TECHNICAL FIELD:

The invention relates to processes for the preparation of phosphate salts of unsaturated cinacalcet free base, whereby utilising it as an intermediate of high purity to produce Cinacalcet hydrochloride with very low impurities and it further relates to improved solvent systems, and in particular to a solvent system for use in the production of Cinacalcet hydrochloride.

BACKGROUND OF THE INVENTION:

Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone ("PTH") by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetics 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, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.

Cinacalcet (INN) is a drug that acts as a calcimimetic which has the following structure:

Cinacalcet Hydrochloride has approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCI lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood.
U.S. Patent No. 6,011,068 generally describes cinacalcet and its pharmaceutically acceptable acid addition salts.

U.S. Patent No. 6,211,244 describes cinacalcet and related compounds, and their pharmaceutically acceptable salts. Processes for the preparation of cinacalcet and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,211,244; 7,250,533; 5,648,541; 7,247,751; and 7,393,967; PCT Publication Nos. WO06/127933; WO06/125026; WO06/127941; WO07/062147; WO07/112280; WO07/127445; WO07/127449; WO08/058235; WO08/000423; WO08/035212; WO08/058236; WO08/063645; and WO08/068625.

The process claimed in the above prior arts results in the product with high impurity profile. To overcome this shortcoming, PCT applications WO2010067204 and WO2011033473 disclose the processes and intermediates which are capable of reducing the above said impurities. Also, claimed are the salts forms of intermediates which are highly efficient to produce impurity free final products.

One among them is the phosphate salt form of cinacalcet unsaturated base which is disclosed in the above said PCT application. This intermediate is considered to be an efficient precursor for the production of highly pure Cinacalcet final product.

The raw material source, 3-(trifluoromethyl)cinnamaldehyde disclosed in the prior art is available commercially prepared using different route of synthesis (i.e., 3-(trifluoromethyl) aniline, 3-(trifluoromethyl) benzaldehyde and 3-(trifluoromethyl) cinnamic acid). The purity of 3-(trifluoromethyl)cinnamaldehyde prepared by any of the above-mentioned source varies between 85%-95% and the oily nature of raw material limits purification. Being dark brown oil with 90% purity, the process of removing the impurities as well as getting the compound with desirable description in that stage is not feasible. This impure starting material when converted to this intermediate by series of reaction, results into the compound containing impurities as well. This may result in carrying forward the process impurities, thereby decreasing the yield and purity of the final product.

In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. See ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7A, Current Step 4 Version (November 10, 2000).

Also, the above said prior arts above said prior arts do not describe the specific conditions for producing the specific intermediate producing the above said specific intermediate.

Moreover, it is known in the art to use a variety of different solvents in the production of Cinacalcet hydrochloride. However, all of the solvents used possess major disadvantages.

SUMMARY OF THE INVENTION:

The present invention is directed to overcome the above said disadvantages and fulfills the necessity of best mode to produce the phosphate salt of cinacalcet unsaturated base which is then used for conversion to Cinacalcet HCI salt with efficient solvent system.

OBJECTIVE OF THE INVENTION:

It is the primary objective of the present invention is to employ synthetic processes to produce the intermediate compound of formula I with a high degree of purity.

It is the further objective of the present invention is to employ synthetic processes to produce the intermediate compound of formula

with a high degree of purity which in turn may be subjected to the final cinacalcet preparation.

It is the further objective of the present invention is to employ synthetic processes which are considered to be best mode, which is consistent in terms of yield and purity, for producing the efficient intermediate.

It is further objective of the present invention is to produce Cinacalcet hydrochloride by employing improved solvent systems, and in particular to a solvent system for use in the production of Cinacalcet hydrochloride.

DESCRIPTION OF THE INVENTION:

The term "purity" as used herein throughout the description and claims refers to chemical purity and/or polymorphic purity. Chemical purity may be determined for example by HPLC and polymorphic purity may be determined by XRPD analysis.

