FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF CINACALCET OR A
HYDROCHLORIDE SALT THEREOF"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivli (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved and industrially advantageous process for preparation of Cinacalcet base of formula (I) or a hydrochloride salt thereof of formula (II).

More particularly the present invention relates to the field of organic chemistry and more particularly to synthetic process for an economically viable and industrially advantageous process for the preparation of Cinacalcet or a hydrochloride salt thereof.
BACKGROUND OF THE INVENTION:
Cinacalcet, namely N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-l-aminopropane of formula (I), is a known compound with anti-hyperparathyroid action, marketed as the hydrochloride salt under trade name Sensipar®. Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Cinacalcet is indicated for treatment of Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis and to treat Hypercalcemia in adult patients with Parathyroid Carcinoma.
U.S. Pat. No. 8,575,393 discloses a process for the preparation of Cinacalcet. This process involves reaction of 3-[3-(trifluoromethyl)phenyl]propan-l-ol with methanesulfonyl chloride, followed by treating the intermediate so obtained with (R)-l-naphthylethylamine in presence of potassium carbonate to get Cinacalcet base which is then converted to Cinacalcet HC1 salt. The major disadvantage with the above process is the formation of an undesired and genotoxic carbamate impurity.
The process disclosed in '393 patent suffers from various other disadvantages, such as:
a) low yield, low HPLC purity;
b) formation of genotoxic impurities such as the carbamate impurity and varoius
byproducts.

U.S. Pat. No. 6,211,244 discloses a process for the preparation of Cinacalcet. This process involves treating 3-trifluoromethylcinnamonitrile with diisobutyl aluminum hydride, followed by treating the intermediate aluminum-imine complex with (R)-l-(l-naphthyl)ethylamine, and reducing the intermediate imine with ethanolic sodium cyanoborohydride to get Cinacalcet base. The major disadvantage of the process disclosed in U.S. Pat. No. 6,211,244 is the use of flammable and toxic reagents such as titanium isopropoxide, ethanolic or methanolic cyanoborohydride.
US patent No 7,294,735 discloses a process for the preparation of Cinacalcet hydrochloride, comprising the steps of dissolving Cinacalcet, containing Cinacalcet carbamate impurity in an amount of about 3 area percent to-4-about 6 area percent as determined by a chromatographic method, in acetone, a linear or a branch-chain Cz-8 ether, mixtures thereof or with water; adding hydrogen chloride to obtain a precipitate; and recovering the Cinacalcet hydrochloride. The major disadvantage with the above process is the formation of an undesired and genotoxic carbamate impurity.
The process of the present invention has advantages of improved yield and increased productivity. The process is also industrially scalable, and cost effective. The inventors of the present invention have found an improved process which avoids above mentioned disadvantages.
SUMMARY OF INVENTION:
The present invention provides a process for preparation of Cinacalcet base of formula (I) or a hydrochloride salt thereof of formula (II),

comprising:
a) converting a compound of formula A to a compound of formula B in presence of a
suitable solvent and an organic base;


b) reacting the compound of formula B with a compound of formula C in presence of a
suitable solvent and an organic base to obtain cinacalcet base, a compound of formula
I;

c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a
compound of formula II;

d) purifying cinacalcet hydrochloride obtained in step c) using a suitable solvent.
The present invention provides a process for purification of a cinacalcet hydrochloride comprising:
a) treating cinacalcet hydrochloride with alcoholic solvent followed by optionally treating
with water;
b) optionally isolating the cinacalcet hydrochloride and
c) treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.
An object of the present invention provides a process for the preparation of Cinacalcet hydrochloride that has improved storage stability which is substantially free of degradation impurities.
It has been surprisingly found that the process according to the present invention provides cinacalcet hydrochloride that has superior stability profile.

DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification the term "suitable solvent" includes, but is not limited to alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; halogenated hydrocarbon such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as n-hexane, n-heptane and the like; organic nitrile such as acetonitrile, benzyl cyanide, undecyl nitrile and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2-pyrrolidone; water; or mixtures thereof.
As used throughout the specification the term "suitable base" includes organic and inorganic bases. An organic base used includes, but is not limited, to amine bases (primary, secondary or tertiary amines) such as methylamine, ethylamine, n-propylamine, isopropylamine, triethylamine, N,N-diisopropylethylamine and the like, heterocyclic compounds such as pyridine, piperidine and the like. Inorganic base used, includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkali metal hydride such as sodium hydride, sodium borohydride and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, caesium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
The present invention provides a process for preparation of Cinacalcet base of formula (I) or a hydrochloride salt thereof of formula (II),

comprising:
a) converting a compound of formula A to a compound of formula B in presence of a
suitable solvent and an organic base;


b) reacting the compound of formula B with a compound of formula C in presence of a
suitable solvent and an organic base to obtain cinacalcet base, a compound of formula
I;

c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a
compound of formula II;

d) purifying cinacalcet hydrochloride obtained in step c) using a suitable solvent.
In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B.

In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B in the presence of a suitable solvent to obtain a compound of formula B.
In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B in the presence of a halogenated hydrocarbon to obtain a compound of formula B.

In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B in the presence of a suitable solvent and a suitable base to obtain a compound of formula B. The suitable solvent and the suitable base used are as described supra. Preferably the suitable solvent selected is halogenated hydrocarbon and the suitable base selected is an organic base. More preferably, the suitable solvent selected is dichloromethane and the suitable base selected is triethylamine.
In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B in the presence of dichloromethane as solvent and triethylamine as base to obtain a compound of formula B. The reaction may be preformed at a temperature of about 0°C to 30°C, preferably at a temperature of about 5°C to 25°C, more preferably at a temperature of about 5°C to 15°C.
In one embodiment, step (a) comprises converting a compound of formula A to a compound of formula B using methanesulfonyl chloride in the presence of dichloromethane as solvent and triethylamine as base to obtain a compound of formula B. The reaction may be preformed at a temperature of about 0°C to 30°C, preferably at a temperature of about 5°C to 25°C, more preferably at a temperature of about 5°C to 15°C.
After completion of the reaction in step (a), suitable work up may be performed before proceeding to step (b). In one embodiment, after completion of reaction in step (a), the reaction mixture can be treated with water at about 0°C to 30°C, more preferably at a temperature of about 20°C to 30°C. The reaction mass may be optionally stirred. The organic layer may be separated and washed with hydrochloric acid and the layers subsequently separated. The organic layer may be washed with water. The organic layer may be dried and further degassed to obtain the compound of formula B.

The compound B obtained in step a) may be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.

In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising converting a compound of formula A to a compound of formula B.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising converting a compound of formula A to a compound of formula B using methanesulfonyl chloride in the presence of dichloromethane as solvent and triethylamine as base to obtain a compound of formula B. The reaction may be preformed at a temperature of about 0°C to 30°C.
In one embodiment, step (b) comprises reacting the compound of formula B with a compound of formula C in presence of a suitable solvent to obtain a compound of formula I.
In one embodiment, step (b) comprises reacting the compound of formula B with a compound of formula C in presence of an organic nitrile to obtain a compound of formula I.
In one embodiment, step (b) comprises reacting the compound of formula B with a compound of formula C in presence of a suitable solvent and an organic base to obtain a compound of formula I. The suitable solvent and the suitable base used are as described supra. Preferably the suitable solvent selected is an organic nitrile and the suitable base selected is an organic base. More preferably, the suitable solvent selected is acetonitrile and the suitable base selected is diisopropylethyl amine.

In one embodiment, step (b) comprises reacting the compound of formula B with a compound of formula C in presence of acetonitrile as solvent and diisopropylethyl amine as base to obtain a compound of formula I. The reaction may be preformed at a temperature of about 70°C to 100°C, preferably at a temperature of about 75°C to 95°C, more preferably at a temperature of about 80°C to 90°C.
After completion of the reaction in step (b), suitable work up may be performed before proceeding to step (c). In one embodiment, after completion of reaction in step (b), the reaction

mixture may be evaporated under vacuum and degassed. Further the reaction mass may be treated with dichloromethane and water with optional stirring. The layers can be separated and the organic layer obtained may be washed with water and layers separated. The pH can be adjusted to 1-2 using hydrochloric acid solution. The organic layer obtained may be washed with hydrochloric acid solution and layers separated. The organic layer obtained may be washed with water and 10% sodium bicarbonate solution. The organic layer may be evaporated to obtain the compound of formula I as brown oil.

