WO2008035381A2

WO2008035381A2 - Process for the preparation of amine derivatives as calcimimetics

Info

Publication number: WO2008035381A2
Application number: PCT/IN2007/000416
Authority: WO
Inventors: Chidambaram Venkateswaran Srinivasan; Perminder Singh Johar; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2006-09-22
Filing date: 2007-09-18
Publication date: 2008-03-27
Also published as: WO2008035381A3

Abstract

The present invention relates to a novel process for preparing amine derivatives of formula (I), and pharmaceutically acceptable salts and complexes thereof, wherein Ar1or Ar2 is either naphthyl or phenyl optionally substituted with 0 to 5 subslituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy; q is 0-2; and R is H, by reducing novel amide intermediates of formula (II) wherein Ar1, Ar2 and q are same as described above. Particularly the present invention relates to an industrially advantageous process for the preparation of cinacalcet hydrochloride of formula (III) using novel amide intermediate of formula (VIII), wherein X is H, halo like chloro, bromo or iodo.

Description

PROCESS FOR THE PREPARATION OF AMBSTE DERIVATIVES AS

CALCIMIMETICS

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing amine derivatives of formula I, as calcimimetics,

Formula I

wherein Ar_\ or Ar ₂ is either naphthyl or phenyl optionally substituted with 0 to 5 substitiienls each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH₂OH, CONH2,, CN, acetoxy; q is 0-2; and R is H₁ and pharmaceutically acceptable salts and complexes thereof, by reducing novel amide intermediates of formula II

Formula II

wherein Ar_t, Ar ₂ and q are same as described above.

Particularly the present invention relates to an industrially advantageous process for the preparation of cinacalcet hydrochloride. The present invention also relates to novel synthetic intermediates useful in the process of the present invention.

The present invention also relates to novel crystalline forms of cinacalcet hydrochloride and processes for preparing the same.

BACKGROUND OF THE INVENTION

Calcimimetics are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the parathyroid glands and other tissues. They lower the threshold for CaSR activation by extracellular calcium ions and diminish parathyroid hormone (PTH) release from parathyroid cells. By targeting the molecular mechanism that modulates PTH secretion on a minute-to-minute basis, calcimimetic compounds offer a novel approach to managing excess PTH secretion in several clinical disorders.

Amine derivative of formula I were disclosed in PCT application WO 94/18959, United States patent nos. 6,21 1,244, 6,313, 146, 6,031,003, 6,001,068, 6,01 1,884, 5,962,314, 5,858,684, 5,841,368, 5,763,569, 5,688,938 etc.

T „„ Formula I

wherein Ar_/ or Ar ₂ is either naphthyl or phenyl optionally substituted with 0 to 5; q is 0-2; and R is H, q is 0-2; and R is H, lower alkyl.

The method disclosed in the above patents for the preparation of these compounds includes the reductive amination of a commercially available aldehyde or ketone with a primary amine in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride and titanium isopropoxide.

Alternatively some compounds were prepared from the condensation of a primary amine with an aldehyde or ketone in the presence of titanium (IV) isopropoxide. The resulting intermediate imines were then reduced in situ by the action of sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride. Optionally the intermediate enamine was catalytically reduced using palladium dihydroxide on carbon.

Various compounds were prepared by a diisobiitylaliiminum hydride (DIBAL-H) mediated condensation of an amine with a nitrile. The resulting intermediate imine is reduced in situ by the action of sodium cyanoborohydride or sodium borohydride. The intermediate alkenes were reduced by catalytic hydrogenation in ethanol using palladium on carbon. Further the compounds obtained were converted to their corresponding salts by treatment of the free base with acid in a suitable solvent. The prior art processes use expensive reagents and are not amenable to an industrial scale up.

An important drug that acts as a calcimimetic agent is cinacalcet hydrochloride of formula III and is chemically known as N-(l-naphthaIen-l-yIethyl)-3-[3-(trifIuoromethyl)phenyl]-propaπ- 1 -amine hydrochloride. Formula HI

Cinacalcet hydrochloride is used to treat hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumors and chronic renal failure. The above patents are completely silent about the specific process for the preparation of cinacalcet. Further, the above patents provide only the mass spectral data; otherwise the patents are unable to touch upon the physicochemical characterization data of cinacalcet and its salts thereof. The patents do not disclose any possibility or observation that the compound exists in different polymorphic forms. Consequently, there is an ongoing search for new polymorphic forms of drugs, which may provide for improved performance thereof. '

A single molecule, such as cinacalcet hydrochloride, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties, such as melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. There is a widely recognized need for, and it would be highly advantageous to have new and distinct crystalline forms of cinacalcet hydrochloride.

In view of this, it is the principal object of the present invention to provide an efficient and novel process for the preparation of pure amine derivatives of formula I, which is unique with respect to its simplicity, cost effectiveness and convenience to operate on industrial scale.

Another object of the present invention is to provide novel intermediates that play a crucial role in the preparation of amine derivatives as calcimimetics. Another main object of the present invention is to provide an efficient and cost-effective method for the preparation of highly pure cinacalcet hydrochloride in high yield.

Yet another object of the present invention is to provide novel crystalline forms of cinacalcet hydrochloride and processes for preparing the same.

SUMMARY OF THE INVENTION

Accordingly, the present invention teaches an efficient and industrially advantageous process for the preparation of amine derivative of formula 1 S L Formula I

wherein Ar_/ and Ar_? is either naphthyl or phenyl optionally substituted with O to 5 substitiients each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CFLOH, CONH2,, CN, acetoxy; q is 0-2; and R is H, and pharmaceutically acceptable salts and complexes thereof by reducing novel amide intermediate of formula II,

N^ ^Ar₂

Il » Formula II

wherein Ar i, Ar₂ and q are as described above.

Another object of the present invention is to provide a process for the preparation of amide intermediate of formula II

^{Fθl lπula} H wherein Ar], Ar_∑ and q are as described above, which comprises introducing an acyl group of the formula IV,

Ar₁- xo —

* Formula IV wherein X = H or halo, wherein halo can be chloro, bromo or the like;

is as described above, into the amino group of molecule of formula V or a salt thereof.

H₂N-^ _>*CH₃

Ar₂ Formula V wherein Ai'₂ is as described above.

The present invention is also directed to a process, wherein introduction of acyl moiety into amino group is performed by reacting a compound of formula V or a salt thereof, H₂TSL ^CH₃

Ar₂ Formula V

wherein Ar₂ is as described above with a compound of formula VI or a salt or reactive derivative thereof.

_Ar- ^-^COOH Formula VI

X wherein Ai¹ _I and X are as described above

Another object of the present invention is to provide a process for the preparation of compound of formula VI, .

COOH

Ar Formula VI x wherein Ar i and X are as described above from amino compound of formula VII.

Ai _I-NH₂ Formula VII wherein Ar₁ is as described above

Yet another object of the present invention is to provide a novel and efficient process for the preparation of cinacalcet of formula HIa and pharmaceutically acceptable acid addition salt thereof

Formula-IIIa

using novel intermediate of formula VIII,

Formula VIII

wherein X = H or halo, wherein halo can be chloro, bromo or the like. One another object of the present invention is to provide novel intermediates, their pharmaceutically acceptable salts, including solvates, hydrates, enantiomers and the preparation thereof along with processes for preparing the same and its conversion to cinacalcet hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the powder X-ray diffraction pattern for cinacalcet hydrochloride Form A. Figure 2 illustrates the powder X-ray diffraction pattern for cinacalcet hydrochloride Form B. Figure 3 illustrates the Differential Scanning Calorimetry for cinacalcet hydrochloride Form A

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a new and efficient process for preparing amine derivative of formula I,

Formula I

wherein Ar i, Ar_∑: R and q are as described above starting from amino compound of formula VII.

According to one embodiment of the present invention, the amine derivative of formula I is formed by initially introducing an acyl group of the formula IV,

Ar,-

* Formula IV wherein X is H or halo;, halo can be chloro, bromo or the like while Ar_\ is as described above, into the amino group of molecule of formula V or a salt thereof,

H₂N- >^CH3

Ar₂ Formula V wherein Ar₂ is as described above, under conditions effective to produce compounds of formula I in high yield and purity. One method of synthesizing amine derivatives of formula I is by acylating a compound of formula V or a salt thereof, with a compound of formula VI or a salt or a reactive derivative thereof, and reducing the resulting compound of formula II.

The acylation reaction can be conducted advantageously and smoothly in the presence of a solvent. As said solvent, use may be made of the common solvents and their mixtures unless such solvents do not interfere with the present reaction. There may be mentioned, therefore, such solvents as water, acetone, tetrahydrofuran, toluene, ethylbenzene, xylene, isopropylether, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like. This reaction may proceed more advantageously when to the solvent there is added a suitable base selected from organic tertiary amine such as pyridine, triethylamine, N,N-dimethylaniline or inorganic base like alkali metal bicarbonate, carbonate, hydroxide, alkaline earth metal carbonate, hydroxide and the like. While the reaction temperature is virtually optional, the reaction usually is carried out under cooling or at room temperature. The reaction is generally completed within several minutes to several hours.

