FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
AN IMPROVED PROCESS FOR THE PREPARATION OF CINACALCET
HYDROCHLORIDE
PIRAMAL ENTERPRISES LIMITED, A COMPANY INCORPORATED UNDER COMPANIES ACT 1956, WHOSE ADDRESS IS PIRAMAL TOWER GANPATRAO KADAM MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA;
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Cinacalcet ((αR)-a-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthaIenemethanamine) represented herein by formula I (hereinafter referred to as the compound of formula (I)) or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Cinacalcet is chemically described as, (αR)-a-methyl-Ar-[3-[3-
(trifluoromethyl)phenyl]propyl]-1 -naphthalenemethanamine or its pharmaceutically acceptable salts and is structurally represented herein below as formula I

Cinacalcet hydrochloride is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. It has one chirai center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity. Tecalcet hydrochloride was the first compound from this class (calcimimetic agents) to be extensively studied and most of the pharmacological data is available for this compound. Cinacalcet hydrochloride was developed in an effort to improve on the poor pharmacokinetics and metabolism of tecalcet hydrochloride (IDrugs. 2003 Jun; 6(6), 587-92). Cinacalcet hydrochloride is available in the market under the trade name Sensipar®.
The process for the preparation of cinacalcet (the compound of formula I) or its pharmaceutically acceptable salts as reported in the product patent and the subsequent prior arts involves use of complex and hazardous reagents, such as titanium (IV) isopropoxide for the preparation of imines from the reaction of primary amine with

aldehyde or ketone. The titanium (IV) isopropoxide, which is a hazardous reagent, is a flammable liquid and vapours of which, if inhaled, are harmful and cause eye, skin and respiratory tract irritation. In view of this, process for the preparation of cinacalcet involving use of such hazardous reagent is not feasible for large scale manufacturing and thus, industrially not viable. Also, titanium (IV) isopropoxide is a costly reagent, making the process for preparation of cinacalcet expensive.
The process for the preparation of cinacalcet of formula I is disclosed in US Patent No.
6011068 and the publication, Drugs of Future, 2002, 27(9), 831-836. The process
involves reaction of primary amine with an aldehyde or ketone using titanium (IV)
isopropoxide to obtain an imine i.e. (αR)-a-methyl-Ar-[3-[3-
(trifluoromethyl)phenyl]propylidene]-1 -naphthalenemethanamine (the compound of formula IV). The resulting imine was then reduced in-situ using sodium cyanoborohydride, sodium borohydride or sodium triacetoxyborohydride to yield cinacalcet.
US Patent Application Publication No. 2011/0295037 discloses in example 1 a process for the preparation of cinacalcet hydrochloride comprising reaction of (aR)-a-Methyl-l-naphthalenemethanamine (the compound of formula II) with 3-(trifluoromethyl) benzenepropanal (the compound of formula III) in the absence of titanium (IV) isopropoxide and stirred for 15 minutes to yield (αR)-a-methyl-N-[3-[3-(trifluoromethyl)phenyl]propylidene]-l-naphthalenemethanamine (the compound of formula IV). The resulting compound of formula IV was then reduced using sodium triacetoxyborohydride to yield cinacalcet crude base, which on further acidification with hydrochloric acid yields cinacalcet hydrochloride with 68.5% overall yield. The said process although avoids use of hazardous reagent such as titanium (IV) isopropoxide, the process involves use of another complex reagent such as sodium triacetoxyborohydride for the reduction of compound of formula IV to yield cinacalcet. Also, the overall yield of the product obtained by the said process is only 68.5%.
The process for the preparation of cinacalcet (the compound of formula I) or its pharmaceutically acceptable salts can be improved in terms of industrial applicability and cost by providing simple process using non-hazardous and mild reagents for the

