FIELD OF THE INVENTION
The present invention provides a novel process for preparing cinacalcet of formula I,

(Formula Removed)

and its pharmaceutically acceptable salts thereof
The present invention also provides novel nitrogen protected synthetic intermediates
useful in the process of the present invention Particularly, the present invention
provides an industrially advantageous process for the preparation of cinacalcet
hydrochloride
BACKGROUND OF THE INVENTION
Cinacalcet of formula I, and cinacalcet hydrochloride are novel calcimimetic agents
that modulate the extra cellular calcium sensing receptor by making it more sensitive
to the calcium suppressive effects on parathyroid hormone and is chemically known
as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(tnfluoromethyl)phenyl]-l-aminopropane

(Formula Removed)

It is used in the treatment of primary and secondary hyperparathyroidism Hyperparathyroidism is characterized by high levels of circulating calcium due to an increased secretion of parathyroid hormone by one or more of the parathyroid glands Hyperparathyroidism can lead to osteoporosis, patients with renal failure suffering from secondary hyperparathyroidism have for example an increased risk of renal bone disease, soft-tissue calcifications and vascular disease
Calcium receptor-active molecules like cinacalcet and its pharmaceutically acceptable salts thereof were disclosed in PCT publication WO 1994/18959, US patents 6,211,244, 6,313,146, 6,031,003, 6,001,068, 6,011,884, 5,962,314, 5,858,684, 5,841,368, 5,763,569 and 5,688,938 etc US patent 6,211,244 discloses the process for the preparation of calcium receptor-active molecules like cinacalcet, but does not

provide any example for the preparation of cinacalcet and its pharmaceutically acceptable salt thereof
The method disclosed in the above patents for the preparation of these compounds includes the reductive animation of a commercially available aldehyde or ketone with a primary amine in the presence of sodium cyanoborohydnde or sodium tnacetoxyborohydnde
Alternatively, some compounds were prepared by the condensation of a primary amine with an aldehyde or ketone in the presence of titanium (IV) isopropoxide The resulting imine intermediate were then reduced in situ by the action of sodium cyanoborohydnde, sodium borohydnde, or sodium tnacetoxyborohydnde and the enamines were then catalytically reduced using palladium dihydroxide on carbon Vanous compounds were prepared by a dnsobutylaluminium hydnde (DIBAL-H) mediated condensation of an amine with a nitnle The resulting lmine intermediate was reduced in situ by the action of sodium cyanoborohydnde or sodium borohydnde The intermediate alkene was reduced by catalytic hydrogenation in ethanol using palladium on carbon Further, the compounds obtained by the above processes were converted to corresponding hydrochlonde salts by treatment of the free base with hydrogen chlonde gas in ether or hexane in combination with hydrogen chlonde gas The processes disclosed here involve the use of expensive reagents In addition, the compounds prepared there are purified by the column chromatography
Drugs of future 2002, 27(9), 831-836 discloses a process for the preparation of cinacalcet according to general process disclosed in US patent 6,211,244 The process involves the reaction of 1-acetylnaphthalene with 3-[3-(tnfluoromethyl)phenyl]propyl amine in presence of titanium isopropoxide to produce an imine which on treatment with methanohc sodium borohydnde gives racemic base which is then resolved by chiral chromatography
U S Patent 7,250,533 discloses a process for the synthesis of cinacalcet by first converting hydroxyl moiety of 3-(3-tnfluoromethylphenyl)propanol into a compound

containing good leaving group and further combining the same with (R)-1-naphthylethylamine in the presence of a base in an organic solvent to obtain cinacalcet according to the following scheme

(Scheme Removed)

Intermediate, 3-(3-tnfluoromethylphenyl)propanol is prepared by the heck coupling of l-bromo-3-tnfluoromethylbenzene with ethylacrylate to give unsaturated ester, followed by reduction to give corresponding saturated alcohol
PCT publication WO 2007/127445 discloses a process for the preparation of cinacalcet by the condensation of reactive derivative of 3-(3-tnfluoromethylphenyl)propanoic acid with (R)-l-naphthylethylamine to give N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(tnfluoromethyl)phenyl]propanamide, which is then reduced to give cinacalcet and its pharmaceutically acceptable salts as shown in the following scheme

(Scheme Removed)

Similar process is also disclosed in PCT publications WO 2008/035381, WO 2008/058235, Indian application no 555/MUM/2007, articles, Tetrahedron Letters 2008 49(1) 13-15 and Synthetic Communications 2008 38 (10) 1512-1517 PCT publication WO 2007/127449 discloses a process for the preparation of cinacalcet by condensation of 3-bromotnfluorotoluene with an allylamine of following formula

(Formula Removed)
in the presence of a catalyst and at least one base to obtain unsaturated cinacalcet which is then reduced to give cinacalcet
PCT publication WO 2008/063645 discloses a process for the preparation of cinacalcet by condensing a compound of following formula,
(Formula Removed)
wherein X is C1-C3 alkyl sulfonate, substituted and non-substituted C6-C10 aryl sulfonate or halogen
with (R)-l-naphthylethylamine using minimal amount of solvent and optionally, in the presence of a base
PCT publication WO 2008/068625 discloses a process for the preparation of cinacalcet by reductive animation of 3-(3-tnfluoromethylphenyl)propanal with (R)-l-naphthylethylamine in the presence of sodium tnacetoxyborohydnde As discussed above, most of the prior art processes involve the use of reagents such as titanium isopropoxide and dnsobutylaluminium hydride, which are expensive and have to be handled in large volume when the process is employed on large scale These moisture sensitive and pyrophonc reagents require special handling One of the processes involve the use of ethylacrylate which is a known carcinogen, highly flammable, may cause violent reaction on exposure to moisture and unstable to oxidizing agent Use of compound like ethylacrylate is not advisable due its instability to above conditions Use of column chromatography for the purification, chiral chromatography for the isolation of chiral compounds, use of expensive and harmful reagent make the processes known in the prior art not amenable to an industrial scale up
Therefore, there is an urgent need in the art to develop a process for the preparation of cinacalcet and its pharmaceutically acceptable salts thereof, which is industrially applicable, does not involve the use of harmful and expensive reagent like


ethylacrylate and dnsobutylaluminium hydnde Thus, the present invention provides
an industrially advantageous, process for the preparation of cinacalcet and its
pharmaceutically acceptable salts using novel intermediates The process of the
present invention is cost effective, eco-fnendly, commercially viable as well as
reproducible on industrial scale and meets the needs of regulatory agencies
OBJECT OF THE INVENTION
It is the principal object of the present invention to provide an efficient and novel
process for the preparation of cinacalcet and its pharmaceutically acceptable salts
thereof, 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 process for the preparation
of synthetic intermediates
Yet another object of the present invention is to provide novel synthetic intermediates
that play a crucial role in the preparation of cinacalcet and its pharmaceutically
acceptable salts thereof
SUMMARY OF THE INVENTION
According to one aspect, the present invention provides a novel and industrially
advantageous process for the preparation of cinacalcet of formula I,

(Formula Removed)
and its pharmaceutically acceptable salts thereof,
which comprises the steps of
(a) providing a compound of formula II including isomers or mixture thereof,

(Formula Removed)
wherein R1, R2, R3 and R4 are hydrogen, or R1, R2 together, form a double bond provided R3 and R4 are hydrogen or R3, R4 together, form a double bond provided R1

and R2 are hydrogen, or R1, R2, R3 and R4 all are combined together to form triple bond
(b) converting the hydroxyl group of compound of formula II into a good leaving
group to obtain compound of formula III including isomers or mixture thereof,

(Formula Removed)

wherein R1, R2, R3 and R4 are as defined above and X is a good leaving group, preferably selected from halide such as chloro, bromo, wdo, or sulphonyloxy functional group of general formula -OSO2R' wherein R' is selected from straight chain or branched C1-10 alkyl group, substituted or unsubstituted C1-10 aryl group, substituted or unsubstituted C1-10 heteroaryl group having one or more hetero atoms selected from nitrogen, sulfur or oxygen
(c) condensing the compound of formula III with the compound of formula IV,

(Formula Removed)

wherein Z is an amine protecting group
in presence of a suitable base to prepare a compound of formula V, and

(Formula Removed)

wherein R1, R2, R3, R4 and Z are as defined above
(d) converting the compound of formula V to cinacalcet of formula I and its
pharmaceutically acceptable salts thereof
According to yet another aspect, the present invention provides a novel process for the preparation of compound of formula II including isomers or mixture thereof by reducing the compound of formula VI including isomers or mixture thereof,
(Formula Removed)

wherein R1, R2, R3 and R4 are as defined above and R5 can be selected from
hydrogen, alkyl or any suitable activating group
using a suitable reducing agent
According to another aspect, the present invention provides novel intermediate of
formula V including salts, hydrates, solvates, racemates, enantiomers, polymorphs,
derivatives thereof and process for preparing the same and their conversion to
cinacalcet and pharmaceutically acceptable salts thereof
DETAILED DESCRIPTION OF THE INVENTION
As described herein "all the intermediate as well as final product" includes salts,
hydrates, solvates, racemates, enantiomers, polymorphs, derivatives thereof
The present invention provides a novel and industrially advantageous process for the
preparation of cinacalcet of formula I,

