.2 degrees 2Θ. It may be further characterized by the additional XRPD peaks at about 20.1 , 21.3, 22.6, 23.7 and 24.6 ± 0.2 degrees 2Θ.

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.

EXAMPLE 1 : PREPRATION OF 3-TRI FLU ROM ETHYL 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 (10Og) 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 °C. 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 °C. The reaction mass was maintained at about 65 °C 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 48°C 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 °C 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 °C 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 ⁰C 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 °C 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 °C 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 °C for about 3 hours.

After the reaction was completed, water (400 ml) was added to the reaction mass and cooled to about 5°C. 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 ⁰C. 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 ⁰C. 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 °C 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 °C. 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 50-60°C followed by washing with water (2 x 1000 ml) at 50-60⁰C. The organic layer was distilled off completely at below 60⁰C 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 50-60⁰C.

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 ⁰C 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 °C. 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 ⁰C 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- NAPHTHALEN E-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 ⁰C under vacuum for about 9 hours to afford 2.6 g of title compound. Purity By HPLC: 96.73%. Mas

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 °C 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 °C to afford 17 g of the title compound.

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

NAPHTHALENE-I-YL-ETHYLKMS-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 (2^350 ml). The organic layer was then washed with water (2^350 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-(1 -NAPHTHALENE-I-YL-ETHYLJ-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 ⁰C under vacuum to afford 2.1 g of the title compound.

EXAMPLE 19: PROCESS FOR THE PREPARATION OF Cl NACALCET 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 °C 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 ⁰C 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 30⁰C. (-)-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 75°C 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 ⁰C 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 ⁰C. 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 ⁰C for about 15 minutes. The resultant reaction solution was cooled to about 40 ⁰C 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 ⁰C and checked for clear dissolution. After a clear dissolution was obtained, the reaction mass was distilled at about 55 ⁰C 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 ⁰C 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-1-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 °C and maintained for about 50 hours. The reaction mass was then cooled to about 5 ⁰C. 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 ⁰C under a vacuum of about 650 mm/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.

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 a free base of cinacalcet of the formula (I):

(I) said process comprising treating a compound of the formula (II):

(N) where Ri and R₂ are both hydrogen, or Ri and R₂, together, form a double bond, with a reducing agent effective to reduce an amide to a secondary amine, whereby providing said free base of cinacalcet.

2. The process of claim 1 , further comprising reacting a compound of the formula (III):

where Ri and R₂ are both hydrogen, or Ri and R₂, together, form a double bond, and R₃ is hydrogen, C₁-C₃ alkyl or -C(O)-CH₃; with a compound of the structure

thereby producing said compound of the formula (II).

3. The process of claim 2, wherein Ri and R₂, together, form a double bond.

4. The process of claim 3, wherein said treating step comprises, sequentially: i) converting said compound of the formula (II) to an intermediate of the structure:

ii) further reducing said intermediate produced in step i) to cinacalcet.

5. The process of claim 2, wherein R₁, R₂, and R₃ are all hydrogen.

6. The process of claim 5, further comprising reducing a compound of the structure:

to provide said compound of the formula (III).

7. The process of claim 1 , wherein said reducing agent is selected from the group consisting of vitride and lithium aluminum hydride.

8. The process of claim 2, further comprising i) providing a racemic amide of the structure

ii) treating said racemic amide with a resolution agent to produce said compound of the structure:

9. The process of claim 8, wherein said resolution agent is naproxen.

10. The process of claim 8, further comprising i) providing a compound of the structure

ii) treating said compound of step i) with ammonium formate to produce said compound of the structure

11. A compound of the structure

12. A compound of the structure

13. A process for making a free base of cinacalcet, said process comprising: i) providing a compound of the structure

ii) converting said compound produced in step (i) to a compound of the structure

j

iii) converting said compound produced in step (ii) to a compound of the structure

wherein X is a leaving group; and iv) without isolating, coupling said compound produced in step (iii) with the compound of the structure

thereby producing said free base of cinacalcet.

14. The process of claim 10, wherein X is bromo.

15. The process of claim 1 , further comprising converting said free base of cinacalcet to a hydrochloride salt of cinacalcet, wherein said free base is not isolated.

16. A process for making a free base of cinacalcet of the formula (I):

said process comprising: i) providing a racemic compound of the formula (X)

(X). where Ri and R₂ are both hydrogen, or Ri and R₂, together, form a double bond; ii) reducing said compound of the formula (X) to produce a racemic compound of the structure

iii) resolving said racemic compound produced in step ii) thereby producing said free base of cinacalcet.

17. The process of claim 16, further comprising reacting a compound of the formula (III):

(III) where Ri and R₂ are both hydrogen, or Ri and R₂, together, form a double bond, and R₃ is hydrogen, C₁-C₃ alkyl or -C(O)-CH₃; with a racemic compound of the structure

thereby producing said compound of the formula (X).

18. The process of claim 17, further comprising treating a compound of the formula

with acetic anhydride to produce said compound of the formula (III), wherein Ri and R₂, together, form a double bond, and R₃ is hydrogen.