The starting materials used in the preparation of amine derivative of formula I are either procured from the market or prepared by the conventional methods. The compound of formula V is commercially available or prepared by the methods known in the prior art. The compound of formula VI is prepared by different methods starting from amino compound of formula VII.

The present invention also teaches a process of preparing compound of formula VI,

_M{^y^C00H Formula VI x wherein Ar i, and X are as described above, by reacting amine of formula VII,

Ai _I-NH₂ Formula VII wherein Ar_/, is as described above, with alkene derivative of formula

in the presence of diazotization reagents, acid and catalyst to afford a compound of formula X.

Formula X

wherein R" can be selected from CN, CONR R², COOR ', wherein R' is hydrogen or an aικyι group, R¹ and R² can be independently selected from H or lower alkyl group, while X is selected from H, halo, provided both R ' and X cannot be H simultaneously.

As the diazotization reagents, nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, the like are conveniently employed and, among them, sodium nitrite and amyl nitrite, are generally used. The reaction is generally conducted in the presence of an acid at a selected temperature within the range of -20 to 2O⁰C for a selected time of one to several hours. The acid employed in the reaction is exemplified by hydrochloric acid, hydrobromic acid, or the like and catalyst can be selected from copper (II) oxide, copper (I) oxide, copper halides like copper chloride, copper bromide and the like. The solvent used can be selected from water, acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, alcohols having C₁-C₄ alkyl group and mixtures thereof.

The compound of formula X, wherein R"=CN, CONR¹R² or COOR ', R ' is alkyl, X=HaIo may be further transformed into corresponding acid of formula VI, by using conventional methods such as hydrolysis, reduction, and hydrodehalogenation.

According to one embodiment of the present invention, the compound of formula X, wherein R " is CN, and X=HaIo, is hydrodehalogenated to form intermediate of formula X, wherein R "=CN and X-H. This intermediate is further hydrolysed to corresponding acid using acid catalyzed or base catalyzed hydrolysis to afford a compound of formula VI.

According to another embodiment of the present invention, the compound of formula X, wherein R " is CN, CONR¹R² or COOR ', R ' is alkyl, and X is halo, is first hydrolysed in the presence of acid or base to afford an intermediate of formula VI, wherein R" is COOH and X is halo. This intermediate is further hydrodehalogenated to afford compound of formula VI, wherein X=H.

The acid and basic hydrolysis of the above nitrile, amide or ester derivative of compound of formula X may also be carried out by the methods reported in prior art.

Hydrodehalogenation can be conducted by using sodium dithionite, zinc-acetic acid, zinc- potassium iodide, or magnesium, catalytic dehydrogenation, metal catalyst selected from platinum, ruthenium, osmium, iridium, and especially palladium, raney-nickel, along with a suitable solvent chosen from water, alcohol having CpC₄ alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof. Preferably the reaction can favorably be conducted in the presence of zinc, acetic acid and water. The above reactions can be carried out advantageously in the presence of solvent. Any solvent which can dissolve both starting materials may be employed so far as it does not disturb the reaction, and more preferably one is exemplified by alcohols such as methanol, ethanol, propanol, the like, ketones such as acetone, methyl ethyl ketone, the like, ethers such as ether, tetrahydrofuran, dioxane, the like, or mixture thereof.

The introduction of acyl group to amino group is accomplished by converting acid derivative of formula X ( T? " is COOH) or formula VI to the corresponding reactive derivative like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester thereof.

Preferably acylation is carried out by reacting acid chloride derivative of compound of formula VI, with a compound of formula V to prepare compound of formula II, which is further reduced to obtain compound of formula I.

The reduction conditions employed for reducing compound of formula II may be selected from the known reduction methods and preferably catalytic reduction employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper- chromium oxide, and the like, reduction means employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam and the like, reduction means employing metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, with additives such as iodine, sulfuric acid, lewis acids and the like, reduction means treating with metals such as zinc, iron, and the like in solvents such as acetic acid, formic acid, or aqueous mixture thereof, and in the presence of borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, ^!borane-lewis acid, borane-triphenylphosphine and the like. The reaction conditions such as reaction temperature, pressure, sort of the solvent, reaction time and others may be selected suitably according to sort of starting material and reduction means etc.

In yet another embodiment, the present invention is directed to amide intermediate of formula IX,

Formula IX

wherein Ar j, Aiχ X and q are as described above, prepared by direct acylation of compound of formula VI with compound of formula V. The amide intermediate of formula IX is then converted to compound of formula II by hydrodehalogenation. While hydrodehalogenation of compound of formula IX can be performed by reaction with zinc in the presence of inorganic or organic acid like acetic acid, hypophosphorous acid and the like along with water with or without using organic solvents such as toluene, xylene, hexane, tetrahydrofuran, isopropyl ether, methyl tertiary butyl ether, dioxane and the like and mixture thereof.

In another embodiment of the present inventioti_j the amide intermediate of formula II can also be prepared by reacting a compound of formula XI,

Formula XI

wherein Ar₂ is as defined above, with amino compound of formula VII

Ai _I-NH₂ Formula VII wherein Ar i is as defined above.

The above reaction can be conducted in the presence of sodium nitrite, acid and catalytic amount of catalyst. The acid used in the above transformation can be selected from hydrochloric acid, hydrobromic acid or the like and catalyst can be selected from copper (II) oxide, copper (I) oxide, copper halide and the like.

While according to yet another embodiment of the present invention, calcimimetic agents of formula I can be converted to pharmaceutically acceptable salt thereof by one pot process by reducing the novel amide compound of formula II using reducing agent selected from borane compounds and metal hydrides such as BH₃-THF, BH₃-DMS, BH₃-amine, BH₃-lewis acid, BH₃-PPh₃ and the like, lithium aluminium hydride, sodium borohydride in the presence of additives like iodine, sulfuric acid or lewis acids along with mineral acid like hydrochloric acid, hence without isolating the base. The reaction can be conducted in the presence or absence of an organic solvent thus affording the salt in high yield and purity.

Specific compound arising from the amine derivative of formula I include cinacalcet hydrochloride of formula-Ill, Formula-IH

In a preferred embodiment of the present invention, cinacalcet hydrochloride of formula III may be prepared by the scheme as shown below:

ation

reduction

wherein R " and X are as described above.

According to the scheme, the starting material 3-trifluoromethylaniline is diazotized and reacted with alkene derivative of formula CH₂=CHR" to afford a compound of formula XII. Formula XII

wherein R " is as described above, and X—halo selected fi'om chloro, bromo, the like.

Specifically, 3-trifluoromethylaniline is reacted with alkene derivative of formula CH₂=CHR." in the presence of diazotization reagent, dilute mineral acid and catalyst at a temperature of about -20 to 20⁰C. The mineral acid can be selected from hydrochloric acid, hydrobromic acid, and the like and diazotization reagent is selected from amongst, but not limited to nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, and the like. Preferably sodium nitrite is employed. The catalyst can be selected from amongst, but not limited to copper (II) oxide, copper (I) oxide, and the like. After initiation of the reaction, the reaction mass is stirred for few hours at ambient temperature and it takes 10-20 hours for completion of reaction. Thereafter the product is extracted with a suitable organic solvent such as toluene to obtain a compound of formula XII.

The compound of formula XII is then transformed to yet another key intermediate, m- trifluoromethylhydrocinnamic acid of formula XIII by several methods.

Formula XIII

According to one embodiment of the present invention, the compound of formula XII is hydrolyzed to corresponding acid analogue of formula XIV,

Formula XIV

wherein X is as defined above, by acid or basic hydrolysis, followed by dehydrohalogenation to afford m- trifluoromethylhydrocinnamic acid of formula XIII.

Specifically, compound of formula XII {wherein R" is CN, COOR '; X is halo) is hydrolyzed to corresponding acid analogue by refluxing the compound of formula XII and a suitable acid preferably selected from hydrochloric acid, hydrobromic acid and the like for a period of 2-10 hours, cooling the reaction mixture to 25-3O⁰C followed by extraction with a suitable organic solvent preferably toluene to afford an acid compound of formula XIV.

The acid compound of formula XIV is then dehydrohalogenated by the methods well known in art, preferably by treatment with zinc in the presence of aqueous acetic acid at a temperature of about room temperature to -118⁰C. After completion of reaction, acetic acid is distilled off completely and reaction mass is cooled to room temperature and then treated with chilled concentrated inorganic acid, preferably selected from hydrochloric acid, hydrobromic acid and the like to afford m-trifluoromethylhydrocinπamic acid of formula XIII.

In the preferred embodiment of the present invention, acid analogue of compound of formula XII can optionally be isolated and can optionally be purified by giving base-acid treatment in a suitable inert solvent selected from amongst, but not limited to toluene, isopropyl ether, methyl tertiarybutyl ether, ethyl benzene and xylene. Preferably toluene is employed.

