Claims:We claim –
1. A process for the preparation of Cinacalcet of formula (I) or its pharmaceutically acceptable salt, comprising the steps of:
i) coupling 3-[3-(trifluoromethyl) phenyl] propanoic acid of formula (II) with (1R)-1-(1-naphthyl) ethanamine of formula (III) in presence of O-xylene to obtain N-[(1R)-1-(1-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl] propanamide of formula (IV), and
ii) reducing N-[(1R)-1-(1-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl] propanamide of formula (IV) using a reducing agent to obtain Cinacalcet of formula (I).
2. The process as claimed in claim 1, wherein the reducing agent is selected from the group comprising Vitride, BF3 etherate, and sodium borohydride in the presence of Iodine.
3. The process as claimed in claim 2, wherein the reducing agent is BF3 etherate and sodium borohydride in the presence of Iodine.
4. The process as claimed in claim 1, wherein the reaction in step i) is carried out at 138-145°C.
5. The process as claimed in claim 1, wherein the reaction in step ii) is carried out at 40-70°C.
6. The process as claimed in Claim 1, wherein Cinacalcet obtained in step ii) is converted to Cinacalcet Hydrochloride by reacting with hydrochloric acid.
7. A process for the preparation of compound of formula (II) by hydrogenation of 3-(Trifluoromethyl)cinnamic acid, wherein hydrogenation is carried out in an alcoholic solvent in the presence of metal catalyst.
8. The process as claimed in claim 7, wherein the alcoholic solvent is selected from the group comprising methanol, ethanol, and i-propanol.
9. The process as claimed in claim 7, wherein the metal catalyst is selected from the group consisting of palladium on carbon, Raney nickel, platinum, and platinum oxide.
10. The process as claimed in claim 7, wherein the catalyst used is in 1-4% wt/wt.
11. The process as claimed in claim 7, wherein the reduction carried out under pressure of 2-7 kg/Cm3.
12. A process for the purification of Cinacalcet hydrochloride comprising the steps of:
I) preparing suspension of Cinacalcet Hydrochloride in water;
II) adding acetonitrile to the suspension of step I) to obtain a mixture;
III) heating the mixture of step II) to a temperature greater than 75°C till reaction solution becomes clear;
IV) cooling the solution of step III) to room temperature;
V) chilling the solution of step IV) to 10-15°C; and
VI) isolating Cinacalcet Hydrochloride.
13. The process as claimed in claim 12, wherein Cinacalcet Hydrochloride is crystalline Form 1.
14. The process as claimed in claim 12, wherein the water used in step I) is 6-10V.
15. The process as claimed in claim 12, wherein the acetonitrile used in step II) is 14-18V. , Description:Field of the Invention
The present invention in general relates to the field of process chemistry and, more particularly, relates to a process for preparing Cinacalcet and its pharmaceutically acceptable salts having chiral purity and of higher yield and higher HPLC.

Background of the Invention
Cinacalcet, chemically (R)-N-[1-(1-naphthyl)ethyl]-3-[3 (trifluoromethyl)phenyl]propan -1-amine and of following structure:

belong to a class of compounds referred as calcimimetics that 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 decreases serum calcium levels. Cinacalcet is used to treat increased amount of parathyroid, in the people with long-term kidney disease, who are on dialysis. It is also used to treated amounts of calcium in people with an overactive parathyroid gland or in people with cancer of the parathyroid gland.

Cinacalcet was broadly disclosed in U.S. Patent No. 6,011,068 but was particularly described in U.S. Patent No. 6,211,244. According to the ‘244 patent, Cinacalcet may be prepared by reacting 1-acetylnaphthalene with 3-[3-(trifluoromethyl)phenyl] propylamine in the presence of to produce a corresponding cinacalcet isoimine, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet by chiral lipid chromatography.

In accordance to alternative process disclosed in the ‘244 patent, Cinacalcet may be prepared by treating 3-fluoromethylcinnamonitrile with diisobutyl aluminum hydride, followed by treating the intermediate aluminum-imine with (R)-1-(1-naphthyl) ethyl amine, and reducing the intermediate imine with ethanolic sodium cyanoborohydride.

However, both these processes of the ‘244 patent require use of reagents such as titanium isopropoxide, which is highly expensive and extremely toxic, and ethanolic or methanolic sodium cyanoborohydride, which is highly toxic and flammable, and not environmentally friendly, making the processes not industrially safe and scalable.