The compound I obtained in step b) may be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
The inventors of present invention have surprisingly found that replacing potassium carbonate as base which is employed in the US '393 with an amine base for preparation of the compound of formula I, eliminates the hazards associated with generation of genotoxic carbamate impurity.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising reacting the compound of formula B with a compound of formula C in presence of a suitable solvent and an organic base to obtain a compound of formula I.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising reacting the compound of formula B with a compound of formula C in presence of acetonitrile as solvent and diisopropylethyl amine as base to obtain a compound of formula I. The reaction may be preformed at a temperature of about 70°C to 100°C, preferably at a temperature of about 75°C to 95°C, more preferably at a temperature of about 80°C to 90°C.

In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C to obtain a compound of formula I.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B using methanesulfonyl chloride in the presence of dichloromethane and triethylamine at a temperature of about 0°C to 30°C to obtain a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C in presence of acetonitrile and diisopropylethyl amine at a temperature of about 70°C to 100°C to obtain a compound of formula I.
In one embodiment, step (c) comprises converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II.

In one embodiment, step (c) comprises converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II in presence of a suitable solvent and an alcoholic mineral acid to obtain a compound of formula II. The suitable solvent used is as described supra. Preferably the suitable solvent selected is an ether and the alcoholic mineral acid selected is an alcoholic hydrochloric acid. More preferably, the suitable solvent selected is diisopropyl ether and the alcoholic mineral acid selected is 30-35% isopropanolic hydrochloric acid.
In one embodiment, step (c) comprises converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II in presence of diisopropyl ether as

solvent and about 30-35% isopropanolic hydrochloric acid as an alcoholic mineral acid to obtain a compound of formula II. The reaction may be preformed at a temperature of about 30°C to 60°C, preferably at a temperature of about 35°C to 55°C, more preferably at a temperature of about 40°C to 50°C.
After completion of the reaction in step (c), suitable work up may be performed before proceeding to step (d). In one embodiment, after completion of reaction in step (c), the reaction mixture may be cooled to about 25°C to 30°C. The reaction mass may be optionally stirred. The reaction mass obtained may be filtered and further washed with diisopropyl ether to obtain wet cake. The wet cake obtained may be dried to get the compound of formula II.

The compound II obtained in step c) may be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II in presence of diisopropyl ether as solvent and about 30-35% isopropanolic hydrochloric acid as an alcoholic mineral acid to obtain a compound of formula II. The reaction may be preformed at a temperature of about 30°C to 60°C.

In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C to obtain a compound of formula I;
(c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a
compound of formula II.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B using methanesulfonyl chloride in the presence of dichloromethane and triethylamine at a temperature of about 0°C to 30°C to obtain a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C in presence of acetonitrile and diisopropylethyl amine at a temperature of about 70°C to 100°C to obtain a compound of formula I;
(c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II in presence of diisopropyl ether and about 30-35% isopropanolic hydrochloric acid at a temperature of about 30°C to 60°C to obtain a compound of formula II.
In one embodiment, step (d) comprises purifying cinacalcet hydrochloride obtained in step c) using a suitable solvent. The suitable solvent used is as described supra. Preferably the suitable solvent selected is an alcohol or an organic nitrile or mixture of an alcohol & an organic nitrile. More preferably, the suitable solvent selected is methanol or acetonitrile or mixture of methanol & acetonitrile.
In one embodiment, the process for purifying cinacalcet hydrochloride obtained in step c) comprising,
i. treating cinacalcet hydrochloride with alcoholic solvent followed by optionally
treating with water; ii. optionally isolating the cinacalcet hydrochloride and

iii. treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.
In one embodiment, the process for purifying cinacalcet hydrochloride obtained in step c) comprising,
i. treating cinacalcet hydrochloride with methanol followed by optionally treating
with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with acetonitrile.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising the process for purifying cinacalcet hydrochloride obtained in step c) using a suitable solvent.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising the process for purifying cinacalcet hydrochloride obtained in step c) comprising:
i. treating cinacalcet hydrochloride with alcoholic solvent followed by optionally
treating with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.
In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C to obtain a compound of formula I;
(c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II;
(d) process for purifying cinacalcet hydrochloride obtained in step c) comprising,
i. treating cinacalcet hydrochloride with alcoholic solvent followed by optionally
treating with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.