According to another embodiment of the present invention, the compound of formula XII is first hydrodehalogenated to form intermediate of formula XV,

Formula XV

wherein R " is as defined above, followed by acidic or basic hydrolysis to afford a compound of formula XIII by the methods reported in prior art or to be exemplified in the present invention.

Acid employed for hydrolysis can be selected from amongst inorganic acids like hydrochloric acid, hydrobromic acid and the like; organic acid selected from methylsufonic acid, p- tolylsulfonic acid, the like or mixtures thereof, whereas base can be selected from alkali metal hydroxide, alkali earth metal hydroxide. Preferably sodium hydroxide, potassium hydroxide and the like can be employed. Hydrolysis can be done in the presence of suitable solvent selected from Ci-C₄ alcohols, monoethylene glycol and the like. Reaction can be performed at a temperature of about room temperature to reflux temperature.

According to yet another embodiment of the present invention, the compound of formula XII can be transformed to m-trifluoromethylhydrocinnamic acid of formula XIII via another intermediate, namely m-trifluoromethylcinnamic acid of formula XVI or salt thereof. Formula XVI

Specifically, the compound of formula XII is first hydrolysed to compound of formula XlV and thereafter converted to cinnamic acid analogue of formula XVI. The salts of compound of formula XVI include lithium, sodium, potassium, trialkylammonium and the like. Generally acid compound of formula XIV is treated with base in suitable solvent optionally in the presence of a phase transfer catalyst. The suitable solvent can be selected from water, isopropyl i alcohol, tetrahydrofuran, ethyl nitrile, toluene, cyclohexane, methylenedichloride, the like or mixtures thereof and phase transfer catalyst can be selected from tetra alkyl ammonium halide, triethyl amine, trialkyl aryl halide, preferably benzyltriethylammonium chloride is employed. The base is selected from tertiary organic bases like trialkyl amines, 1,8- diazabicyclo[5.4.0]undec-7-ene; aqueous alkali metal hydroxide, alkali metal carbonate or bicarbonates, alkali metal being selected from lithium, sodium, potassium, and the like; preferably sodium hydroxide, sodium carbonate are employed. The reaction is accomplished at temperature of 40-60⁰C followed by the removal of solvent under vacuo. Thereafter reaction mass is diluted with water at 0⁰C and acidified with mineral acid preferably hydrochloric acid. The resulting solid is filtered, washed, and dried to afford m-trifluoromethylcinnamic acid of the formula XVI.

Further, compound of formula XVI is then reduced to m-trifluoromethylhydrocinnamic acid of formula XIII by the methods well known in art. In the preferred embodiment, reduction is performed by catalytic reduction, employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, and the like in the presence of hydrogen transfering agents like formic acid, ammonium formate, cyclohexene and dihydrogen.

The conversion of the compound of formula XII to m-trifluoromethylhydrocinnamic acid of formula XIII can also be performed by other methods known per se or as exemplified in the context of the present invention.

Yet another embodiment of the present invention provides a process for the conversion of compound of formula XIII to novel and key intermediate of formula VIII, Formula VIII

wherein X is hydrogen, halo selected from chloro, bromo and the like which comprises introducing an acyl group of formula IVa,

Formula IVa

wherein X ^'= H or halo, wherein halo can be chloro, bromo or the like; into the amino group of molecule of formula Va or a salt thereof

Formula Va

Typically, the conversion of compound of formula XIII to novel and key intermediate of formula VIII can be effected by initially converting m-trifluoromethylhydrocinnamic acid of formula XIII to its reactive derivative like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester by reaction with a reagent like phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide like acetyl chloride, pivaolyl chloride, allcyl chlorofoπnate, lewis acid like boric acid, and the like.

Preferably m-trifluoromethylhydrocinnamic acid of formula XIII is treated with thionyl chloride in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100⁰C followed by the removal of solvent and thionyl chloride by distillation to afford the corresponding acid chloride analogue.

The reactive derivative preferably acid chloride derivative of compound of formula XIII so formed is made to react with R-(+)-l(l-naphthyl)ethylamine of formula Va to afford amide derivative of formula Villa, which is novel and key intermediate in the preparation of cinacalcet and therefore represents further part of the invention. Formula Villa

Alternatively the amide compound of formula II may be prepared by acylation of different intermediates as discussed. The acylation reaction can be performed by following the general conditions of acylation as discussed above. Specifically, the functional derivative of compound of formula XIV in the suitable solvent is added to a suitable aqueous base, with or without the presence of catalytic amount of catalyst like 4-dimethylaminopyridine, followed by the addition of R-(+)-l(l-naphthyl)ethylamine in the suitable organic solvent at a temperature of -10 to 10⁰C and constant stirred for few hours at ambient temperature, washed with aqueous sodium carbonate, and dried to afford (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)- propionamide of the formula Villa in high yield and purity.

The suitable solvent can be selected from water, toluene, ethyl benzene, xylene, isopropylether, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether, toluene, and the like. Base can be selected from organic bases like pyridine, triethylamine, N,N- dimethylaniline, or inorganic bases like alkali bicarbonate, carbonates like sodium hydrogen carbonate and the like.

In yet another embodiment of the present invention, compound of formula XIV can directly be acylated with R-(+)-l(l-naphthyl)ethylamine under general acylation conditions as described in present invention to give yet another novel intermediate of formula VIIIb that represents further part of the invention,

Formula VIIIb

wherein X halo selected from chloro, bromo, iodo, and converted to amide derivative of formula Villa by dehydrohalogenation. Typically compound of formula VIIIb is hydrodehalogenated by reacting the same with aqueous acetic acid and adding zinc powder to it at about ambient temperature. Reaction mass is then heated to 50-70⁰C for few hours. Acetic acid is removed by the conventional methods like distillation. To the reaction mass, inert solvent preferably toluene followed by concentrated mineral a,cid preferably hydrochloric acid is added with constant stirring. The organic layer is separated, washed with water and solvent removed under vacuum to afford amide derivative of formula Villa that can further be converted to cinacalcet of formula IHa and pharmaceutically acceptable salt thereof.

Formula-Ilia

Reduction of amide derivative of formula Villa to cinacalcet hydrochloride of formula III can be effected by stirring a solution of amide derivative of formula Villa in a suitable solvent selected from tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyltertiarybytylether at a temperature of below 10⁰C, in the presence of suitable reducing agent, followed by heating to a temperature of 50-70⁰C with continuous stirring for few hours. Reducing agent can be selected from metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, with additives such as iodine, sulfuric acid, lewis acids; or borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethy (sulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like. Solvent is distilled off under vacuo followed by the addition Of Ci-C₄ alcohol at a temperature of below 5°C with stirring for few minutes. Alcohol is then distilled off under vacuo followed by the addition of mineral acid specifically hydrochloric acid at 0-5⁰C. This is followed by stirring at about ambient temperature for few hours and further heating to 80-95⁰C for few hours. The reaction mass is then cooled to ambient temperature, filtered, washed with water and dried to afford cinacalcet hydrochloride of formula III in high purity and yield.

In yet another embodiment of the present reaction, m-trifluoromethylcinnamic acid of formula XVI can directly be acylated with R-(+)-l(l-naphthyl)ethylamine under general acylation conditions as described in present invention to give yet another novel in intermediate, (R)-N-(I- naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide having formula XVII, that represents further part of the invention, Formula XVII

Compound of formula XVII is then reduced using suitable reducing agent to cinacalcet hydrochloride of formula III.

Typically, a solution of (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acryl amide having formula XVII in a suitable solvent is cooled to a temperature of below 5⁰C with constant stirring. This is followed by the addition of reducing agent selected from amongst borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like, followed by heating a temperature of 50-70⁰C. Solvent can be selected from toluene, xylene, ethyl benzene, isopropyl ether, methyl tertiary butyl ether. Solvent is then removed by distillation under vacuum followed by the addition of alcoholic solvent preferably methanol at a temperature of below 5⁰C with constant stirring. Solvent is then distilled off under vacuo followed by addition of mineral salt preferably hydrochloric acid at a temperature of below 5⁰C, followed by heating at a temperature of 85-9O⁰C. The reaction mass is then extracted with chlorinated solvent preferably dichloromethane and concentrated in vacuum to afford cinacalcet hydrochloride in high yield and purity. >

In the specific embodiment of the present invention, (R)-N-(I -naphthalen-1 -y 1-ethy l)-3 -(3 - trifluoromethyl-phenyl)-propionamide of the formula Villa can be converted to cinacalcet acid addition salt in one step by suspending the amide intermediate of formula Villa in a suitable solvent, cooling to a temperature of below 10⁰C under constant stirring followed by the addition of suitable reducing agent with heating to 60-65⁰C. Reducing agent can be selected from the one mentioned earlier, preferably borane complexes selected from amongst borane- tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane- triphenylphosphine and the like are used. Solvent can be selected from amongst, but not limited to tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyl tertiarybutyl ether, the like and mixtures thereof. Solvent is distilled off under vacuo followed by the addition of alcoholic solvent preferably methanol at a temperature of O⁰C with constant stirring for few minutes. Alcoholic solvent is distilled off under vacuo followed by the addition of suitable acid preferably hydrochloric acid at a temperature of below 5°C, followed by heating at 80-100⁰C. The reaction mass is then cooled to ambient temperature, filtered, washed with water and dried to afford cinacalcet acid addition salt, preferably cinacalcet hydrochloride in high yield and purity.

