FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 3-(3-(trifiuoromethyl)phenyl-N-((R)-1 -(naphthalen-1 -yl)ethyl)prop-2-en-1 -amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula Ila.

BACKGROUND OF THE INVENTION

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

Cinacalcet is a second generation calcimimetic agent, 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 levei:i'vvithiri 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 cardiovasculHr death.

Cinacaicet 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 Cinacaicet 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 Cinacaicet.

According to the generic process disclosed in US '244 Cinacaicet may be prepared by reacting 3-[3-(trifluoromethyl)phenyl]propylam}rie (V) with i-acetybaphthalene (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 Cinacaicet (la), and resolution of the racemic Cinacaicet by chira! liquid chromatography to produce Cinacaicet (lb).


us '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethylcinnamonitrile (VJIT) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (IX), which is further reacted with (R)-1-(l-naphthyl)ethyIamine (X) to produce an imine (Vila), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyl-N-((R)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (11) 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)-1-(l-naphthyl)ethy)amine (X) with 3-[3-(trifluoromethyl)pheny]]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., taking 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)-1-(l-naphthyl)ethyiamine (X) to produce Cinacalcet (lb). The reagents described in the patent, which have good leaving groups are thionyl halide, aliphatic suifonyl halide and aromatic sulfonyl halide.


us 7,393,967 discloses a process for the preparation of Cinacalcet, which comprises, condensing 3-bromotrifluorotoluene (XH) with allyl amine (XTIl) to produce 3-(trifiuoromethyl)phenyl-N-((R)-1-(naphtha!en-1-yl)ethyi)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-(trifluoroniethyI)cinnamic acid (XI) is reduced to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid (Xla) followed by converting to corresponding reactive derivative (XIV), which is further condensed with (R)-1-(l-naphthyl)ethylamine (X) in the presence of a base to produce N-[(l S)-1-^(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XV) and reducing the N-[(lS)-1-(l-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XV) - to produce Cinacalcet (lb).


Wo 2008/068625 A2 discloses condensation of 3-[3 (trifuoromethyl)phenyl]propionaldehyde (III) with (R)-1-(l-naphthyl)ethylamine (X) in the absence of titanium isopropoxide to produce Cinacalcet (lb).


Hence, there is a need to develop a process, which provides Cinaca'c^it hydrochloride (I) 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-(trifluoromethyl)phenyl-N-((R)-J-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (JI), which is further purified by making its hydrochloride salt (ITa) 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-(tnfluoromethyl)phenyl-N-((R)-1-(naphthaIen-1-yl)ethyl)prop-2-en-1-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-(trifluoromethyl)phenyl-N-((R)-1-(naphthalen-l -yl)ethy!)prop--2-en-1-aiiiine hydrochloride of Formula (Ila), . which comprises:

(ii) treating 3-(3-(trifluoromethyl)pheny!-N-((R)-1 -(naphthalen-1 -yl)ethyl)prop-_2-en-1-amine (unsaturated Cinacalcet) (II) with hydrochloric acid.

In another embodiment, the present invention also relates to the use of above 3-(3-(trif!uoromethyl)phenyl-N-((R)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (lla) 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)-1-(naphthalen-I-yl)ethyl)prop-2-en-1-amine hydrochloride (unsaturated Cinacalcet hydrochloride) of Formula (lla).

Reductive amination of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Ilia) with (R)-1-(l-naphthyi)ethylamine (X), in the presence of a reducing kgent selected from sodium triacetoxyborohydride, sodium cyanoborohydride (NaBHsCN) in a solvent selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, acetonitriie to produce 3-(trifluoromethyl)phenyl-N-((R)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (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)phenyI-N-((R)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (II) 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)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (II).

Alternatively, 3-(3-(trifluoromethyl)phenyl-N-((R)-1-(naphthalen-1-yl)ethyi)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, €3,6 esters, Cg-g cyclic, aromatic and aliphatic hydrocarbons and mixtures thereof. More preferably, the solvent is ethyl acetate, dichioromethane (DCM), toluene or mixtures thereof.

3-(3-(Trifluoromethyl)phenyl-N-((R)-1-(naphthalen-1-yl)ethyl)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, tetrahydrofuran, ethers, ethylacetate, methyl isobutyl ketone (MIBK), ketone, toluene to produce hydrochloride salt of 3-(3-(trifluoromethyl)phenyl-N-((R)-1 -(naphthaien-1 -yl)ethy])prop-2-en-1-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-(trifluoromethy!)phenyi-N-((R)-1-(naphthaIen-i-yi)ethyI)prop-2-en-I-amine hydrochloride (unsaturated Cinacatcet 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)-1-(naphthalen-1-yl)ethyl)prop-2-en-1-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 ] 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-(trifiuoromethy!)pheny!)propyl(P.)-1,(naph!halem-1-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.

EXAMPLE:

Stage-1:

Preparation of 3-(3-(trifluoroinethyl)phenyl-N-((R)-1-(naphthaIen-I- yl)ethyI)prop-2-en-1-amine hydrochloride (uusalurated Cinacalcet HCI) (Ila) 3-[3-(Trifluoromethyl)phenyl]-2-propenal (10 g, 50 mmol) was added to a solution of (R)-1-(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 triaceloxyborohydride (prepared separately by treating 2.6 g of sodium borohydride and 12.5 g of acetic acid in 50 ml of tetrahydrofuran) were added at 10-!5°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 HCI 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 HCI as white solid (10.7 g, 55%). 'H NMR (CDCI3) (5 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, IH), 3.39(m, IH), 1.97 (d, 3H); MS (m/z): 356.1 [M+1].

Stage-2:

Preparation of Cinacalcet HCI

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. Acetonitrile (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% Carbamate impurity: 0.01%

WE CLAIM

1. A process for the preparation of 3-(3-(trifluoromethyl)phenyl-N-((R)-1-(naphthaien-1-yl)ethyl)prop-2-en-1-amine liydrochloride of Formula (Ila), . which comprises:


(ii) 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 reducing agent used in step (i) is selected from sodium triacetoxyborohydride, sodium cyanoborohydride.

3. The process according to claim 1, wherein thr. reductive aminatioi? is carried out in presence of a solvent.

4. The process according to claim 3, wherein the solvent is selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, acetonitrile.

5. The process according to claim 1, wherein 3-(3-(trifluoromethyl)phenyl-N-((R)-!-(naphthalen-1-yl)ethyl)prop-2-en-1-amine (unsaturated Cinacalcet) (II) is treated with hydrochloric acid is carried out in presence of a solvent.

6. The process according to claim 5, wherein solvent is selected from acetonitrile, MIBK, ethylacetate.

7. The process according to claim 1, wherein 3-(3-(trifluoromethyl)phenyl-N-((R)-1-(naphthalen-1-yi)ethyl)prop-2-en-1-amine hydrochloride of Form a (Ila) 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.

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