FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal of Formula Ilia.

The present invention relates to an improved process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propen-1 -ol (IVb).

The compounds of Formulae Tlla and IVb are key precursors in the preparation of Calcimimetic agent, Cinacalcet hydrochloride of Formula I.

BACKGROUND OF THE INVENTION

N-[(lR)-l-(l-Naphthyl)ethyl]-3-[3-(trifluoromethyI)phenyl]propan-l-amine hydrochloride is generically known as Cinacalcet.

Cinacalcet is a second generation calcimimetic ag'^ni, which decreases the secretion of parathyroid hormone (PTH) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH are an indicator of secondary hyperparathyroidism associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.

Cinacalcet is marketed under the name Scnsipar in the US and, in Europe, it is marketed under the name Mimpara and Parareg . It has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.

NPS Pharmaceuticals disclosed generically Cinacalcet and its pharmaceutically acceptable salts as calcium receptor-active molecules in US 6,011,068, US 6,313,146 and disclosed specifically in US 6,211,244. The above patents do not provide any examples for the preparation of Cinacalcet.
According to the generic process disclosed in US '244 Cinacalcet may b'e prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylamine (V) with l-acetylnaphtha!ene (VI) in the presence of titanium (IV) isopropoxide, to produce an imine (VII) , which is further reacted with ethanolic or methanolic sodium cyanoborohydride to produce racemic Cinacalcet (la), and resolution of the racemic Cinacalcet by chiral liquid chromatography to produce Cinacalcet (lb).


us '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethyIcinnamonitrile (VIII) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (IX), which is further reacted with (R)-l-(l-naphthyl)ethylamine (X) to produce an imine (Vila), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyI-N-((R)-1 -(naphthalen-1 -yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) and reducing unsaturated Cinacalcet to produce Cinacalcet (lb).


Similarly, using the process disclosed in US '244, as well as Drugs of the Future 2002, 27(9), 831-836, Cinacalcet may be prepared by reacting (R)-l-(l-naphthyl)ethylamine (X) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (HI) in the presence of titanium (IV) isopropoxide to produce intermediate compound imine (VII), which is further reduced usine ethanolic sodium cvanoborohvdride.


The above processes involve the use of flammable and highly toxic reagents, such as titanium (IV) isopropoxide, which is highly hygroscopic, expensive, toxic and ethanohc or methanolic sodium cyanoborohydride, which is highly toxic and flammable, and not environmentally friendly, making the process difficult on commercial scale.

US 7,250,533 discloses a process for the preparation of Cinacalcet, wherein 3-[3-trifluoromethyi)phenyl]propanol (IV) is converted to a compound with a good leaving group (IVa), which is further condensed with (R)-l-(l-naphthyI)ethylamine (X) to produce Cinacalcet (lb). The reagents described in the patent, which have good leaving groups are thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide.

us 7,393,967 discloses a process for the preparation of Cinacalcet, which comprises, condensing 3-bromotrifluorotoluene (XII) with allyl amine (XITI) to produce 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II), which is flirther reduced in presence of ?d/C to produce Cinacalcet (lb).

us 2007/0259964 Al discloses a process for the preparation of Cinacalcet (lb), wherein 3-(trifluoromethyl)cinnamic acid (XI) is reduced to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid (XIa) followed by converting to corresponding reactive derivative (XIV), which is further condensed with (R)-l-(l-naphthyl)ethylamine (X) in the presence of a base to produce N-[(1S)-1-(1-naphthyl)ethyi]-3-[3-trifluoromethyl)phenyI]propanr;rnide (XV) andr-educing the N-[(lS)-l-(l-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XV) to produce Cinacalcet (lb).


The major disadvantage with the above process is the formation of (~ 2%) desfluoro Cinacalcet (Ic), due to the use of strong reducing agent such as BH3. The separation of undesired desfluoro Cinacalcet (Ic) from Cinacalcet (lb) is difficult and required repeated crystallization, resulting in a significant loss of yield.