preparation of cinacalcet that would provide the compound in good yield and purity. The process for the preparation of cinacalcet hydrochloride disclosed in the prior arts references mainly involves use of hazardous and complex reagents, such as titanium (IV) isopropoxide or sodium triacetoxyborohydride for the preparation of cinacalcet. Thus, there is a need to develop a process for the preparation of cinacalcet hydrochloride, which is industrially feasible, cost-effective and efficient.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of cinacalcet (described herein as the compound of formula I) or its pharmaceutically acceptable salts from (aR)-a-Methyl-l-naphthalenemethanamine (the compound of formula II) and 3-(trifluoromethyl)benzenepropanal (the compound of formula III).
Another object of the present invention is to provide a process for the preparation of cinacalcet hydrochloride.
Another object of the present invention is to provide a process for the preparation of cinacalcet hydrochloride, which is industrially applicable and cost-effective.
SUMMARY OF THE INVENTION
In accordance with the objects of the present invention there is provided a process for the preparation of cinacalcet (the compound of formula I) or its pharmaceutically acceptable salts comprising the steps of:
(a) reacting (αR)-a-Methyl-l-naphthaienemethanamine (the compound of formula II) with 3-(trifluoromethyl)benzenepropanal (the compound of formula III) using sulphuric acid in the presence of methylene dichloride as a solvent to yield imine (the compound of formula IV);
(b) reducing the compound of formula IV using sodium borohydride (NaBH4) to yield cinacalcet (the compound of formula I).

The process further comprises conversion of cinacalcet to its pharmaceutically acceptable salts, particularly hydrochloride salt.
The process of the present invention is schematically represented herein below:


In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the use of hazardous reagents such as titanium (IV) isopropoxide or sodium triacetoxyborohydride, thereby making the process industrially feasible, cost-effective and efficient.
DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Cinacalcet (the compound of formula I) or its pharmaceutically acceptable salts;

comprising the steps of: (a) reacting (aR)-a-Methyl-l-naphthalenemethanamine (the compound of formula ID

with 3-(trifluoromethyl) benzenepropanal (the compound of formula III)

using sulphuric acid in the presence of methylene dichloride as a solvent to yield imine (the compound of formula IV),


(b) reducing the compound of formula IV using sodium borohydride (NaBH4) to yield cinacalcet (the compound of formula I).
In an embodiment of the present invention, the process for the preparation of cinacalcet, (the compound of formula I) further comprises reaction of cinacalcet obtained in step (b) with aqueous hydrochloric acid to yield cinacalcet hydrochloride.

In accordance with an embodiment of the present invention, in the step (a) said reaction is carried out using said compound of formula II and said compound of formula III in the ratio ranging from 0.5:5 to 5:0.5 mole equivalent.
In accordance with an embodiment of the present invention, in the step (a) said reaction is carried out using 0.05 to 1.3 mole equivalent of sulphuric acid.
In accordance with an embodiment of the present invention, in the step (a) said reaction is carried out at a temperature range of 0°C to 5°C.
In accordance with an embodiment of the present invention, the compound of formula IV obtained in the step (a) may be isolated from the reaction mixture. The isolation of

compound of formula IV may be carried out by distillation or evaporation of methylene dichloride.
In accordance with an embodiment of the present invention, in the step (b) said reaction is carried out using 1 to 5 mole equivalent of sodium borohydride.
In accordance with an embodiment of the present invention, in the step (b) said reaction is carried out at a temperature range of 0°C to 5°C.
In accordance with an embodiment of the present invention, in the step (b) the reduction of compound of formula IV may be carried out in-situ without isolation of compound of formula IV using sodium borohydride to yield cinacalcet (the compound of formula I).
In accordance with an embodiment of the present invention, in the step (b) the reduction of compound of formula IV may be carried out using isolated compound of formula IV, obtained in step (a) using sodium borohydride to yield cinacalcet (the compound of formula I).
In accordance with an embodiment of the present invention, cinacalcet hydrochloride is obtained in a yield of > 85% and purity of > 93%.
In accordance with the present invention, the starting material, (aR)-a-Methyl-1-naphthalenemethanamine (the compound of formula II) in methylene dichloride and 3-(trifluoromethyl)benzenepropanal (the compound of formula III) in methylene dichloride charged to the reaction flask containing methylene dichloride cooled at a temperature of 0°C to 5°C. To the resulting reaction mixture was then charged sulphuric acid and the reaction mixture was stirred for 1 hour. At this stage the reaction mixture was monitored on high performance liquid chromatography (HPLC) for the formation of the compound of formula IV. To the resulting reaction mixture then charged methanol and sodium borohydride with stirring at a temperature of 0°C to 5°C for 2-5 hours to obtain the residue. Filter the residue obtained and wash the resulting filtrate, i.e. methylene dichloride with water. The filtrate obtained was then treated with hydrochloric acid. The methylene dichloride layer was then concentrated and the resulting reaction mixture was

