DESCINTRODUCTION

Aspects of the present application relate to processes for the preparation of Cinacalcet HC1 and its intermediate thereof.

The drug compound having the adopted name “Cinacalcet HC1” has chemical names: (R)-N-(1-(naphthalen-1-yl) ethyl)-3-(3-(trifluoromethyl) phenyl) propan-1-amine hydrochloride; ((R)-N-(3-(3-(trifluoromethyl)-phenyl)propyl)-1-(1-naphthyl)-ethylamine) hydrochloride and can be represented by structural formula (I) below.

Cinacalcet HC1 belongs to calcimimetic class of compounds and is useful for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease and hyper calcaemia in patients with parathyroid carcinoma. Cinacalcet hydrochloride is available in the market under the brand names Sensipar in the United States and Mimpara in Europe in the form of a tablet.

US 6,211,244 B1 describes Cinacalcet and discloses various processes to prepare related compounds or salts thereof (i) by condensation of primary amines with carbonyl compounds in the presence of Ti(OiPr)4 to give intermediate imines which can be reduced insitu with sodium cyanoborohydride or Sodium triacetoxyborohydride ; (ii) by reductive amination of carbonyl compounds with primary amines in the presence of sodium cyanoborohydride or Sodium triacetoxy borohydride ; (iii) by DIBAL mediated condensation of an amine with nitrile compound to give imine intermediate which is reduced insitu with sodium cyanoborohydride or sodium borohydride. The resultant enriched mixtures were purified to single diastereomer by HPLC or recrystallization.

Drugs of the future 2002, 27(9), 832 also discloses a similar process of reacting of 1- naphthyl ethyl amine with 3-(3-trifluoromethyl phenyl) propanaldehyde by means of Ti(OiPr)4 to get corresponding imine followed by reduction with sodium cyanoborohydride.

WO2006/125026A2 discloses alternative process for Cinacalcet by converting hydroxyl group of 3-(3-trifluoromethyl phenyl) propanol to a good leaving group and then combining with 1- naphthyl ethyl amine in presence of base.

WO2007/127445A2 discloses the process of combining reactive derivative of 3-trifuoromethyl phenyl propanoic acid with 1- naphthyl ethyl amine in presence of base to obtain corresponding propanamide intermediate followed by reduction to obtain Cinacalcet.

WO2007/127449A1 discloses the process of heating the mixture of 3-bromo Trifluoro toluene and allyl amine compound to obtain unsaturated Cinacalcet base and reducing to Cinacalcet.

The processes for the preparation of Cinacalcet HC1 described in the literature are costly or hazardous to handle or technically difficult to practice at an industrial scale or result in low yield or quality of the product. There remains a need to provide economically and industrially viable process, which avoids hazardous chemical handling and lengthy work-ups for the preparation of Cinacalcet with the desired quality for use directly to prepare pharmaceutical formulations.

SUMMARY

In the first aspect, the present application provides processes for the preparation of Cinacalcet or its HC1 salt, comprising

a) reacting a 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV) to provide imine compound of formula (V);

b) reducing the imine compound of formula (V) with a reducing agent to obtain Cinacalcet free base of formula (Ia); and

c) converting Cinacalcet free base to its hydrochloride salt of formula (I) and

d) optionally, re-crystallizing Cinacalcet HC1 in solvent.

In the second aspect, the present application provides one pot process for the preparation of Cinacalcet or its HC1 salt, which comprises:

a) reacting 3-(3-trifuoromethyl phenyl) propanol of formula (II) with (R)-1- naphthyl ethyl amine of formula (IV) in the presence of a transition metal complex to give Cinacalcet free base;

b) optionally, converting Cinacalcet free base to its hydrochloride salt.

In the third aspect, the present application provides a one pot process for the preparation of the Cinacalcet or its HC1 salt, which comprises:

a) reacting a 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV) in the presence of metal triflate and reducing agent to obtain Cinacalcet free base

b) optionally, converting Cinacalcet free base to its hydrochloride salt.

In the fourth aspect, the present application provides process for the preparation of 3-(3-trifluoro methyl phenyl) propanaldehyde of formula (III), comprising reaction of 1- bromo-3-trifluormethyl benzene of formula VI with allyl alcohol of formula VII in presence of Palladium catalyst and solvent.

In the fifth aspect, the present application provides the process to prepare 3-(3-trifluoromethyl phenyl) propanaldehyde of formula (III) comprising reaction of 3-trifluoromethyl aniline of formula VIII with allyl alcohol of formula VII in presence of Nitrous acid, Palladium catalyst and solvent.

In the sixth aspect, the present application provides process for the preparation of Cinacalcet HC1 by reacting Cinacalcet free base with hydrochloric acid in solvent and optionally, re-crystallizing Cinacalcet HC1 in solvent.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustrative X-ray powder diffraction pattern of Cinacalcet HC1 prepared by the method of Example No 11.

Figure 2 is an illustrative Differential scanning calorimetric thermogram of Cinacalcet HC1 produced by the process of the present application.

Figure 3 is an illustrative Infrared spectrum of Cinacalcet HC1 produced by the process of the present application.

DETAILED DESCRIPTION

In the first aspect, the application provides processes for the preparation of Cinacalcet or its HC1 salt, embodiments comprising

a) reacting 3-(3-trifluoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV) to provide imine compound of formula (V);

b) reducing the imine compound of formula (V) insitu with a reducing agent to obtain Cinacalcet free base; and

c) converting the Cinacalcet free base to its hydrochloride salt and

d) optionally, re-crystallizing Cinacalcet HC1.

The above process can be illustrated by Scheme 1.

The individual steps of the process are described herein below.

(R)-1- naphthyl ethyl amine of formula (IV) is commercially available or can be prepared according to any of the processes known in art.

3-(3-trifuoromethyl phenyl) propanaldehyde intermediate of formula (III) can be prepared by the procedures known in art or the procedures described and exemplified in present application.

The starting materials can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.

Alternatively 3-(3-trifuoromethyl phenyl) propanaldehyde intermediate of formula (III) can be prepared by the following procedure.

3-(3-trifuoromethyl phenyl) propanol of formula (II) which is one of the starting materials for the preparation of Cinacalcet HC1, may be prepared according to any of the processes disclosed in the art.

3-(3-trifuoromethyl phenyl) propanaldehyde intermediate of formula (III) can be prepared by the oxidation of 3-(3-trifuoromethyl phenyl) propanol of formula (II) with a hypochlorite, in the presence of TEMPO and aqueous hydrogen carbonate to give 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III).

Hypochlorite may include, but are not limited to sodium hypochlorite, calcium hypochlorite and the like.

Reaction between 3-(3-trifuoromethyl phenyl) propanol and hypochlorite can be carried out in the mole ratio of about 1:1 to about 1:2 respectively.