WO 2008/068625 A2 discloses condensation of 3-[3-
(trifluoromethyl)phenyl]propionaldehyde (III) with (R)-I-(l-naphthyl)ethylamine (X) in the absence of titanium isopropoxide to produce Cinacalcet (lb).

us 7,294,735 discloses a process for the purification Cinacalcet hydrochloride by treating Cinacalcet base having 3 to 6% of 3-(3-(trifluoromethyl)phenyl)propyl-(R)-l-(naphthalen-l-yl)ethyl carbamate (Cinacalcet carbamate) (XVI).in a solvent selected from acetone, C2-8 ethers and water with hydrochloric acid.

Tetrahedron Letters (2004), 45, 8355. discloses a process for the preparation of precursor
Compound of the Cinacalcet, namely 3-[3- (trifluoromethyl)phenyl]propionaldehyde (III) by reducing3-(trifluoromethyl)cinnamic acid (XI) to the corresponding alcohol (IV) followed by Swern oxidation.
The process is as shown in Scheme -VIII below:


EP 0 194 764 Bl discloses a process for the preparation of 3-[3-(trifluoromethyl)-phenyljpropionaldehyde (III) by reacting 3-trif1iioromethylbromobenzene (XII) with propargyl alcohol in presence of bis(triphenylphosphine)palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to produce the corresponding alcohol (IV), which is further oxidised by a Swern oxidation.

The above processes involve the use of reagents, such as oxalyl chloride and dimethyl sulfoxide in the Swern oxidation, which are unstable and does not result in high yield, making the process difficult on industrial scale.

Further, the major disadvantage with the above processes is the formation of an undesired desfluoro compound (Illb) due to the use of strong reducing agent lithiumaluminum hydride (LiAIH4). The separation of undesired desfluoro compound (Illb) from 3-[3-rifluoromethyl)phenyl]propionaldehyde(111), and 3-[3- (trifluoromethyl)phenyl]propanoI (IV) is difficult. The final product Cinacalcet is therefore, strongly contaminated with undesired desfluoro Cinacaicet (- 2%) (Ic) and required repeated crystallization, resulting in a signiiicant loss of yield.

WO 2008/035212 A2 discloses a process for the preparation of 3-[3- trifluoromethyl)phenyl]propionaldehyde (III), by reacting 3-[3- trifluoromethyl)phenyl]propanol (IV) with sodium hypochlorite / 2,2,6,6,- tetramethy-l-piperidinyloxi free radical (TEMPO).

The process is as shown in Scheme -X below:

Hence, there is a need to develop a process, which provides 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia) and 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) with good yields on a commercial scale.
The present invention is specifically directed towards the process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia), which avoids very low temperature oxidation conditions (-70 to -80°C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).

The present invention also specifically directed towards the process for the preparation of 3-[3-(trifiuoromethyl)pheny!]-2-propen-l-ol (IVb) by reducing mixed anhydride of Formula (XVIII) in the absence of strong reducing agents.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and effective process for the preparation of 3-[3-(trifluoromethyl)pheny!]-2-propen-l-ol (IVb) with good yields on a commercial scale.


which comprises:
oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) with oxidizing agent in presence of nitroxyl compound £s a catalyst in the presence of solvent to produce 3-[3-(trifluoromethyl)phenyi]-2-propenal (Ilia).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the present invention provides an improved process for the preparation of 3-[3-(trifluoromethyl)pheny!]-2-propen-l-oi (IVb).

The process comprises, reacting 3-(trifluoromethyl)cinnamic acid (XI) with alkyl chloroformate in the presence of a suitable base and in a suitable solvent to produce a mixed anhydride (XVIII). The suitable base used in the reaction includes but are not limited to triethy! amine, isopropyl ethylamine, 4-(dimethylamino) pyridine, potassium carbonate. The solvent used in the reaction is ethyl acetate, tetrahydrofuran or toluene and the like. The most preferred solvent is toluene. The reaction may be performed at a temperature ranging from -20°C to about 35°C Sused oh tKe solvent or mixture of solvents used for the reaction. Alkyl chloroformate is added slowly in a drop-wise manner. Most preferably, this addition is while maintaining the reaction mixture at a temperature of about -20°C to about 5°C. The reaction mixture containing mixed anhydride (XVIII) is (optionally, the salts can be removed by washing with water at low temperature) filtered to remove residual salts and reagents. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce mixed anhydride (XVIII).