treated with isopropyl alcohol. To the resulting reaction mixture then charged water with stirring for 30 minutes and subsequently the reaction mixture was cooled to 5°C to 10°C for 1 hour. Filter and dry the resulting product to yield cinacalcet hydrochloride in yield of > 85% yield and purity of > 93%.
The starting material, (αR)-a-Methyl-l-naphthalenemethanamine of formula II and 3-(trifluoromethyl) benzenepropanal of formula III are prepared using the process as disclosed in the US Patent No. 6011068, which is incorporated herein by reference.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be constructed in anyway to limit the scope of the present invention.
EXAMPLES:
Example -1
To the reaction flask charged methylene dichloride (325 ml) and cooled to a temperature of 0°C to 5°C. To the reaction flask then charged compound of formula II (0.12 mole) in methylene dichloride and compound of formula III (0.12 mole) in methylene dichloride and sulphuric acid (0.02 mole) and stirred the reaction mixture for 1 hour. To the resulting reaction mixture then charged methanol and sodium borohydride (0.26 mole) with stirring at a temperature of 0°C to 5°C for 2-5 hours to obtain the residue. Filter the residue obtained and wash the filtrate with water. The filtrate obtained then treated with hydrochloric acid. The methylene dichloride layer then concentrated and treated the resulting reaction mixture with isopropyl alcohol. To the resulting reaction mixture then charged water with stirring for 30 minutes and subsequently cooled the reaction mixture to 5°C to 10°C for 1 hour to obtain the product, cinacalcet hydrochloride. Filter and dry the product obtained to yield cinacalcet hydrochloride with 86% yield and purity 95%.
Example -2
To the reaction flask charged methylene dichloride (700 ml) and cooled to a temperature of 0°C to 5°C. To the reaction flask then charged compound of formula II (0.25 mole) in methylene dichloride and compound of formula III (0.25 mole) in methylene dichloride

and sulphuric acid (0.04 mole) and stirred the reaction mixture for 1 hour. To the resulting reaction mixture then charged methanol and sodium borohydride (0.53 mole) with stirring at a temperature of 0°C to 5°C for 2-5 hours to obtain the residue. Filter the residue obtained and wash the filtrate with water. The filtrate obtained then treated with hydrochloric acid. The methylene dichloride layer then concentrated and treated the resulting reaction mixture with isopropyl alcohol. To the resulting reaction mixture then charged water with stirring for 30 minutes and subsequently cooled the reaction mixture to 5°C to 10°C for 1 hour to obtain the product, cinacalcet hydrochloride. Filter and dry the product obtained to yield cinacalcet hydrochloride with 86% yield and purity 95%.

WE CLAIM:
1. A process for the preparation of (αR)-a-methyl-N-[3-[3-
(trifluoromethyl)phenyl]propyl]-l-naphthalenernethanamirie (Cinacalcet)
represented by the following formula I or its pharmaceutically acceptable salts;

comprising the steps of:
(a) reacting (aR)-a-Methyl-1 -naphthalenemethanamine represented by the following formula II,

with 3-(trifluoromethyl) benzenepropanal represented by the following formula HI,


using sulphuric acid in the presence of methylene dichloride as a solvent to yield a (αR)-a-methyl-N-[3-[3-(trifluoromethyOphenylJpropylidene]-!-naphthalenemethanamine (imine) represented by the following formula IV,

(b) reducing the compound of formula IV using sodium borohydride (NaBFLj) to yield cinacalcet (the compound of formula I).
2. The process as claimed in claim 1 further comprises conversion of cinacalcet to its pharmaceutically acceptable salts.
3. The process as claimed in claim 1, wherein the said step (b) is carried out in-situ without isolation of compound of formula IV.
4. The process as claimed in claim 1, wherein in the step (a) the compound of formula IV is isolated.
5. The process as claimed in claim 1, wherein in the step (a) said reaction is carried out using the compound of formula II and the compound of formula III in the ratio ranging from 0.5:5 to 5:0.5 mole equivalent.
6. The process as claimed in claim 1, wherein in the step (a) said reaction is carried out using 0.05 to 1.3 mole equivalent of sulphuric acid.
7. The process as claimed in claim 1, wherein said step (a) is carried out at a temperature range of 0°C to 5°C.

8. The process as claimed in claim 1, wherein in the step (b) said reaction is carried out using 1 to 5 mole equivalent of sodium borohydride.
9. The process as claimed in claim 1, wherein said step (b) is carried out at a temperature range of 0°C to 5°C
10. A process for preparation of cinacalcet or its pharmaceutically acceptable salts of formula I substantially as herein described with reference to examples 1 and 2.