(Formula Removed)

and its pharmaceutically acceptable salts thereof starting from compound of formula II including isomers or mixture thereof
According to one aspect of the invention, hydroxy group of compound of formula II, including isomers or mixture thereof is converted to a good leaving group in presence of an activating reagent in a suitable solvent to form a compound of formula III including isomers or mixture thereof
Generally, the compound of formula II in a suitable solvent is reacted with an activating reagent containing a good leaving group in a suitable solvent and maintaining the reaction mixture at a temperature of 0 °C to 180 °C The reaction temperature may vary depending upon the nature of activating agent The time for obtaining the compound of formula III depend upon the quantity as well as nature of starting compound, activating reagent and reaction conditions, preferably reaction is maintained for half an hour to 24 hours, more preferably till the completion of the reaction Activating reagent containing the good leaving group is generally a

conjugate base Activating reagent includes, but not limited to thionyl halide, aliphatic or aromatic sulfonyl halide, phosphorous halides, phosphorous oxyhahde and the like, preferably the activating reagent is thionyl bromide or thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, 4-mtrobenzenesulfonyl chloride or p-toluenesulfonyl chloride, phosphorus trichloride, phosphorous pentachloride, phosphorous oxychlonde, phosphorous tnbromide and the like Solvent includes, but not limited to water, halogenated solvents such as dichloromethane, chloroform, C2-8 ether such as isopropyl ether, methyl tert-butyl ether, C3-8 aromatic and aliphatic hydrocarbon such as toluene, xylene, ethyl benzene, C2-5 nitnle such as acetomtnle, C3-8 ketone such as acetone, ethyl methyl ketone, methyl isobutyl ketone, amide solvents such as dimethyl formamide, dimethylacetamide, N-methylpyrrohdone, and the like or mixture thereof The reaction can be preferably carned out in anhydrous or hydrous conditions Anhydrous conditions can be created by employing anhydrous starting material, reagents as well as solvent or moisture can be removed by azeotropic distillation of water It is advantageous to add a suitable base to the reaction mixture Base can be an orgamc or an inorgamc base Organic base includes tertiary amines selected from tnethylamine, N,N-dusopropylethyl amine, pyridine, and the like or combination thereof Inorgamc base includes but not limited to alkali or alkaline metal hydroxide, carbonate, bicarbonate and the like or combinations thereof, preferably the base can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide and the like
In a preferred aspect, the compound of formula II wherein the R1, R2, R3 and R4 are hydrogen, has the structure of formula IIa including isomers or mixture thereof,

(Formula Removed)

is converted to corresponding compound of formula IIIa including isomers or mixture thereof, by the similar process as described above

(Formula Removed)
wherein X is a good leaving group
In another preferred aspect, compound of formula II wherein the R1, R2 , together, form a double bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond provided R1 and R2 are hydrogen, has the structure of formula IIb including isomers or mixture thereof,

(Formula Removed)

which is converted to corresponding compound of formula Mb, by the similar process as described above

(Formula Removed)

wherein X is as defined above
In yet another preferred aspect, compound of formula II wherein the Rlt R2, R3 and R4 all are combined together to form triple bond, has the structure of formula IIc including isomers or mixture thereof,

(Formula Removed)

which is converted to corresponding compound of formula IIIc, by the similar process as described above

(Formula Removed)

wherein X is as defined above
According to another aspect, the present invention provides a process for the
preparation of compound of formula IIIa
Generally, the compound of formula IIIa can be prepared by the reduction of
compound of formula 111b or IIIc with a suitable reducing agent Similarly, the


compound of formula IIIb can be prepared by the selective reduction of compound of formula IIIc with a suitable reducing agent The reduction reaction can be performed by catalytic hydrogenation (hydrogen over a metal catalyst) The metal catalyst includes, but not limited to transition metal, transition metal on support (where support can be carbon or barium sulfate), organometallic compounds of transition metal (homogenous catalyst), or other transition metal derivative or platinum dioxide and the like The transition metal includes, but not limited to palladium, platinum, rhodium, ruthenium or nickel and the like The hydrogen pressure employed in the reaction can be from 1 to 5 atmospheres The hydrogenation is carned till the completion of the reaction, preferably for 1 to 24 hours Reducing agents include, but not limited to borane complexes such as borane- tetrahydrofuran, borane-dimethylsulfide, borane amine, borane lewis base, borane-tnphenylphosphme and the like, hydride transfer reagent The reducing agents, MBR6H or MAIR6H that can be used with or without cocatalysts include, but not limited to cobalt or nickel derivatives and with or without ligands like dimethylglyoxime and the like (wherein M can be metal like alkali metal or alkaline earth metal or transition metal or a suitable metal and R6 can be any ligand selected from alkoxy, RN, (R)2N, (R)3N, RCOO, RS, CN and the like, R is selected from susbtututed or unsubstiututed alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and the like), or other appropriate reducing reagent as mentioned in comprehensive organic transformation by Richard C Larock The suitable solvent for the reduction reaction can be selected depending upon the reaction conditions and nature of reducing agent Suitable solvents includes, but not limited to water, C1-5 alcohol such as methanol, ethanol, isopropanol, tert-butanol, n-butanol, C5-8 aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, C3-8 ester such as ethyl acetate, C2-8 ether such as isopropyl ether, tert-butyl ether, and the like or mixture thereof According to another aspect, the present invention provides a process for the preparation of compound of formula V,

(Formula Removed)

wherein R1, R2, R3 and R4 are as defined above, Z is an amine protecting group and can be selected from allyl, substituted allyl, linear, branched or cyclic C1-8 alkyl, substituted linear, branched or cyclic C1-8 alkyl, linear, branched or cyclic C1-8 alkenyl, substituted linear, branched or cyclic C1-8 alkenyl, linear, branched or cyclic C1-8 alkynyl, substituted linear, branched or cyclic C1-8 alkynyl, -CN, -SO2R'', -COOR'' wherein R" can be alkyl, alkenyl, alkynyl, or aryl, -CONR"'R'" wherein R"' and R"" can be same or different and individually selected from alkyl, alkenyl, alkynyl, or aryl, or and the like, all the above groups can be substituted at carbon with a group selected from alkyl, alkoxy or aryl and like, preferably Z is selected amongst carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzyloxycarbonyl group, p-methoxyphenyl, tert-butyldimethylsilyl, other sulfonyl such as p-nitrobenezenesulfonyl, methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl group, and the like
by the condensation of the compound of formula III with a compound of formula IV in presence of a base

(Formula Removed)
wherein Z is as defined above
Generally, the condensation reaction can be performed in the presence of a base in a suitable solvent at a temperature of about 0 to 100 °C for few minutes to several hours The reaction temperature and time can vary depending upon the nature of the protecting group, preferably, reaction is carried out till the completion of the reaction Solvent includes, but not limited to water, C1-5 alcohol, C3-8 ketone, C5 % aliphatic or aromatic hydrocarbon, C3-7 ester, C2-8 ether, C2-5 nitnle, amide solvents such as


dimethylformamide, N-methylpyrrohdone, dimethylacetamide, aprotic solvents such as dimethylsufoxide, and the like or mixture thereof Suitable bases can be an organic or an inorganic base Organic bases include, but not limited to tertiary amines, RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth metal), or alkoxide of alkali or alkaline earth metal Inorganic bases, includes but not limited to alkali or alkaline earth metal hydride, or hydroxide or carbonate or bicarbonate, or MNH2 or MNS1R7 (wherein M can be alkali metals and R7 can be C1-8 aliphatic or aromatic hydrocarbons and the like), or organometalhc bases with or without additives Optionally, a phase transfer catalyst can be added to the reaction mixture Phase transfer catalyst includes, quaternary ammonium compounds benzyl tnmethylammomum chloride and bromide, cetyl tnmethylammomum bromide, phosphonium compounds or synthetic resins, tetrabutylammonium bromide or chloride, benzyltnethylammonium chloride, tetrabutylammonium hydroxide, tricaprylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate, tetrabutylammonium hydrogensulfate, hexadecyltnbutylphosphomum bromide, hexadecyltnmethyl ammonium bromide or resin amberlite IRA-410 and the like Phase transfer catalyst may be present in an amount of about 0 05 to about 1 0 mol, preferably 0 05 to 0 5 mol equivalents The compound of formula V can be isolated from the reaction using a suitable conventional method depending upon the nature of the compound of formula V
In a preferred embodiment of the present invention, the compound of formula V wherein the R1, R2, R3 and R4 are hydrogen has structure formula Va,

(Formula Removed)

wherein Z is as defined above
may be prepared by the condensation of compound of formula IIIa with compound of
formula IV and further forms the inventive part of the invention

In a more preferred embodiment of the present invention, the compound of formula Va wherein Z is p-mtrobenzenesulfonyl has structure of formula Va-1

(Formula Removed)

may be prepared by the condensation of compound of formula IIIa with compound of formula N-1

(Formula Removed)

Generally, the process involves the condensation reaction of compound of formula IIIa (wherein X is as defined above) with compound of formula N-1 in the presence of a base in a suitable solvent at a temperature of about 10 to 100 °C for few minutes to several hours, preferably till the completion of the reaction Solvent includes, but not limited to water, C1-5 alcohol such as methanol, ethanol, isopropanol, C3-8 ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, C5-8 aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, C3-7 ester such as ethyl acetate, C2-8 ether such as isopropyl ether, methyl tert-butyl ether, C2-5 rutnle such as acetomtnle, amide solvents such as dimethylformamide, N-methylpyrrohdone, dimethylacetamide and aprotic solvents such as dimethylsufoxide,and the like or mixture thereof Suitable bases can be an organic or an inorgamc base Organic bases include, but not limited to tertiary amines, RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth metal), or alkoxide of alkali or alkaline earth metal Inorganic bases, includes but not limited to alkali or alkaline earth metal hydride, or hydroxide or carbonate or bicarbonate, or MNH2 or MNS1R7 (wherein M and R7 are as defined above), or organometallic bases with or without additives, preferably base is selected from such as potassium carbonate, sodium hydroxide,

sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, and the like It is advantageous to perform the reaction optionally in the presence of phase transfer catalyst that includes, but not limited to quaternary ammonium compounds benzyl tnmethylammonium chloride and bromide, cetyl trimethylammoniurn bromide, phosphomum compounds or synthetic resins, tetrabutylammonium bromide or chloride, benzyltnethylammonium chloride, tetrabutylammonium hydroxide, tncaprylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate, tetrabutylammonium hydrogensulfate, hexadecyltnbutylphosphonium bromide, hexadecyltnmethyl ammonium bromide or resin amberlite IRA-410 and the like, preferably benzyltnethylammomum chloride The phase transfer catalyst may be present in an amount of about 0 05 to about 10mol, preferably 0 05 to 0 5mol equivalents The compound of formula Va-1 can be isolated from the reaction mixture using suitable techniques known in the art such as removal of solvent from the reaction mixture by evaporation, distillation and the like Specifically, condensation of compound of formula III (wherein x is p-toluenesulfonyl) with compound of formula N-1 is accomplished in the presence of a base and optionally in the presence of phase transfer catalyst in a suitable solvent The reaction can preferably be conducted at a temperature of room temperature to 90°C and it takes about 10-15 hours for the completion of reaction After completion of reaction, the reaction mass is cooled and neutralized using water and dilute acid solution Thereafter the solvent can be removed by distillation and another solvent may be added to resulting residue to isolate the solid compound Another solvent can be selected from aliphatic or aromatic hydrocarbon such as n-heptane, cyclohexane, n-hexane, ether such as isopropyl ether and the like or mixture thereof Preferably, another solvent may be selected from any solvent in which the desired product is having no solubility or less solubility
In still another more preferred embodiment of the present invention, the compound of formula Va wherein Z is tert- butyloxycarbonyl has structure of formula Va-2

