FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003

'SS3R3S-"

PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESSES FOR PREPARING CINACALCET HYDROCHLORIDE


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India

The following specification particularly describes the invention:


PROCESSES FOR PREPARING CINACALCET HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to a process for preparing Cinacaicet hydrochloride (I) comprising (a) providing a solution of free base of cinacaicet in a solvent selected from a sulfolane, ethylene glycol or dimethoxyethane, and mixtures thereof; (b) treating said solution with hydrochloric acid to obtain a reaction mixture; (c) optionally adding an anti-solvent to the said reaction mixture; and (d) recovering precipitated cinacaicet hydrochloride.
BACKGROUND OF THE INVENTION:
Cinacalcet belongs to the calcimimetics class of compounds, which is useful 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 is described chemically as N-[l-(R)-(-)-(l-naphthyl)ethyI]-3-[3-(trifluoromethyl)phenyl]-l-aminopropane hydrochloride, which has the structural formula

Cinacaicet hydrochloride is marketed as Sensipar® in the USA and as Mimpara® in Europe. It is available as 33, 66 and 99 mg tablets of cinacaicet hydrochloride equivalent to 30, 60 and 90 mg of cinacaicet free base respectively.
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U.S. Patent No. 6,011.068 generally describes cinacalcet and it's pharmaceutical^ acceptable acid addition salts.
U.S. Patent No. 6,211.244 describes cinacalcet and its pharmaceutically acceptable acid addition salt and process for the preparation of the same in analogues way. According to this patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-(3-(trif1uoromethyl)phenyl)propylamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography.
Further, according to the process disclosed in U.S. Pat. No. 6,211,244, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-I-(l-naphthy!)ethylamine (II) with 3-(3-trifluoromethylphenyl) propanai (HI) in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride, according to the scheme-1.
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Scheme-1

