DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF CINACALCET

We, Tyche Industries Limited,
a company incorporated under the companies act, 1956 having address at
C-21/A, Road No.9, Film Nagar, Jubilee Hills, Hyderabad – 500096, India.

The following specification particularly describes the nature of the invention and manner in which it is to be performed.
Field of the Invention
The present invention relates to an improved process for the preparation of Cinacalcet of Formula I.

More particularly, the present invention relates to the process for the preparation of 1-(naphthalen-5-yl)ethanamine or its salts of Formula II which are used as intermediates in the preparation of Cinacalcet.

Background of the Invention
Calcimimetics are a class of orally active, small molecules that decrease the secretion of 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 oversecretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of parathyroid hormone (PTH), an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. As a calcimimetic, Cinacalcet Hydrochloride is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with Cinacalcet Hydrochloride lowers serum levels of PTH, as well as the calcium/phosphorus ion product in the blood.

Cinacalcet hydrochloride is commercially available as Sensipar® or Mimpara®. It is chemically known as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the empirical formula C22H22F3N.HCl. The molecular weight of the hydrochloride salt is 393.9 g/mol and the free base is 357.4 g/mol. There is one chiral center in the molecule, and the R enantiomer is the more potent enantiomer. The structural formula of Cinacalcet is as shown below:

Cinacalcet was first described and claimed in U.S. Pat. No.6,211,244. This patent describes a specific method for producing Cinacalcet by reacting 1-acethylnaphthalene with 3-[3-(trifluoromethyl)phenyl]propylamine in the presence of titanium isopropoxide to produce the corresponding isoimine intermediate, followed by treating the isoimine intermediate with sodium cyanoborohydride in methanol to give racemic Cinacalcet and finally resolution of the racemic Cinacalcet base by chiral liquid chromatography to give Cinacalcet. The process is shown in the scheme I given below:

Scheme I
The patent also discloses a process for the preparation of Cinacalcet, which includes the treatment of 3-trifluoromethylcinnamonitrile with diisobutyl aluminum hydride to give aluminum-imine complex, which is treated with (R)-1-(1-naphthyl)ethylamine to give imine intermediate and reducing the imine intermediate with sodium cyanoborohydride in ethanol to give Cinacalcet.The process is shown in the scheme II given below:

Scheme II
The patent also discloses another process for the preparation of Cinacalcet, which involves reaction of (R)-1-(1-naphthyl)ethylamine with 3-[3-trifluoromethyl)phenyl]propionaldehyde in the presence of titanium isopropoxide to produce imine intermediate, followed by treatment with sodium cyanoborohydride in ethanol to give Cinacalcet. The process is also disclosed in Drugs of the Future (2002), 27 (9): 831 which is shown in the scheme III given below:
Scheme III
The chiral separation methods used in the processes to obtain the desired enantiomer is industrially not feasible and economically not viable. Further, the processes require the use of reagents such as titanium isopropoxide and sodium cyanoborohydride which are highly toxic, flammable, expensive and not environmentally friendly, making the processes difficult to apply on industrial scale.
CN application No. 101735070 discloses a process for the resolution of racemic 1-(naphthalen-5-yl)ethanamine with D-tartaric acid in the presence of alcohol and water followed by separation and basification of the obtained enantiomeric salt to obtain the R-(+)-1-(1-naphthyl)ethylamine. The process is shown in the scheme given below:

Scheme IV
CN application No. 103420845 discloses a process for the resolution of racemic 1-(naphthalen-5-yl)ethanamine with tartaric acid in mixture of methanol and water to give R-(+)-1-(1- naphthyl)ethylamine tartrate salt followed by addition ofalkali solution for adjusting the pH to 9-12 to give R-(+)-1-(1-naphthyl)ethylamine. The process is shown in the scheme given below:

Scheme V

Most of the reported processes involves the use of R-(+)-1-(1-naphthyl)ethylamine in the preparation of Cinacalcet which inturn is prepared by the use of resolving agents in different solvents.