(Formula Removed)

may be prepared by the condensation of compound of formula IIIa with compound of formula N-2

(Formula Removed)

Typically, the process involves the condensation reaction of compound of formula IIIa (wherein x is as defined above) with compound of formula N-2 m the presence of a base in a suitable solvent at a temperature of about 0 to 100 °C for few minutes to several hours, preferably till the completion of the reaction Solvent includes, but not limited to water, C1-5 alcohol such as methanol, ethanol, isopropanol, tert-butanol, C3 8 ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, C5-8 aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, C3-7 ester such as ethyl acetate, butyl acetate, C2-8 ether such as tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, C2-5 nitnle such as acetomtnle, amide solvents such as dimethylformamide, N-methylpyrrohdone, dimethylacetamide and aprotic solvents such as dimethylsulfoxide and the like or mixture thereof There is no limit on the nature of the solvent used for reaction, provided they have no effect on other functionalities The base used for the reaction can be selected from an organic such as to tertiary amines, RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth meta)l, or alkoxide of alkali or alkaline earth metal, or an inorganic base that alkali or alkaline earth metal hydride, or hydroxide or carbonate, or alkoxide or bicarbonate, or MNH2 or MNS1R7 (wherein M and R7 are as defined above), or organometallic bases with or without additives, preferably base is selected from such as potassium hydroxide, potassium tertiary butoxide, sodium tertiary butoxide,

sodium hydride, sodium hydroxide and the like Optionally the reaction can be conducted in the presence of phase transfer catalyst which can be selected from the list as described above The compound of formula Va-2 can be preceded as such for the next step or isolated from the reaction mixture The isolation may be earned out using a suitable techniques known in the art, such as extraction from a suitable solvent followed removal of solvent from the reaction mixture by evaporation, distillation and the like, any other methods can be employed
Specifically, condensation of compound of formula Ilia (wherein x is p-toluenesulfonyl or methanesulfonyl) with compound of formula N-2 is accomplished using a base in a suitable solvent The reaction can optionally be performed in presence of phase transfer catalyst The reaction can be preferably conducted at a temperature of 10 to 70°C and it takes about 1-25 hours for the completion of reaction The compound of formula Va-2 can be isolated from the reaction mixture using any conventional methods Specifically, the compound of formula Va-2 is isolated from the reaction by the addition of water followed by layer separation using a water immiscible solvent Preferably water immiscible solvents employed mclude halogenated solvents such as dichloromethane, chloroform, ethers such as 2-methyl tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene and the like or mixture thereof Thereafter, intermediate compound of formula Va-2 is recovered from the solution by any suitable techniques such as removal of solvent using distillation, evaporation and the like
Similarly, the compound of formula V wherein the R1, R2, together, form a double bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond provided R1 and R2 are hydrogen, has structure formula Vb,

(Formula Removed)

wherein Z is as defined above

may be prepared by the condensation of compound of formula IIIb with compound of formula IV and further forms the inventive part of the invention Similarly, the compound of formula V wherein the R1, R2, R3 and R4 all are combined together to form triple bond, has structure formula Vc,

(Formula Removed)

wherein Z is as defined above
may be prepared by the condensation of compound of formula IIIc with compound of formula IV and further forms the inventive part of the invention The resulting compound of formula V may be characterized by various spectroscopic techniques like 1H and 13C Nuclear magnetic resonance (NMR), Ultraviolet spectroscopy (UV), Mass spectrometry (MS), Infrared spectroscopy (IR) Further X-ray diffraction pattern of the compound provide information whether compound exist in crystalline or amorphous form The compound of formula Va-1 exists in solid from, it can occur in different polymorphs or in amorphous form The crystalline or amorphous nature of the compound is charactenzed by X-ray diffraction pattern Further, the compound of formula V, including salts, hydrates, solvates, racemates, enantiomers, polymorphs thereof forms a part of the present invention Specifically, the compound of formula Va-1 is charactenzed by 1H-NMR (CDCl3) showing peaks at δ 8 46 (d,lH), 8 25 (d,2H),7 93 (d,2H), 7 82 (m,2H), 7 59 (t,lH), 7 52 (t,lH), 7 35 (m,3H), 7 26 (m,lH), 6 90 (m,2H), 6 07 (dd,lH), 3 07 (m,2H), 2 18 (t,2H), 1 37 (m,lH), and 0 8 (m,lH)
Also compound of formula Va-2 is charactenzed by 1H-NMR (CDCl3) showing peaks at 8 07 (bs,lH), 7 74 (d,lH), 7 67 (d,lH), 7 24-7 44 (m,4H), 7 19 (d,lH), 7 08 (t,lH), 6 80 (bs,lH), 6 71(d,lH), 6 0 (m,lH), 2 7 (m,2H), 2 0 (m,2H), 1 48 (d,3H), 1 40 (s,9H), 1 13 (m,lH), and 0 77 (m,lH)


The compound of formula V, if desired can be purified to enhance the purity of the desired intermediate or to remove undesired impurities in the intermediate using suitable methods Any suitable purification procedure such as, for example, crystallization, denvatisation, slurry wash, salt preparation, various chromatographic techniques, solvent, anti-solvent crystallization or combination of these procedures, may be employed to get purified material However, other equivalent procedures such as acid-base treatment could, also be used, to punfy the intermediate of formula V Solvents used for the purification may be selected depending upon the nature of the compound to be purified, however the solvent can be chosen amongst water, C\ 6 alcohols such as methanol, ethanol, tert-butanol, isopropanol, aliphatic C3 6 ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, aliphatic or aromatic hydrocarbons such as toluene, xylene, ethyl benzene, n-heptane, cyclohexane, n-hexane, C3-6 ethers such as methyl tertiary butyl ether, isopropyl ether, 2-methyl tetrahydrofuran, dioxane, 1,2-dimethoxy ethane and the like or mixture thereof in suitable proportion
Specifically, the compound of formula Va can be crystallized using a suitable solvent, in which the compound has some solubility either at room temperature or at higher temperature, that includes C1-6 alcohols such as methanol, ethanol, isopropanol, n-butanol, tert-butanol, aliphatic C3-6 ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, aliphatic or aromatic hydrocarbons such as toluene, xylene, ethyl benzene and the like or mixture thereof Alternatively, the compound of formula Va can be purified by slurry wash in a suitable solvent, in which the compound has low solubility as compared to impurities, such solvent includes but not limited to aliphatic hydrocarbon such as n-heptane, cyclohexane, hexanes, n-hexane, ether such as methyl tertiary butyl ether, isopropyl ether, 1,2-dimethoxyethane, dioxane, 2-methyl tetrahydrofuran, tetrahydrofuran and the like or mixture thereof in any suitable proportions
Alternatively, intermediate compound of formula Va can be purified by using a special treatment to remove any specific impurity such as compounds of formulae Vb

and Vc, which may be present in the intermediate compound of formula Va For example, if any impurity having alkene functionality is present in the intermediate compound of formula Va then it can be removed using a suitable reagent that either bind with the alkene functionality to form a complex or change the nature of the alkene impurity so that it can be easily removed or isolate from the reaction mixture by using suitable methods like extraction or filtration and the like Suitable regent can be selected from oxidizing agent such as potassium permanganate, potassium dichromate, chromic acid, or silver salts such as silver nitrate that bind with the alkene functionality Preferably, the intermediate compound of formula Va is treated with a suitable reagent for few minutes to several hours The reaction can optionally be earned out in the presence of inert solvent that includes but not limited to halogenated solvent such as dichloromethane, aliphatic or aromatic hydrocarbon such as toluene, and the like or mixture thereof Optionally a suitable phase transfer catalyst can be added to the reaction mixture and selected from the list as given described above Thereafter, purified intermediate free from alkene impurity can be isolated from the reaction mixture by filtration or by the addition of water to make the reaction mixture biphasic The desired product can be extracted from mixture by the removal of solvent from the organic layer
In this way, the solvent and type of purification required to enhance the purity of the intermediate can be chosen based on the nature of intermediate of formula V and impurity to be removed Similarly, compound of formula Vb and Vc can be purified using a suitable methods The purification processes can be repeated or used in combination with other till the desired purity of the intermediate is achieved According to another aspect, present invention provides a process for the conversion of intermediate compound of formula V including salts, hydrates, solvates, racemates, enantiomers, polymorphs thereof to cinacalcet of formula I and its pharmaceutically acceptable salts thereof
In a preferred embodiment of the present invention, the compound of formula Va, may be converted to cmacalcet and its pharmaceutically acceptable salts thereof

