FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Cinacalcet hydrochloride of Formula (I).

BACKGROUND OF THE INVENTION

Cinacalcet hydrochloride is chemically known as N-[(lR)-l-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l -amine hydrochloride.

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 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 brand name Sensipar® in the US and, in Europe, it is marketed under the brand 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.

Cinacalcet and its pharmaceutically acceptable salts as calcium receptor-active molecules is disclosed in US 6,011,068, US 6,313,146 and US 6,211,244. The above patents do not provide any specific 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 (II) with 1 -acetylnaphthalene (III) in the presence of titanium (IV) isopropoxide, to produce an imine (IV), 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).

Scheme-I
US '244 also generically discloses a variant process for the preparation of Cinacalcet by reacting 3-trifluoromethylcinnamonitrile (V) with diisobutylaluminum hydride to produce intermediate aluminum-imine complex (VI), which is further reacted with (R)-l-(l-naphthyl)ethylamine (VII) to produce an enimine (VIII), followed by reduction using ethanolic sodium cyanoborohydride to produce 3-(3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (IX) and reducing unsaturated Cinacalcet to produce Cinacalcet (lb). The process is as shown in Scheme -II below:

Scheme-11
Similarly, using the another variant 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 (VII) with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (X) in
the presence of titanium (IV) isopropoxide to produce intermediate compound imine (IV), which is further reduced using ethanolic sodium cyanoborohydride.

The process is as shown in Scheme -III below:

US 7,250,533 discloses a process for the preparation of Cinacalcet, wherein 3-(3-(trifluoromethyl)phenyl]propanol (XI) is converted to a compound with a good leaving group (XIa), which is further condensed with (R)-l-(l-naphthyl)ethylamine (VII) 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. The process is as shown in Scheme -IV below:

US 7,393,967 discloses a process for the preparation of Cinacalcet, which comprises, condensing 3-bromotrifluorotoluene (XII) with allyl amine (XIII) to produce 3-(trifluoromethyl)phenyl-N-((R)-1 -(naphthalen-1 -yl)ethyl)prop-2-en-1 -amine (unsaturated Cinacalcet) (IX), which is further reduced in presence of Pd/C to produce Cinacalcet (lb). The process is as shown in Scheme -V below:

Cinacalcet (lb)
Scheme-V
US 2007/0259964 Al discloses a process for the preparation of Cinacalcet (lb), wherein 3-(trifluoromethyl) cinnamic acid (XIV) is reduced to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid (XlVa) followed by converting to corresponding reactive derivative (XV), which is further condensed with (R)-l-(l-naphthyl)ethylamine (VII) in the presence of a base to produce N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide (XVI), followed by reduction to produce Cinacalcet (lb). The process is as shown in Scheme -VI below:

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 (X) with (R)-l-(l-naphthyl)ethylamine (VII) in the absence of titanium isopropoxide to produce Cinacalcet (lb). The process is as shown in Scheme -VII below:

WO 2010/015935 A2 discloses a process for the preparation of Cinacalcet by condensing 3-[3-(trifluoromethyl)phenyl]-2-propenal (Xa) with (R)-l-(l-naphthyl)ethylamine (VII) in the presence of reducing agent to produce 3-(trifluoromethyl)phenyl-N-((R)-l-(naphthalen-l-yl)ethyl)prop-2-en-l-amine (unsaturated Cinacalcet) (IX), followed by treating with HC1 to produce unsaturated Cinacalcet hydrochloride (IXa), which is further reduced in presence of hydrogenation catalyst in a solvent to produce Cinacalcet hydrochloride (I). The process is as shown in Scheme -VIII below:

Scheme-VIII
The present invention is specifically directed towards the process for the preparation of Cinacalcet hydrochloride (I) of high purity and yield, wherein condensation of 3-[3-(trifluoromethyl)phenyl]-2-propenal (Xa) with (R)-l-(l-naphthyl)ethylamine (VII) is carried out in the presence of a catalyst.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of Cinacalcet hydrochloride (I) with good yields on a commercial scale.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of N-[(1R)-1-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-l -amine hydrochloride of Formula (I),
Formula I

which comprises:
(i) condensing 3-[3-(trifluoromethyl)phenyl]-2-propenal (Xa),
Formula Xa

with (R)-l-(l-naphthyl)ethylamine (VII),
Formula VII

in the presence of a catalyst to produce Schiff base of formula (VIII),
Formula VIII