The mole ratio of 3-(3-trifuoromethyl phenyl) propanol and TEMPO (2,2,6,6-Tetremethyl 1-piperidinyloxy free radical) used may range from about 1: 0.001 to about 1: 0.03 respectively.

Oxidation of 3-(3-trifuoromethyl phenyl) propanol with a hypochlorite, in the presence of TEMPO and aqueous hydrogen carbonate can be carried out optionally in the presence of KBr. Use of KBr accelerates the rate of reaction and it can be attributed to the generation of HOBr, which is a stronger oxidant than HOCl.

The mole ratio of 3-(3-trifuoromethyl phenyl) propanol and KBr used may range from about 1: 0.001 to about 0.1 respectively.

Hydrogen carbonate can be used to maintain the pH of the reaction medium below 9 in oxidation of 3-(3-trifuoromethyl phenyl) propanol, as further greater pH tends to retard reaction rates. Hydrogen carbonates that can be used in this step include but not limited to: sodium hydrogen carbonate, potassium hydrogen carbonate and the like.

The mole ratio of Hydrogen carbonates can be used may range from about 1:0.5 to 1:8 respectively.

This reaction can be carried out in the presence of a inert solvent. Inert solvents may include, but are not limited to: Water, C2-C6 nitriles, halogenated hydrocarbons, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 ethers, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

Temperatures for carrying out this reaction may range from about -20ºC to about 50ºC.

The time required for the reaction between 3-(3-trifuoromethyl phenyl) propanol and NaOCl may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer for the preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde with desired yield and purity.

The above reaction may be carried out by taking a mixture of solvent, 3-(3-trifuoromethyl phenyl) propanol, TEMPO and KBr and adding an aqueous solution of sodium bicarbonate. Optionally cooling the above mixture and then slowly adding sodium hypochlorite and stirring for the completion of the reaction, followed by work-up, optionally in the presence of any of the quenching agent known in the art and water to obtain the 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III).

3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) obtained can be directly taken forward to the Step a) without isolation or can be isolated from the reaction mass. This isolated product may optionally be purified by techniques known in art like re-crystallization, slurrying, column chromatography or fractional distillation, etc.

Step a) of scheme-1 of present application involves reacting 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV), to obtain imine intermediate compound of formula (V).

In embodiments of step a), the reaction between 3-(3-trifuoromethyl phenyl) propanaldehyde and (R)-1- naphthyl ethyl amine is carried out in the mole ratio of 1:0.9 to 1:1.6 respectively.

In embodiments of step a), reaction can be carried out in the presence of inert solvents. Inert solvents that may be used include, but are not limited to: C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

In embodiments of step a), the reaction of the 3-(3-trifuoromethyl phenyl) propanaldehyde with (R)-1- naphthyl ethyl amine can be carried out at temperatures ranging from about -30 ºC to about 50ºC.

In embodiments of step a), the reaction between 3-(3-trifuoromethyl phenyl) propanaldehyde and (R)-1- naphthyl ethyl amine can be carried out for time sufficient for the formation of imine compound of formula (V). Preferably reaction can be carried out in about 0.5 to about 10 hours or longer.

The product of step a) can be isolated or can be directly used without isolation in the next step.

Optionally an additional polar solvent can be added to the reaction mixture to complete reaction. In embodiments of step a), polar solvent may include but not limited to: water, methanol, ethanol or the like.

Step b) of scheme-1 of present application involves reducing the imine compound of formula (V) by the addition of a reducing agent to obtain Cinacalcet free base. Addition of reducing agent can be carried out either by single lot or lot wise (multiple lots). Preferably, reducing agent addition can be carried out by lot wise.

In an embodiment of step b), reaction mixture of step a) containing the imine compound of formula (V) can be directly taken forward for step b) without isolation in an insitu process. The insitu process involves reacting 3-(3-trifuoromethyl phenyl) propanaldehyde compound of formula (III) with (R)-1- naphthyl ethyl amine in a solvent to provide imine compound of formula (V) followed by insitu reduction of imine compound with a reducing agent to obtain Cinacalcet free base of formula (Ia). Optionally the reducing agent can be added to the pre-cooled reaction mixture of step a).

Reducing agent that can be used for the reduction of imine compound of formula (V) in step c) include, but are not limited to, sodium borohydride, Lithium aluminium hydride, sodium triacetoxy borohydride, sodium cyano borohydride and the like.

In embodiments of step b), the reaction between imine compound of formula (V) and reducing agent can be carried out in the mole ratio of 1:1.5 to 1:2.5 respectively.

In embodiments of step b), reaction can be carried out in the presence of inert solvents. Inert solvents that may be used include, but are not limited to: C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

In embodiments of step b), the reduction of imine compound of formula V with a reducing agent can be carried out at temperatures ranging from about -30ºC to about 50ºC.

In embodiments of step b), the reduction of imine compound of formula V with a reducing agent can be carried out for time sufficient for the formation of Cinacalcet free base of formula Ia. Preferably reaction can be carried out in about 0.5 to about 10 hours or longer.

The product obtained from step b), Cinacalcet free base of formula (Ia) may optionally be purified, using any suitable techniques known to person skilled in the art.

Step c) of the scheme-1 of the present application can be carried out by reacting Cinacalcet free base that is obtained from step b) with hydrochloric acid in inert solvent to obtain Cinacalcet HC1 of formula (I) and optionally re-crystallizing Cinacalcet HC1 in inert solvent.

In an embodiment, the salt formation can be carried out according to any of the procedures disclosed in the art. Such procedures include, but not limited to: combining Cinacalcet base with hydrochloric acid.

The process for preparation of Cinacalcet HC1 and its re-crystallization can be carried out according to the processes described and exemplified in the present application.

In the second aspect, the present application provides one pot process for the preparation of Cinacalcet or its HC1 salt, comprising

a) reacting 3-(3-trifuoromethyl phenyl) propanol of formula (II) with (R)-1- naphthyl ethyl amine of formula (III) in the presence of a Transition metal complex in a inert solvent, to give Cinacalcet;

b) optionally, converting the Cinacalcet free base to its hydrochloride salt.

According to the present application, Cinacalcet can be synthesized by converting 3-(3-trifuoromethyl phenyl) propanol into its carbonyl derivative 3-(3-trifuoromethyl phenyl) propanaldehyde by the removal of hydrogen with a transition metal complex. The carbonyl derivative being reactive than the precursor alcohol, readily reacts in situ with (R)-1- naphthyl ethyl amine to give corresponding imine intermediate. Thereafter transition metal complex returns the barrowed hydrogen, leading to reduction of imine intermediate to Cinacalcet.

Process of this aspect of present application can be illustrated as depicted in scheme-2.

The individual steps of the process are described herein below.

3-(3-trifuoromethyl phenyl) propanol which is one of the starting materials for the preparation of Cinacalcet HC1, can be prepared according to any of the processes disclosed in the art. (R)-1- naphthyl ethyl amine is commercially available or can be prepared according to the processes known in art. The starting materials can be purified by techniques known in art like column chromatography, fractional distillation or acid-base treatment.