The isolation of Cinacalcet as hydrochloride salt is not specifically disclosed in US 6,211,244. The said prior art exemplifies the synthesis and isolation of cinacalcet structural analogues. The hydrochloride salt of the said analogues is prepared by precipitation of using HC1 (g) in ether or hexane in combination with HC1 (g) in ether. However, this method is not suitable to large scale production.
PCT publication WO 2006/127933 discloses that the crystalline cinacalcet hydrochloride currently marketed as SENSIPAR® is characterized as crystalline Form-I having powder XRD peaks at about 13.9, 19.0, 21.3, and 25.5.±.0.2 degrees 2.theta. This crystalline form may be further characterized by a powder XRD pattern with peaks at about 15.0, 15.5, 16.0, 17.9, 23.7, and 24.3.±.0.2 degrees 2.theta. This publication discloses a various process for the preparation of cinacalcet hydrochloride Form-I.
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Further, PCT Publication WO 2006/127941 relates to amorphous cinacalcet hydrochloride and to a process for its preparation.
Other publications also disclose processes for the preparation of cinacalcet hydrochloride and its polymorph include WO 2008/058236, WO 2008/068625 and WO 2008/000423.
There still exists a need for a process for the preparation of crystalline cinacalcet hydrochloride, which may be scaled up for large scale synthesis.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for the preparation of cinacalcet hydrochloride comprising:
(a) providing a solution of free base of cinacalcet in a solvent selected from a sulfolane, ethylene glycol or dimethoxyethane, and mixtures thereof;
(b) treating said solution with hydrochloric acid to obtain a reaction mixture;
(c) optionally adding an anti-solvent to the said reaction mixture; and
(d) recovering precipitated cinacalcet hydrochloride.
In another aspect, the present invention provides a process for the preparation of cinacalcet hydrochloride Form I with a high degree of chemical purity.
In yet another aspect, the present invention provides a pharmaceutical composition comprising cinacalcet hydrochloride prepared according to present invention and at least one pharmaceutical^ excipient.
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BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS:
Fig. 1: This figure indicates X-ray diffraction pattern of crystalline form of cinacalcet hydrochloride obtained according to the instant invention.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The present invention may. however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
The present invention relates, in general, to a process for the preparation of cinacalcet hydrochloride. In preferred aspect, the present invention provides a process for the preparation of cinacalcet hydrochloride Form-I.
Cinacalcet hydrochloride Form I is characterized by powder XRD peaks at about 13.9, 19.0, 21.3, and 25.5.±.0.2 degrees 2.theta. This crystalline form i.e. cinacalcet hydrochloride Form-I may be further characterized by a powder XRD pattern with peaks at about 15.0, 15.5, 16.0, 17.9, 23.7, and 24.3.±.0.2 degrees 2.theta. Cinacalcet
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hydrochloride Form I is further characterized by having a high chemical purity, according to high performance liquid chromatography (HPLC).
In another aspect, the present invention provides a process for the preparation of cinacalcet hydrochloride more particularly, cinacalcet hydrochloride Form-I have a degree of chemical purity in the range of about 99.0% to about 99.8%. In general, the present invention provides a process for the preparation of cinacalcet hydrochloride comprising:
(a) providing a solution of free base of cinacalcet in a solvent selected from a sulfolane. ethylene glycol or dimethoxyethane, and mixtures thereof;
(b) treating said solution with hydrochloric acid to obtain a reaction mixture;
(c) optionally adding an anti-solvent to the said reaction mixture; and
(d) recovering precipitated cinacalcet hydrochloride.
In step (a), the fr&e base of cinacalcet and solvent are mixed at room temperature in at least an amount sufficient to obtain a solution. Wherein, the solvent is selected from the group comprising of sulfolane, ethylene glycol or dimethoxyethane and mixture thereof. Preferably, the solvent is in amount of from about 1 to about 20 ml per gram of cinacalcet base.
In step (b), the solution as obtained in step (a) is treated with either gaseous or aqueous hydrochloric acid. Particularly, when the solution is treated with aqueous hydrochloric acid, the acid is in an amount sufficient to react with almost all amount of cinacalcet base, more preferably an amount from about 0.5 to 5 moles per mole of cinacalcet base. The aqueous solution of hydrochloric acid is added in drop-wise or in one portion. The addition of hydrochloric acid may be carried out at a room temperature.
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Preferably, the reaction mixture obtained after addition of hydrochloric acid is stirred for about 30 minutes to about 5 hours.
In step (c), the reaction mixture obtained in step (b) is optionally added with anti-solvent. Particularly, in case when cinacalcet hydrochloride is not completely isolated even after stirring the reaction mixture for sufficient time; in that case anti-solvent is added in the amount necessary to precipitate solid cinacalcet hydrochloride.
The anti-solvent is a solvent in which cinacalcet hydrochloride has a low solubility, preferably, the anti-solvent is selected from the group comprising of water, cyclic or non-cyclic hydrocarbon, aliphatic or branched ethers, esters, ketones and mixture thereof. More preferably, the anti-solvent is selected from the group comprising water, xylene, n-heptane, n-hexane, n-pentane, diisopropyl ether, dimethyl ether, diethyl ether, MTBE, cyclohexane, THF, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone or mixtures thereof.
Combining the solution with the anti-solvent can be accomplished either in one portion or drop-wise. The amount of anti-solvent should be 2 to 10 times by volume of solvent used in step (a). The addition of anti-solvent may be carried out at a room temperature. Seeding crystals may be added before or after initiating the precipitation.
The reaction mixture obtained after the addition of the anti-solvent is preferably stirred for at least about 10-15 minutes, more preferably from about 10 minutes to about 10 hours at room temperature.
In step (d), Cinacalcet hydrochloride may be recovered by any method known in the art, such as filtering, washing, preferably washing with the solvent used and drying. Drying is carried out at a temperature of from about 45°C to about 55°C in hot air oven or under vacuum.
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The present invention also provided pharmaceutical compositions of cinacalcet hydrochloride prepared according to the processes described herein, and one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical compositions may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the formulations include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyi cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrin, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl
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cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutical^ acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
The various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully.
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.
Esample-1:
Preparation of 3-trifluoromethylphenyI cinnamic acid
3-Trifluoromethylbenzaldehyde (100 gm), malonic acid (65.7 gm) and piperidine (48.8 gm) in dry cyclohexane (800 ml) were heated at 80°C-85°C for 6 h. After completion of the reaction, the reaction mass was cooled to about room temperature followed by addition of water (300 ml) and again added with concentrated hydrochloric acid (30%, 100 ml) diluted with water (100 ml). The reaction mass was stirred for 30 minutes at room temperature and cooled to about J2±3°C. The separated solid was filtered and washed with 200 ml water. The wet cake was taken into another flask and added with water (1000 ml). The reaction mass were heated to about 90±3°C and maintained for about 2 hours at the same temperature, and then reaction mass was cooled to about 28±3°C, and stirred for 1 hour. The separated solid was filtered and washed with water (200 ml). The resultant solid was dried in hot air oven at'60°C-65°C. (Weight = 104 gm, purity-99.84%)
Example-2:
Preparation of Methyl-3-trifluoromethylcinnamate . ..... ,