Reducing the mixed anhydride (XVIII) with a suitable reducing agent in a solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb). The suitable reducing agent is selected from sodium borohydride, zinc borohydride, calcium borohydride. Most preferred reducing agent is sodium borohydride. The solvent used in the reaction includes, but not limited to water, dioxane, toluene, THF or mixtures thereof. Most preferred solvent is THF. The reaction may be performed at a temperature ranging from -10°C to about 35°C based on the solvent or mixture of solvents used for the reaction. After the completion of reaction, as ascertained by the known methods such as HPLC, acetone is added to the reaction mass and extracted with a solvent selected from toluene, ethyl acetate, dichloromethane, hexane and the solvent is removed to produce 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb).

It has been observed that Cinacalcet prepared by using 3^[3-(trifluorcmethyl)phenyl]-2-propen-I-oI (IVb) prepared by above reaction conditions results in desfluoro Cinacalcet impurity (Ic) to a less than 0.03% by HPLC analysis.

According to another embodiment, the present invention also provides a process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Illa).

The process comprising, oxidizing 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) with oxidizing agent using nitroxyl compound as a catalyst in presence of solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia). The suitable oxidising agent used in the reaction is selected from sodium hypochlorite. The nitroxyl compound used is selected from 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO). Suitable solvent is inert organic solvent selected from acetonitrile, alcohols such as methanol, ethanol, n-propanol, isopropanol, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane, aromatic solvents such as toluene, halogenated solvents such as dichloromethane, dichloroethane, chloroform, esters such as ethyl acetate, butyl acetate, isopropyl acetate or ethers such as diethyl ether, tetrahydrofuran or tert-butyl methyl ether and/or mixtures thereof. Preferably, the solvent is MDC or acetonitrile. Preferably, the oxidation reaction is performed using between approximately 0.9 to approximately 2.0 moles of sodium hypochlorite per mol of 3-[3-(trifluoromethy])phenyl]-2-propen-l-ol (IVb), preferably approximately 1.05 moles. It was found to be advantageous to add the sodium hypochlorite in portions to the reaction mixture. After addition of sodium hypochlorite, acid is added to maintain the pH of the reaction mixture pH of 8-9.5. The acid is selected from aqueous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonic acid, trifluoroacetic acid, and acetic acid. More preferably, aqueous HCl is added.

Oxidation reaction is conducted using a range of temperatures of approximately 0°C to approximately 25°C and for a time of approximately 10 to approximately 60 minutes. More preferably below 15°C, and for a time of r.ppfoximately 20 to approximately 60 minutes. 3-[3-(trifluoromethyl)phenyl]-2-propenal (llla) produced in the above reaction is isolated from the reaction mass by diluting the reaction mass with a solvent selected from dichloromethane, toluene and water followed by layer separation and solvent removal.

The major advantage realized with the process (oxidation) of the present invention is that it avoids very low temperature oxidation conditions (-70 to -80°C) as well as the unpleasant odors associated with the prior-art procedures (Swern oxidation).

In another embodiment, the present invention also relates to the use of above compounds 3-[3-(trifluoromethyl)phenyl]-2-propen-1 -ol (IVb) and 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia) to produce Cinacalcet hydrochloride.

3-(3-(Trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyi)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ila) can be prepared by reductive amination of 3-[3-(trifluoromethy!)phenyl]-2-propenal (Ilia) with (R)-l-(l-naphthy!)ethylamine (X), in the presence of a reducing agent selected from sodium triacetoxyborohydride, sodium cyanoborohydride'.:(NaBH3CN) in a
solvent selected from ethyl acetate, tetrahydrofliran, isopropyl acetate, acetonitrile to produce 3-(trif!uoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l- amine (unsaturated Cinacaicet) (II). The reaction may be performed at a temperature ranging from about 0°C to about 50°C based on the solvents used for the reaction. The above reaction is conducted in presence of an acid selected from acetic acid. The reaction mixture containing the 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacaicet) (11) is cooled and residual salts and reagents are filtered from the reaction mixture. The filter cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce crude 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacaicet) (II).

Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-1 -(naphthalen-1 -yl)ethyl)prop-2-en-1-amine (unsaturated Cinacaicet) (II) thus ohtfinsd may be recoV's^red from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C4-8 ethers, chlorinated solvents, C3.6 esters, C5.8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof
3-(3-(Trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-y!)ethyl)prop-2-en-l-amine (unsaturated Cinacaicet) (II) produced by any of the above methods is treated with hydrochloric acid in a solvent selected from acetonitrile, THF, ethers, ethylacetate, methyl isobutyl ketone (MIBK), ketone, toluene to produce hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacaicet hydrochloride) (Ila), which is isolated by evaporating the solvent or precipitation of compound from the reaction mixture, by cooling the reaction mixture, followed by addition of an organic solvent.

Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-1-amine hydrochloride (unsaturated CInacalcet hydrochloride) of Formula (Ila) can also be prepared by converting 3-[3-(trifluoromethyl)phenyl]-2-pr6pen-l-ol (IVb) into a good leaving group by reacting with a reagent containing the leaving group, which is selected from thionyl halide, aliphatic sulfonyl halide and aromatic sulfonyl halide. More preferably, the thionyl halide is either thionyl bromide or thionyl chloride, while the preferred aliphatic sulfonyl halide is methanesulfonyl chloride and the preferred aromatic sulfonyl halide is benzenesulfonyl chlorine, 4-nitr6benzene3ulfonyi chloride or p-toluenesulfonyl chloride.

The suitable inert organic solvents for the above reaction include but are not limited to halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform; ether, toluene and the like. The reaction may be performed at a temperature ranging from 0°C to about 35°C based on the solvent or mixture of solvents used for the reaction. The reagent containing the leaving group is added to the solution of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) in the organic solvent. More preferably, the reagent is added slowly in a drop-wise manner. Most preferably, this addition is while maintaining the reaction mixture at a temperature of about 0°C to about 10°C.

The reaction is carried out in presence or absence of a base. When the leaving group is sulfonyl chloride, the reaction is carried out in presence of a base. Preferably, the organic base is an amine, more preferably, triethylamine, diisbpropyicthylamine, and pyridine. The sufficient period of time necessary for obtaining compound (IVc) will depend on the parameters of the reaction. Preferably, maintaining the reaction mixture for about 4 to about 24 hours. More preferably, the reaction mixture is maintained for about 8 hour to about 15 hours.

The compound (IVc) obtained by the above process can be isolated by precipitation of compound from the reaction mixture or by removing the solvent from the reaction mixture.

The compound (IVc) is condensed with (R)-l-(l-naphthyl)ethylamine (X) in the presence of suitable base in a solvent to produce 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II). The suitable base used in the reaction is selected from an inorganic base such as alkali carbonate, more preferably, K2CO3, NaaCOa, CS2CO3, NaHCOs or KHCO3. The most preferred base is K2CO3. The solvent is an organ;? solvent selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone, more preferably acetonitrile. The reaction may be performed at a temperature ranging from about 25°C to about reflux temperature of the solvent or mixture of solvents used for the reaction. The reaction time is about 5 to about 24 hours, more preferably about !0 to about 20 hours. After completion of the reaction, filtering off the salts obtained in the reaction and evaporating to obtain a residue. The residue containing 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (IT) in a solvent selected from toluene, methyl isobutyl ketone (MIBK) is washed with acidic solution, followed by washing with sodium chloride solution and isolated 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-'l-amine (unsaturated Cinacalcet) (II) by removing the solvent.

Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (II) thus 'M-)ir''-nQd"ii'',ayhG ib<^mi'.r-^6 from the reaction mixture by extraction from the reaction mixture using a solvent selected from the group consisting of C4.8 ethers, chlorinated solvents, C3-6 esters, C5.8 cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof More preferably, the solvent is ethyl acetate, dichloromethane (DCM), toluene or mixtures thereof.

3-(3-(Trifluoromethy l)pheny 1-N-((R)-1 -(naphthalen-1 -yl)ethy l)prop-2-en-1 -amine (unsaturated Cinacalcet) (II) produced by any of the above methods is treated with hydrochloric acid in a solvent selected from acetonitrile, THF, ethers, ethylacetate, methyl isobutyl ketone (MIBK), ketone, toluene to produce hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethy!)prop-2-en-l-amine (unsaturated Cinacalcet hydrochloride) (Ha), which is isolated by evaporating the solvent or precipitation of compound from the reaction mixture, by cooling the reaction mixture, followed by addition of an organic solvent.