Considering the importance of Cinacalcet there is need for a simple, economical and industrially viable process for the synthesis of Cinacalcet. With a view to find a simple process the inventors diligently worked and identified a robust and economical process for the preparation of R-(+)-1-(1-naphthyl)ethylamine or its salts.

Objective of the Invention
The main objective of the present invention is to provide cost-effective and commercially viable process for the preparation of Cinacalcet and its pharmaceutically acceptable salts with high yield and purity.
Another objective of the present invention is to provide a robust and simple process for the preparation of R-(+)-1-(1-naphthyl)ethylamine or its salts of Formula IIa with high yield and purity.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Cinacalcet of Formula I or a pharmaceutically acceptable salt thereof, which comprises
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with chiral acid in an aqueous medium to form an enantiomeric salt of compound of Formula IIa,

ii) converting compound of Formula IIa to Cinacalcet of Formula I and

iii) optionally converting compound of Formula I to its pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides an improved process for the preparation of R-(+)-1-(1-naphthyl)ethylamine or its salts of Formula IIa,

which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with chiral acid in an aqueous medium to form an enantiomeric salt of compound of Formula IIa.

Detailed Description of the Invention
The main embodiment of the present invention provides an improved process for the preparation of Cinacalcet or its pharmaceutically acceptable salts of Formula I, which involves the use of (R)-1-naphthylethylamine or its salt of Formula IIa.

Chiral acid used for resolution are selected from acids having D-configuration such as malic acid, mandelic acid, 2-chloromandelic, 3-chloromandelic, 4-chloromandelic acid, tartaric acid, diacetyl tartaric acid, di-p-anisolyl tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, camphorsulfonic acid.
In a most preferred embodiment, the present invention provides an improved process for the preparation of R-(+)-1-(1-naphthyl)ethylamine tartrate salt of Formula IIb,

which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with D(-)tartaric acid in the presence of water to form an enantiomeric salt of compound of Formula IIb.

In another most preferred embodiment, the present invention provides an improved process for the preparation of Cinacalcet of Formula I or a pharmaceutically acceptable salt thereof, which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with D(-)tartaric acid in water to form an enantiomeric salt of compound of Formula IIb,

ii) converting compound of Formula IIb to Cinacalcet of Formula I and

iii) optionally converting compound of Formula I to its hydrochloride salt.

The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES
Example-1:
Preparation of (RS)-1-(1-Naphthyl)ethylamine (Formula-II):
A mixture of 1-(1-napthyl)ethanoneoxime (100g), Raney nickel (20g), 1% methanolic ammonia solution was stirred under hydrogen pressure at 3.5-4.0 Kg/cm² at 58-62ºC for about 3-4h. The catalyst was removed by filtration and washed with methanol (400ml), and the filtrate was concentrated in vacuo to obtain the thick residue. The residue was taken in toluene (400ml) and water(1200ml) was added, the pH was adjusted between 1 and 2 using hydrochloric acid, the mixture was stirred for about 15-20 min, and the organic layer was separated and discarded. The aqueous layer was further washed with toluene (2x300ml) and separated. The pH of the aqueous layer was washed to 11-12 using C.S. lye, and the desired compound was extracted in toluene (2x500ml). The organic layer was washed with water and distilled to get the product.
Yield: 85.0g (92.4%)

Example-2:
Prepration of (R)-(+)-1-(1-Naphthyl)ethylamine tartrate (Formula-IIb)
Into 1L RB flask, water 200ml and D(-)-tartaric acid (21.7g,0.14mol) were charged at 25-35ºC. The reaction mass was heated to 90-95ºC and (RS)-1-(1-Napthyl)ethylamine (25g,0.14mol) was added. The mass was stirred for about 1hr at 90-95ºC. The reaction mass was cooled to80-85ºC, filtered and washed with acetone (50ml). Recrystallization from water gave (R)-(+)-1-(1-Napthyl)ethylamine tartrate.
Yield:15.0g (31.9%)