According to one aspect of the present invention, there is provided the process for preparing for phosphate salt of (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl) allyl] amine of formula I:
Comprising:

a) Dissolving (1 -naphthalen-1 -yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine in an organic solvent;

b) cooling the reaction mixture obtained in step (a);
c) providing the source of phosphate;
d) maintaining the reaction mass obtained in step (c) for sufficient time;
e) cooling the reaction mixture obtained in step (d);
f) isolating highly pure compound of formula I.

The preparation methods of (1 -naphthalen-1 -yl-ethyl)-[3-(3-trifluoromethylphenyl) allyl] amine can be performed by any known method in the literature.

The process of the present invention possesses two further distinct advantages in that the description of the intermediate compounds as well as the final compound improved appreciably and the final API meets the required colour description. A further advantage of this process is that it results in the removal of potential impurities, which gets carried over from the starting material (formed by different routes), at the initial stages of the process and it is evident from Table-1 that the purity of the final API is enhanced by the process according to this invention. Those skilled in the art will immediately recognize the economic benefits of such a process.

Table-l: Purity of unsaturated cinacalcet phosphate prepared from 3-(trifluoromethyl) cinnamaldehyde with different starting materials

In certain embodiments of the first aspect, the organic solvent system comprises an ester (such as ethyl acetate), ketone (such as acetone), a nitrite (such as acetonitrile), or mixtures thereof. Preferably the organic solvent system comprises ethyl acetate, acetonitrile, acetone or mixtures thereof.

The reaction mass obtained in step (a) may be maintained for sufficient time about 0 to 15°C and more preferably at about 5 to 15°C.

In certain embodiments of the first aspect, Phosphorus source is selected from phosphoric acid, salts derived from phosphoric acid, mineral phosphates or mixtures thereof. Particularly good results have been obtained with aqueous solution of 85% phosphoric acid and 95% phosphoric acid.

The reaction mass obtained in step (c) may be maintained for sufficient time about 35-55°C and more preferably at about 45-55°C.

The reaction mass obtained in step (d) may be subjected to cooling at about 0 to 15°C and more preferably at about 5 to 15°C.

Isolation of pure compound of formula I in step (f) may preferably be carried out by methods known such as filtration.

The isolated solid may be further dried by using conventional techniques. The drying may be carried out at temperatures of about 35-50°C. The drying may be carried out for any time periods necessary for obtaining a desired purity, such as about 1 to about 10 hours, or longer.

Preferably, the first aspect of the invention provides compound of formula I having a purity of greater than 99%, preferably greater than 99.8%, most preferably greater than 99.95%.

Phosphate salts of the unsaturated cinacalcet base can be treated with a base and can be reduced to cinacalcet free base by following any known method in the available literature.

According to the other aspect of the invention, there is provided process for the preparation of cinacalcet hydrochloride thereof comprises of: a) subjecting the crude compound of formula II

in solvent system consisting of methylcyclohexane at room temperature;

b) adding a solution of ethyl acetate in hydrochloride to the solution obtained in
step (a);

c) maintaining the solution obtained in step (b) for sufficient time; and

d) isolating cinacalcet hydrochloride.

Preferably, the other aspect of the invention provides compound of formula II having a purity of greater than 99%, preferably greater than 99.8%, most preferably greater than 99.95% and it is suitable for use in medicine and it is evident from the Table-2:

Table 2: Purity of cinacalcet hydrochloride formed from pure phosphate salt of unsaturated Cinacalcet free base

The purity of cinacalcet hydrochloride as well as pure phosphate salt of unsaturated Cinacalcet free base was measured by High performance liquid chromatography (HPLC) and the conditions are provided herewith:

Chromatographic Conditions:
Column : Sunfire C18 (250 X 4.6) mm, 5u
Wavelength : 225 nm
Flow Rate : 1.0 mL/min
Injection Volume : 20 pL
Column temperature : 30°C
Run Time : 50 min
Preparation of Mobile Phase:
Buffer preparation: Weigh accurately and transfer about 1.54 g of Ammonium acetate in 1000 ml_ of water. Mix well and filter through 0.45 u nylon membrane filter and degas.