Generally, the deprotecting agent and the reaction conditions for deprotection of amine protecting group is chosen appropriately depending upon the nature of protecting group The amino-protecting group can be removed using conventional procedures and reagents For example, benzyl protecting group or substituted benzyl protecting group can be removed by selective hydrogenolysis in the presence of a catalyst, such as palladium and the like, a tert-butoxycarbonyl group can be removed by treatment with strong acid, such as hydrochloric acid, p-toluenesulfonic acid, tnfluoroacetic acid and the like, 9-fluorenylmethyloxycarbonyl can be removed by treatment with a suitable base, a tert-butyldimethylsilyl group can be removed by treatment with a source of fluoride ions, such as tnethylamine tnhydrofluonde and the like, p-methoxyphenyl can be removed by ammonium cerium (IV) nitrate, p-toluenesulfonyl group can be removed by treatment with concentrated acid such as hydrobromic acid, sulfuric acid and the like or by strong reducing agents such as sodium in liquid ammonia, sodium naphthalene and the like, sulfonamide can be deprotected by substituted or unsubstituted thiophenol, samarium iodide, tributyltin hydride Appropriate deprotecting agent can be perceived by those well versed in the art from 'Protecting Groups by Philip J Kocienski (Thieme, 2000)' or 'Protective Groups m Organic Synthesis by Theodora W Greene, Peter G M Wuts' or available and well documented in the literature The solvent employed in the reaction can be chosen depending upon the nature of the protecting group to be removed After the completion of the reaction, cinacalcet can be isolated from the reaction mixture or in situ converted to cinacalcet pharmaceutically acceptable salts Thus, compound of formula Va, including salts, hydrates, solvates, racemates, enantiomers, polymorphs thereof can be directly converted to cinacalcet pharmaceutically acceptable salts In a more preferred embodiment of the present invention, it provides a process for the preparation of cinacalcet and its pharmaceutically acceptable salts thereof by the deprotecting the intermediate compound of formula Va-1
Typically, the process involves the reaction of compound of formula Va-1 with a suitable deprotecting agent at a temperature 0 to 100°C, till the completion of the

reaction Any deprotecting reagent can be employed in the reaction that can effectively remove p-mtrobenzenesulfonyl group, and selected from any reagent known in the art for such purpose Preferably, suitable deprotecting agent includes but not limited to substituted or unsubstituted thiophenol, samarium iodide, tnbutyltm hydride and the like Preferably, deprotecting agent used is substituted or unsubstituted thiophenol There is no restriction on the nature of the solvent employed for the reaction, provided it has no adverse effect on other functionality Particularly, the solvent includes but not limited to ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, amide solvents such as dimethylformamide, dimethylacetamide, aprotic solvent such as dimethylsulfoxide, nitnles such as acetonitnle, propionitnle and the like or mixture thereof in any suitable proportions The reaction is additionally carned using base with or without phase transfer catalyst Base employed for the reaction can be organic or inorganic base Organic base include but not limited to amines such as tnalkylamine Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonates, hydrides, alkoxide thereof such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate and the like The phase transfer catalyst includes, but not limited to quaternary ammonium compounds benzyl tnmethylammonium chloride and bromide, cetyl tnmethylammonium bromide phosphonium compounds or synthetic resins, tetrabutylammonium bromide or chloride, benzyltnethylammonium chloride, tetrabutylammonium hydroxide, tncaprylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate, tetrabutylammonium hydrogensulfate, hexadecyltnbutylphosphonium bromide, hexadecyltnmethyl ammonium bromide or resin amberlite IRA-410 and the like After the completion of reaction, the desired compound 1 e cinacalcet can be isolated from the reaction mixture or reaction mixture is used, as such, for the next step 1 e preparation of cinacalcet pharmaceutically acceptable salts Cinacalcet can be isolated from the reaction mixture by any conventional method in the art Specifically, cinacalcet can be isolated from the reaction by removal of solvent, extraction with a suitable solvent,

layer separation and the like Cinacalcet thus obtained or the reaction mixture is made to react with a suitable acid to form cinacalcet pharmaceutically acceptable salts In one another more preferred embodiment of the present invention, it provides a process for the preparation of cinacalcet and its pharmaceutically acceptable salts thereof by the deprotecting the intermediate compound of formula Va-2 Typically, the process involves the reaction of compound of formula Va-2 with a suitable deprotecting agent at a temperature 0 to 100 °C for few minutes to several hours, preferably till the completion of the reaction Any deprotecting reagent can be employed in the reaction that can effectively remove tert-butyloxycarbonyl group, and selected from any reagent known in the art for such purpose Preferably, suitable deprotecting agent includes concentrated or aqueous strong acid such hydrochloric acid or tnfluoroacetic acid, hydrobromic acid, hydroiodic acid, phosphonc acid, and the like The acid employed for reaction can be gaseous, aqueous or solvent saturated with acid, mixture of acid with a solvent There is no restriction on the nature of the solvent used herein but specifically includes ethers such as isopropyl ether 1,2-dimethoxyethane, dioxane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, alcohols such as methanol, ethanol, propanol, tert-butanol, esters such as ethyl acetate, isobutyl acetate, aliphatic or aromatic hydrocarbons such as toluene, amide solvents such as dimethylformamide, aprotic solvent such as dimethylsulfoxide, and the like or mixture thereof After the completion of reaction, the desired compound l e cinacalcet can be isolated from the reaction mixture or reaction mixture is used as such for the next step, preparation of cinacalcet pharmaceutically acceptable salts Cinacalcet can be isolated from the reaction mixture by any conventional method in the art It is advantageous to proceed with the reaction mixture to synthesize cinacalcet hydrochloride
Alternatively, the compound of formula Va-2 can be converted to cinacalcet hydrochloride without isolation of cinacalcet freebase, by using hydrochloric acid for the deprotection, it directly gives cinacalcet hydrochloride Hydrochloric acid employed for reaction can be gaseous, aqueous or solvent saturated with hydrogen

chloride, mixture of hydrochloric acid with a solvent There is no restriction on the nature of the solvent used herein but specifically includes ethers such as isopropyl etherl,2-dimethoxyethane, dioxane, 2-methyl tetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, alcohols such as methanol, ethanol, propanol, tert-butanol, esters such as ethyl acetate, isobutyl acetate, aliphatic or aromatic hydrocarbons such as toluene, amide solvents such as dimethylformamide, aprotic solvent such as dimethylsulfoxide, and the like or mixture thereof Cinacalcet hydrochloride, thus prepared, can be isolated by using any conventional techniques In another preferred embodiment of the present invention, it provides a process for the preparation of cinacalcet and its pharmaceutically acceptable salts thereof from intermediate compounds of formulae Vb or Vc The process comprises reducing the compounds of formulae Vb or Vc to form compound of formula Va which is then converted to cinacalcet and its pharmaceutically acceptable salts thereof as described above
Generally, the compound of formula Vb or Vc is reduced in presence of reducing agent and a suitable solvent at a temperature of 25 to 100 °C to form a compound of formula Va The reduction reaction can be performed by any methods known in prior art for the complete reduction of double or triple bonded functionality Preferably, reduction can be carned out by catalytic hydrogenation (hydrogen over a metal catalyst) The metal catalyst includes, but not limited to transition metal, transition metal on support (where support can be carbon or barium sulfate), organometallic compounds of transition metal (homogenous catalyst), or other transition metal derivative or platinum dioxide and the like The transition metal includes, but not limited to palladium, platinum, rhodium, ruthenium or mckel and the like The hydrogen pressure employed in the reaction can be from 1 to 5 atmosphere The hydrogenation is earned till the completion of the reaction, preferably for 1 to 24 hours Reducing agents include, but not limited to borane complexes such as borane-tetrahydrofuran, borane-dimethylsulfide, borane amine, borane lewis base, borane-tnphenylphosphine and the like, hydride transfer reagent The reducing agents

MBR6H or MAlR6H can be used with or without cocatalysts, but not limited to cobalt or nickel derivatives and with or without hgands like dimethylglyoxime and the like (wherein M can be metal like alkali metal or alkaline earth metal or transition metal or a suitable metal and R6 can be any hgand selected from alkoxy, RN, (R)2N, (R)3N, RCOO, RS, CN and the like, R is selected from susbtututed or unsubstiututed alky I, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and the like), or other appropriate reducing reagent as mentioned in comprehensive organic transformation by R C Larock Suitable solvents includes, C1-5 alcohol, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, C2-8 ether, water and the like or mixture thereof The resulting compound of formula Va is then converted to cinacalcet and its pharmaceutically acceptable salts thereof by the process as described above According to another aspect, the present invention provides another process for the preparation of cinacalcet and its pharmaceutically acceptable salts thereof by the reduction of intermediate compound of formula Vc to compound of formula Vb which is then converted to cinacalcet or pharmaceutically acceptable salts thereof by
a) conversion of compound of formula Vb in to Va which is deprotected to give cinacalcet and its pharmaceutically acceptable salts thereof, or
b) simultaneous reduction of double bond as well as removal of amine protecting group to give cinacalcet and its pharmaceutically acceptable salts thereof
According to another aspect, the present invention provides a process for the preparation of cinacalcet and pharmaceutically acceptable salts thereof from intermediate compounds of formulae Vb or Vc by the simultaneous reduction of double or triple bond as well as removal of amine protecting group Cinacalcet free base, if isolated in the process of present invention can be converted to its pharmaceutically acceptable salts by the processes known in the prior art Specifically, cinacalcet free base is dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution, ester and the like or mixture thereof, containing the appropriate acid and then isolated by evaporating the solution Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid,

sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfomc acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate and others Preferably cinacalcet hydrochlonde is prepared by treating cinacalcet with hydrochloric acid at 0°C to 130 °C temperature for few minutes to few hours The source of hydrogen chloride include but not limited to aqueous hydrochloric acid, hydrogen chloride gas or mixture thereof with suitable solvent selected from alcohol, ester, ether and the like Preferably, the source of hydrogen chloride includes methanohc hydrochlonde, ethyl acetate hydrochlonde, and the like The hydrochlonde formation can be carned out in the a solvent selected from ester such as ethyl acetate, ethers such as isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, nitnles such as acetomtnle, alcohols such as methanol and the like or mixture thereof Cinacalcet hydrochlonde can be isolated from the reaction mixture by the suitable methods such as distillation, evaporation, extraction with a solvent and the like
The processes of the present invention can be shown by following schemes Scheme I