The process further comprises, reducing 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-1 -yl)ethy l)prop-2-en-1 -amine hydrochloride (unsaturated Cinacalcet hydrochloride) (Ila), preferably, by catalytic hydrogenation (i.e., with hydrogen in the presence of catalyst) to produce Cinacalcet hydrochloride (I). The hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(napnthaleri-l-yl)efhyl)pip-2-en-I-amine (unsaturated Cinacalcet hydrochloride) (Ila) may be dissolved in a lower alcohol selected from Cj-C4 aliphatic, straight chain or branched alcohol, and exposed to H2 pressure in the presence of a catalyst such as Pd/C or Pt02 or Raney nickel. Preferably, hydrogen is present at a pressure of about 1 atmosphere to about 1,000 psi. Typically, the hydrogenation is carried out over a period of about 1 to about 6 hours to produce Cinacalcet hydrochloride. The reaction mixture containing Cinacalcet hydrochloride is cooled and filtered. The filtered cake is then washed and the solvent is removed from the filtrate under reduced pressure to produce Cinacalcet hydrochloride, which is isolated by the addition of organic solvent selected from acetonitrile, ether, heptane, methyl isobuty! ketone (MIBK).

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLES:
Kvample 1
Stage-1:
Method a:

Preparation of 3-[3-(trifluoromethyl)phenyI]-2-propen-l-ol (IVb)
Ethyl chloroformate (78.05 g, 719 mmol) was slowly added to a mixture of 3-(trifluoromethyl)cinnamic acid (100 g, 463 mmol) and triethyiamine (56.1 g, 555 mmol) in toluene (800 ml) at ~5°C to -10°C and stirring was continued at 0°C for 3 hrs. The reaction mass was filtered to remove triethyiamine HCl salts and washed with toluene (200 ml). The filtrate was concentrated to produce mixed anhydride (133 g). Aqueous sodium borohydride solution (26.38 g, 694 mmol in water 82 ml) was added slowly to a mixture of mixed anhydride in dioxane (400 ml) at 0-5^C and stirred for 2 hrs. Acetone (40 ml) was added and concentrated the reaction mass. Toluene (400 ml) and water (200 ml) were added to the residue and the aquebus layer waS extracted with toluene (200 ml). Combined toluene layer was washed with water and concentrated under reduced pressure to get 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (84.2 g, 90%).

Method b:
Ethyl chloroformate (19.5 g, ISO mmol) was slowly added to a mixture of 3-(trifluoro-methy!)cinnamic acid (25 g, 116 mmol) and triethyiamine (14.61 g, 145 mmol) in toluene (200 ml) at -5°C to -10°C and stirring was continued at 0°C for 3 hrs. The reaction mass was filtered to remove triethyiamine HCl salts and washed with toluene (50 ml). The filtrate was concentrated to get mixed anhydride (31.5 g, 95%). Aqueous sodium borohydride solution (6.6 g, 174 mmol in water 21 ml) was added slowly to a mixture of mixed anhydride in tetrahydrofuran (100 ml) at 0-5°C and stirred for 2 hrs. Acetone (10 mi) was added and concentrated the reaction mass. Toluene (100 ml) and water (50 ml) were added to the residue, and the aqueous layer waii "'xtracted with toluene (50 ml). Combined toluene layer was washed with water, concentrated under reduced pressure to produce 3-[3-(trifluoromethyl)phenyI]-2-propen-l-ol (17.3 g, 74%).

Stage-2:
Preparation of 3-[3-(trifluoromethyl)phenyI]-2-propenaI (Ilia)
Sodium bicarbonate solution (8.3 g, 99 mmol in water 85 ml) was added to a solution of 3-[3-(trifluoromethy0phenyl]-2-propen-l-oI (20 g, 99 mmol), TEMPO free radical (0.22 g) and acetonitrile (80 ml). -13% Sodium nypochlorite solution (73.8 g) was added to the above reaction mass over a period of 20 min at 0-5°C with stirring while maintaining the pH of the reaction mass at 8.5-9.5 using dil. HCI. After 1 hr additional stirring, methylene chloride (80 ml) followed by water (70 ml) were added. The organic layer was washed with sodium sulphite solution followed by sodium chloride solution. The organic layer was concentrated to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal(17.4g, 88%).