Mobile Phase 'A': Prepare a mixture of 950 ml_ of Buffer and 50 ml_ of Methanol. Mix well and degas.

Mobile Phase 'B': Prepare a mixture of 900 ml_ of Acetonitrile and 100 mL of Methanol. Mix well and degas.

Diluent: Water: Acetonitrile (1:1) v/v
The above description briefly outlines the preferred embodiments of the present invention, which enables those skilled in the art to understand the detailed description that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art would appreciate that they can readily use the disclosed concept and specific embodiment as a basis for preparation of similar derivatives. Those skilled in the art would realize such an equivalent concept does not depart from the spirit and scope of the invention in its broadest sense.

Best-Mode:
Example-1:

Preparation of (1 -naphthalen-1 -vl-ethvl)-r3-(3-trifluoromethvlphenyl)allvnamine phosphate using 3-(trifluoromethyl)cinnamaldehvde formed from 3-(trifluoromethyl)cinnamic acid

A solution of (R)-naphthylethylamine, 38.50g (0.225 moles, 0.9 mol eq) in methanol (250.0ml) was added drop-wise to an ice-cooled solution (5-10°C) of 3-(trifluoromethyl) cinnamaldehyde, 50.Og (0.249 moles, 1.0 mol eq; Purity by HPLC 93%) in methanol (250.0ml) under nitrogen atmosphere over a period of 30-45min. After the completion of addition, the reaction mixture was warmed to 25-30° C and stirred for about 3.5 hours for reaction completion. Again the reaction mass was cooled to 0-5°C and sodium borohydride, 4.72 g (0.125 moles, 0.5 mole eq) was added portion wise in lots at the same temperature. Warmed the reaction mixture to 25-30°C and stirred till the completion of the reaction (HPLC; 1 hour).

Methanol was distilled out at 40-45°C under vacuum and the residue obtained was taken in toluene (200ml) and water (100ml). The pH of the aqueous layer was adjusted around 5.5 using dilute hydrochloric acid, separated and the aqueous layer was back extracted with toluene (100ml). The toluene layers were combined, washed with 1.0% sodium bicarbonate solution (100ml) and then with DM water (100 ml). The separated toluene layer was distilled out at 50-55°C under vacuum to obtain an oily residue. 20% Aqueous acetone (125ml) was added to the above oil and cooled to 5-10°C. A solution of 85% phosphoric acid (25.92ml) in 20% aq. acetone (25ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55X and stirred for 45 min.
Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with 20% aq.acetone (50ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-2:
Preparation of (1-naphthalen-1-vl-ethvl)-r3-(3-trifluoromethvlphenvl)allyl1amine phosphate using 3-(trifluoromethyl)cinnamaldehvde formed from 3-(trifluoromethvl)benzaldehvde

A solution of (R)-naphthylethylamine, 15.0g (0.0749 moles, 0.9 mole eq) in methanol (75.0ml) was added drop-wise to an ice-cooled solution (5-10°C) of 3-(trifluoromethyl) cinnamaldehyde, 12.83g (0.0749 moles, 1.0 mole eq; Purity by HPLC 86%) in methanol (75.0ml) under nitrogen atmosphere over a period of 30-45min. After the completion of addition, the reaction mixture was warmed to 25-30° C and stirred for about 3.5 hours for reaction completion. Again the reaction mass was cooled to 0-5°C and sodium borohydride, 1.4 g (0.037 moles, 0.5 mole eq) was added portion wise in lots at the same temperature.

Warmed the reaction mixture to 25-30°C and stirred till the completion of the reaction (HPLC; 1 hour).