(Scheme Removed)

Scheme II

(Scheme Removed)

In another embodiment of the present invention, racemic cinacalcet or pharmaceutically acceptable salts thereof can be prepared by the condensation of compound of formula III with racemic compound of formula IV to form racemic compound of formula V which is then converted to racemic cinacalcet and its pharmaceutically acceptable salts thereof by following the same process as described in the present invention Racemic cinacalcet and pharmaceutically acceptable salts thereof thus prepared can be subjected to a chiral resolution to obtain (R)-cinacalcet

and pharmaceutically acceptable salts thereof The resolution can be performed by treating the racemic compound with a suitable resolving agent in suitable solvents Resolving agent includes, but not limited to naproxen, tartaric acid, mandelic acid, 2,3 4,6-di-O-isopropylidene- 2-keto-glucomc acid and the like Suitable solvents for the resolution includes, but not limited to C1-5 alcohols, C3-8 ketone, halogenated solvents, C1-6 straight chain, branched, or aromatic chloro hydrocarbons, ethers, preferably the solvents can be selected from acetone, ethyl methyl ketone, diethyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, tetrahydrofuran, diethylether, methyl tertiary-butyl ether, 1,4-dioxane and the like, and mixtures thereof or their combinations with water in various proportions The salt of the racemate with enantiomeric acid is separated and then the desired diastereomenc salt is converted to cinacalcet or pharmaceutically acceptable salts thereof
The final product, cmacalcet or cmacalcet hydrochlonde thus prepared by the process of present invention can be purified to enhance the purity of the final API or to remove undesired impurities in the intermediate using a conventional methods Any suitable purification procedure such as, for example, crystallization, denvatisation, slurry wash, salt preparation, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material However, other equivalent procedures such as acid-base treatment could, also be used The solvents used for the purification of final compound and intermediates of the present invention may be selected depending upon the nature of the compound to be purified, however the solvent can be chosen amongst water, C1-6 alcohols such as ethanol, isopropanol, aliphatic C3-6 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, aliphatic or aromatic hydrocarbons such as toluene, n-heptane, cyclohexane, C3-6 ethers such as methyl tertiary butyl ether, isopropyl ether, nitnles such as acetonitnle and the like or mixture thereof in suitable proportion


Specifically, cinacalcet hydrochloride can be purified by slurry wash in a suitable solvent, in which the compound has low solubility as compared to impurities, such solvent include but not limited to ester such as ethyl acetate, ethers such as drisopropyl ether, methyl tertiary butyl ether, diethyl ether, hydrocarbon solvents such as n-heptane and the like or mixture thereof in any suitable proportion, at 15°C to reflux temperature of the solvent employed The proportion of the solvents in mixture can vary from 1 1 to 1 100, preferably 1 9, more preferably 1 1 Alternatively, cinacalcet hydrochloride can be crystallized using a suitable solvent Starting compounds of formula II can be prepared by the methods known in the prior art such as the methods reported in EP 0194764 A1 or the processes of the present invention described here
According to another aspect, the present invention provides a novel process for the preparation of compound of formula II by the reduction of compound of formula VI,

(Formula Removed)

wherein R1, R2, R3 and R4 are as defined above and R5 can be selected from hydrogen, alkyl such as methyl, ethyl and the like or any suitable activating group in presence of a reducing agent
In one variant of the compound of formula VI, the R1, R2, R3, and R4, all are hydrogen and thus compound of formula VI has the structure VIa

(Formula Removed)

wherein R5 is as defined above
In another variant of the compound of formula VI, the R1 and R2, together, form a double bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond provided R/ and R2 are hydrogen and thus compound of formula VI has the structure VIb,

(Formula Removed)

wherein R5 is as defined above
In one variant of the compound of formula VI, the R1, R2, R3, and R4, all together,
form a triple bond and thus compound of formula VI has the structure VIc,

(Formula Removed)

wherein R5 is as defined above
According to one aspect of the invention, the present invention provides a process for the preparation of compound of formula IIa by the reduction of compound of VI Specifically, the compound of formula VI can be reduced to compound of formula IIa The reduction can be performed by catalytic hydrogenation (hydrogen over a metal catalyst) The metal catalyst includes, but not limited to transition metal, transition metal on support (where support can be carbon or barium sulfate), organometalhc compounds of transition metal (homogenous catalyst), or other transition metal derivative or platinum dioxide and the like The transition metal includes, but not limited to palladium, platinum, rhodium, ruthenium or nickel and the like The hydrogen pressure employed in the reaction can be from 1 to 5 atmospheres The hydrogenation is earned till the completion of the reaction, preferably for 1 to 24 hours Reducing agents include, but not limited to borane complexes such as borane- tetrahydrofuran, borane-dimethyl sulfide, borane amine, borane lewis base, borane-tnphenylphosphine and the like, hydride transfer reagent The reducing agents MBR6H or MAlR6H {wherein M and R6 are as defined above) can be used with or without cocatalysts include, but not limited to cobalt or nickel derivatives and with or without ligands like dimethylglyoxime and the like or other appropriate reducing reagent as mentioned in comprehensive organic transformation by Richard C Larock The suitable solvent for the reduction reaction can be selected depending upon the reaction conditions and nature of reducing agent


Suitable solvents includes, but not limited to C1-5 alcohol, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, C2-8 ether, water and the like or mixture thereof According to another aspect, the present invention provides a novel process for the preparation of compound of formula lib by the reduction of compound of VI Specifically, the compound of formula lib is prepared by the reduction of compound of formula VIc or alternatively, by the selective reduction of compound of formula VIb The reduction reaction can be performed by using reducing agents and solvent as described above for the reduction
According to another aspect, the present invention provides a novel process for the preparation of compound of formula IIc by the reduction of compound of VIc According to another aspect, the present invention provides another process for the preparation of compound of formula IIa or IIb
The compound of formula IIa can be prepared by the reduction of compound of formula IIb or IIc with a suitable reducing agent Similarly, the compound of formula IIb can be prepared by the selective reduction of compound of formula IIc with a suitable reducing agent Reducing agent can be selected from as mentioned m comprehensive organic transformation by Richard C Larock or as mentioned above Similarly, starting compounds of formula IV can be prepared by the methods known in the prior art
Specifically, the starting compound of formula IV can be prepared by the introduction of amine protecting group in 1-naphthalen-l-yl-ethylamme and isomers thereof The protecting group on the 1-naphthalen-l-yl-ethylamine and isomers thereof can be introduced using any appropriate reagent suitable for the protection and condensation and which can be removed at the later stage using appropriate deprotecting agent Appropriate reagent and appropriate deprotectmg agent for amine can be perceived by those well versed in the art from 'Protecting Groups by Philip J Kocienski (Thieme, 2000)' or 'Protective Groups in Organic Synthesis by Theodora W Greene, Peter G M Wuts' or available and well documented in the literature The suitable protecting group includes, but not limited to aromatic or aliphatic sulfanyl halide,


aryl, substituted aryl, alkoxy carbonyl, substituted alkoxy carbonyl, aryloxy carbonyl, substituted aryloxy carbonyl, silicon derivatives and the like where substituent can be selected from halogen, alkyl and the like Preferably protecting group is selected amongst carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyl oxycarbonyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzyloxycarbonyl group, p-methoxyphenyl, tert-butyldimethylsilyl, other sulfonyl such as p-nitrobenezenesulfonyl, methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl group, and the like Suitable solvent includes, but not limited to halogenated hydrocarbon, C3-8 ketone, C5-8 aliphatic or aromatic hydrocarbon, C3-8 ester, C2-8 ether, water, C2-5 nitnles, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and the like or mixture thereof Suitable bases can be selected from an organic or an inorganic base Organic bases includes, but not limited to tertiary amines, RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth metal), or alkoxide of alkali or alkaline earth metal Inorganic bases, includes but not limited to alkali or alkaline earth metal hydride, or hydroxide or carbonate or bicarbonate, or MNH2 or MNS1R7 (wherein M and R7 are as defined above), or organometallic bases with or without additives Optionally, a phase transfer catalyst can be added to the reaction mixture Phase transfer catalyst can be selected from the list as described above The phase transfer catalyst may be present in an amount of about 0 05 to about 10mol, preferably 0 05 to 0 5mol equivalents Specifically, the compound of formula N-1 can be prepared by the reaction of 1-naphthalen-1-yl-ethylamine or isomers thereof with suitable reagent containing p-nitrobenzene sulfonyl group using a suitable base with or without phase transfer catalyst at a temperature sufficient for the completion of the reaction The suitable reagent can be selected amongst p-mtrobenzenesulfonyl haides, anhydride or mixed anhydride thereof, preferably reaction is carned out using p-mtrobenzenesulfonyl halide The reaction is generally carried for few minutes to several hours, preferably for 5 hours, more preferably till the completion of the reaction The reaction is carned out in the presence of the solvent that includes water, halogenated solvent such as


