FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula Ila.

The compound of formula (11) is a key intermediate in the preparation of Calcimimetic agent, Cinacalcet hydrochloride of hormula 1.

BACKGROUND OF THE INVENTION

N-[( 1R)-1 -(1 -Naphthyl)ethyl]-3-[3-(trif1uoromethyl)phenyl]propan-l -amine hydrochloride is generically known as Cinacalcet.

Cinacalcet is a second generation calcimimetic agent, which decreases the secretion of parathyroid hormone (PTH) by activating calci'.'m receptors. The spcretion 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. CaJcimimetics 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 Sensipar® 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 molec::les 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 be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylamine (V) with 1-acetylnaphthalene (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-trif!uoromethylcinnamonitrile (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-(trif!uoromethyl)phenyl-N-((R)-l-(naphthalen-l-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-naphthyi)ethylamine (X) with 3-[3-(trif!uoromethyl)phenyl]propionaldehyde (III) in the presence of titanium (IV) isopropoxide to produce intermediate compound imine (VII), which is further reduced using ethanolic sodium cyanoborohydride.

The above processes involve the use of flammable and highly toxic reagents, such as titanium (IV) isopropoxide, which is highly hygroscopic, expensive, toxic and ethanolic 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-(trifluoromethyl)phenyl]propanol (IV) is converted to a compound with a good leaving group (IVa), which is further condensed with (R)-l-(l-naphthyl)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 compriseSj condensing 3-bromotrifluorotoluene (XII) with allyl amine (XIII) to produce 3-(trifluoromethyi)phenyI-N-((R)-1 -(naphthalen-1 -yi)ethy()prop-2-en-1 -amine (unsaturated Cinacalcet) (II), which is further reduced in presence of Pd/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 wich (R)-I-(l- naphthyl)ethylamine (X) in the presence of a base to produce N-[(1S)-1-(1- naphthyl)ethyl]o-[3-trifluoromethyl)phenyl]propanamide (XV) and reducing the N- [(1S)-] -(! -naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XV) to produce Cinacalcet (lb). wo 2008/068625 A2 discloses condensation of 3-[3-

(trifiuoromethyl)phenyl]propionaldehyde (III) witli (R)-l-(l-naphthyl)ethyIamine (X) in the absence of titanium isopropoxide to produce Cinacalcet (lb).

Cinacalcet (lb) prepared by the above processes contains 3-(3-(trifluoromethyl)phenyI)propyl-(R)-l-(naphthalen-l-yl)ethyl carbamate (Cinacalcet carbamate) (XVI) as an impurity in various amounts using different reaction conditions. Removal of Cinacalcet carbamate (XVI) in Cinacalcet hydrochloride (I) is often proved to be difficult and requires repeated crystallizations. Additionally, a second and third crystallization reduces yield as some Cinacalcet hydrochloride (I) remains uncrystallized and is not recovered from the liquid phase.

Hence, there is a need to develop a process, which provides Cinacalcet hydrochloride (1) with high chemical purity and optical purity.

The present invention is specifically directed towards the reductive amination in the absence of titanium (IV) isopropoxide to produce 3-(3-(trifIuoromethyI)phenyl-N-((R)-l-(naphthalen-I-yl)ethy!)prop-2-en-l-amine (unsaturated Cinacalcet) (11), which is further purified by making its hydrochloride salt (Ila) and can be used as such to produce Cinacalcet hydrochloride (I) of high purity and yield.

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)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine hydrochloride of Formula (Ila) with good yields on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of 3-(3-(trifluoromethy l)phenyl-N-((R)-1 -(naphthalen-1 -yl)ethy l)prop-2-en-1 -amine hydrochloride of Formula (Ila), which comprises:

(i) reacting 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb),

wherein X represents Ci, Br, C1.3 alkyl sulfonate or Ce-io aryl sulfonate; (ii) condensing compound of Formula IVc with (R)-l-(l-naphthyl)ethylamine (X) in the presence of base in a solvent.

Formula X to produce 3-(3-(trifluoromethyI)pheny!-N-((R)-l-(naphthalen-l-yi)ethyI)prop-2-en-I-amine (unsaturated Cinacalcet) (11), (iii) treating 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l- yI)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) with hydrochloric acid.

In another embodiment, the present invention also relates to the use of above 3-(3-(trifluoromethyI)phenyI-N-((R)-1 -(naphthalen-1 • y!)ethyi)prop-2-en-1 -arfiine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ila) to produce Cinacalcet hydrochloride (I).

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)phenyl-N-((R)-l-(naphthalen-l-yI)ethyl)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (Ila).

The process comprises, converting 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb) into a good leaving group by reacting with a reagent containing the leaving group, which is selected from thionyl halide, aliphatic .«','!fonyl halide and arcrnatic 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 chloride, 4-nitrobenzenesulfonyl chloride orp-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 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-(tnfluoromethyI)phenyl]-2-propen-l-oi (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, tri ethyl amine, diisopropylethylamine, 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-(I-naphthyI)ethylamine (X) in the presence of suitable base in a solvent to produce 3-(3-(tr!fluoromethyl)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, Na2C03, Cs2C03,NaHC03 or KHCO3. The most preferred base is K2CO3. The solvent is an organic solvent selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone, more preferably acetonitriie. 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 10 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) (U) 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)phenyi-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II) by removing the solvent.