Methanol was distilled out at 40-45X under vacuum and the residue obtained was taken in toluene (60ml) and water (30ml). The pH of the aqueous layer was adjusted around 5.5 using dilute hydrochloric acid, separated and the aqueous layer was back extracted with toluene (30ml). The toluene layers were combined, washed with 1.0% sodium bicarbonate solution (30ml) and then with DM water (30 ml). The separated toluene layer was distilled out at 50-55°C under vacuum to obtain an oily residue. 20%

Aqueous acetone (5ml) was added to the 0.5g of above oil and cooled to 5-10°C. A solution of 95% phosphoric acid (0.14ml) in 20% aq. acetone (5ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with 20% aq.acetone (2.5ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-3:
Preparation of (1-naphthalen-1-vl-ethvl)-r3-(3-trifluoromethvlphenyl)allvnamine phosphate using 3-(trifluoromethyl)cinnamaldehvde formed from 3-(trifluoromethvQaniline

A solution of (R)-naphthylethylamine, 200.Og (1.0 moles, 0.9 mole eq) in methanol (1000.0ml) was added drop-wise to an ice-cooled solution (5-10°C) of 3-(trifluoromethyl) cinnamaldehyde, 153.9g (0.898 moles, 0.9 mole eq; Purity by HPLC 93%) in methanol (1000.0ml) under nitrogen atmosphere over a period of 30-45min. After the completion of addition, the reaction mixture was warmed to 25-30° C and stirred for about 3.5 hours for reaction completion. Again the reaction mass was cooled to 0-5°C and sodium borohydride, 18.9 g (0.49 moles, 0.5 mole eq) was added portion wise in lots at the same temperature. Warmed the reaction mixture to 25-30°C and stirred till the completion of the reaction (HPLC; 1 hour). Methanol was distilled out at 40-45°C under vacuum and the residue obtained was taken in toluene (800ml) and water (400ml). The pH of the aqueous layer was adjusted around 5.5 using dilute hydrochloric acid, separated and the aqueous layer was back extracted with toluene (400ml). The toluene layers were combined, washed with 1.0% sodium bicarbonate solution (400ml) and then with DM water (400 ml). The separated toluene layer was distilled out at 50-55°C under vacuum to obtain an oily residue. 20% Aqueous acetone (400ml) was added to the 0.5g of above oil and cooled to 5-10°C. A solution of 85% phosphoric acid (103.2ml) in 20% aq. acetone (100ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with 20% aq.acetone (200ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-4:
Preparation of (1 -naphthalen-1 -yl-ethyl)-r3-(3-trifluoromethylphenyl)alylnamine phosphate in ethyl acetate:

Ethyl acetate (5ml) was added to 0.5g of (1 -naphthalen-1 -yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine taken in a 50.ml flask and cooled to 5-10°C. A solution of 95% phosphoric acid (0.14ml) in ethyl acetate (5ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with ethyl acetate (2.5ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-5:
Preparation of (1 -naphthalen-1 -yl-ethyl)-r3-(3-trifluoromethvlphenvl)allyllamine phosphate in acetonitrile:
Acetonitrile (6.8ml) was added to 1.7g of (1 -naphthalen-1 -yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine taken in a 50.ml flask and cooled to 5-10°C. 95% Phosphoric acid (0.47ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with acetonitrile (3.4ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-6:
Preparation of (1 -naphthalen-1 -yl-ethvlH3-(3-trifluoromethylphenvl)allvnamine phosphate in acetone:

Acetone (25.0ml) was added to 10.0g of (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine taken in a 50.ml flask and cooled to 5-10°C. 85% Phosphoric acid (3.4ml) was added drop-wise to the above reaction mass to form white solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with acetone (20.0ml) and dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as off-white to white solid.