Novel amide intermediates encompassed by the invention may be characterized by at least one of mass spectra (MS), infra-red spectroscopy (IR), ¹H or ¹³C Nuclear magnetic resonance spectroscopy (NMR) or differential scan calorimetry (DSC).

Cinacalcet can also be isolated as cinacalcet free base but it is usually more convenient to isolate cinacalcet as acid addition salt. Cinacalcet can be converted to pharmaceutically acceptable salt thereof by the methods well . known in art. Generically, pharmaceutically acceptable salts can be prepared by dissolving the free base of cinacalcet in a suitable solvent, -containing the appropriate acid and isolating the salt there from. In yet another embodiment of the present invention, the reaction can also be effectively performed in the absence of solvents. In yet another embodiment, cinacalcet free base can be converted to its hydrochloride salt by refluxing a mixture of cinacalcet free base and ammonium chloride in alcoholic solvent like methanol for a time sufficient to convert to its hydrochloride salt.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonatc, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Preferably, cinacalcet is isolated as corresponding hydrochloride.

According to yet another embodiment of the present invention, the acid addition , salts of the cinacalcet may be converted to the corresponding free base by treating with a suitable inorganic base, such as carbonate, bicarbonate or hydroxide, typically in the presence of a solvent, and at a temperature of between about 10⁰C and 50⁰C. The free base form is isolated by conventional means, such as extraction with an organic solvent. The solvent can be selected from ethers like isopropyl ether, methyl tertiary butyl ether, xylene, ethyl benzene, isopropyl ether and halides like dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and the like.

The desired compound and intermediates prepared as such can be separated and purified by various means known per se such as, for example, concentration, conversion of liquid properties, transfer to another solvent and extraction with a solvent, crystallization, centrifuge, recrystallization, fractional distillation, chromatography, and the like. In the preferred embodiment of the present invention, cinacalcet hydrochloride can optionally be purified by refluxing cinacalcet hydrochloride in a suitable organic solvent selected from amongst, but not limited to nitriles, methyl isobutyl ketone, C, -C₄ alcohol, ethyl acetate, dimethyl acetamide, diethyl ether, toluene, xylene, isόpropyl ether, dioxane, dimethylformamide, dimethylsulfoxide, N-methyl pyrolidine, hexane, tetrahydrofuran, methylene dichloride, chloroform, methyl tertiary butyl ether and mixtures thereof for a time sufficient to obtain highly pure cinacalcet hydrochloride having purity greater than 99% by HPLC.

The present process has the advantage of being regio-selective, involving relatively mild reaction conditions and no racemization of the chiral starting material.

The present invention further provides novel polymorphic forms of cinacalcet hydrochloride. The cinacalcet hydrochloride crystalline forms encompassed by the invention may be characterized by at least one of Karl Fisher or TGA, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC).

Melting point was conducted using a Polmon MP Apparatus with a sample weight of about 10 mg.

^■ X-ray diffraction pattern was measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.

DSC analysis was performed using a Mettler Toledo 823^e. The crucible was crimped and punched prior to analysis. The weight of the samples was about 3-5 mg; the samples were scanned at a rate of 10°C/mm from 50⁰C to 220⁰C. Standard 40 μl aluminum crucibles covered by lids with 2 holes were used.

However, it is to be understood that the X-ray diffraction (XRD) patterns reported as absolute positions in the figures are intended to include the normal amount of positional variation due to experimental error, operator error, differences in equipment, technique, packing, contamination, and the like. However, based on this technique, particularly in conjugation with other techniques like infra red spectra and endotherms, one of ordinary skill in this art will be able to identify whether or not a compound is cinacalcet hydrochloride in accordance with the present invention. It should be kept in mind that slight variations in the observed 2Θ angles values are expected, based on the specific diffractometer employed, the analyst, and the sample preparation techniques. More variation is expected for the relative peaks intensities, which is largely affected by particle size of the sample. Thus, identification of exact crystalline form of a compound should be based primarily on observed 2Θ angles with lesser importance attributed to relative peak intensities. One embodiment of the invention encompasses a crystalline anhydrous cinacalcet hydrochloride form, herein defined as Form A. Form A may be characterized by X-ray powder diffraction pattern as shown in Fig.l . Form A may furthermore be characterized by a melting point range of about 175⁰C to about 177°C. Differential Scanning Calorimetry ("DSC") thermogram of the crystalline form shows two endothermic curves at about 162°C to about 172°C and at about 180⁰C to about 185°C, substantially as depicted in Fig. 3. Form A may be considered anhydrous having moisture content of about less than 0.7% w/w as measured by Karl Fisher titration method.

As used herein, the term "anhydrous" refers to cinacalcέt hydrochloride crystal form with less than about 0.7% moisture, preferably less than 0.5% moisture, more preferably less than 0.1% moisture.

Another embodiment of the present invention encompasses cinacalcet hydrochloride Form B characterized by X-ray powder diffraction pattern as depicted in Fig.2.

Another embodiment of the present invention encompasses methods of preparing crystalline cinacalcet hydrochloride form A by recrystallizing cinacalcet hydrochloride from a suitable solvent and isolating the highly pure Form A.

In more detailed embodiment, the present invention encompasses process for preparing crystalline cinacalcet hydrochloride form A comprising dissolving cinacalcet hydrochloride in a solvent to form a mixture, heating the mixture to reflux preferably at a temperature of from about 60°C to about 14O⁰C, inducing precipitation by cooling or removing the solvent by distillation or evaporation and isolating the cinacalcet hydrochloride form A.. The isolation of cinacalcet hydrochloride form A can be effected by conventional procedures well known in art such as distillation, evaporation, centrifugation, filtration and the like.

The solvent used can be selected from, but not limited to protic or aprotic solvents preferably alcohols, ketones, ethers, halogenated solvent, hydrocarbons, acid derivatives including anhydrides, esters, halides, amides, nitriles, the like and mixtures thereof. Preferably the solvent can be selected from isopropanol, methylene chloride, acetonitrile, isobutyronitrile, toluene, xylene, methyl isopropyl ketone, methyl isobutyl ketone, and the like.

Another embodiment of the invention encompasses a method of preparing crystalline cinacalcet hydrochloride form A comprising dissolving cinacalcet hydrochloride in a solvent such as cyclic ether to form a mixture, heating the mixture to below solvent's boiling point until cinacalcet hydrochloride dissolves, cooling the mixture to about room temperature to about 4⁰C, adding an anti-solvent to obtain the precipitate and isolating cinacalcet hydrochloride form A. The isolation of cinacalcet hydrochloride may be accomplished by conventional procedures well known in art such as distillation, evaporation, centrifugation, filtration and the like.

The solvent used is cyclic ether and preferably selected from dioxane, tetrahydrofuran and the like.

The anti-solvent can be selected from, but not limited to water, protic or aprotic solvents preferably alcohols, ketones, ethers, preferably aliphatic; halogenated solvent, hydrocarbons, acid derivatives including anhydrides, esters, halides, amides, nitriles, the like and mixtures thereof. Preferably the anti-solvent is selected from diethyl ether, isopropyl ether and methyl tertiary butyl ether. As used herein, the term "antisolvent" refers to a poor solvent for the substance in question which when added to a solution of the substance, causes the substance to precipitate.

According to yet another embodiment of the present invention cinacalcet hydrochloride form A can be prepared directly from cinacalcet by reacting it with hydrochloric acid in the presence of organic solvent. Preferably the organic solvent can be selected from isopropanol, methylene chloride, acetonitrile, toluene, xylene, methyl isopropyl ketone, methyl isobutyl ketone, isobutyronitrile and the like.

According to another embodiment <of the present invention cinacalcet hydrochloride Form B can be prepared from cinacalcet by reacting it with hydrochloric acid in the presence of water.

The following examples illustrate the invention, but do not limit its scope.