dichloromethane, chloroform, ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, isopropyl ether, toluene, acetonitnle and the like or mixture thereof Base and phase transfer catalyst employed for the reaction are as described above Also specifically, the compound of formula N-2 can be prepared by the reaction of 1-naphthalen-l-yl-ethylamine or isomers thereof with a suitable reagent containing tert-butyloxycarbonyl group using a suitable base with or without phase transfer catalyst at a temperature sufficient for the completion of the reaction The suitable reagent can be selected amongst ditertiarybutyl dicarbonate and any other that is capable of introducing tert-butyloxycarbonyl group and the like The reaction is generally earned for few minutes to several hours, preferably till the completion of the reaction The reaction is preferably earned out in the presence of the solvent that includes water, ether solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, ethers such as isopropyl ether, methyl tert-butyl ether, halogenated solvents such as dichloromethane, chloroform and the like or mixture thereof Base and phase transfer catalyst employed for the reaction are as desenbed above
The intermediates of the present invention can be isolated or used as such in the next step without isolation or optionally recovered from the reaction mixture by suitable techniques known in pnor art such as evaporation, filtration or washing and the like Isolation and punfication of final compound and intermediates desenbed here in the present invention can be effected, if desired, by any suitable separation or punfication procedure such as, for example, filtration, extraction, crystallization, denvatization, slurry wash, salt preparation or combination of these procedures However, other equivalent procedures such as acid-base treatment could, of course, also be used Preferably, intermediates are used directly in the next stage without any punfication The order and manner of combining the reactants at any stage of the process are not cntical and may be vaned The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order Wherever required, progress of the reaction is monitored by


suitable chromatographic techniques such as High performance liquid chromatography (HPLC) or thin layer chromatography (TLC) As used, herein the term "conventional methods" may be varied depending upon the nature of the reactions, nature product of the reaction, medium of the reaction and the like the suitable conventional methods can be selected amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centnfugation or by decantation, addition of water immiscible organic solvent, addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable
The intermediate described here in the present invention include their salts, hydrates, solvates, racemates, enantiomers, polymorphs and the like
The major advantage of the present invention is to provide a novel, efficient and industrially advantageous process for preparation of cinacalcet and its pharmaceutically acceptable salts thereof Further, the present invention also provides novel mtrogen protected intermediates that can be efficiently used in the commercial synthesis of cinacalcet and its pharmaceutically acceptable salts thereof Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention
Example 1 Preparation of 3-(3-trifluoromethyl-phenyl)-propan-l-ol
Method A To a solution of 3-(3-tnfluoromethyl-phenyl)-propionic acid (5g, 0 023mol) in tetrahydrofuran (25 ml) was added borane-dimethylsufide (1 74g, 0 023mol) and refluxed for 2 hours Reaction mixture was cooled and methanol (10 ml) was added at 5-10 °C Solvents were distilled off followed by addition of isopropylether (25 ml) and 5N hydrochlonc acid (20 ml) The reaction mixture was heated at 45-50 °C for 2 hours and then cooled to 25-30 °C The layers were


separated, organic layer was washed with water, dried and evaporated to give 411g of the title compound
Method B A solution of 3-(3-tnfluoromethyl-phenyl)-propiomc acid (300g, 1 375mol) in toluene (1 5 L) was azeotroped for 1 hour and cooled to 40-45 °C Thereafter, borane-dimethylsufide (126 52g, 1 67mol) was added and reaction mixture was heated for 3-4 hours at 85°C and cooled to 0-5°C The reaction mixture was quenched with methanol (900ml) and stirred at 0-5°C for 1 hour Solvent was distilled off under vacuum 50-55°C The resulting residue was dissolved in toluene (900ml) and washed with water (600ml) Toluene was distilled off under vacuum at 60-65°C to give 274 38g of the title compound having purity 97% by HPLC
Example 2 Preparation of toluene-4-sulfomc acid 3-(3-tnfluoromethyl-phenyl)-propyl ester
p-Toluenesulfonyl chloride ( 11 21g, 0 0588mol) was added to a solution of 3-(3-trifluoromethyl-phenyl)-propan-l-ol (10g, 0 049mol), triethylamine (9 0 ml,
0 06468mol), 4-N,N-dimethylaminopyridine (0 66g, 0 0054mol) in dichloromethane
(50 ml) at 25-30 °C The reaction mixture was stirred at a temperature of 35-40 °C for
15 hours Thereafter, the layers were separated and dichloromethane layer was
washed with water (2x20 ml) and dried over anhydrous sodium sulphate Solvent was
distilled off to give 15g of title compound
Example 3 Preparation of toluene-4-sulfonic acid 3-(3-trifluoromethyl-phenyl)-propyl ester
To a stirred solution of p-toluenesulfonyl chloride (360g, 1 89mol) in dichloromethane (10 L), triethylamine (243g, 2 4mol) and 4-N,N-dimethyl amino pyridine (21g, 0 17mol) was added Thereafter, the reaction mixture was cooled to 0° to -5°C followed by addition of 3-(3-tnfluoromethyl-phenyl)-propan-l-ol (350g,
1 714mol) and maintained at 0 to 10°C temperature for 3 hours Water (1 05 L) was
added to the reaction mixture and stirred for 15 minutes Layers were separated and


washed sequentially with sodium carbonate (1 05 L, 10%), hydrochloric acid (1 05L, 1N) and water (1 05 L) The organic layer was dried over anhydrous sodium sulphate and was distilled off under vacuum at 25-30°C to give 522g of title compound having purity 97 67% by HPLC
Example 4 Preparation of methanesulfonic acid 3-(3-trifluoromethyl-phenyl)-propyl ester
To a stirred solution of 3-(3-tnfluoromethyl-phenyl)-propan-l-ol (250g, 1 224mol) and tnethylamine (148 52g, 1 47mol) in dichloromethane (1 25 L), methanesulfonyl chloride (161 32g , 1 41mol) was added at 25°C to 40°C and reaction mixture was stirred for 2-3 hours at 40°C Thereafter, reaction mixture was washed with deminerahzed water (500ml x 3) and dried over anhydrous sodium sulfate The dichloromethane was distilled off to give 335g of title compound having purity 91 58% by HPLC
Example 5 Preparation of (R)-(l-naphthalen-l-yl-ethyl)-carbamic acid tert-butyl ester
Method A (R) 1-Naphthalen-l-yl-ethylamine (5 0g, 0 029mol) was added to a mixture of di-tertiarybutyl dicarbonate (10 0g, 0 045mol) in water (25 ml) and tetrahydrofuran (0 5 ml) at 25-30 °C and stirred for 5 hours Reaction mixture was then extracted with dichloromethane (3x15 ml) The combined extracts were washed with water and solvent was distilled to give 8 2g of title compound having purity 99 2% by HPLC
Method B To a solution of (R)-l-naphthalen-l-yl-ethylamine (150g, 0 876mol) in dichloromethane (750ml), di-tertiarybutyl dicarbonate (210 3g, 0 964mol) was added at ambient temperature and stirred for 2 hours Dichloromethane was distilled off followed by addition of n-heptane (150ml) and then n-heptane was distilled off Again n-heptane (900ml) was added to the resulting residue and stirred The resulting


product was filtered and dried in vacuum (150 mm Hg) at 45-50°C to give 223g of the title compound having purity 99 8% by HPLC
Example 6 Preparation of (R)-(l-naphthalen-l-yl-ethyl)-[3-(3-tnfluoromethyl-phenyl)-propyl]-carbamic acid tert-butyl ester
Method A (R)-(l-Naphthalen-l-yl-ethyl)-carbamic acid tert-butyl ester (1 5g, 5 528 mmol) was added to a mixture of sodium hydride (50% dispersion in mineral oil,
0 402g, 0 0084mol) and dimethylsulfoxide (10 ml) and stirred for 30 minutes at 50-55 °C followed by addition of a solution of toluene-4-sulfomc acid 3-(3-tnfluoromethyl-phenyl)-propyl ester (20g, 5 58 mmol) in dimethylsulfoxide (1 ml) The reaction mixture was heated at 50-55 °C for 1 hour Thereafter, the reaction mixture was cooled to 5 °C, quenched with ice-water (20 ml), extracted with isopropyl ether (3x25 ml) Combined isopropyl ether layer was washed with water (2x20 ml) and dried over anhydrous sodium sulphate Solvent was distilled off to give
1 9g of title compound
Method B (R)-(l-Naphthalen-l-yl-ethyl)-carbamic acid tert-butyl ester (210g, 0 774mol) was added to a stirred suspension of sodium hydroxide (124g, 31mol) in dimethylsulfoxide (1 05 L) at 15-20°C and stirred for 30 minutes Thereafter, methanesulfonic acid-3-(3-tnfluoromethyl-phenyl)-propyl ester (284g, 1 006mol) was added to reaction mixture at 20-25°C and stirred for 20 hours at 25-30°C The reaction mixture was cooled to 10-15°C followed by addition of chilled water (2 1 L) The reaction mixture was extracted with toluene (1 0 L x 2) and combined toluene extracts were washed with brine (420 ml xl) Then solvent was distilled off under vacuum at 50-60°C to give 374g of the title compound having purity 83 59% by HPLC
Example 7 Preparation of cinacalcet hydrochloride
Method A (R)-( 1 -Naphthalen-1 -yl-ethyl)-[3 -(3-trifluoromethyl-phenyl)-propyl]-carbamic acid tert-butyl ester (1g) was added to 5N hydrochloric acid (15 ml) and

reaction mixture was heated at 80-85 °C for 6 hours and then at 25-30 °C for 1 hour Isopropyl ether (5 ml) was added to the reaction mixture and stirred for 5 minutes The reaction mixture was filtered, washed with water (2 ml), then with isopropyl ether (2 ml) and dried to give 0 4g of title compound having purity 99 52% by HPLC
Method -B To (R)-(l-naphthalen-l-yl-ethyl)-[3-(3-tnfluoromethyl-phenyl)-
propyl]-carbamic acid tert-butyl ester (374g, 0 817 moles) was added ethyl acetate-HC1 (12%, 2 33 L) at 20-25°C in a duration of 2-4 hours The reaction mixture was then cooled to 0-5°C followed by washing with chilled water (1 1L x 3) The organic layer was dried over anhydrous sodium sulphate followed by removal of ethyl acetate by distillation under vacuum (150 mm/Hg) at 50-55°C The resulting product was stirred in ethyl acetate isopropyl ether (19, 1 75 L) for 1hour, filtered and dried under vacuum at 50°C to give 227g of the title compound having purity 99 81% by HPLC
Example 8 Preparation of (R)-N-(l-naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide
Method A To a stirred solution of (R)-l-napthalen-l-yl-ethylamine (100g, 0 583mol) tnethylamine (97 64 ml, 0 701mol) and 4-N,N-dimethyl amino pyridine (7 13g l0mol %) in dichloromethane (500 ml), p-mtrobenzene sulphonyl chloride (129 42g, 0 584mol) was added at 25-30°C and stirred 6-8 hours The reaction mixture was washed successively with aqueous hydrochlonc acid (150 ml x 2), deminerahzed water (300 ml x 2) and dried over anhydrous sodium sulphate Dichloromethane was distilled off to give 200g of title compound, which was further dissolved in isopropanol (1 0 L) at 80-85°C, stirred at room temperature for 3 hours, filtered and dried under vacuum to give 167g of title product having purity 85 40% by HPLC
Method B A solution of (R)-l-napthalen-l-yl-ethylamine (200g, 1 17mol) in dichloromethane (1 5 L) was added to a stirred solution of sodium carbonate (371 4g,