Step a) of this aspect in the present application involves reaction between 3-(3-trifuoromethyl phenyl) propanol of formula (II) and (R)-1- naphthyl ethyl amine of formula (IV), in the presence of a transition metal complex to provide Cinacalcet.

Transition metal complex, that can be used may include, but not limited to : RuCl2 (PPh3)3, RHC12(PPh3)3, IrCl2(PPh3)3, PdCl2, Pd(OAc)2, 5% Pd/C, Pd(dba)2, NiCl2, Cu2O, other complexes with transition metals Ru, Rd, Ir, Au and the like.

In embodiments of step a), Reaction between 3-(3-trifuoromethyl phenyl) propanol and R)-1- naphthyl ethyl amine can be carried out in the mole ratio of about 1: 0.6 to about 1:3 respectively. Preferably, the reaction can be carried out in a mole ratio of about 1:0.9 to 1: 1.1.

In embodiments of step a), the Transition metal complex used in the reaction may be a catalytic amount. The mole ratio of 3-(3-trifuoromethyl phenyl) propanol to transition metal complex may range from about 1:0.001 to about 1: 0.5 respectively. Preferably, the reaction can be carried out in a mole ratio of 1:0.005 to 1: 0.05.

In embodiments of step a), reaction between 3-(3-trifuoromethyl phenyl) propanol and R)-1- naphthyl ethyl amine can be carried out in the presence of a inert solvent. Inert solvents that may be used include, but are not limited to: C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

Temperatures for carrying out step a) may range from about 0ºC to reflux temperature of the solvent used.

The time required for the reaction between 3-(3-trifuoromethyl phenyl) propanol and R)-1- naphthyl ethyl amine in step a) may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer for the preparation of Cinacalcet with desired yield and purity.

In embodiments of step a), 3-(3-trifuoromethyl phenyl) propanol, (R)-1- naphthyl ethyl amine and transition metal complex can be added at a time or can be added one after another and heat the reaction mixture and stir at reflux temperature for the time sufficient to complete reaction.

In an embodiment, (R)-1- naphthyl ethyl amine can be added to the mixture of 3-(3-trifuoromethyl phenyl) propanol and transition metal complex in a solvent, followed by heating the reaction mixture and stirring at reflux for time sufficient to complete reaction followed by work-up to obtain the Cinacalcet free base.

In embodiments of step a), the obtained Cinacalcet may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like. The product obtained by the process of present application may optionally be purified, using any suitable techniques known to person skilled in the art.

Step b) of scheme-2 of the present application can be carried out by reacting Cinacalcet free base that is obtained from step a) with hydrochloric acid in inert solvent to obtain Cinacalcet HC1 of formula (I) and optionally re-crystallizing Cinacalcet HC1 in inert solvent.

In an embodiment, the salt formation can carried out according to any of the procedures disclosed in the art. Such procedures include, but not limited to: combining Cinacalcet base with hydrochloric acid.

The process for preparation of Cinacalcet HC1 and its re-crystallization can be carried out according to the processes described and exemplified in the present application

In the third aspect, the present application provides a one pot process for the preparation of the Cinacalcet or its HC1 salt, which comprises:

a) reacting a 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV) in the presence of metal triflate to obtain Cinacalcet free base and

b) optionally, converting Cinacalcet free base to its hydrochloride salt.

Process of this aspect of present application can be illustrated as depicted in scheme-3

The individual steps of the process are described herein below.

3-(3-trifuoromethyl phenyl) propanaldehyde of formula III which is one of the starting materials for the preparation of Cinacalcet HC1, can be prepared according to any of the processes disclosed in the art or according to the processes described and exemplified in the present application. (R)-1- naphthyl ethyl amine is commercially available or can be prepared according to the processes known in art. The starting materials can be purified by techniques known in art like re-crystallization, slurrying, column chromatography, fractional distillation or acid-base treatment.

Step a) of this aspect in the present application relates to one pot reductive amination of 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) with (R)-1- naphthyl ethyl amine of formula (IV), in the presence of metal triflate to provide Cinacalcet free base.

In an embodiment of step a), a reducing agent can be used in the reaction between 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) and (R)-1- naphthyl ethyl amine of formula (IV) in presence of metal triflate.

In embodiments of step a), reaction can be carried out using 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) and (R)-1- naphthyl ethyl amine of formula (IV) in the mole ratio ranging from about 1: 0.8 to about 1: 1.5 respectively.

In embodiments of step a), the metal triflates that can be used include, but not limited to Iron triflate (Fe (OTf)3)), Scandium triflate, Aluminium triflate and the like.

In embodiments of step a), reaction can be carried out using 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) and metal triflate in the mole ratio ranging from about 1: 0.001 to 0.1 respectively.

In embodiments of step a), reducing agent that can be used include, but not limited to: sodium borohydride, Lithium aluminium hydride, sodium triacetoxy borohydride, sodium cyano borohydride and the like.

In embodiments of step a), reaction can be carried out using 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) and a reducing agent in the mole ratio ranging from about 1: 0.5 to 1:2 respectively.

In embodiments of step a), reaction between 3-(3-trifuoromethyl phenyl) propanaldehyde and (R)-1- naphthyl ethyl amine in presence of metal triflate can be carried out in the presence of inert solvent. Inert solvents that may be used include, but are not limited to: halogenated hydrocarbons, C1-C6 alcohols, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, C3-C6 ketones or mixtures thereof.

In an embodiment of step a), to the mixture of 3-(3-trifuoromethyl phenyl) propanaldehyde and solvent, (R)-1- naphthyl ethyl amine is added. To this above mixture metal triflate is added and then reducing agent is added later. Optionally an additional polar solvent can be added to the reaction mixture to complete reaction, followed by recovering the product by suitable work-up procedure known in art.

In embodiments of step a), polar solvent may include but not limited to: methanol, ethanol or the like.

Step b) of scheme-2 of the present application can be carried out by reacting Cinacalcet free base that is obtained from step a) with hydrochloric acid in inert solvent to obtain Cinacalcet HC1 of formula (I) and optionally re-crystallizing Cinacalcet HC1 in inert solvent.

In an embodiment, the salt formation can carried out according to any of the procedures disclosed in the art. Such procedures include, but not limited to: combining Cinacalcet base with hydrochloric acid.

The process for preparation of Cinacalcet HC1 and its re-crystallization can be carried out according to the processes described or exemplified in the present application.

In the fourth aspect, the present application provides the process for the preparation of 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III by reacting 1- bromo-3-trifluormethyl benzene of formula VI with allyl alcohol of formula VII in presence of Palladium catalyst and inert solvent.

The starting materials, 1- bromo-3-trifluormethyl benzene of formula VI and allyl alcohol of formula VII are commercially available or can be prepared according to the processes known in art.