EXAMPLES

Example 1; Preparation of m-trifluoromethyl-α-chlorohydrocinnamonitrile

Concentrated hydrochloric acid (129ml) was added to the chilled solution of m-trifluoromethyl aniline(lθθg) and demineralized water(176 ml) followed by the addition of acrylonitrile (121 g) at 0-5 ⁰C along with chilled aqueous sodium nitrite solution (45.1 g in 65 ml of water). Allowed it to stir at 0-5⁰C for 20 minutes and then at 20⁰C for 1 hour. The reaction mixture was further cooled to 0-5⁰C and copper (I) oxide (6 g )was added at 0-5⁰C. The reaction mixture was further stirred for 2 hours at 0-5⁰C and at room temperature for 15 hours. After completion of reaction, toluene was added, and the layers were separated. The aqueous layer was extracted twice with toluene and combined organic layer was washed with demineralized water, and dried over sodium sulphate. The solvent was distilled under vacuum at 50⁰C to yield 144 g of the title compound. Example 2: Preparation of m-trifluorotnethyl-α-chlorohydrocinnamic acid m-Trifluoromethyl-α-chlorohydrocinnamonitrile(50g) was treated with concentrated hydrochloric acid (200ml )at room temperature and thereafter heated at 80-85°C for 4 hours. The reaction mixture was then cooled to room temperature and toluene was added with constant stirring and layers were separated. The aqueous layer was extracted with toluene and combined organic layer washed with demineralized water. To the toluene layer, 10% sodium bicarbonate (330ml) was added and stirred, the layers were separated. The aqueous layer was cooled to 0- 5°C and chilled concentrated hydrochloric acid was added till pH of about 1. To the reaction mass, toluene was added, and layers were separated, washed with demineralized water and dried over sodium sulfate. The organic layer was distilled under vacuum at 50⁰C to give 36 g of the title compound.

Example 3: Preparation of m-trifluoromethylhydrocinnamic acid

To m-trifluoromethyl-α-chlorohydrocinnamic acid (30 g) was added aqueous acetic acid (126 ml) and stirred at room temperature. Zinc powder (23.2 g) was added and the mixture was stirred at room temperature for half an hour and at 35⁰C for further half an hour. Acetic acid was distilled off completely at 85-90⁰C at 2mm Hg and reaction mass was cooled to room temperature and treated with chilled concentrated hydrochloric acid (50 ml). To the reaction mass, toluene was added, stirred and layers were separated. The aqueous layer was extracted with toluene and combined organic layer was washed with demineralized water. To the toluene layer, 10% sodium bicarbonate was added till a pH of 9.5 and stirred, the layers were separated. The aqueous layer was cooled to 0-5⁰C and chilled concentrated hydrochloric acid was added till pH of about 1. The aqueous layer was extracted with toluene. The toluene layer was washed with demineralized water, dried over sodium sulfate and distilled out completely to obtain 21.7 g of the title compound.

Example 4: Preparation of m-trifluoromethyl-α-bromohydrocinnamic acid

Concentrated hydrobromic acid (15.1ml) was added to the chilled solution of m-trifluoromethyl aniline (5g) and demineralized water(9 ml) followed by addition of acrylic acid (8.2Ig) at 0- 5⁰C along with chilled aqueous sodium nitrite solution (2.3 g of sodium nitrite in 3.3 ml of water). Allowed it to stir at 0-5⁰C for 20 minutes and then at 20⁰C for 1 hour. The reaction mixture was further cooled to 0-5⁰C and copper (I) oxide (0.3g) was added at 0-5⁰C. The reaction mixture was further stirred for 2 hours at same temperature and at room temperature for further 15 hours. After completion of reaction, toluene was added, and layers were separated. The aqueous layer was extracted with toluene and combined toluene layer was washed with demineralized water. The toluene was distilled under vacuum to afford 8 g of the title compound.

Example 5: Preparation of m-trifluoromethyl α-bromohydrocinnamonitrile

To a stirred mixture of 3-trifluoromethylaniline (250.Og, 1.55moles) and demineralized water (440ml) was added hydrobromic acid (754ml) over 1 hour at 0-5⁰C followed by addition of acrylonitrile (368ml) maintaining temperature 0-5⁰C. A solution of sodium nitrite (11 Ig sodium nitrite in 160ml of water) was added at same temperature and stirring was continued for 1.5 hours followed by the addition of copper (I) oxide (14.6g). The reaction mixture was initially stirred at 0-5°C for 2 hours and then at 20-25⁰C for 15 hours. The product was extracted with toluene (200 ml x 3). The organic extracts were combined and washed with water (500ml x2). Toluene was removed under reduced pressure to give 395g of the title compound.

Example 6: Preparation of m-trifluoromethyl-a-broniohydrocinnainic acid

A mixture of m-trifluoromethyl-α-bromohydrocinnamonitrile(385g) and hydrochloric acid (2.3 litres) was refluxed for 7.5 hours, cooled to 25-30⁰C followed by extraction with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford 374g of the crude title compound. The crude product was taken in toluene (600ml) and aqueous sodium hydroxide (1.0 1, 15%) was added at 10-15⁰C and stirred for 15 minutes. The layers were separated and aqueous layer was washed with toluene (200ml x2), acidified with hydrochloric acid (500ml) at 10-15⁰C and extracted with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure) to afford the title compound which was used as such in the next step.

Example 7: Preparation of ni-trifluoromethylcinnamic acid

To a suspension of m-trifluoromethyl-α-bromohydrocinnamic acid obtained in example 6, isopropanol (1.42 1) and benzyltriethylammonium chloride (10.85g), aqueous sodium hydroxide (340 ml, 56%) was added slowly. The temperature was raised to 55-60⁰C, stirred for 7 hours and isopropanol was removed in vacuo. Water (500ml) was added to the reaction mass, stirred and cooled to 0⁰C and acidified with hydrochloric acid (450ml). The solid was filtered, washed with water and dried in vacuo at 5O⁰C to afford 204g of the title compound.

Example 8: Preparation of m-trifluoromethylhydrocinnamic acid

A suspension of m-trifluoromethylcinnamic acid (194g) isopropyl alcohol (970ml) and Pd/C (19.4g, 10%) was hydrogenated for 4 hours at 1.0 kg/cm² hydrogen pressure. After completion of reaction, the reaction mass was filtered through hyflo bed, and concentrated in v&bub&oUU. afford 195g of the title compound.

Example 9: Preparation of methyl m-trifluoromethyl-α-bromohydrocinnamate

To a mixture of 3-trifluoromethylaniline (1Og) and demineralized water (18ml) was added - hydrobromic acid (30ml) over lhour at 0-5⁰C followed by addition of methyl aery late (21 ml) at 0-5⁰C. A solution of sodium nitrite (4.5g) in water (6.5ml) was added at above temperature and stirring continued for 1.5 hour followed by the addition of copper (I) oxide (0.6g). The reaction mixture was initially stirred at 0-5⁰C for 2 hour and then at 20-25⁰C for 15 hour. The product was extracted with toluene (50 ml x 3). The organic extracts were combined and washed with water (30ml x2). Toluene was removed under reduced pressure to give 19g of the title product.

Example 10; Preparation of methyl m-trifluoroniethylhydrocinnamate

To a mixture of methyl m-trifluoromethyl-α-bromohydrocinnamate (14g), acetic acid (53ml) and demineralized water (2.8ml), was added zinc powder (4.4g) at 20-25⁰C. Reaction mass was then heated to 60-65⁰C for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene was added followed by addition of cone, hydrochloric acid. The reaction mixture was stirred for 10 minutes and the toluene layer was separated. Toluene layer was washed with water and toluene was removed under vacuo to afford 1Og of the title compound.

Example 11 Preparation of m-trifluoromethylhydrocinnamic acid

A mixture of methyl m-trifluoromethyl-hydrocinnamate(0.5g), isopropanol (2.5ml) and sodium hydroxide (0.9g) was stirred at room temperature for 6 hours. Isopropanol was distilled off, water (2ml) added and washed with isopropyl ether. Reaction mixture was then acidified with hydrochloric acid, extracted with dichloromethane, organic layer separated and concentrated in vacuo to give 0.44g of title compound.

Example 12: Preparation of m-trifluoromethylhydrocinnamonitrile

To a mixture of m-trifluoromethyl-α-bromohydrocinnamonitrile (392 g), acetic acid (1.49 1) and demineralized water (78.4 ml), was added zinc powder (138.3 g) at 20-25⁰C. The temperature of reaction mass was raised to 60-65⁰C and heated for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene (500 ml) and cone, hydrochloric acid (500 ml) were added, stirred for 10 minutes and the layers were separated. Organic layer was washed with water and toluene was removed under vacuo to afford 249g (88.5%) of the title compound. Example 13; Preparation ofm-trifluoromethylcinnamonitrile

To a suspension of m-trifluoromethyl-α-bromohydrocinnamonitrile (I g), acetone (5ml) and benzyltriethylammoniumchloride (81mg), was added sodium carbonate (1.14g) and water (0.3ml). The temperature was raised to 40-45⁰C, stirred for 7 hours and acetone was removed in vacuo. Water (5ml) was added to the reaction mass, stirred and cooled to 0⁰C and acidified with hydrochloric acid. The product was extracted with isopropylether, washed with water. The solvent was concentrated in vacuo and dried to afford 0.65g of m- trifluoromethylcinnamonitrile.

Example 14:Preparation of m-trifluoromethylhydrocinnamic acid

A stirred mixture of m-trifluoromethylhydrocinnamonitrile (243.45g) and hydrochloric acid (1.2 litres) was refluxed for 4.5 hours, cooled to 25-30⁰C followed by extraction with toluene (500 mlx3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford 25Og (94%) of the title compound.