3 5mol), water (2 OL) and tnethylbenzylammonium chloride (26 6g, 0 117mol) at 25° -35°C Thereafter, p-mtrobenzenesulfonyl chlonde (310 6g, 140mol) and dichloromethane (500ml) were added to the reaction mixture followed by stirring at 38° to 40°C for 4 hours Layers were separated and successively washed with sodium carbonate (1 0 L, 10%), 5N hydrochloric acid (1 0L) and water (1 0L) The organic layer was distilled off To the resulting residue, n-heptane (1 6L) was added, stirred, filtered and dried under vacuum to give 413g of the title product having purity 88 14%by HPLC
Example 9 Purification of (R)-N-(l-naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide
(R)-N-(l-naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide (400g, having purity 88 14% by HPLC) was dissolved in ethanol (800ml) at 85-90°C, and stirred at 25° to 30°C for 3 hours The resulting product was filtered and dried under vacuum to give 330g of pure title compound having purity 89 14% by HPLC
Example 10 Preparation of (R)-4-nitro-N-(l-naphthalen-l-yl-ethyl)-N-[3-(3-trifluoromethyl-phenyl)-propy1] -benzene sulphonamide
Method A (R)-N-(l-Naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide (5g,) was added to a stirred suspension of potassium carbonate (5 8g), and toluene (50ml) The reaction mixture was stirred for 1 hour at ambient temperature Thereafter, toluene-4-sulfonic acid 3-(3-tnfluoromethyl-phenyl)-propyl ester (10 05g) was added to the reaction mixture and heated at 85-90°C for 15 hours The reaction mixture was then cooled to 25°C, washed with deminerahzed water (30 ml x 2) and dned over sodium sulphate The solvent was distilled off and n-heptane (50 ml) was added to the resulting residue The reaction mixture was stirred for 2 hours, filtered and dned under vacuum to give 6 5g of title compound having punty 93% by HPLC
Method B (R)-N-(l-Naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide (10 0g, 0 028 mol) was added to a stirred suspension of potassium carbonate (1162g, 0.08mol), triethylbenzylammonium chloride (0.63g, 10mol%) and methyl isobutyl ketone (100 ml) and stirred for 1 hour at room temperature. Thereafter, toluene-4-sulfonic acid 3-(3-trifluoromethyl-phenyl)-propyl ester (15.lg, 0.042mol) was added to the reaction mixture and heated at 85-90°C for 15 hours. The reaction mixture was then cooled to 25°C, washed with demineralized water (30 ml x 2), aqueous hydrochloric acid (30 ml, 1%) and dried over sodium sulphate. The solvent was distilled off and n-heptane (50 ml) was added to the resulting residue. The reaction mixture was stirred for 2 hours, filtered and dried under vacuum to give 14.5g of title compound having purity 95% by HPLC.
Method C: (R)-N-(l-Naphthalen-l-yl-ethyl)-4-nitro-benzenesulfonamide (320g, 0.9mol) was added to a stirred suspension of potassium carbonate (434.15g, 3.14mol), triethylbenzylammonium chloride (20.47g, 10 mol%) and toluene (2.5L) and stirred for 1 hour at 25-30°C. Thereafter, toluene-4-sulfonic acid 3-(3-trifluoromethyl-phenyl)-propyl ester (483g, 1.35mol) in toluene (700ml) was added to the reaction mixture and heated at 65-70°C for 15 hours. The reaction mixture was then cooled to 25°C. Water (3.2 L) was added to the reaction mixture, stirred and filtered. The organic layer was separated and washed sequentially with water (3.2L), hydrochloric acid (1%, 960ml) and again water (960ml x2). The solvent was distilled off under vacuum (150 mm/Hg) at 65-70°C. To the resulting residue n-heptane (320ml) was added, stirred for 3 hours, filtered and dried to give 470g of title compound having purity 94% by HPLC.
Example 11: Purification of N-(l-naphthaLen-l-yl-ethyl)-4-nitro-N-[3-(3-trifluoromethyl-phenyl)-propyl]-benzenesulfonamide
Method A: To a stirred solution of (R)-N-(l-naphthalen-l-yl-ethyl)-4-nitro-N-[3-(3-trifluoromethyl-phenyl)-propyl]-benzenesulfonamide (0.5g) in dichloromethane (5ml), silver nitrate (3mg) was added and stirred the mixture for 24 hours. Demineralized water (5 ml) was added to the reaction mixture and layers were separated. The organic layer was washed with demineralized water (5mlx2). The

solvent was distilled off. The resulting product was crystallized with isopropanol (2 ml) to give 0.3g of title compound having purity 99.28% by HPLC.
Method B: N-( 1 -naphthalen-1 -yl-ethyl)-4-nitro-N-[3 -(3 -trifluoromethyl -phenyl) propyl] -benzenesulfonamide of (12g, purity 95%) was dissolved in isopropanol (70 ml) at 85-90°C. The mixture was cooled to ambient temperature, filtered and dried under vacuum at 45-50°C to give 10.6g of title compound having purity 98.75% by HPLC.
Method C: To a stirred solution of (R)-N-(l-naphthalen-l-yl-ethyl)-4-nitro-N-[3-(3-trifluoromethyl-phenyl)-propyl]-benzenesulfonamide (440g, having purity 94%) in dichloromethane and benzyltriethylammonium chloride (9.23g, 0.041mol), a solution of potassium permanganate (8.25g, 0.0522mol) in water (1.64L) was added at 25° to 30°C. The reaction mixture was stirred for 24 hours at 25° to 30°C and filtered through hyflo-bed. The dichloromethane solution was washed with water (1.0 L x 2), treated with activated carbon (44g) for 1 hour and filtered. Dichloromethane was distilled off under vacuum at 30° to 40°C to afford the title compound. The resulting product was dissolved in isopropanol (1.32 L) at 85-90°C. The reaction mixture was cooled to 25-30°C, filtered and dried under vacuum at 40-45°C to give 337g of title compound as crystalline solid having purity 99.53% by HPLC.
Example 12: Preparation of Cinacalcet free base
A suspension of thiophenol (3.4 ml), potassium carbonate (8g), acetonitrile (50ml) and benzyltriethylammonium chloride (0.37g) was stirred for 1 hour at ambient temperature. Thereafter, N-( 1 -naphthalen-1 -yl-ethyl)-4-nitro-N-[3 -(3 -trifluoromethyl-phenyl)-propyl]-benzenesulfonamide (9g) was added to the reaction mixture and heated at 60-70°C for 5-8 hours. The solvent was distilled off. To the resulting residue, water (27ml) and toluene (45ml) were added and stirred. Layers were separated and toluene was distilled off to give title compound.

Example 13: Preparation of cinacalcet hydrochloride
(R)-N-( 1 -Naphthalen-1 -yl-ethyl)-4-nitro-N-[3 -(3-trifluoromethyl-phenyl)-propyl]-benzenesulfonamide (300g, 0.553mol) was added to a stirred suspension of potassium carbonate (228.78g, 1.655mol), thiophenol (91.4g, 0.83mol), and benzyltriethyl- ammonium chloride (12.58g, 0.055mol) in dimethylsulfoxide (900ml) at 25° to 35°C and stirred for 24 hours. Water (1.8 L) and isopropyl ether (1.5 L) were added to the reaction mixture and further stirred. Layers were separated and organic layer was washed with water (600ml x2). Solvent was distilled off. To the resulting residue, ethyl acetate-hydrochloride (9%, 246 ml) was added at 0-5°C and stirred at 20-25°C for 2 hours. Thereafter, toluene (3 L) and water (1 L) were added to the mixture and stirred. Layers were separated and organic layer was distilled off at 60-65°C under vacuum. Isopropyl ether (2.4 L) was added to the above residue and refluxed for further 24 hours. The reaction mixture was, then, cooled to ambient temperature, filtered, and dried to give 180g of the title compound having purity 99.43% by HPLC.
Example 14: Purification of cinacalcet hydrochloride
Method A: Cinacalcet hydrochloride (180g, having purity 99.43%)) in isopropyl ether (1.44 L) was refluxed for 5 hours. The reaction mixture was cooled to ambient temperature, filtered and dried to give 177g of the title compound having purity 99.72% by HPLC.
Method B:Cinacalcet hydrochloride (200g) was stirred in ethyl acetate: isopropyl ether (1:1, 1.05 L) at room temperature for 2 hours. The reaction mixture was filtered and dried at 50°C to give 190g of the title compound having purity 99.81% by HPLC.