In one embodiment, the present invention provides a process for the preparation of Cinacalcet base, a compound of formula (I) or Cinacalcet hydrochloride, a compound of formula (II), comprising,
(a) converting a compound of formula A to a compound of formula B using methanesulfonyl chloride in the presence of dichloromethane and triethylamine at a temperature of about 0°C to 30°C to obtain a compound of formula B;
(b) reacting the compound of formula B with a compound of formula C in presence of acetonitrile and diisopropylethyl amine at a temperature of about 70°C to 100°C to obtain a compound of formula I;
(c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a compound of formula II in presence of diisopropyl ether and about 30-35% isopropanol- hydrochloric acid mixture at a temperature of about 30°C to 60°C to obtain a compound of formula II;
(d) process for purifying cinacalcet hydrochloride obtained in step c) comprising,
i. treating cinacalcet hydrochloride with methanol followed by optionally treating
with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with acetonitrile.
In one embodiment, process for purification of a cinacalcet hydrochloride comprises:
i. treating cinacalcet hydrochloride with alcoholic solvent followed by optionally
treating with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.
In one embodiment, process for purification of a cinacalcet hydrochloride comprises:
i. treating cinacalcet hydrochloride with methanol followed by optionally treating
with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with acetonitrile.


In one embodiment, process for the purification of cinacalcet hydrochloride comprises recrystallization of compound of formula (II) from methanol at a temperature of about 25 °C to 30°C.
In one embodiment, purification of crude cinacalcet hydrochloride comprises treating crude cinacalcet hydrochloride with methanol. The process comprising stirring crude cinacalcet hydrochloride with methanol at a temperature of about 25°C to 30°C for about 30 minutes to obtain clear solution. The clear solution obtained may be optionally treated with charcoal, stirred and filtered hot. The filtrate obtained may be heated to about 50°C to 55°C and optionally washed with water. The reaction mass may be cooled to about 25°C to 30°C and stirred for about 60 mins. The reaction mass may be filtered, the cake obtained may be washed and dried at about 50°C to 70°C. The dried cake may be treated with acetonitrile at about 75 °C to 80 °C and stirred to get clear solution. The clear solution obtained may be treated with charcoal, stirred and filtered hot. The filtrate may be cooled to about 25 °C to 30°C and stirred for about 1-4 hours. The reaction mass obtained may be filtered and washed with acetonitrile. The wet cake so obtained may be dried at about 50°C to 60°C for about 10-12 hours to get pure cinacalcet hydrochloride as white solid with 99.9% HPLC purity.
The inventors of present invention have surprisingly found that the process of purification of cinacalcet hydrochloride as per present invention increases the purity and stability of cinacalcet hydrochloride.
"Crude cinacalcet hydrochloride" in the context of the present invention means cinacalcet hydrochloride having a HPLC purity of less than about 97.0%.
Cinacalcet hydrochloride manufactured by the present invention is substantially free from impurities. Typically Cinacalcet hydrochloride is of high HPLC purity such as atleast about 98%, 99% or 99.5%, by weight pure. Correspondingly, the level of impurities may be less than about 1%, 0.5% or 0.1%, by weight, as determined by using high performance liquid chromatography (HPLC).