U.S. Patent No. 7,449,603 describes process for preparation of Cinacalcet comprising reducing 3-trifluoromethyl cinnamic acid to obtain 3-[3-(trifluoromethyl) phenyl] propanoic acid. The acid is converted to 3-[3-(trifluoromethyl) phenyl] propanoic acid chloride, which is coupled with (R)-1-naphthylethyl amine in presence of base to obtain N-[(1S)-1-(1-naphthyl) ethyl]-3-[3-trifluoromethyl) phenyl] propan-amide, which is reduced to obtain cinacalcet.

European Patent No. 1 883 618 teaches process for preparation of Cinacalcet hydrochloride Form 1 by providing a solution of Cinacalcet base in a solvent in which Cinacalcet hydrochloride has a low solubility, acidifying the solution with hydrochloric acid to obtain a reaction mixture, which is maintained to obtain and recover precipitated Cinacalcet hydrochloride crystal Form I.

Despite there have been many processes reported and known in the art for the preparation of Cinacalcet but there still remains a need for an improved process, which is environmentally friendly yet industrially scalable to provide higher yield.

Summary of the Invention
The presence invention provides a process for the preparation of Cinacalcet and its pharmaceutically salts with high chiral purity and higher yield.

The present invention further provides a process purification and crystallization of Cinacalcet Hydrochloride to yield chirally pure Form 1.

These and other features of the invention will become more apparent from the following detailed description along with the accompanying drawing.

Brief Description of Drawings
Fig 1 represents XRD of Cinacalcet Hydrochloride Form 1 obtained by the process of the present invention.

Detailed Description of the Invention
The present invention describes an improved process for the preparation of chirally pure Cinacalcet and its pharmaceutically acceptable salts with higher yield.

In a first embodiment of the present invention, as illustrated in Scheme 1, the process comprising i) coupling of 3-[3-(trifluoromethyl)phenyl]propanoic acid of formula (II) with (1R)-1-(1-naphthyl) ethanamine of formula (III) in presence of O-xylene to form N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propanamide of formula (IV); and ii) reduction of amide (IV) formed in stage (i) using suitable reducing agents to form Cinacalcet of formula (I).

Scheme 1
Preferably, step (i) is carried out at 138-145°C; more preferably at 140°C. The ratio of mol equivalents of compound (II) to mol equivalents of compound (III) is preferably 1-3:1; more preferably 1.2:1.

Reducing agent in step (ii) is preferably selected from Vitride, BF3 etherate and Sodium borohydride in presence of Iodine. In a preferred embodiment, step (ii) is carried out using sodium borohydride and BF3 etherate.

Generally lower temperature is required to be maintained for the reactions involving BF3 etherate. However, in the present invention, the addition of BF3 etherate is done at 35-45°C. The controlled addition of BF3 etherate to the mixture of sodium borohydride and compound of formula (IV) even at 38-42°C yields good results.

Preferably, reaction is carried out in etheral solvent selected from cyclopentyl methyl ether, 1,4-Dioxane, dimethoxymethane, dimethoxyethane, di-tert-butyl ether, ethyl tert-butyl ether, methoxyethane, methyl tert-butyl ether, tetrahydrofuran, dimethoxyethane, 2-methyltetrahydrofuran, di-isopropyl ether and diglyme; more preferably in tetrahydrofuran. The reaction is preferably maintained at 40-70°C; more preferably at 60-65°C. Cinacalcet base obtained is converted to its hydrochloride salt by reacting with hydrocloric acid. Cinacalcet hydrochloride obtained after work up is dried preferably at temperature range of 45-90°C, more preferably at 50-70°C.

In another aspect of the embodiment of the invention, Cinacalcet Hydrochloride is purified by using mixture of acetonitrile and water. The hydrochloride salt is dissolved in a mixture of predefined volume of acetonitrile and predefined volume of water at a predefined temperature. The mass is maintained till completion of the reaction and cooled gradually at room temperature and further below 20°C at 10-15°C. Cinacalcet Hydrochloride is isolated as pure crystalline solid.

In yet another aspect of the embodiment of the invention, the water used in the process is preferably 6-10 vol; more preferably is 8 vol and acetonitrile used is preferably 14-18 vol; more preferably 16 vol. Hydrochloride salt is dissolved in a mixture of solvent preferably at a temperature =75°C; more preferably at 80-85°C. After completion of the reaction, the mass is cooled gradually to 10-15°C. Isolation of pure Cincacalcet hydochloride is preferably done by filtration. After drying at 50-55°C, Cinacalcet hydrochloride Form 1 is obtained and characterized by XRD as illustrated in fig 1.