WE CLAIM
1). A process for the preparation of cinacalcet and its pharmaceutically acceptable salt thereof, which comprises the step of:
(a) providing a compound of formula II including isomers or mixture thereof;

(Formula Removed)
wherein R1, R2, R3 and R4 are hydrogen or R1, R2, together, form a double bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond provided R1 and R2 are hydrogen or R1, R2, R3 and R4 all are combined together to form triple bond.
(b) converting the hydroxyl group of compound of formula II into a good leaving
group to obtain compound of formula III including isomers or mixture thereof

(Formula Removed)

wherein R1, R2, R3 andR4 are as defined above and X is a good leaving group,, by reaction in presence of activating agent and solvent;
(c) condensing the compound of formula III with the compound of formula IV,

(Formula Removed)

wherein Z is an amine protecting group and can be selected from allyl; substituted allyl; linear, branched or cyclic C1-8 alkyl; substituted linear, branched or cyclic C1-8 alkyl; linear, branched or cyclic C1-8 alkenyl; substituted linear, branched or cyclic C1-8 alkenyl; linear, branched or cyclic C1-s alkynyl; substituted linear, branched or cyclic C1-8 alkynyl; -CN; -SO2R''; -COOR" wherein R" can be alkyl, alkenyl , alkynyl, or aryl; -CONR'"R'"

wherein R"' and R"" can be same or different and individually selected from alkyl, alkenyl, alkynyl, or aryl; or and the like; all the above groups can be substituted at carbon with a group selected from alkyl, alkoxy or aryl and like, in presence of a suitable base to prepare a compound of formula V; and

(Formula Removed)

wherein R1, R2, R3, R4 and Z are as defined above. (d) converting the compound of formula V to cinacalcet of formula I and pharmaceutically acceptable salts thereof.
2). The process according to claim 1, wherein in step b) activating agent is selected from thionyl halide, aliphatic or aromatic sulfonyl halide, phosphorous halides, phosphorous oxyhalide and the like, preferably thionyl bromide, thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride, phosphorus trichloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous tribromide and the like; and solvent includes water, halogenated solvents such as dichloromethane, chloroform; C2-8 ether such as isopropyl ether, methyl tert-butyl ether; C3-8 aromatic and aliphatic hydrocarbon such as toluene, xylene, ethyl benzene; C2-5 nitrile such as acetonitrile; C3-8 ketone such as acetone, ethyl methyl ketone; methyl isobutyl ketone; amide solvents such as dimethyl formamide, dimethylacetamide, N-methylpyrrolidone; and the like or mixture thereof.
3). The process according to claim 1, wherein step b) is carried out additionally in the presence of base, which is selected from organic base such as triethylamine, N,N-diisopropylethyl amine, N-methylpyrrolidone or an inorganic base such alkali or alkaline metal hydroxide, carbonate, bicarbonate and the like or combination thereof, preferably triethylamine, sodium hydroxide, potassium hydroxide,

sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide and the like or combination thereof.
4). The process according to claim 1, wherein in step c) base includes organic base and inorganic base and is selected from tertiary amines; RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth metal); or alkoxide of alkali or alkaline earth metal; alkali or alkaline earth metal hydride, or hydroxide or carbonate or bicarbonate; or MNH2 or MNSiR7 (wherein M can be alkali metals and R7 can be C1-8 aliphatic or aromatic hydrocarbons and the like); or organometallic bases with or without additives.
5). The process according to claim 1, wherein step c) is carried out in the presence of phase transfer catalyst which includes benzyl trimethylammonium chloride and bromide, cetyl trimethylammonium bromide, phosphonium compounds or synthetic resins, tetrabutylammonium bromide or chloride; benzyltriethyl ammonium chloride; tetrabutylammonium hydroxide; tricaprylmethylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyltributyl phosphonium bromide; hexadecyltrimethyl ammonium bromide or resin amberlite IRA-410 and the like.
6). The process according to claim 1, wherein R1, R2, R3 and R4 are hydrogen.
7). The process according to claim 1, wherein the R1, R2, together, form a double
bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond
provided R1 and R2 are hydrogen. 8). The process according to claim 1, wherein the R1, R2, R3 and R4 all are combined
together to form triple bond.
9). A process for the preparation of cinacalcet of formula I and its pharmaceutically
acceptable salts thereof which comprises the step of: a), providing a compound of formula IIa including isomers or mixture thereof;

(Formula Removed)
b). converting the hydroxyl group of compound of formula IIa into a good leaving group to obtain compound of formula IIIa including isomers or mixture thereof

(Formula Removed)

wherein X is a good leaving group by reaction in presence of activating agent and solvent; c). condensing the compound of formula Ilia with the compound of formula IV

(Formula Removed)

wherein Z is an amine protecting group and can be selected from allyl; substituted allyl; linear, branched or cyclic C1-8 alkyl; substituted linear, branched or cyclic C1-8 alkyl; linear, branched or cyclic C1-8 alkenyl; substituted linear, branched or cyclic C1-8 alkenyl; linear, branched or cyclic C1-8 alkynyl; substituted linear, branched or cyclic C/s alkynyl; -CN; -SO2R"; -COOR" wherein R" can be alkyl, alkenyl , alkynyl, or aryl; -CONR'"R'" wherein R'" and R"" can be same or different and individually selected from alkyl, alkenyl, alkynyl, or aryl; or and the like; all the above groups can be substituted at carbon with a group selected from alkyl, alkoxy or aryl and like, in presence of a suitable base to prepare a compound of formula Va; and

(Formula Removed)

wherein Z is as defined above
d). converting the compound of formula Va to form cinacalcet of formula I and its pharmaceutically acceptable salts thereof.
10). The process according to claim 9, wherein in step b) activating agent is selected from thionyl halide, aliphatic or aromatic sulfonyl halide, phosphorous halides, phosphorous oxyhalide and the like, preferably thionyl bromide, thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride, phosphorus trichloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous tribromide and the like; and solvent includes water, halogenated solvents such as dichloromethane, chloroform; C2-8 ether such as isopropyl ether, methyl tert-butyl ether; C3-8 aromatic and aliphatic hydrocarbon such as toluene, xylene, ethyl benzene; C2-5 nitrile such as acetonitrile; C3-8 ketone such as acetone, ethyl methyl ketone; methyl isobutyl ketone; amide solvents such as dimethyl formamide, dimethylacetamide, Af-methylpyrrolidone; and the like or mixture thereof.
11). The process according to claim 9, wherein step b) is carried out additionally in the presence of base, which is selected from organic base such as triethylamine, N,N-diisopropylethyl amine, N-methylpyrrolidone or an inorganic base such alkali or alkaline metal hydroxide, carbonate, bicarbonate and the like or combination thereof, preferably triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide and the like or combination thereof.
12). The process according to claim 9, wherein in step c) base includes organic base and inorganic base and is selected from tertiary amines; RM or RMgX (wherein R can be alkyl or aryl and M can be alkali or alkaline earth metal); or alkoxide of alkali or alkaline earth metal; alkali or alkaline earth metal hydride, or hydroxide or carbonate or bicarbonate; or MNH2 or MNSiR7 (wherein M can be alkali metals and R7 can be C1-8 aliphatic or aromatic hydrocarbons and the like); or organometallic bases with or without additives.
13). The process according to claim 9, wherein step c) is carried out in the presence of phase transfer catalyst which includes benzyl trimethylammonium chloride and

bromide, cetyl trimethylammonium bromide phosphonium compounds or synthetic resins, tetrabutylammonium bromide or chloride; benzyltriethyl ammonium chloride; tetrabutylammonium hydroxide; tricapryl methylammonium chloride, dodecyl sulfate, sodium salt, such as sodium lauryl sulfate; tetrabutylammonium hydrogensulfate; hexadecyltributylphosphonium bromide; hexadecyltrimethyl ammonium bromide or resin amberlite IRA-410 and the like. 14). The process according to claim 9, wherein in step d) process for conversion of compound of formula Va to cinacalcet comprising the step of: a), reacting the compound of formula Va with a suitable deprotecting agent; b). optionally, isolating cinacalcet from the reaction mixture; and c). converting the same to cinacalcet pharmaceutically acceptable salts thereof.
15). The process according to claim 14, wherein step a) when Z is a tert-butoxycarbonyl group, then deprotecting agent is selected from strong acid.
16). The process according to claim 14, wherein step a) when Z is a p-nitrobenzene sulfonyl group, then deprotecting agent is selected from substituted or unsubstituted thiophenol, or samarium iodide, tributyltin hydride and the like.
17). A compound of formula V
(Formula Removed)

wherein R1, R2, R3 and R4 are hydrogen or R1, R2, together, form a double bond provided R3 and R4 are hydrogen or R3, R4, together, form a double bond provided R1 and R2 are hydrogen or R1, R2, R3 and R4 all are combined together to form triple bond; and
wherein Z is an amine protecting group and can be selected from allyl; substituted allyl; linear, branched or cyclic C1-8 alkyl; substituted linear, branched or cyclic C1-8 alkyl; linear, branched or cyclic C1-8 alkenyl; substituted linear, branched or cyclic C1-8 alkenyl; linear, branched or cyclic C1-

s alkynyl; substituted linear, branched or cyclic C1-8 alkynyl; -CN; -SO2R''; -COOR" wherein R" can be alkyl, alkenyl , alkynyl, or aryl; -CONR'"R'" wherein R'" and R"" can be same or different and individually selected from alkyl, alkenyl, alkynyl, or aryl; or and the like; all the above groups can be substituted at carbon with a group selected from alkyl, alkoxy or aryl and like. 18). The compound according to claim 17, wherein R1, R2, R3 and R4 are hydrogen has structure of formula Va

(Formula Removed)

wherein Z is as defined above. 19). The compound according to claim 18, wherein Z is selected amongst carbobenzyloxy, p-methoxybenzyl carbonyl, tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, benzyloxycarbonyl group, p-methoxyphenyl, tert-butyldimethylsilyl; other sulfonyl such as p-nitrobenezensulfonyl, methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl group, and the like
20). The compound according to claim 19, wherein Z is p-nitrobenezensulfonyl or tert-butyloxycarbonyl.