Example 15: Preparation of m-triflnoromethylhydrocinnamic acid

A mixture of m-trifluoromethylhydrocinnamonitrile (5g), demineralized water (4ml), monoethylene glycol (10ml) and sodium hydroxide (4g) was stirred at 125°C for 9 hours. Reaction mixture was acidified, extracted with toluene. Toluene was concentrated in vacuo to give 4.6g of title product.

Example 16: Preparation of (R)-N-(l-naphthaIen-l-yl-ethvI)-3-(3-trifluoromethyI-phenyI)- propionaniide

A mixture of m-trifluoromethylhydrocinnamic acid (5g), toluene (50ml), boric acid (7mg) and R-(+)-l(l-naphthyl)ethylamine (3.7g) was refluxed azeotropically for 12 hours and cooled to ambient temperature. The product was filtered, washed with lN-hydrochloric acid and water and dried to afford 8.5g of (R)-N-(l-Naphthalen-l-yl-ethyl)-3-(3-triflιιoromethy]-phenyl)- propionamide.

Melting point: 116-119°C MS (m/z): 372.2[M⁺¹]

IR (KBr) (v_max, cm^'1): 3301(N-H stretching), 1643(C=O stretching), 1556(aromatic C=C stretching).

¹H NMR (CDCl₃) (δpptn): 7.2-8.0(1 IH, m, Ar-H), 5.84(1H, m, C-H), 5.84(1H, m, N-H), 3.00(2H, m, CH₂), 2.39(2H, t, CH₂), 1.54(3H, m, CH₃). ¹³C-NMR (CDCl₃) (δppm): 20.57, 31.27, 37.87, 44.60, 122.49, 122.82, 123.10, 123.30, 124.99, 125.17, 125.53, 125.89, 126.56, 128.36, 128.80, 128.89, 131.02, 131.94, 133.88, 138.08, 141.72, 170.38, 130.52.

Example 17: Preparation of (R)-N-(l-naphthvIen-l-vIethvO-3-f3IYtrifluoromethyl- phenyl] propionamide

A mixture of m-trifluoromethylhydrocinnamic acid (5g) in toluene (25ml) and thionyl chloride (2.5ml) was initially stirred at room temperature for half an hour and then heated at 100-110⁰C for 4-5 hours. The solvent was distilled and reaction mass was cooled to room temperature and to this methylenechloride (20ml) was added. In a separate flask R-(+)-l(l-naphthyl)ethylamine (3.9g) was taken in methylenedichloride(25 ml), cooled to 0-5 ⁰C and triethylamine (4.8 ml) was added at 0-5⁰C. To this chilled solution, acid chloride solution in methylenedichloride prepared above, was added at 0-5⁰C and stirred. After completion of reaction, chilled concentrated hydrochloric acid (20 ml) was added, stirred and the layers were separated. The organic layer was washed with water and solvent was distilled to isolate 7.96 g of (R)-N-(I- naphthylen- 1 -ylethyl)-3-[3 [(trifluoromethyl- phenyl] propionamide.

Example 18: Preparation of (R)-N-(l-naphthaIen-l-yl-ethyl)-3-(3-trifluoromethyl-phcnvI)- propionamide

A mixture of m-trifluoromethylhydrocinnamic acid (24Og, 1.1 mole), toluene (1.2 1) and thionylchloride (120ml) was heated to 85-90⁰C for 4 hours. Toluene and thionylchloride were distilled off under reduced pressure. After complete removal of thionylchloride, methyl- tertiarybutylether (1.1 litre) was added to the acid chloride at 20-25⁰C. This Acid chloride solution in methyltertiarybutylether was added to a prestirred mixture of aqueous sodium carbonate (199g in 800ml of water), ■ R-(+)-l(l-naphthyl)ethylamine (179g) and methyltertiarybutyl- ether (1.63 1) at 5 to 10⁰C over of 30 minutes. Stirring was continued for 1.0 hour at 20-25⁰C, methyltertiarybutylether layer was separated, washed with aqueous sodium carbonate, IN hydrochloric acid (720ml) and demineralized water (720ml). The organic layer was distilled under vacuo and dried in oven at 45-5O⁰C to afford 35Og of the title compound.

Example 19: Preparation of (R)-2-bromo-N-(l-naphthalen-l-yl-ethyl)-3-(3- trifluoromethyl-phenvD-propionamide

A mixture of m-trifluoromethyl-α-biOmohydrocinnamic acid (1Og), toluene (50 ml ) and thionyl chloride (3.6ml) was heated to 85-90⁰C for 4 hours. Toluene and thionylchloride were distilled off under reduced pressure. After complete removal of thionylchloride, methyltertiarybutylether (75ml) was added at 20-25⁰C. This acid chloride solution in methyltertiarybutylether was added to a prestirred mixture of aqueous sodium carbonate (6.1g+24ml), R-(+)-l(l- naphthyl)ethylamine (4.6g) and methyltertiarybutylether (75ml) at 5 to 1O⁰C over of 30 minutes. Stirring was continued for 1 hour at 20-25⁰C, methyltertiarybutylether layer separated, washed with aqueous sodium carbonate, IN hydrochloric acid and demineralized water. The organic layer was distilled under vacuo and dried in oven at 45 - 5O⁰C to afford 6.8g of the title product.

Melting point: 122.5-124.2⁰C MS (m/z): 333 [M-I]

IR (ICBr) (υ_max, cm^"'): 3290.52, 1651.75, 1612.7, 1539.57, 1450.64, 1348.8, 1332, 1215.48, 1 180.94, 1 119.57, 968.85, 801.17, 776.49, 697.52.

¹H NMR (CDCl₃) (δppm): 7.2-8.3 (1 lH,m), 6.43 (IH, m), 5.87 (IH, m), 4.48 (IH, m), 2.65 (IH, m), 1.63 (3 H, m).

Example 20: Preparation of (R)-N-(l-Naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl- phenvQ-propionamide

Zinc powder (0.22g) was added to a mixture of (R)-2-bromo-N-(l-naphthalen-l-yI-ethyl)-3-(3- triflιιorornethyl-phenyl)~piOpionamide (0.5g), acetic acid (2ml) and demineralized water (0.1ml) at 20-25⁰C. Reaction mass was then heated at 60-65⁰C for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene and cone, hydrochloric acid were added, stirred for 10 minutes and the layers were separated. Organic layer was washed with water and toluene was removed under vacuo to afford 0.4g of the title compound.

Example 21: Preparation of Cinacalcet hydrochloride

To a solution of (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-piOpionamide (350g) in tetrahydrofuran (1.4 1) at 0-5⁰C, borane dimethylsulphide complex (179 ml) was added, and heated at 60-65⁰C for 4 hours. Tetrahydrofuran was distilled off under vacuo. Methanol (1.05 1) was added at 0⁰C and stirred for another 30 minutes. Methanol was distilled off under vacuo and the residue was treated with hydrochloric acid (2.1 1) at 0-5⁰C. The reaction mixture was stirred at 25-30⁰C for 2.0 hours and further at 85-90⁰C for 2.0 hours. The reaction mass was then cooled to 25-3O⁰C, filtered, washed with water and dried to afford 37 Ig of the title compound. The product so obtained was recrystallized with acetonitrile to afford pure cinacalcet hydrochloride having purity of 99.67% by HPLC. Example 22: Preparation of (RVN-(l-naphthalen-l-γl-ethylV3-(3-trifluoromethyl- phenvD-acrylamide

A mixture of m-trifluoromethylcinnamic acid (5g), toluene (25ml) and thionyl chloride (2.5ml) was heated to 85-9O⁰C for 4 hours. Toluene and thionyl chloride were distilled off under reduced pressure. After complete removal of thionyl chloride, methyl tertiary butyl ether (25ml) was added to the acid chloride at 20-25⁰C. This solution was added to a prestirred mixture of aqueous sodium carbonate (4.1g + 16ml), R-(+)-l(l-naphthyl)ethylamine (3.76g) and methyl tertiary butyl ether (25ml) at 5 to 10⁰C over of 30 minutes. Stirring was continued for 1.0 hour at 20-25⁰C, methyl tertiary butyl ether layer separated, washed with aqueous sodium carbonate, IN hydrochloric acid and demineralized water. The organic layer was distilled under vacuo and dried in oven at 45-50⁰C to afford 7.5g of the title compound.

Melting point: 177-18O⁰C MS (m/z): 333 [M-I]

IR (KBr) (υ_max, cm^'1): 3290.52, 1651.75, 1612.7, 1539.57, 1450.64, 1348.8, 1332, 1215.48, 1180.94, 11 19.57, 968.85, 801.17, 776.49, 697.52.

¹H NMR (CDCl₃) (δppm): 7.45-8.2 (l lH,m), 7.7 (IH, d), 6.4 (IH, d), 6.08 (IH, m), 5.84 (IH, m), 1.76 (3H, d).