Inert solvents that may be used in the process of this aspect include, but are not limited to: N,N - dimethyl formamide , N,N - dimethyl acetamide , C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

In embodiments of this aspect, the reaction between 1-bromo-3-trifluormethyl benzene and allyl alcohol may be carried out with the mole ratio of about 1: 0.8 to 1:3 respectively.

Palladium catalysts that can be used in the process of this aspect include, but limited to Pd(OAc)2, Pd (Cl2), Pd/C and the like.

In embodiments of this aspect, reaction can be carried out using 1-bromo-3-trifluormethyl benzene and palladium catalyst with a mole ratio ranging from about 1:0.001 to 1: 0.1 respectively.

In an embodiment of this aspect, a phase transfer catalyst (PTC) can be used in the reaction between 1- bromo-3-trifluormethyl benzene of formula VI with allyl alcohol of formula VII in presence of Palladium catalyst and solvent.

Phase transfer catalyst (PTC) used in the process of this aspect includes but not limited to Catalysts that are useful in the reaction include, but are not limited to: Quaternary ammonium or phosphonium salts such as tetra butyl ammonium bromide, tetra butyl ammonium chloride, tetra methyl ammonium chloride, tetra methyl ammonium hydroxide, benzalkonium chloride, benzethonium chloride, methyl benzethonium chloride, cetyl trimethylammonium bromide, dimethyl dioctadecyl ammonium chloride, tetra butyl phosphonium chloride, tetra butyl phosphonium bromide, tetra phenyl phosphonium chloride, tetra phenyl phosphonium iodide, tetra methyl phosphonium iodide or the like.

In embodiments of this aspect, reaction can be carried out using 1-bromo-3-trifluormethyl benzene and Phase transfer catalyst in a mole ratio of about 1: 1 to 1:3 respectively.

In embodiments of this aspect, Hydrogen carbonates can be used in the process of this aspect and hydrogen carbonates includes, but not limited to sodium hydrogen carbonate, potassium hydrogen carbonate and the like.

In embodiments of this aspect, reaction can be carried out using 1-bromo-3-trifluormethyl benzene and hydrogen carbonate with a mole ratio of about 1: 1 to 1:5 respectively.

In embodiments of this aspect, reaction can be carried out at temperature of about -10°C to about reflux temperature of the solvent. Preferably the temperature may range about 40°C-80°C. The time required for the reaction to complete varies widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer for the preparation of 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III with desired yield and purity.

In an embodiment of this aspect, the present application provides the process to prepare Cinacalcet HC1 comprising the step of reacting 1- bromo-3-trifluormethyl benzene of formula VI with allyl alcohol of formula VII in presence of Palladium catalyst and inert solvent to obtain 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III.

In the fifth aspect, the present application provides the process to prepare 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III by reacting 3-trifluoromethyl aniline of formula VIII with allyl alcohol of formula VII in presence of Nitrous acid, Palladium catalyst and inert solvent.

The starting materials, 3-trifluoromethyl aniline of formula VIII and allyl alcohol of formula VII are commercially available or can be prepared according to the processes known in art.

Inert solvents that can be used in the process of this aspect include, but are not limited to: C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones or mixtures thereof.

In an embodiment of this aspect, the reaction between 3-trifluormethyl aniline and nitrous acid can be carried out by using source of nitrous acid known to a person skilled in art like that include, but not limited to NaNO2/ H2SO4 or NaNO2/HC1 and the like.

In embodiments of this aspect, the reaction can be carried out using 3-trifluormethyl aniline and NaNO2 in the mole ratio of about 1:1 to about 1: 1.5.

In embodiments of this aspect, the reaction can be carried out using 3-trifluormethyl aniline and sulfuric acid or hydrochloric acid in the mole ratio of about 1: 1 to 1:3 respectively.

Palladium catalysts that can be used in the process of this aspect include, but limited to Pd (OAc)2, Pd (Cl2) , Pd/C and the like.

In embodiments of this aspect, the reaction can be carried out using 3-trifluormethyl aniline and Palladium catalyst in the mole ratio of about 1: 0.001 to 1:0.1 respectively.

In embodiments of this aspect, reaction can be carried out using 3-trifluormethyl aniline and allyl alcohol with the mole ratio of about 1: 0.8 to 1:4 respectively.

In an embodiment of this aspect, the reaction can be carried out where in the allyl alcohol is added after the addition of nitrous acid source and palladium catalyst to 3-trifluormethyl aniline.

In embodiments of this aspect, reaction can be carried out at temperature of about -10°C to about 40°C. Preferably the temperature may range about -10°C to about 30°C. The time required for the reaction to complete varies widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer for the preparation of 3-(3-trifluoromethyl phenyl) propanaldehyde with desired yield and purity.

In an embodiment of this aspect, the present application provides the process to prepare Cinacalcet HC1 comprising the step of reacting 3-trifluormethyl aniline of formula VIII with allyl alcohol of formula VII in presence of Nitrous acid, Palladium catalyst and inert solvent to obtain 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III.

3-(3-trifluoromethyl phenyl) propanaldehyde of formula (III) prepared by the any of the processes described or exemplified in the present application or according to the procedures known in art can be optionally converted to its bisulphite adduct by treating 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III with a metal bisulphite to enhance the purity.

The regio isomer formed during preparation of 3-(3-trifluoromethyl phenyl) propanaldehyde during the coupling allyl alcohol of formula VII with 3-trifluormethyl aniline of formula VIII (like in Heck Matsuda reaction), can be eliminated through this adduct formation, since the regio isomer will not take part in the adduct formation with metal bisulphite.

Metal bisulphites that can be used for the preparation of this bisulphite adduct include, but not limited to: alkaline metal bisulphites such as sodium bisulphite, potassium bisulphite or the like.

The bisulphite adduct can be prepared, by treating 3-(3-trifluoromethyl phenyl) propanaldehyde of formula III with metal bisulphite in the mole ratio ranging from about 1: 5 to about 1: 20.

The solvent that can be used for the above bisulphite adduct formation includes, but not limited to C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, aliphatic or cyclic C2-C6 ethers, C2-C6 nitriles, halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones, water or mixtures thereof.

The suitable temperature for the bisulphite adduct formation, may range at about 30°C to boiling temperature of the solvent used. The process for the preparation of bisulphite adduct can be carried out for time sufficient for its formation.

The bisulphite adduct prepared by the above process, can either be used

(i) directly with (R)-1- naphthyl ethyl amine of formula (IV) in the presence a base to obtain Imine intermediate of formula V or Cinacalcet free base or its HC1 salt according to the any of the procedures described or exemplified in the present application or the procedures known in art or

(ii) the bisulphite adduct can be treated with a base to obtain 3-(3-trifluoromethyl phenyl) propanaldehyde and then it is reacted with (R)-1- naphthyl ethyl amine of formula (IV) to obtain the Imine intermediate of formula V or Cinacalcet free base or its HC1 salt according to the any of the procedures described or exemplified in the present application or the procedures known in art.