Stage-3:
Preparation of 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCI) (Ila) 3-[3-(Trifluoromethyl)phenyi]-2-propenal (10 g, 50 mmol) was added to a solution of (R)-l-(l-naphthyl)ethylamine (8.46 g, 49 mmol) in tetrahydrofuran (250 ml). The resulting clear solution was stirred for 15 min, and acetic acid (4 g) and sodium triacetoxyborohydride (prepared separately by treating 2;6 g of sodiiini borohydride and 12.5 g of acetic acid in 50 mi of tetrahydrofuran) were added at I0-i5''C. After stirring for 2 hr at room temperature, the reaction mass was concentrated. The resulting residue was dissolved in methylene chloride (150 ml) and washed with IN HC! solution to remove unreacted amine. Separated organic layer was washed with sodium carbonate solution. The organic layer was concentrated to produce unsaturated Cinacalcet base (16.2 g). The residue containing unsaturated Cinacalcet base was dissolved in acetonitrile (20 ml) and acidified with HCI. The resulting mass was concentrated and product was isolated from acetonitrile to produce unsaturated Cinacalcet HCl as white solid (10.7 g, 55%). 'H NMR (CDCI3) (6 ppm): - 10.82 (br.s, IH), 10.34 (br.s, IH), 7.27-8.30 (m, IIH), 6.47 (m, IH), 6.16 (d, IH), 5.25 (m, IH), 3.71 (m, lH),3.39(m, IH), 1.97 (d, 3H); MS (m/z): 356.1 [M+1]. :

Stage-4:
Preparation of Cinacalcet HCl
A mixture of unsaturated Cinacalcet hydrochloride (9g, 23 mmol) and 5% Pd/C (0.9g) in methanol (90 ml) was hydrogenated at 3 Kg/cm^ for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. Acetonilrile (36 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr, filtered and dried to produce Cinacalcet hydrochloride (7.6 g, 84%). HPLC purity. 99.7% Desfluoro impurity: 0.02%

Example 2:
Stage-1:
Preparation of l-(3-chloro-l-propenyl)-3-(trifluoromethyl)benzene Thionyi chloride (17.7 g, 148 mmol) was added to a mixture of 3-[3-(trifluoromethyl)phenyI]-2-propen-l-ol (20, 99 mmol), toluene (20 ml) and few drops of DMF and refluxed for 4 hrs. Concentrated the reaction mass to produce l-(3-chioro-Upropenyl)-3-(trifluoromethyl)benzene (21.4 g, 98%).

Stage-2:
Preparation of 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen-l- yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCl) (Ha) l-(3-Chloro-I-propenyl)-3-(trifluoromethyl)benzene (20 g, 91 mmol) was added to a mixture of (R)-l-(l-naphthyI)ethylamine (15.19g, 89 mmol), K2CO3 (25 g, 181 mmol), potassium iodide (0.08 g) and methyl isobutyl ketone (MIBK) (10 ml). After refluxing for 13 hrs, the salts were removed by filtration. Organic layer was washed with IN HCl followed by aqueous sodium bicarbonate solution. 2N HCl (60 ml) was added to this organic layer and concentrated. Acetonitrile (60 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to produce unsaturated Cinacalcet hydrochloride (10.2 g, 28.8%).

Stage-3:
Preparation of Cinacalcet HCl
A mixture of unsaturated Cinacalcet hydrochloride (9 g, 23 mmol) and 5% Pd/C (0.9g) in methanol (90 ml) was hydrogenated at 3 Kg/cm^ for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. A-rctonitrile (36 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr., filtered and dried to produce Cinacalcet hydrochloride (7.3 g, 81%). HPLC purity; 99.6% Desfluoro impurity: 0.02%
Example 3:

Stage-1:
Preparation of 3-(trif1uoron]ethyl)cinnaniyl metbanesuJfonate Methanesulfonyl chloride (12.47 g, 109 mmol) was added to a mixture of 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (20 g, 99 mmol), diisopropylethylamine (16.6 g, 128 mmol) and methylene chloride (300 ml) at 0-5°C. After stirring the reaction mass at 25-30°C for 18 hrs, pre cooled IN HCl (30 ml) was added. The organic layer was separated and washed with sodium chloride solution. The organic layer was concentrated under reduced pressure to produce .3-(trifluorom_ethyl)cinnamyl methanesulfonate (21.4 g, 77%).