In one embodiment, the cinacalcet hydrochloride prepared by process of present invention as described above is stable. The cinacalcet hydrochloride prepared by the process of present invention as described above is substantially stable under storage at about 40°C/75% RH, 30°C/65% RH and 25°C/60% RH for at least about 3 months.
In one embodiment, the cinacalcet hydrochloride prepared by present invention is in stable crystalline form I with XRD 2θ peaks at about 13.8°, 18.9°, 21.2°, 24.2° and 25.4°.
An important feature of the present invention is that the cinacalcet hydrochloride obtained by

Sr.
No Name of Impurities IUPAC Structure 40°C/ 75% RH 30°C/ 65% RH 25°C/ 60% RH
1 CIN-
Alcohol 3 -(3 -(trifluoromethyl) phenyl)propan-1 -ol Not detected Not detected Not detected
2 CIN-Mesyl 3 -(3 -(trifluoromethyl)
phenyl)propyl
methanesulfonate Not detected Not detected Not detected
3 CIN-
Amine (R)-l-(naphthalen-l-yl)ethanamine Not detected Not detected Not detected
4 CIN-N-Oxide 3 -(3 -(trifluoromethyl) phenyl)-N-((R)-l-(naphthalen-1-yl)ethyl)propan-l-amine N-Oxide Not detected Not detected Not detected
5 CIN-
Dimer 3 -(3 -(trifluoromethyl)
phenyl)-N-(3-(3-
(trifluoromethyl)
phenyl) propyl)-N-
((R)-l-(naphthalen-l-
yI)ethyl)propan-l-
amine Not detected Not detected Not detected
6 S-Isomer 3 -(3 -(trifluoromethyl)
phenyl)-N-((S)-l-
(naphthalen-8-
yl)ethyl)propan-l-
amine Not
detected Not detected Not detected
7 Total impurities - - 0.048% 0.043% 0.053%

X-ray powder diffraction profile for Cinacalcet hydrochloride was obtained using an X-ray Diffractometer (X' Pert Pro, PANalytical). The measurement were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°); target, Cu; filter, Ni; detector, pixel [1D]; Scanning Mode; PSD Length [°2 Theta] =3.35; generator 45KV ; tube current 40mAmp. The sample were scanned in the full 29 range of 2-50° with a "time-per-step" 23.97 seconds.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

The present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example-1: Preparation of 3-(3-(trifluoromethyl)phenyl)propyl methanesulfonate
(compound B)
3-(3-(trifluoromethyl)phenyl)propan-l-ol (compound A) (250 g, 1.224 mole) was suspended in dichloromethane (1.0 L) at about 5-15° C. Triethylamine (185.83 g, 1.836 mole) was added at about 5-15° C under stirring. A solution of methanesulfonyl chloride (182.33 g, 1.591 mole) in dichloromethane (250 mL) was added drop wise to the reaction mass within 1.5- 2 hours. The reaction mass was charged with water (625 mL) at about 20 - 30° C and layers separated. The organic layer was washed with 10% hydrochloric acid (660 mL) and layers separated. The organic layer was washed with water (625 mL). The organic layer was dried under vacuum to get the title compound as light yellow oil with 96% HPLC purity (338 gms, Yield 98%).
Example-2: Preparation of 3-(3-(trifluoromethyl) phenyl-N-(R)-l-(naphthalene-l-yl) ethyl) propan-1-amine) (Cinacalcet base) (compound I)
A solution of (R)-l-(napthalen-l-yl)ethanamine (compound C) (400.26 g, 2.338 mole) in acetonitrile (1.65 L) was charged with diisopropylethyl amine (226.62 g, 1.753 mole). 3-(3-(trifluoromethyl)phenyl) propyl methanesulfonate (compound B) (330 g, 1.169 mole) obtained in example 1 was added under stirring at about 25 - 30 ° C. The reaction mass was heated to about 80 - 85 ° C and stirred for about 24 h. The solvent was evaporated completely after reaction completion under vacuum to obtain oil which was further degassed at about 50 - 55 ° C under vacuum for about 2 h. The reaction mass was charged with dichloromethane (2.64 L) followed by water (1.98 L) and stirred. The organic layer was separated and washed with water (1.98 L) and layers separated. pH was subsequently adjusted with 10% HC1 solution and layers separated. The organic layer was washed with 10% hydrochloric acid (2.64 L) solution. The organic layer was washed successively with water (1.98 L) and 10% sodium bicarbonate solution (2.64 L). The organic layer was washed with water (1.98 L) and dried over sodium sulphate. The organic layer was evaporated at about 40 ° C under vacuum to obtain oil which was further degassed at about 50 - 55 ° C under vacuum for about 2 h to obtain Cinacalcet base as brown oil.