The bisulfate adduct prepared according to the above process, can be purified by the processes known in art such recrystallization, slurrying, chromatography and the like before using it.

In the sixth aspect, the present application provides process for the preparation of Cinacalcet HC1 by combining Cinacalcet free base with hydrochloric acid in inert solvent and optionally re-crystallizing Cinacalcet HC1 in inert solvent.

In an embodiment of this aspect, Cinacalcet HC1 can be prepared by any of the procedures known in the art or include, but not limited to: combining solution of Cinacalcet free base with hydrochloric acid.

In embodiments of this aspect, Cinacalcet base can be combined with any source of hydrogen chloride known to person skilled in art. Such sources include, but not limited to: Concentrated HC1, diluted aqueous or organic solution of HC1, gaseous HC1 or salts containing hydrochloric acid like ammonium chloride to obtain Cinacalcet hydrochloride.

In embodiments of this aspect, the reaction of Cinacalcet free base with hydrochloric acid can be carried out with hydrochloric acid in an amount sufficient to react substantially with the entire Cinacalcet base. Preferably the reaction can be carried out in the mole ratio of 1: 0.8 to 1:1.2 of free base and acid respectively.

Inert solvent that can be used for the preparation of Cinacalcet HC1 includes, but not limited to C5-C8 aliphatic or aromatic hydrocarbons like Hexane, Heptane, benzene, toluene, C3-C6 esters like ethyl acetate, methyl acetate, butyl acetate, aliphatic or cyclic C2-C6 ethers like dimethyl ether, diethyl ether, methyl ter. butyl ether, di isopropyl ether, C2-C6 nitriles like acetonitrile, propionitrile, halogenated hydrocarbons like dichlormethane, dichloroethane, chloroform, tetra chloromethane, C1-C6 alcohols, methanol, ethanol, propanol, isopropyl alcohol, butanol, pentanol, C3-C6 ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof.

In an embodiment of this aspect, Cinacalcet free base can be prepared by any of the processes disclosed in the present application.

In an embodiment of this aspect, Cinacalcet free base and solvent can be combined to obtain a solution optionally by heating. Acidifying this solution with hydrochloric acid slowly in an amount sufficient to react with substantially the entire Cinacalcet base and continue stirring for sufficient time for the formation of Cinacalcet HC1 salt. Combining this reaction mixture with antisolvent and continue stirring for sufficient time to precipitate HC1 salt of Cinacalcet. Optionally cooling the reaction mass before further stirring to completely precipitate HC1 salt of Cinacalcet.

In an embodiment, precipitation of Cinacalcet HC1 can be effected either (i) by adding antisolvent to the solution containing Cinacalcet HC1 or (ii) by adding the solution containing Cinacalcet HC1 to antisolvent.

In an embodiment of this aspect, Cinacalcet or its HC1 salt obtained by the processes described herein can be purified by any method known in the art such as re-crystallization from single or mixture of solvents; solvent-anti solvent technique; acid base treatment; slurring in single or mixture of solvents; or chromatography to improve its purity. Any of the inert solvents described in the present application, can be used for the purification.

In an embodiment of this aspect, Cinacalcet HC1 prepared by the any of the processes of the present application can be further re-crystallized in inert solvent, optionally involving carbon treatment.

Inert solvent that can be used for the re-crystallization of Cinacalcet HC1 includes, but not limited to C5-C8 aliphatic or aromatic hydrocarbons like Hexane, Heptane, benzene, toluene, C3-C6 esters like ethyl acetate, methyl acetate, butyl acetate, aliphatic or cyclic C2-C6 ethers like dimethyl ether, diethyl ether, methyl ter. butyl ether, di isopropyl ether, C2-C6 nitriles like acetonitrile, propionitrile, halogenated hydrocarbons like dichloromethane, dichloroethane, chloroform, tetra chloromethane, C1-C6 alcohols, methanol, ethanol, propanol, isopropyl alcohol, butanol, pentanol, C3-C6 ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, water or mixtures thereof.

In embodiments of this aspect, precipitation of the Cinacalcet HC1 directly from the reaction mass or in purification step can be effected by employing any of the techniques known to a person skilled in art that include, but not limited to: cooling the reaction mass, removal of solvent, combining with an antisolvent, etc., or combination of techniques thereof.

Precipitation by cooling crystallization includes, but not limited to: crystallization by controlled cooling, crash cooling of the reaction mass and the like.

Precipitation by solvent removal includes, but not limited to: solvent evaporation under atmospheric pressure or under reduced pressure / vacuum, spray drying, freeze drying and the like.

Precipitation by combining reaction mass with an antisolvent wherein antisolvent is a solvent in which Cinacalcet HC1 has low solubility. Antisolvents include, but not limited to: C2-C6 aliphatic or cyclic ethers; C5-C8 aliphatic or aromatic hydrocarbons; water or mixtures thereof.

In an embodiment, precipitation of HC1 salt of Cinacalcet can be effected by combining the solution containing Cinacalcet HC1 at high temperature with antisolvent followed by cooling the reaction mass.

In embodiments, Cinacalcet HC1 can be isolated by employing any of the techniques known to a person skilled in art. Techniques for the isolation of Cinacalcet HC1 include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.

The Cinacalcet hydrochloride isolated by the processes of application can be subjected to drying at suitable temperatures, such as about 40-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.

The processes of the present application produces Cinacalcet HC1 having particle size of about D90 less than about 100 microns, or less than about 50 microns and D50 less than about 50 microns, or less than about 25 microns, or less than about 12 microns.
The processes of the present application produces Cinacalcet HC1 having bulk density of about more than 0.1 gm/cc, or more than 0.15 gm/cc, or more than 0.20 gm/cc and tab density of about more than 0.25 gm/cc, or more than 0.30 gm/cc or more than 0.35 gm/cc.

Cinacalcet hydrochloride obtained according to processes of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions.

In an aspect, the present application provides pharmaceutical compositions containing a therapeutically effective amount of Cinacalcet hydrochloride prepared by the processes of application, together with one or more pharmaceutically acceptable excipients.

The processes of present application produces Cinacalcet hydrochloride with a chemical purity of greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.9% as determined using high performance liquid chromatography (HPLC).

The processes of present patent application provide Cinacalcet HC1 substantially free of starting materials, other optical or regio isomers and bye products.

The processes of present patent application provide Cinacalcet HC1 having each of the impurities selected from (R)-(+)-1-(1-Naphthyl) ethyl amine, (R)-N-(1-(naphthalene -2-yl ) ethyl) -3-(3-(trifluoromethyl) phenyl)propan-1 amine hydrochloride (Regio isomer of Cinacalcet HC1), (S)-N-((R)-1-(naphthalene -1-yl ) ethyl) -2-(3-(trifluoromethyl) phenyl)propan-1 amine (Diastereo isomer-1) and (R)-N-((R)-1-(naphthalene -1-yl ) ethyl) -2-(3-(trifluoromethyl) phenyl)propan-1 amine (Diastereo isomer-2) in an amount less than about 0.1%, or less than about 0.05%, or less than about 0.01% as determined using high performance liquid chromatography (HPLC).