Example-3:
Preparation of S-(-)-1-(1-Naphthyl)ethylamine tartrate:
Into 1L RB flask, water 200ml and L(+) Tartaric acid (21.7g,0.14mol) were charged at 25-35ºC. The reaction mass was heated to 90-95ºC and (RS)-1-(1-napthyl)ethylamine (25g,0.14mol) added. The mass was stirred for 1hr at 90-95ºC.The reaction mass was cooled to80-85ºC and filtered and washed with acetone (50ml). Recrystallization from water gave S-(-)-1-(1-Napthyl)ethylamine tartrate.
Yield:12.0g(25.5%)

Example-4:
Preparation of Cinacalcet Hydrochloride (I) under solvent free conditions
3-[3-(trifluoromethyl)phenyl]propionaldehyde (5.9 g, 0.029 mol) was added to (R)-(1-naphthyl)ethylamine (5 g, 0.029 mol) for 30 min at room temperature and stirred for 1hour. Mixture of boric acid (1.81g, 0.029 mol) and sodium borohydride (1.08g, 0.029 mol) was slowly added lot wise for about 1 hour at room temperature. Stirred for 12 hours at room temperature, Completion of reaction was monitored by TLC. After the completion of reaction slowly added aqueous sodium bicarbonate (6 g in 100 ml water) for 30min. Extracted the reaction mass with ethylacetate (70 ml). Wash the ethylacetate layer with water (20 ml). Distilled off ethyl acetate under vaccum and charged hexane (100 ml) and water (20 ml). Slowly added con.HCl for about 30 min to get pH 1 to 3.Stirred for 3 hours at room temperature and filtered followed by washing with mixture of hexane and water. Crude product is dissolved in acetonitrile (30 ml) and heated to 50-60ºC. The clear solution was cooled to 0-5ºC and stirred for about 2 hours. Filtered the reaction mass followed by washing with chilled acetonitrile (10 ml).The wet product was dried under vaccum at 50ºC to yield Cinacalcet Hydrochloride as a white solid, (9.2 g, 80%). ,CLAIMS:We claim,
1. An improved process for the preparation of Cinacalcet of Formula I or a pharmaceutically acceptable salt thereof, which comprises
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with chiral acid in an aqueous medium to form an enantiomeric salt of compound of Formula IIa,

ii) converting compound of Formula IIa to Cinacalcet of Formula I and

iii) optionally converting compound of Formula I to its pharmaceutically acceptable salts thereof.

2. An improved process for the preparation of R-(+)-1-(1-naphthyl)ethylamine or its salts of Formula IIa,

which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with chiral acid in an aqueous medium to form an enantiomeric salt of compound of Formula IIa.

3. The process claimed in claims 1 and 2 wherein the chiral acid used is selected from malic acid, mandelic acid, 2-chloromandelic, 3-chloromandelic, 4-chloromandelic acid, tartaric acid, diacetyl tartaric acid, di-p-anisolyl tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, camphorsulfonic acid.

4. An improved process for the preparation of R-(+)-1-(1-naphthyl)ethylamine tartrate salt of Formula IIb,

which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with D(-)tartaric acid in the presence of water to form an enantiomeric salt of compound of Formula IIb.

5. An improved process for the preparation of Cinacalcet of Formula I or a pharmaceutically acceptable salt thereof, which comprises:
i) treating racemic 1-(1-naphthyl)ethylamine of Formula II

with D(-)tartaric acid in water to form an enantiomeric salt of compound of Formula IIb,

ii) converting compound of Formula IIb to Cinacalcet of Formula I and

iii) optionally converting compound of Formula I to its hydrochloride salt.

Dated this Seventh (7th) day of October 2015.
__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883