Example-3: Preparation of Cinacalcet hydrochloride (compound II)
Cinacalcet base obtained in example 2 was charged with diisopropyl ether (2.814 L) and heated to about 40 - 50 ° C . 30-35% IPA-HC1 (122 mL) was added dropwise. The precipitated solid was stirred at about 40 - 50 ° C for about 1 h. The reaction mass was cooled at about 25 - 30 ° C and stirred for about 2 h. The reaction mass was filtered and cake washed with diisopropyl ether (804 mL). The wet cake was dried at about 50 - 55 ° C for about 10-12 h to yield 406 g (Yield-88%) desired crude Cinacalcet hydrochloride as off-white solid with 97% HPLC purity.
Example-4: Purification of Cinacalcet hydrochloride
A mixture of crude Cinacalcet hydrochloride (365 g, 0.926 mole) in methanol (730 mL) was stirred at about 25 °C - 30 °C for about 30 min to obtain clear solution. To this were charged activated charcoal (9.12 g) and stirred at about 25 °C - 30 °C for about 30 min. The reaction mixture was filtered and washed with methanol (365 mL). The filtrate obtained was heated to about 50 °C - 55 °C and purified water (2.92 L) was added slowly at about 50 °C - 55 °C. The reaction mixture was cooled to about 25 °C - 30 °C and stirred for about 1 h. The reaction mass was filtered, washed with purified water (365 ml) and dried. The wet cake was dried at about 55 °C - 60 °C for about 12 h. To the dried cake (300 g) was added acetonitrile (2.1 L) and heated to about 75 °C - 80 °C. The reaction mixture was stirred at about 75 °C - 80 °C to get clear solution. Then clear reaction mass was hot filtered and washed with hot acetonitrile (300 mL). The filtrate was cooled to about 25 °C - 30°C and stirred for about 2 h. The reaction mass was filtered and washed with acetonitrile (300 ml). The wet cake was dried at about 50 - 55 ° C for about 12 h to yield 274 g (Yield-75%) desired pure Cinacalcet hydrochloride as white solid with 99.9% HPLC purity.

We claim:
1. A process for preparation of Cinacalcet base of formula-I or hydrochloride salt thereof of formula-II comprising:

a) converting a compound of formula A to a compound of formula B in presence of a
suitable solvent and an organic base;

b) reacting the compound of formula B with a compound of formula C in presence of a
suitable solvent and an organic base to obtain cinacalcet base, a compound of formula
I;

c) converting cinacalcet base, the compound of formula I to cinacalcet hydrochloride, a
compound of formula II;

d) purifying cinacalcet hydrochloride obtained in step c) using a suitable solvent.

2. A process according to claim 1, wherein the suitable solvent used in step (a) is halogenated hydrocarbon.
3. A process according to claim 1, wherein the suitable solvent used in step (b) is an organic nitrile.
4. A process according to claim 1, wherein the suitable solvent used in step (d) is an .alcohol or an organic nitrile or mixture of an alcohol and an organic nitrile.
5. A process according to claim 1, wherein the organic base used in step (a) is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and tertiary butylamine.
6. A process according to claim 1, wherein the organic base used in step (b) is selected from the group consisting of triethylamine, N,N-diisopropylethylamine and tertiary butylamine.
7. A process according to claim 1, wherein the purification step d) comprises,
i. treating cinacalcet hydrochloride with alcoholic solvent followed by optionally treating
with water; ii. optionally isolating the cinacalcet hydrochloride and iii. treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.
8. A process according to claim 7, wherein the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the organic nitrile is acetonitrile.
9. A process for purification of a cinacalcet hydrochloride comprising:

a) treating cinacalcet hydrochloride with alcoholic solvent followed by optionally treating with water;
b) optionally isolating the cinacalcet hydrochloride and
c) treating the cinacalcet hydrochloride obtained in step b) with an organic nitrile.

10. A process according to claim 9, wherein the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the organic nitrile is acetonitrile.