(R)-N-(1-(naphthalene-2-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (regio isomer of Cinacalcet HC1)

(S)-N-((R)-1-(naphthalene-1-yl)ethyl)-2-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (Diastereo isomer-1)

(R)-N-((R)-1-(naphthalene-1-yl)ethyl)-2-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (Diastereo isomer-2)

The Regio isomer of Cinacalcet HC1, Diastereo Isomer-1 and Diastereo Isomer-2 are not known earlier. The inventors of the present application surprisingly found that these impurities may be formed when Cinacalcet hydrochloride is produced as per the methods known in the art or as per the methods described according to the present application. However, these impurities can be reduced to less than 0.1% when produced and purified as per the methods described in the present application.

The processes of present patent application provide Cinacalcet HC1 having any other unknown single maximum impurity less than about 0.1%, or less about 0.05% or less than about 0.02% as determined using high performance liquid chromatography (HPLC).

The Regio isomer of Cinacalcet HC1 can be controlled by controlling the impurity, 1-(2-Naphthyl) ethyl amine in (R)-(+)-1-(1-Naphthyl) ethyl amine. The impurity can be reduced by purifying the (R)-(+)-1-(1-Naphthyl) ethyl amine by the methods known in the art such as recrystallization, slurrying or column chromatography etc. in an amount less than about 0.15%, or less than about 0.05%, or less than about 0.01%. Controlling of 1-(2-Naphthyl) ethyl amine in (R)-(+)-1-(1-Naphthyl) ethyl amine leads to the production of Cinacalcet hydrochloride having Regio isomer of Cinacalcet HC1 in an amount less than about 0.1%, or less than about 0.05%, or less than about 0.01%.

The purity of Cinacalcet HC1 and its related substances or its impurities may be analyzed using various methods. A representative useful HPLC method is described below.

Chromatographic conditions: A liquid chromatograph equipped with variable wavelength detector and integrator.

Column : Symmetry shield RP 18, 250 x 4.6 mm, 5.0µm
Flow : 1.5 ml/min
Column Oven Temperature: 35°+2°C.
Wave length : 223 nm
Injection volume : 10 µL
Run Time : 65min
Elution : Gradient
Diluent : Acetonitrile: Water in 1: 1 ratio

Mobile Phase preparation:

Buffer: Dissolve 0.02M of Potassium dihydrogen phosphate in 1000 ml Water, add 1.0ml of triethylamine and mix well. Adjust the pH to 6.6 with dilute Phosphoric acid.

Mobile phase A: Mixture of Buffer and Acetonitrile in the ratio of 80 : 20.
Mobile phase B: Mixture of Acetonitrile and Buffer in the ratio of 80: 20.

Gradient program:
Time in min 0.01 2.5 25 30 60 60.1 65
% Mobile phase-B 55 55 80 95 95 55 55

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like. The term "reacting" is intended to represent bringing the chemical reactants together under conditions that cause the chemical reaction indicated to take place.

An “inert solvent” is an solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.

An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.

A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example-1: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde

Mixture of 1- bromo-3-trifluormethyl benzene (5.0 g) and N,N - dimethyl formamide (80 mL) are cooled to 0°C and added allyl alcohol (1.93 g), tetra butyl ammonium bromide (10.7 g), NaHCO3 (4.6 g) and Pd(OAc)2 (0.25 g) at 0°C. After stirring for 10 min, slowly heated the reaction mixture to 55°C and maintained for 2hours at same temperarture and then stopped heating the reaction mixture after completion of reaction. Added water (240 mL) at 30°C and extracted the compound into ethyl acetate (4x100 mL). Washed the combined ethyl acetate layer with water (3x240 mL) and then with saturated NaCl solution (100 mL). Separated the ethyl acetate layer and distilled the solvent under vacuum at 30-40°C to obtain the title compound. Yield: 2.3 g.

Example-2: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde

Mixture of 3-trifluoromethyl aniline (5.0 g) and acetonitrile (50 mL) are stirred for 5 min at 28°C and cooled to 10°C. Sulfuric acid solution (3.47 mL sulfuric acid in 34.7mL water) is added slowly at 10°C for 3 min. To the above mixture Pd(OAc)2 (69.6 mg) in acetonitrile (25 mL) is added at 10°C and then Sodium nitrite solution (2.56 g of Sodium nitrite in 5.12 mL of water) is added at 10-15°C in 7 min to the reaction mixture and maintained under stirring for 5 min at same temperature. Allyl alcohol (2.16 gm) is slowly added to the reaction mixture at 14°C and maintained for 30 min at 14-20°C. Then the reaction mass is quenched with water (50 mL) at 25°C after completion of reaction and extracted with ethyl acetate (50 mL). This ethyl acetate layer is washed with saturated sodium chloride solution (2x50 mL) and distilled the solvent at 38°C under vacuum to obtain title compound. Yield: 5.5 g; Purity: 70.16% by HPLC.

Example-3: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde

Mixture of 3-trifluoromethyl aniline (10.0 g) and acetonitrile (100 mL) are stirred for 5 min at 27°C and sulphuric acid solution (12.7 g of sulphuric acid in 127 mL of water) is added at 27°C and maintained under stirring for 15 min at same temperature. Then added allyl alcohol (7.92 g) followed by addition of 5% Pd/carbon (5.0 g) in acetonitrile (50 mL) at 27°C. After 10 min of stirring at same temperature sodium nitrite solution (5.3 g in 12 mL of water) is charged at 27°C and stirred for about 45 min at same temperature. Then the reaction mass was warmed to 44°C and stirred for 30 min at about 38-44°C and then stirred for 15.5 hours at 30°C. Then the reaction mass was quenched with water (150 mL) and extracted with ethyl acetate (150 mL). Separated the organic layer and again extracted the aqueous layer with ethyl acetate (150 mL). Washed the combined organic layer with water (150 mL) and distilled the separated organic layer completely under vacuum at 50°C to obtain the title compound. Yield: 11.2 g; Purity: 57.89% by HPLC.

Example 4: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde

Mixture of 3-(3-trifuoromethyl phenyl) propanol (50 g) in toluene (250 mL) is cooled to 10°C and added TEMPO (191.3 mg), potassium bromide (582.8 mg) at 10°C and sodium bicarbonate solution ( 102.85 g in 1028.5 mL water) at 5°C to the reaction mixture and further cooled it to -2° and added 11% NaOCl solution (232 mL) in 5 min at -2° to -4°C and stirred the reaction mass for 30 min at same temperature. Stopped stirring and quenched the reaction mass with 10% Na2S2O3 (500 mL) at -2° and then stirred for 2min. Separated the organic layer and extracted the aqueous layer with toluene (150 mL). Combined the above organic layers and washed with water (500 mL) and then with 10% sodium chloride solution (500 mL) and separated the toluene solution containing the title compound. Yield (based on assay): 36.68 g; solution assay: 10.15%; solution Purity: 95.39%.