(ii) reducing Schiff base of formula (VIII) in the presence of H2 and a catalyst to produce Cinacalcet free base,

(iii) treating Cinacalcet free base with HC1 to produce Cinacalcet hydrochloride (1).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of N-[(1R)-1-(l-naphthyl)ethyi]-3-[3-(trifluoromethyI)phenyI]propan-l-amine hydrochloride(Cinacalcet hydrochloride) of Formula I.

The process comprises, condensing 3-[3-(trifluoromethyl)phenyl]-2-propenal (Xa) with (R)-l-(l-naphthyl)ethylamine (VII), in the presence of a catalyst selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, titanium isopropoxide, titanium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, under neat reaction conditions without solvent to produce Schiff base (VIII). The reaction may be performed at a temperature ranging from about 0°C to about 50°C for a period of about 1 to 5 hours.

After completion of reaction as ascertained by the known detection methods reported in the art such as HPLC, solvent is added to the reaction mixture and residual salts and reagents are filtered from the reaction mixture. The filter bed is then washed and the filtrate containing Schiff base (VIII) is used as such in the next step.

The solvent used in the above reaction is selected from C2-8 ethers such as dimethyl ether, diethyl ether, dimethoxyethane, ethylene oxide, dioxane, tetrahydrofuran, anisole and the like, chlorinated solvents such as methylene chloride, trichloroethylene, methyl chloroform, ethylene dichloride, propylene dichloride, tetrachloroethylene, trichloroethane and the like, C3.6 esters methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, and the like, C5-8 cyclic, aromatic and aliphatic hydrocarbons such as cyclohexane, n-hexane, heptane, toluene, xylenes and mixtures thereof.

Optionally, condensation reaction is also carried out in the presence of a suitable solvent selected from C2-8 ethers such as dimethyl ether, diethyl ether, dimethoxyethane, ethylene oxide, dioxane, tetrahydrofuran, anisole and the like, chlorinated solvents such as methylene chloride, trichloroethylene, methyl chloroform, ethylene dichloride, propylene dichloride, tetrachloroethylene, trichloroethane and the like, C3-6 esters methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, and the like, C5-8 cyclic, aromatic and aliphatic hydrocarbons such as cyclohexane, n-hexane, heptane, toluene, xylenes and mixtures thereof.

The process further comprises, reducing Schiff base (VIII), preferably, by catalytic hydrogenation i.e., with hydrogen in the presence of catalyst to produce Cinacalcet free base. The Schiff base (VIII) in a solvent selected from C2-8 ethers such as dimethyl ether, diethyl ether, dimethoxyethane, ethylene oxide, dioxane, tetrahydrofuran, anisole and the like, chlorinated solvents such as methylene chloride, trichloroethylene, methyl chloroform, ethylene dichloride, propylene dichloride, tetrachloroethylene, trichloroethane and the like, C3-6 esters methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, and the like, C5-8 cyclic, aromatic and aliphatic hydrocarbons such as cyclohexane, n-hexane, heptane, toluene, xylenes and mixtures thereof exposed to H2 pressure in the presence of a catalyst such as Pd/C or PtO2 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 1 to about 6 hours to produce Cinacalcet free base. The reaction mixture containing Cinacalcet free base is cooled and filtered. The filtered bed is then washed and the solvent is removed from the filtrate under reduced pressure to produce Cinacalcet free base.
Cinacalcet free base is treated with HCI in a solvent selected from ethyl acetate, acetonitrile, ether, heptane, methyl isobutyl ketone (MIBK), toluene and precipitating pure Cinacalcet hydrochloride (I) by cooling the solution to about 0-30°C, or by
adding an anti solvent selected from cyclohexane, n-hexane, heptane or mixtures thereof.