Example 23: Preparation of Cinacalcet hydrochloride

To a cooled solution of the (R)- N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)- acrylamide (5g) in tetrahydrofuran (25ml), borane dimethylsulphide complex (4.05g) was added at 0-5 ⁰C. The temperature of reaction mixture was raised to 60-65⁰C and stirred for 4 hour. Tetrahydrofuran was distilled off under vacuo followed by addition of methanol (25ml) at 0⁰C and stirring for another 30 minutes. Methanol was distilled off under vacuo followed by addition of hydrochloric acid at 0-5⁰C, stirring at 25-3O⁰C for 2.0 hours and further heating to 85-90⁰C for 2.0 hours. The reaction mass was extracted with dichloromethane and concentrated in vacuo to afford 4.2g of the compound. The crude material was purified with acetonitrile to afford pure cinacalcet hydrochloride.

Example 24: Preparation of Cinacalcet free base

To a stirred suspension of Cinacalcet hydrochloride (crude, 25Og) in isopropylether (1.25 1) at 25⁰C was added 15% aqueous sodium carbonate solution till a pH of 9.5 at 25⁰C in duration of 15 minutes and stirred for 2.0 hours. Stirring was stopped and the layers separated. The organic layer was washed with water (250ml x2), dried over sodium sulfate, and distilled in vacuo to afford 222g of cinacalcet free base.

Example 25: Preparation of cinacalcet hydrochloride form A

Cinacalcet hydrochloride (12 g) in acetonitrile (36 ml) was heated at 80⁰C for a period of about 10 minutes. The solution was stirred at room temperature for about 2 hours and the solid was filtered and dried under reduced pressure to give cinacalcet hydrochloride form A having purity 99.7% area by HPLC. XRD patterns are same as shown in Fig. 1.

Example 26: Preparation of cinacalcet hydrochloride form A

A suspension of cinacalcet hydrochloride (37Ig) in acetonitrile (1.86 1) was refluxed till complete dissolution and then stirred at 25-3O⁰C for 3 hours. Product was filtered and dried in oven under reduced pressure at 45 - 5O⁰C to afford 315g of cinacalcet hydrochloride form A having water content of 0.05% w/w, as measured by Karl Fisher titration method.

Example 27: Preparation of cinacalcet hydrochloride form A

A suspension of cinacalcet hydrochloride (32g) in methyl isobutyl ketone (165ml) was heated at 9O⁰C till complete dissolution and then stirred at 25-3O⁰C for 3 hours. The precipitated product was filtered and dried at 45 - 5O⁰C under reduced pressure to afford 26g of cinacalcet hydrochloride form A.

Example 28: Preparation of cinacalcet hydrochloride form A

Cinacalcet hydrochloride (3g) was dissolved in toluene (9ml) at 9O⁰C, followed by stirring at 25-3O⁰C for 1 hour. The precipitated product was filtered and dried at 45 - 5O⁰C under reduced pressure to afford 1.7g of cinacalcet hydrochloride form A.

Example 29: Preparation of cinacalcet hydrochloride form A

A suspension of cinacalcet hydrochloride (5g) in isobutyronitrile (45 ml) was refluxed till complete dissolution and then stirred at 25-3O⁰C for 3 hours. Product was filtered and dried under reduced pressure at 45 - 5O⁰C to afford 2.9g of cinacalcet hydrochloride form A.

Example 30: Preparation of cinacalcet hydrochloride form A

A suspension of cinacalcet hydrochloride (1Og) in methylene chloride (20 ml) was refluxed till complete dissolution. The solvent was distilled off and product obtained was dried under reduced pressure at 45 - 5O⁰C to afford 8.5g of cinacalcet hydrochloride form A. Example 31: Preparation of cinacalcet hydrochloride form A

A suspension of cinacalcet hydrochloride (3g) in isopropanol (9ml) was refluxed till complete dissolution and then stirred at 25-3O⁰C for 3 hours. Product was filtered and dried under reduced pressure at 45 - 5O⁰C to afford cinacalcet hydrochloride form A.

Example 32: Preparation of cinaealcet hydrochloride form A

Cinacalcet hydrochloride (3g) was dissolved in dioxane (9ml) by warming, followed by addition of isopropyl ether (9ml) and stirring at 25-3O⁰C for 1 hour. Product was filtered and dried under reduced pressure at 45 - 5O⁰C to afford 1.9g of cinacalcet -hydrochloride form A.

Example 33: Preparation of cinacalcet hydrochloride form A

Cinacalcet hydrochloride (3g) was dissolved in dioxane (9ml) by warming, followed by addition of isopropyl ether (9ml) and stirring at 25-3O⁰C for 1 hour. Product was filtered and dried under reduced pressure at 45 - 5O⁰C to afford 1.9g of cinacalcet hydrochloride form A.

Example 34: Preparation of cinacalcet hydrochloride form A

Cinacalcet hydrochloride (3g) was dissolved in dioxane (9ml) by warming, followed by addition of diethyl ether (9ml) and stirred at 25-3O⁰C for 1 hour. Product was filtered and dried under reduced pressure to afford 1.8g of cinacalcet hydrochloride form A.

Example 35: Preparation of cinacalcet hydrochloride form A

Cinacalcet hydrochloride (3g) was dissolved in dioxane (9ml) by warming, followed by addition of methyl tertiary butyl ether (9ml) and stirred at 25-3O⁰C for 1 hour. The precipitated product was filtered and dried under reduced pressure to afford 2g of cinacalcet hydrochloride form A.

Example 36: Preparation of cinacalcet hydrochloride form B

Cinacalcet (10 g) was treated with dilute hydrochloric acid (40 ml, 6N) and stirred for 1 hour at ambient temperature. After completion , of reaction, the precipitated product was filtered, washed with water and dried to give cinacalcet hydrochloride form B.

Claims

WE CLAIM

1. A process for the preparation of cinacalcet hydrochloride of formula III,

Formula-Ill

which comprises reducing amide intermediate of formula Villa or a salt thereof,

Formula-VIIIa

using a suitable reducing agent at a temperature of below 10⁰C to reflux temperature of solvent, and isolating cinacalcet hydrochloride.

2. The process according to claim 1, wherein solvent is selected from tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyl tertiarybytyl ether and the like.

3. The process according to claim 1, wherein suitable reducing agent is selected form borane complex, metal hydrides with additives, or catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, and the like employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam.

4. The process according to claim 3, wherein borane complex is selected from borane- tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane- triphenylphosphine and the like.

5. The process according to claim 3, wherein metal hydride with additives is selected from lithium alumuinium hydride, diethyl aluminium hydride, sodium aluminium hydride, sodium borohydride, with additives such as iodine, sulfuric acid and lewis acids.

6. A process for the preparation of novel amide intermediate of formula VIII or a salt thereof, FormuIa-VIII

wherein X-H or halo selected from chloro, bromo and the like which comprises introducing an acyl group of formula IVa,

Formula IVa

wherein X = H or halo, wherein halo can be chloro, bromo or the like; into the amino group of molecule of formula Va or a salt thereof.

Formula Va

7. A process for the preparation of amide intermediate of formula Villa or a salt thereof,

Formula-Villa

from a compound of formula XII,

Formula-XII

wherein R" can be selected from CN, CONR¹R², COOR ', wherein R ' is hydrogen or an alkyύ group, R¹ and R² can be independently selected from H or lower alky! group, while X is selected fi'om H, halo, provided both R ' and X cannot be H simultaneously.

8. The process according to claim 7, wherein compound of formula XII is converted to compound of formula Villa which comprises: a) hydrolysing the compound of formula XII with a suitable acid or base to prepare a compound of formula XIV,

FormuIa-XIV

b) treating compound of formula XIV with a suitable base like organic or inorganic base, in the presence of a suitable solvent selected from water, isopropyl alcohol, tetrahydrofuran, ethyl nitrile, toluene, cyclohexane, methylene dichloride, the like or mixtures thereof and optionally a phase transfer catalyst selected from tetraalkyl ammonium halide, trialkyl aryl halide to prepare m-trifluoromethylcinnamic acid of formula XVI or salt thereof,

Formula XVI

c) reducing the compound of formula XVI with suitable reducing agent to prepare m- trifluoromethylhydrocinnamic acid of formula XIII,

Formula-XHI

d) treating m-trifluoromethylhydrocinnamic acid of formula XIII with suitable reagent to prepare the reactive derivative like acid halide, anhydride, active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C, e) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in suitable solvent in the presence of base to afford a compound of formula Villa.

9. A process according to claim 8, wherein acid used during hydrolysis is selected from inorganic acids like hydrochloric acid, hydrobromic acid and the like; organic acid like methylsufonic acid, p-tolylsulfonic acid, the like or mixtures thereof, whereas base used during hydrolysis is selected from alkali metal hydroxide, alkali earth metal hydroxide, organic bases like pyridine, triethylamine, N,N-dimethylaniline.

10. A process according to claim 8, wherein reduction is performed by catalytic reduction, employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium- carbon, rhodium-carbon, copper-chromium oxide, and the like in the presence of

transfering agents like formic acid, ammonium formate, cyclohexene and dihydrogen.