Alternatively, 3-(3-(trifluoromethyl)pheny]-N-((R)-]-(naphthalen-l-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (II) thus obtained may be recovered 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^ es.ters, 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-1 -yl)ethyl)prop-2-en-1 -amine (unsaturated Cinacalcet) (11) produced by any of the above methods is treated with hydrochloric acid in a solvent selected from acetonitriie, 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) (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.

The process further comprises, reducing 3-(3-(trifluoromethyl)phenyI-N-((R)-l-(naphthalen-I-yl)ethyl)prop-2-en-l-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)-i-(r>aphtha!en-l-yl)eihy!)prop-2-en-l-amine (unsaturated Cinacalcet hydrochloride) (Ila) may be dissolved in a lower alcohol selected from C1-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 1000 psi. Typically, the hydrogenation is carried out over a period of about I 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 isobutyl ketone (MIBK).

It has been observed that Cinacalcet hydrochloride produced by the process having Cinacalcet carbamate, 3-(3-(trifluoromethyl)phenyl)propyl(R)-l-(naphthalen-l-yl)ethyl carbamate (XVI) less than 0.01% by HPLC and desfluoro^ Cinacalcet (Ic) less than 0.05% by HPLC without further purification. Further, the process of the present invention does not involve isolation of Cinacalcet freebase and the resulting finished product has high chemical and optical purity according to high performance liquid chromatography (HPLC).

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

Example 1:

Stage-1:

Preparation of l-(3-chIoro-l-propenyl)-3-(trifIuoromethyI)benzene

Thionyl chloride (17.7 g, 148 mmol) was added to a mixture, of 3-[3-(trifIuoromethyl)phenyl]-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-chloro-l-propenyl)-3-(trifluoromethyl)benzene (21.4 g, 98%).

Stage-2:

Preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l- yl)ethyI)prop-2-en-l-amine hydrochloride (unsaturated Cinacalcet HCI) (Ila) l-(3-Chloro-l-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 HCI followed by aqueous sodium bicarbonate solution. 2N HCI (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 HCI

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. Acetonitrile (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% Carbamate impurity: 0.01%

Example 2:

Stage-1:

Preparation of 3-(trif1uoromethyl)cinnainyl methanesulfonate 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-(trifluoromethyl)cinnamyl methanesulfonate (21.4 g, 77%)).

Stage-2;

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

3-(Trifluoromethyi)cinnamyl methanesulfonate (10 g, 36 mmol) was added to a mixture of (R)-l-(l-naphthyl)ethylamine (5.98 g, 35 mmol), K2CO3 (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)-i-(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 HCI (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 HCI:

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

I. A process for the preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-l- (naphthaIen-l-yl)ethyl)prop-2-en-l-amine iiydrochloride (unsaturated Cinacalcet iiydrochloride) of Formula (Ila), which comprises: (i) reacting 3-[3-(trifluoromethyl)phenyl]-2-propen-l-ol (IVb), with a reagent containing the leaving group in a solvent to produce a compound of Formula IVc,

wherein X represents CI, Br, C1.3 alkyl sulfonate or Ce-io ary' sulfonate; (ii) , condensing compound of Formula IVc with (R)-l-(l-naphthyl)ethylamine (X) in the presence of base in a solvent, to produce 3-(3-(trifluoromethyl)phenyl-N-((R)-l -(naphthalen-1 - yI)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (II),

(iii) treating 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-1- yl)ethyl)prop-2-en-1 -amine (unsaturated Cinacalcet) (II) with hydrochloric acid.

2. The process according to claim 1, wherein the reagent containing the leaving group is selected from thionyl halide such as thionyl bromide or thionyl chloride.

3. The process according to claim 1, wherein reagent containing the leaving group is selected from aliphatic sulfonyl halide such as methanesulfonyl chloride.

4. The process according to claim 1, wherein reagent containing the leaving group is selected from aromatic sulfonyl halide such as benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or p-toluenesulfonyl chloride.

5. The process according to claim 1, wherein the solvent used in step (i) is selected from halogenated solvents, such as dichloromethane, ethylene dichloride, and chloroform, toluene and mixtures thereof.

6. The process according to claim 1, wherein when the leaving group reagent is sulfonyl chloride, the reaction is carried out in presence of a base.

7. The process according to claim 6, wherein base is an organic base such as amine, more preferably, triethylamine, diisopropylethyl amine or other tertiary amines.

8. The process according to claim 1, wherein base used in condensation reaction is selected from an inorganic base such as alkali carbonate, more preferably, K2CO3, NasCOa, CssCOs.NaHCOa or KHCO3.

9. The process according to claim 1, wherein solvent used in condensation reaction is selected from acetonitrile, toluene, methyl isobutyl ketone (MIBK), and acetone.

10. The process as claimed in claim 1, wherein 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine hydrochloride of Formula (Ila) is converted to Cinacalcet hydrochloride.