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

EXAMPLES
EXAMPLE 1:
Preparation of Cinacalcet HC1
Titanium isoproxide (2.84 g, 10 mmol) was added to the mixture of 3-[3-(trifluoromethyI)phenyl]-2-propenal (20 g, 100 mmol), (R)-l-(l-naphthyl)ethylamine (15.39 g, 90 mmol) and toluene (250 ml) at 10-15° and stirred for 1 hr. Then, reaction mixture was filtered to remove the salts. The resulting clear solution was hydrogenated at lKg/cm2 in the presence of 5% pd on carbon (1.6 g) at 0-5°C. The reaction mass was filtered to remove the catalyst. The resulting organic layer was concentrated under reduced pressure. Then diluted with ethyl acetate (320 ml) and was washed with IN HC1 solution to remove impurities. The resulting organic layer was concentrated under reduced pressure. Ethyl acetate (96 ml) was added to the resulting residue and raised the temperature to 60°C for 30 min. The pure Cinacalcet HC1 was obtained by the filtration and drying (25.7 g, 65.3%).

EXAMPLE 2:
Preparation of Cinacalcet HC1
Titanium isoproxide (2.84 g, 10 mmol) was added to the mixture of 3-[3-(trifluoromethyl)phenyl]-2-propenal (20 g, 100 mmol) and (R)-l-(l-naphthyl)ethylamine (15.39 g, 90 mmol) at 10-15° and stirred for 1 hr. Then, the reaction mixture was diluted with toluene (480 ml) and filtered to remove the salts.

The resulting clear solution was hydrogenated at 1 Kg/cm2 in the presence of 5% pd on carbon (1.6 g) at 0-5°C. The reaction mass was filtered to remove the catalyst. Then, the filtrate was washed with IN HC1 solution to remove impurities. The resulting organic layer was concentrated under reduced pressure. Ethyl acetate (96 ml) was added to the resulting residue and raised the temperature to 60°C for 30 min. The pure Cinacalcet HC1 was obtained by the filtration and drying (24 g, 61%).

We claim:

1. A process for the preparation of Cinacalcet hydrochloride of Formula (I),
Formula I

which comprises:

(i) condensing 3-[3-(trifluoromethyl)phenyl]-2-propenal (Xa),
Formula Xa

with (R)-1 -(1 -naphthyl)ethylamine (VII),

in the presence of a catalyst to produce Schiff base of formula (VIII), Formula VIII

(ii) reducing Schiff base of formula (VIII) in the presence of H2 and a catalyst
to produce Cinacalcet free base; (iii) treating Cinacalcet free base with HC1 to produce Cinacalcet hydrochloride
(I).

2. The process according to claim 1, wherein the catalyst used in step-(i) is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, titanium isopropoxide, titanium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide.

3. The process according to claim 1, wherein the reaction in step-(i) is carried out without using any solvent.

4. The process according to claim 1, wherein the reaction in step-(i) is optionally carried out in the presence of a suitable solvent selected from C2-8 ethers such as dimethyl ether, diethyl ether, dimethoxyethane, ethylene oxide, dioxane, tetrahydrofuran, anisole and the like, chlorinated solvents such as methylene chloride, trichloroethylene, methyl chloroform, ethylene dichloride, propylene dichloride, tetrachloroethylene, trichloroethane and the like, C3_6 esters methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, and the like, C5.8 cyclic, aromatic and aliphatic hydrocarbons such as cyclohexane, n-hexane, heptane, toluene, xylenes and mixtures thereof.

5. The process according to claim 1, the catalyst used in step-(ii) is selected from Pd/C or Pt02 or Raney nickel.

6. The process according to claim 1, wherein the reduction in step-(ii) is carried out in a solvent selected from C2-8 ethers such as dimethyl ether, diethyl ether, dimethoxyethane, ethylene oxide, dioxane, tetrahydrofuran, anisole and the like, chlorinated solvents such as methylene chloride, trichloroethylene, methyl chloroform, ethylene dichloride, propylene dichloride, tetrachloroethylene, trichloroethane and the like, C3-6 esters methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, and the like, C5.8 cyclic, aromatic and aliphatic hydrocarbons such as cyclohexane, n-hexane, heptane, toluene, xylenes and mixtures thereof.

7. The process according to claim 1, wherein the step-(iii) is carried out in the presence of a solvent selected from ethyl acetate, acetonitrile, ether, heptane, methyl isobutyl ketone (MIBK), toluene or mixtures thereof.