Example-7:
Preparation of (1 -naphthalen-1 -yl-ethyl)-{3-(3-trifluoromethylphenylallvnamine phosphate in 50% aqueous acetone:
50% Aqueous acetone (30.0ml) was added to the 10.0g of (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine taken in a 50.ml flask and cooled to 5-10°C. 85% Phosphoric acid (3.4ml) was added drop-wise to the above reaction mass to form light yellow colour solid. The reaction mass was gradually heated to 50-55°C and stirred for 45 min. Cooled the reaction mass to 5-10°C, stirred for 1 hour and the solid was filtered. Washed the solid with 50% aqueous acetone (20.0ml) and dried under vacuum at 50-55°C to get (1 -naphthalen-1 -yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate as pale-yellow solid.

Example-8:
Preparation of cinacalcet hydrochloride I'd -naphthalen-1 -yl-ethvlH3-(3-trifluoromethylphenvD-propyn-amine hydrochloride!:

Methyl-tert-butyl ether (150ml) and water (150ml) was added to (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine phosphate, 50g (0.110 moles) at 25-30°C taken in a 500ml RB flask. Aqueous ammonia (~25%), 50ml was added dropwise to adjust the pH of the aqueous layer around 8.8 and the layers are separated. The aqueous layer was back extracted with methyl-tert-butyl ether (100ml) and the combined organic layers were washed with water (200ml). The separated organic layer was charged with 10%Pd/C (5.0g) in a 1.0L autoclave and pressurised with hydrogen gas (0.3D0.1Kg/cm2).

The autoclave was refilled with hydrogen gas until no more consumption was observed. After completion of the reaction (HPLC, 4.5h), the reaction mass was filtered through hyflo bed under nitrogen atmosphere and washed the hyflo bed with methyl-tert-butyl ether (50ml).

The filtrate was washed sequentially with water (200ml), 5% aq. acetic acid (200ml), 5% sodium bicarbonate solution (250ml) and finally with water (200ml). The methyl-tert-butyl ether layer was separated and distilled at 40-45°C under vacuum followed by degassing at 50-55°C to obtain an oily residue. Methyl cyclohexane (300ml) was added under stirring to the crude Cinacalcet at 25-30°C, filtered through 0.45 micron and chilled down to 5-10oC. 15% ethyl acetate-HCI (34.9ml) was added drop-wise to
the reaction mass over a period of 45 min to form white solid. The reaction mass further stirred for a period of 2.5 h, filtered and washed with methyl cyclohexane (100ml). The solid was dried under vacuum at 50-55°C to get (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)propyl]amine hydrochloride
(cinacalcet hydrochloride) as white to off-white solid (Y? purity?).

Claims:

1. A process for preparing phosphate salt of (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl) allyl] amine of formula I in high purity comprising:

a) Dissolving (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl)allyl]amine in organic solvent;

b) cooling reaction mixture obtained in step (a);

c) providing a source of phosphate;

d) maintaining reaction mass obtained in step (c) for sufficient time;

e) cooling reaction mixture obtained in step (d);

f) isolating compound of formula I.

2. A process according to claim 1, wherein said organic solvent used in step (a) comprises of esters, ketones, nitriles or mixtures.

3. A process according to claim 2, wherein said organic solvent used in step (a) comprises of ethyl acetate, acetone, acetonitrile or mixtures thereof.

4. A process according to claim 1, wherein said cooling of reaction mixture in step (b) is between 0-15°C.

5. A process according to claim 1, wherein said source of phosphate is phosphoric acid.

6. A process according to claim 1, wherein said reaction mass of step (d) is maintained at about 30-60°C.

7. A process according to claim 1, wherein said cooling of reaction mass in step (e) is between 0-15°C.

8. Phosphate salt of (1-naphthalen-1-yl-ethyl)-[3-(3-trifluoromethylphenyl) allyl] amine of formula I, with HPLC purity of equal to or greater than 99.8% when prepared by a process according to any of claims.

9. A process for preparation of cinacalcet hydrochloride that comprises of:

a) subjecting a crude compound of formula II

in a solvent system comprising of methylcyclohexane

b) adding a solution of ethyl acetate in hydrochloride to solution obtained in step (a);

c) maintaining solution obtained in step (b) for sufficient time; and

d) isolating cinacalcet hydrochloride.