In another embodiment of the present invention, as illustrated in Scheme 2, compound of formula (II) is prepared by hydrogenation of 3-(Trifluoromethyl)cinnamic acid in an alcoholic solvent in the presence of metal catalyst. The reaction is carried out under predefined pressure.

Scheme 2
The metal catalyst used in the reaction is preferably selected from palladium on carbon, Raney nickel, platinum and platinum oxide. The catalyst used is 1% - 4% wt/wt. The alcoholic solvent is preferably selected from methanol, ethanol, i-propanol; more preferably methanol. The pressure applied for the reaction is preferably 2-7 kg/Cm3; more preferably 4-5 kg/Cm3.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

Example 1
Preparation of 3-[3-(trifluoromethyl)phenyl] propanoic acid
Methanol (1.2 L) was charged to Trifluoromethyl cinnamic acid (200 g) at room temperature. 5% Pd on carbon (2 g) was added to the reaction mixture and 4-4.5 kg hydrogen pressure was applied. The reaction mass was stirred for 6 hours. The mass was filtered and washed with methanol (100 ml). Solvent was distilled out completely under vacuum at 40-50°C to yield 3-[3-(trifluoromethyl) phenyl] propanoic acid (200.5 gm) (yield 99.08%)
HPLC Purity: 99.85%

Example 2
Preparation of N-[(1R)-1-(1-napthyl)ethyl]-3-(3-trifluromethyl)phenyl] propanamide
R-(+)-1-(1-naphthyl)ethylamine (131 g) was charged to 3-[3-(trifluoromethyl)phenyl] propanoic acid (200 g) at 25°C. To the reaction mixture O-xylene (150 ml) was added to yield slurry. The slurry was heated to 140-145°C and maintained under stirring for 10 -12 hours. The reaction mass was cooled to 27°C and MDC (1 L) was added. Sodium carbonate (50 g) was added to the mass and stirred for 15 minutes. The layers were separated and organic layer was dried over sodium sulfate. MDC was distilled at 42°C. The mass was stripped with Cyclohexane (50 ml). Cyclohexane (200 ml) was charged to the mass and stirred for 5 hours at 25-30°C. The mass was filtered and washed with cyclohexane to give N-[(1R)-1-(1-napthyl)ethyl]-3-(3-trifluromethyl)phenyl]propanamide (273.5 gm) (Yield: 96.65%)
HPLC Purity:99.88%

Example 3
Preparation of Cinacalcet hydrochoride
THF (1 L) was charged to N-[(1R)-1-(1-napthyl)ethyl]-3-(3-trifluromethyl)phenyl] propanamide (100 g) at room temperature. Sodium borohydride (24.6 g) was added to the reaction mass and heated to 40-42°C. BF3 etherate (128 ml) was added drop wise to the reaction mass over the period of 30-45 minutes. The mixture was maintained for 4 hours at 42°C. The temperature was raised to 60-65°C and maintained for 3 hours. The mass was cooled to 25-30°C and pH of the solution was adjusted to 8 to 9 using 3N sodium hydroxide solution. Toluene (500 ml) was added and stirred for 30 minutes. The aqueous layer was separated and washed with Toluene (100 ml). Both the organic layers were combined and dried on sodium sulftate. The mass was filtered and distilled under vacuum. The oil was dissolved in cyclohexane (600 ml). 10% solution of hydrochloric acid (120 ml) was added to the reaction mass drop wise over 30 minutes. The mass was maintained for 4-5 hours. The mass was filtered and washed with cyclohexane to yield wet cake. It was dried at 50-55°C for 6-8 hours to yield Cinacalcet hydrochloride (96.5 gm).
Purity: 99.83.%

Example 4
Purification for Cinacalcet Hydrochloride
Crude Cinacalcet Hydrochloride (85 g) was charged to water (714 ml) at room temperature. Acetonitrile (136 ml) was charged and the reaction mixture was heated to 80-85°C and maintained for 2 hours. The mass was cooled gradually to room temperature and further cooled to 14°C and maintained for 1 hour. The mass was filtered and washed with water 85 ml. The precipitate was dried at 50-55°C for 6-8 hours to yield Pure Cinacalcet Hydrochloride (95.29%).
HPLC purity: 99.95%