Example-5: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde bisulphite adduct

Combined 3-(3-trifuoromethyl phenyl) propanaldehyde (10 g) and Toluene (100 mL) at 27°C and stirred for 10 min. Then a mixture of sodium bisulphite (71.0 g) and water (100 mL) is added to the above reaction mixture at 27°C and heated to 102°C and then stirred this reaction mixture at same temperature for 1.5 hr. Cooled the reaction mixture to 2°C in 45 min and stirred at 2-3°C for 1 hr. Filtered the solid and washed with toluene (2x20 mL). Wet compound is dried at 50°C under vacuum for about 10 hours to obtain the title compound. Yield: 14.1 g; Purity: 93.38% by HPLC.

Example-6: Preparation of Cinacalcet HC1

To the toluene solution (900 mL) containing 3-(3-trifuoromethyl phenyl) propanaldehyde (50 g), (R)-1- naphthyl ethyl amine (42.28 g) is added at 27°C and cooled to 20°C and stirred for about 3 hr at same temperature. Added methanol (50 mL) followed by sodium boro hydride (18.77gm) to the reaction mixture at 20°C and stirred for about 3.5 hr at 20°C. Added water (500 mL) to the reaction mixture and separated the organic layer and extracted the aqueous layer with toluene (250 mL). Combined the organic layers and washed with water (2x500 mL), then the organic layer is separated and distilled the solvent at 55°C to obtain crude product.

Ethyl acetate (85 mL) is added to the above crude product and heated to 55°C. To this mixture, concentrated hydrochloric acid (26.18 mL) is added and stirred at 55°C for 40 min. Di isopropyl ether (850 mL) is added and stirred for 25 min at 55°C, then water (500 mL) is added at same temperature and stirred for 30min. Cooled the reaction mass to 30°C and stirred for 1.5 hr at same temperature. Filtered the solid and washed with Di isopropyl ether (340 mL). Wet compound is dried at 67°C under vacuum for about 10 hours to obtain the title compound. Yield: 77.5 g; Purity: 99.3% by HPLC.

Example-7: Preparation of Cinacalcet

3-(3-trifuoromethyl phenyl) propanol ( 5 g) , (R)-1- naphthyl ethyl amine (4.3 g) and toluene ( 50 mL) are charged into a round bottom flask at 27°C and stirred for 5-10 minutes at same temperature. Charged RuCl2(PPh3)3 (0.23 g) to the reaction mass at 27°C heated to reflux temperature (110°C) and stirred at reflux for 8 hours for the completion of reaction and then stopped heating the reaction mass. Filtered the reaction mass on hyflo bed and washed the filtrate four times with water (4 x 50 mL) and separated the organic layer. Organic layer is further washed with brine solution (25 mL) and separated. The solvent from the organic layer is distilled completely at 45°C under vacuum to obtain the title compound. Yield: 7.3 g.

Example-8: Preparation of Cinacalcet

To the mixture of 3-(3-trifuoromethyl phenyl) propanaldehyde (2 g) and dichloromethane (10 mL), (R)-1- naphthyl ethyl amine (1.6 g) was added at 27°C and stirred for 10 min at same temperature. To the above reaction mixture Iron triflate [Fe(OTf)3] (0.035 g) is added at 27°C and then after 5 min, sodium borohydride (0.37 g) is added and stirred for 10 min at same temperature. Then methanol (2 mL) is added to the reaction mixture at 27°C and stirred for another 10 min for completion of reaction. The reaction mass is distilled completely under vacuum at 40°C to isolate crude mass. Then 5% NaHCO3 solution (20 mL) is added to the crude and extracted with dichloromethane (20 mL). The organic layer is then washed with 5% NaCl solution (20 mL) and dried with sodium sulfate (2 g). Dried organic layer is then completely distilled under vacuum at 42°C to obtain the title compound. Yield: 3.19 g, Purity: 77.91% by HPLC.

Example-9: Preparation of Cinacalcet

To the pre-cooled mixture of 3-(3-trifuoromethyl phenyl) propanaldehyde bisulphite adduct (3.0 g) and Toluene (30 mL) at 20°C, (R)-1- naphthyl ethyl amine (1.54 g) is added and stirred for 3 hours 50 min at same temperature. Methanol (3.0 mL) is added at 20°C after checking for the absence of starting material and then sodium borohydride (0.68 g) is added lot wise at 20-22°C in 15 min. The reaction mass is stirred for 2.5 hours at 22°C and quenched the reaction mass with water (30 mL) at same temperature after completion of reaction. Organic layer is separated after stirring for 10 min and extracted the aqueous layer with toluene (15mL). Washed the combined organic layer with water (2x 15 mL) and distilled the solvent from the organic layer completely under vacuum at 50°C to obtain the title compound. Yield: 4.5 g; purity: 69.88% by HPLC.

Example-10: Preparation of Cinacalcet

To a stirred mixture of methylene dichloride (30 mL) and 3-(3-trifuoromethyl phenyl) propanaldehyde bisulphite adduct (3 g) under nitrogen atmosphere, Triethylamine (1.08 g) is added at 28°C and stirred for 30 min at same temperature. (R)-1- naphthyl ethyl amine (1.84 g) is added to the reaction mass and stirred for 1 hour at 28°C. And then sodium triacetoxy borohydride (2.9 g) is added at 28°C and stirred for 2 hours 10 min at same temperature and diluted the reaction mass with ethyl acetate (15 mL) after completion of reaction and washed the reaction mass with IN NaOH solution (20 mL) and then with saturated NaCl solution (30 mL). Distilled the organic layer at 40°C under vacuum to obtain the title compound. Yield: 3.15 g; Purity: 57.28% by HPLC.

Example-11: Purification of Cinacalcet HC1

A mixture of acetonitrile (148.8 mL) and water (781.2 mL) at 28°C are combined with Cinacalcet HC1 (93 g) and heated to 75°C to obtain clear solution. Stirred the solution for 35 min at same temperature and then cooled to 29°C in 1 hr. Stirred for an hour at 28-29°C and filtered the solid and washed with water (465 mL). Wet compound is dried at 70°C under vacuum for about 10 hours to obtain the title compound. Yield: 68.5 g; Purity: 99.80% by HPLC.

Example-12: Preparation of Cinacalcet

A mixture of 3-(3-trifuoromethyl phenyl) propanaldehyde (10 g) and toluene (80 mL) are cooled to -2°C and added (R) -1-Naphthyl ethyl amine (10.16 g). Stirred the reaction mass at 1-3°C for 45 min and added methanol (10 mL) at 3°C. Cooled the reaction mass further to -8°C and added sodium borohydride (4.33 g) lot wise. Stirred the reaction mass for 75 min at -3°C and slowly added water (100 mL) to the reaction mass. Separated the organic layer and extracted the aqueous layer with toluene (50 mL). Washed the combined organic layer with water (2X100 mL) and then with brine solution (100 mL). Separated the organic layer and distilled the solvent completely at 55°C to obtain title compound. Yield: 19.1 g.