Stage-2:
Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l- yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCl) (Ha) Method a:

3-(Trifluoromethyl)cinnamyl methanesulfonaie (,iu g, JO mmoi; was added to a mixture of (R)-i-(l-naphthyl)ethyIamine (5.98 g, 35 mmol), K2CO.3 (9.87 g, 71 mmol) and acetonitrile (30 ml). After refluxing for 15 hrs, the salts were removed by filtration. The filtrate was concentrated. Toluene (50 ml) was added to the residue and washed with IN HCl followed by aqueous sodium bicarbonate solution. 2N HCl (30 ml) was added to this organic layer and concentrated. Acetonitrile (30 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to produce unsaturated Cinacalcet hydrochloride (7.7 g, 55%).

Method b:
3-(Trifluoromethyl)cinnamyl methanesulfonate (10 g, 36 mmol) was added to a mixture of (R)-l-(l-naphthyl)ethylamine (5.98 g, 35 mmol), CS2CO3 (13.96 g, 43 mmol) and acetonitrile (30 ml). After refluxing for 15 hrs, the salts were removed by filtration. The filtrate was concentrated. Toluene (50 ml) was added to the residue and" washed with IN HCl followed by aqueous sodium bicarbonate solution. 2N HCl (30 ml) was added to the organic layer and concentrated. Acetonitrile (30 ml) was added to the residue and stirred at 5°C for 2 hr, filtered and dried to get unsaturated Cinacalcet hydrochloride (5.6 g, 40%).

Stage-3:
Preparation of Cinacalcet HCl:
A mixture of unsaturated Cinacalcet hydrochloride (10 g, 25 mmol) and 5% Pd/C (1 g) in methanol (90 ml) was hydrogenated at 3 Kg/cm for 2 hr. The reaction mass was filtered and concentrated under reduced pressure. Acetonitrile (40 ml) was added. The resulting precipitate was stirred at 5°C for 2 hr., filtered and dried to produce Cinacalcet hydrochloride (8.3 g, 83%). HPLC purity: 99.9% Desfluoro impurity: 0.01% Carbamate impurity: 0.01%

WE CLAIM

1. The process for the preparation of 3-[3-(trifIuoromethy0phenyl]-2-propen-l-ol (IVb),

which comprises:
reducing mixed anhydride of Formula (XVIII) with a suitable reducing agent in a solvent,

wherein R represents C1.3 alkyl.

2. The process according to claim 1, wherein suitable reducing agent is selected from sodium borohydride, zinc borohydride, calcium borohydride.

3. The process according to claim 1, wherein solvent is selected from water, dioxane, toluene, THF.

4. The process as claimed in claim I, wherein 3-[3-(trifluoromethyl)phenyl]-2-propen-1-ol (IVb) is converted to Cinacalcet hydrochloride.

5. The process for the preparation of 3-[3-(trifluoromethyl)phenyl]-2-propenal which comprises:
oxidizing 3-[3-(trifluoromethyI)phenyl]-2-propen-l-o! (IVb) with oxidizing agent in presence of nitroxyl compound as a catalyst in the presence of solvent to produce 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia).

6. The process according to claim 5, wherein suitable oxidising agent used in the reaction is selected from sodium hypochlorite.

7. The process according to claim 5, wherein nitroxyl compound used is selected from 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO).

8. The process according to claim 5, further comprising the use of potassium borohydride as a regenerating agent of nitroxyl compound.

9. The process according to claim 5 wherein solvent is inert organic solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane, aromatic solvents such as toluene, halogenated solvents such as dichioromethane, dichloroethane, chloroform, esters such as ethyl acetate, buty! acetate, isopropyl acetate or ethers such as diethyl ether, tetrahydrofuran or tert-butyl methyl ether and/or mixtures thereof

10. The process as claimed in claim 5, wherein 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia) is converted to Cinacalcet hydrochloride.