11. A process according to claim 8, wherein suitable reagent to prepare reactive derivative of m-trifluoiOmethylhydiOcinnamic acid of formula XIII is selected from phosphorous trihalide, phosphorous pentahalide, thionyl halide; organic acid halide like acetyl chloride, pivaolyl chloride, alkyl chloroformate, lewis acid, boric acid, the like.

12. The process according to claim 8, wherein the solvent used during condensation of reactive derivative of compound of formula XIII with R-(+)-l(l-naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like; whereas base is selected from pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali metal bicarbonates and carbonates and the like.

13. The process according to claim 7, wherein compound of formula XII is converted to compound of formula Villa which comprises: a) hydrolysing compound of formula XII with suitable acid or base to prepare a compound of formula XIV,

Formula-XIV

b) treating compound of formula XIV with a suitable reagent to prepare the reactive derivative like acid halide, anhydride, active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C, ^■ c) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a suitable solvent in the presence of base to prepare a compound of formula VIIIb,

Formula-VIIIb

wherein X=¹JmIo selected fi'om chloro, bromo and the like. d) hydrodehalogenating the resulting compound of formula VIIIb to prepare compound of formula Villa.

14. A process according to claim 13, wherein acid used during hydrolysis is selected Hόiiib. inorganic acids like hydrochloric acid, hydrobromic acid and the like; organic acid like methylsiifonic acid, p-tolylsulfonic acid, the like or mixtures thereof, whereas base used during hydrolysis is selected from alkali metal hydroxide, alkali earth metal hydroxide, organic bases like pyridine, triethylamine, N,N-dimethylaniline.

15. A process according to claim 13, wherein suitable reagent to prepare reactive derivative of

1 m-trifluoromethylhydrocinnamic acid of formula XIII is selected from phosphorous trihalide, phosphorous pentahalide, thionyl halide; organic acid halide like acetyl chloride, pivaolyl chloride, alkyl chloroformate, lewis acid, boric acid, the like.

16. The process according to claim 13, wherein the solvent used during condensation of reactive derivative of compound of formula XIII with R-(+)-l (l-naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like; whereas base is selected from pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali metal bicarbonates and carbonates and the like.

17. The process according to claim 13, wherein the hydrodehalogenation is performed using suitable reagent selected from sodium dithionite, zinc-acetic acid, zinc-potassium iodide, or magnesium, catalytic dehydrogenation, metal catalyst selected from platinum, ruthenium, osmium, iridium, and especially palladium, raney-nickel, along with a suitable solvent chosen from water, alcohol having CpC₄ alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof.

18. The process according to claim 7, wherein compound of formula XII is converted to formula Villa which comprises: a) hydrodehalogenating compound of formula XII to prepare a compound of formula XV,

Formula XV

b) hydrolysing compound of formula XV with suitable acid or base to prepare m- trifluoromethylhydiOcinnamic acid of formula XIII, c) treating m-trifliioiOmethylhydrocinnamic acid of formula XIII with a suitable reagent to prepare the reactive derivative like acid halide, anhydride, active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C, d) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a suitable organic solvent in the presence of base at a temperature of -10 to 1O⁰C, to prepare a compound of formula Villa.

19. A process according to claim 18, wherein suitable reagent to prepare reactive derivative of m-trifluoromethylhydrocinnamic acid of formula XIII is selected from phosphorous trihalide, phosphorous pentahalide, thionyl halide; organic acid halide like acetyl chloride, pivaolyl chloride, alkyl chloroformate, lewis acid, boric acid, the like.

20. A process according to claim 18, wherein acid used during hydrolysis is selected from inorganic acids like hydrochloric acid, hydrobromic acid and the like; organic acid like methylsufonic acid, p-tolylsulfonic acid, the like or mixtures thereof, whereas base used during hydrolysis is selected from alkali metal hydroxide, alkali earth metal hydroxide, organic bases like pyridine, triethylamine, N,N-dimethylaniline.

21. The process according to claim 18, wherein the hydrodehalogenation is performed using suitable reagent selected from sodium dithionite, zinc-acetic acid, zinc-potassium iodide, or magnesium, catalytic dehydrogenation, metal catalyst selected from platinum, ruthenium, osmium, iridium, and especially palladium, raney-nickel, along with a suitable solvent chosen from water, alcohol having Ci-C₄ alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof.

22. The process according to claim 18, wherein the solvent used during condensation of reactive derivative of compound of formula XIII with R-(+)-l(l-naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamidc, dimethylsulfoxide, methyltertiarybutylether and the like; whereas base is selected from pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali metal bicarbonates and carbonates and the like.

23. The process for the preparation of cinacalcet hydrochloride of formula III,

Formula-HI

which comprises: a) diazotizing 3-trifluoromethyl-phenylamine in the presence of sodium nitrate, suitable catalyst selected from copper (II) oxide, copper (I) oxide and an acid preferably hydrochloric acid, hydrobromic acid and the like, b) reacting the same with alkene derivative of formula CH₂=OHR", wherein R " is as described above, to afford a compound of formula XII,

Formula-XII

c) converting the same to m-trifluoromethyl hydrocinnamic acid of formula XIII,

Formula-XIII

d) converting m-trifluoromethyl hydrocinnamic acid of formula XIII to reactive derivative like acid halide, anhydride, active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C, e) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in the presence of suitable solvent in the presence of a base at a temperature of -10 to 10⁰C to afford a compound of formula Villa,

Formula- Villa

f) reducing the same using suitable reducing agent at a temperature of below 1O⁰C to reflux temperature of solvent, g) isolating cinacalcet hydrochloride, h) optionally purifying cinacalcet hydrochloride.

24. The process according to claim 23, wherein the solvent used during condensation of reactive derivative of compound of formula XIII with R-(+)-l(l-naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like; whereas base is selected from pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali ^"m'et&iua bicarbonates and carbonates and the like.

25. The process according to claim 23, wherein solvent used during reduction is selected from tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyl tertiarybytyl ether and the like.

26. The process according to claim 23, wherein suitable reducing agent is selected form borane complexes, metal hydrides with additives, or catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, and the like employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam.

27. The process according to claim 26, wherein borane complex is selected from borane- tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane- triphenylphosphine and the like

28. A process for the preparation of cinacalcet hydrochloride of formula 111,

Formula-Ill

which comprises: a) converting compound of formula XVI to reactive derivative like acid halide, anhydride, active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100⁰C, b) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a suitable solvent in the presence of base at a temperature of -10 to 10⁰C to prepare a compound of formula XVII,

Formula XVII

c) reducing the resulting compound of formula XVII in the presence of a suitable solvent, and d) isolating cinacalcet hydrochloride.

29. The process according to claim 28, wherein the solvent used during condensation of reactive derivative of compound of formula XIII with R-(+)-l(l-naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like; whereas base is selected from pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali metal bicarbonates and carbonates and the like.

30. The process according to claim 28, wherein solvent used during reduction is selected from tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyl tertiarybytyl ether and the like.

31. The process according to claim 28, wherein suitable reducing agent is selected form borane complexes, metal hydrides with additives, or catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, and the like employing nascent hydrogen obtained by the co-existence of metals such as sodium, sodium amalgam, aluminum amalgam.

32. The process according to claim 31, wherein borane complex is selected from borane- tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane- triphenylphosphine and the like

33. An amide intermediate of formula Villa, or its salts including solvates, isomers, hydrates and enaπtiomers thereof

Formula-VIIIa

34. An amide intermediate of formula VIIIb or its salts including solvates, isomers, hydrates and enantiomers thereof.

Formula- VIIIb

wherein X is hydrogen, halo like chloro, bromo or iodo.

35. An amide intermediate of formula XVII, or its salts including solvates, isomers, hydrates and enantiomers thereof.

Formula XVII

36. A process for preparing crystalline cinacalcet hydrochloride form A comprising: a) dissolving cinacalcet hydrochloride in a solvent to form a clear solution at reflux; b) inducing precipitation by cooling or distilling the solvent to obtain precipitate, and c) isolating cinacalcet hydrochloride form A.

37. A process according to claim 36, wherein the solvent used is selected from isopropanol, methylene chloride, acetonitrile, isobutyronitrile, toluene, xylene, methyl isopropyl ketone, methyl isobutyl ketone.

38. A process according to claim 36, wherein the solution is cooled to ambient temperature.

39. A process according to claim 36, wherein the solution is cooled to 0-10⁰C.

40. A process for preparing crystalline cinacalcet hydrochloride form A comprising: a) dissolving cinacalcet hydrochloride in a solvent like cyclic ether, b) cooling the mixture to about room temperature to about 4°C; _v c) adding an anti-solvent to obtain precipitate and d) isolating cinacalcet hydrochloride form A.

41. A process according to claim 40, wherein cyclic ether is selected from dioxane, tetrahydrofuran and the like:

42. A process according to claim 40, wherein the anti-solvent is selected from selected from aliphatic ethers.

43. A process according to claim 40, wherein the anti-solvent is selected from diethyl ether, isopropyl ether, methyl ter-butyl ether and the like.