Example-13: Preparation of Cinacalcet HC1

A mixture of Cinacalcet (20 g) and ethyl acetate (22 mL) are heated to 57°C and added Con. HC1 (6.7 mL). Stirred the reaction mass at 57-58°C for 40 min and slowly added to pre-heated Di isopropyl ether (400 mL) at same temperature. Stirred the reaction mass at 58-60°C for 40 min and added water (200 mL) at same temperature. Stirred the reaction mass at 57-60°C for 45 min and cooled the reaction mass to 28°C. Stirred the reaction mass at same temperature for 2 hours and filtered the solid. Washed with water (20 mL) and then with Di isopropyl ether (80 mL). Wet compound is dried at 70°C under vacuum for about 6 hours to obtain the title compound. Yield: 15.2 g; Purity: 99.40 by HPLC.

Example-14: Purification of Cinacalcet HC1

A mixture of acetonitrile (32 mL) and water (68 mL) at 28°C are combined with Cinacalcet HC1 (20 g) and heated to 64°C and added carbon (1 g). Heated the reaction mass to 85-86°C and stirred the reaction mass for 75 min at same temperature. Filtered the reaction mass on Hy-flo bed and added water (100 mL) to the filtrate. Heated the reaction mass to 87°C and stirred for about 1 hour at same temperature. Cooled the reaction mass to 3°C in 70 min and stirred for 2.5 hours at same temperature and filtered the solid and washed with water (100 mL). Wet compound is dried at 65°C under vacuum for about 12 hours to obtain the title compound. Yield: 18.1 g; Purity: 99.96% by HPLC.

Example-15: Preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde

A mixture of 3-trifluoromethyl aniline (200 g) and acetonitrile (2000mL) are cooled to 0°C and slowly added Sulfuric acid solution (255.6 g in 1250 mL of water) in 20 min at 0-1°C. Stirred the reaction mixture for 10 min at 0-2°C and slowly added sodium nitrite solution (105.4 g in 210 mL of water) in 45 min at 0-2°C. Stirred the reaction mixture for 1 hour and added a mixture of palladium acetate (1.39 g) and acetonitrile (600 mL) to the reaction mixture at 15°C and stirred for 10 min at same temperature. Added allyl alcohol (72 g) in 10 min at 17-18°C and stirred the reaction mixture for about 3 hours at 18-19°C. Separated the organic layer and extracted the aqueous layer with toluene (2x1000 mL). Washed the organic layer with water (2000 mL) and saturated brine solution (2x2000 mL). Added sodium bisulfate solution (775 g in 852.5 mL water) to the reaction mixture at 27°C and stirred at same temperature for 15 hours. Cooled the reaction mixture to 18°C and filtered the solid and Washed with toluene (600 mL). The wet solid was stirred in Toluene (600 mL) at 27°C for 60 min and filtered and washed with toluene (600 mL). Stirred the wet solid with water (2000 mL) and Dichloromethane (600 mL) for 10 min at 25°C and separated Dichloromethane layer. Washed the aqueous layer with Dichloromethane (600 mL) and separated Dichloromethane layer. Added 20% NaOH solution (200 mL) to adjust the pH to 12-13 and extracted the aqueous layer with Dichloromethane (1000 mL). Washed the organic layer with water (1000 ml) and then with brine solution (500 mL). Distilled the solvent completely at 39°C under vacuum to obtain the title compound. Yield: 110.4 g.

CLAIMS

We Claim

1. A process for the preparation of Cinacalcet or it HC1 salt, which comprises

a) reacting 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) or its bisulphite adduct with (R)-1- naphthyl ethyl amine of formula (IV) to obtain imine compound of formula (V);

b) reduction of imine compound with a reducing agent to obtain Cinacalcet free base;

c) converting the Cinacalcet free base to its hydrochloride salt and

d) optionally, re-crystallizing Cinacalcet HC1.

2. A one pot process for the preparation of Cinacalcet or it HC1 salt, which comprises

a) reacting 3-(3-trifuoromethyl phenyl) propanol of formula (II) with (R)-1- naphthyl ethyl amine of formula (IV) in the presence of a Transition metal complex to obtain Cinacalcet.

b) optionally, converting Cinacalcet free base to its hydrochloride salt.

3. A process of claim 2, wherein transition metal complex is selected from the group consisting of RuCl2 (PPh3)3, RHC12(PPh3)3, IrCl2(PPh3)3, PdCl2, Pd(OAc)2, 5% Pd/C, Pd(dba)2, NiCl2 and Cu2O.

4. A one pot process for the preparation of the Cinacalcet or its HC1 salt, which comprises:

a) reacting a 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) with (R)-1- naphthyl ethyl amine of formula (IV) in the presence of metal triflate to obtain Cinacalcet free base and

b) optionally, converting Cinacalcet free base to its hydrochloride salt.

5. A process of claim 4, wherein metal triflate is selected from the group consisting of Iron triflate (Fe (OTf)3)), Scandium triflate and Aluminium triflate.

6. A process for the preparation of 3-(3-trifuoromethyl phenyl) propanaldehyde compound of formula (III) comprising reaction of 1- bromo-3-trifluormethyl benzene of formula VI with allyl alcohol of formula VII in presence of Palladium catalyst.

7. A process for the preparation of Cinacalcet or its HC1 salt, comprising

a) preparing 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) according to the process of claim 6.

b) reacting of 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) with (R)-1- naphthyl ethyl amine of formula (IV) to obtain imine compound of formula (V)

c) reducing of imine compound of formula (V) with a reducing agent to obtain Cinacalcet free base; and

d) optionally, converting Cinacalcet free base to its hydrochloride salt.

8. A process for the preparation of 3-(3-trifluoromethyl phenyl) propanaldehyde of formula (III) comprising reaction of 3-trifluoromethyl aniline of formula VIII with allyl alcohol of formula VII in presence of Nitrous acid, and Palladium catalyst

9. A process of claim 8, wherein Palladium catalyst is selected from group consisting of Pd (OAc)2, Pd (Cl2) and Pd/C.

10. A process for the preparation of Cinacalcet or its HC1 salt, comprising

a) preparing 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) according to the process of claim 8.

b) reacting of 3-(3-trifuoromethyl phenyl) propanaldehyde of formula (III) with (R)-1- naphthyl ethyl amine of formula (IV) to obtain imine compound of formula (V)

c) reducing of imine compound of formula (V) with a reducing agent to obtain Cinacalcet free base; and

d) optionally, converting Cinacalcet free base to its hydrochloride salt.