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To a solution of 3-trif!uoromethy]phenyl cinnamic acid (100 g) in methanol (300 ml) was added with sulphuric acid (54.4 gm) in drop-wise manner. The reaction mass was heated to about 65°C-70°C and maintained for about 4 hours. After completion of the reaction, the methanol was distilled at 60°C-80 under vacuum, the reaction mass was cooled to about 27±5°C. Toluene (1000 ml) and water (500 ml) was added to the reaction mass, and then organic layer was separated. The organic layer was washed with sodium carbonate solution (5%. 500 ml), and the organic layer again washed with sodium chloride solution (5%, 500 ml). The organic layer was distilled off under vacuum at 50±3°C, and then reaction mass was added with methanol and methanol was completely distilled off at 50±3°C under vacuum to get the title compound (weight = 105 gm).
ExampIe-3:
Preparation of Methyl-3-trifluormehty 1 phenyl propionate
A solution of Methyl-3-trifluoromethylcinnamate (100 gm) in methanol (300 ml) was taken into hydrogenator. Palladium-carbon (10% w/w) (5 g) was moistened with water (15 ml) and prepared slurry in methanol (200 ml). The prepared palladium slurry was added to hydrogenator and 5-6 kg/cm2 of hydrogen gas pressure was passed into the reaction mass at about 28-35°C for about 4 hours. After completion of the reaction, the reaction mass was filtered through hyflow-bed and bed was washed with methanol (200 ml). The filtrate was distilled completely at about 50±3°C under vacuum, the residue was added with heptane (200 ml) and heptane was distilled at about 50±3°C under vacuum to afford 100 gm compound of title compound (Purity = 99.12%).
Example-4:
Preparation of 3-(3-trifluoromethylphenyl) propanal
A cooled solution (0°C-10°C) of vitride (70 % solution in toluene) in toluene (450 ml) was added with N-methyl piperazine (31.05 gm) solution in toluene (90 ml) at 5±3°C. The solution was heated to 25°C-30°C and maintained at same temperature for 30 minutes. The resultant solution was added to pre-cooled (-25±3°C) solution of Methyl-3-
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trifluormehtyl phenyl propionate (30 gm) in toluene (300 ml) at -25±3°C over a period of about 1.5 to 2 hours. After completion of the reaction, the reaction mass was added with concentrated aqueous hydrochloride solution (180 ml) and water (360 ml) followed by stirring for about 15-20 minutes and then organic layer was separated. The separated organic layer was washed with water (450 ml) followed by washing with sodium carbonate solution (5%, 450 ml). The organic layer was filtered through hyflow bed and bed was washed with toluene (60 ml). The organic layer was distilled off under a vacuum at about 45°C. The residual mass was stripped out with n-heptane (90 ml) to get title compound (weight = 25.6 gm).
Example-5:
Purification of 3-(3-trifluoromethylphenyl) propanal
A solution of 3-(3-trifluoromethylphenyl) propanal (23 gm) in heptane (50 ml) was added with solution of sodium bisulfite (30 gm in 50 ml water). The reaction mixture was added with another amount of heptane (50 ml) and stirred for 2 hrs. The resultant slurry was filtered and washed with heptane (50 ml) and wet material was dried in hot air oven at 50°C-55°C to get bisulphite-adduct (weight = 34.5 gm).
To a solution of bisulphite-adduct (33 gm) in water was added with sodium carbonate solution (45.7 gm in 130 ml water) at room temperature. The reaction mixture was added with ethyl acetate (130 ml) at room temperature and stirred for 15 minutes at 25°C-30°C. Then reaction mixture was added with ethyl acetated (200ml) and stirred for 15 minutes at 25°C-30°C. The organic layer was separated and organic layer was distilled off under a vacuum at 45°C-50°C to get residue. The resultant residue was added with n-hexane (100 ml) and n-hexane was distilled off under a vacuum at 45°C-50°C to get titled compound (weight = 19 gm).
Example-6:
Preparation of Cinacalcet base
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Under nitrogen atmosphere, 3-(3-trifluoromethylphenyl) propanal (18 gm) and toluene (230 ml) were taken into a round bottom flask and cooled to about 2±3°C. The solution of R-1-naphthylethylamine (15.24 gm) in toluene (40 ml) was added to it and reaction mass was stirred for 1 hour at 2±3°C. The resulting solution was added with sodium borohydride (3.36 gm) followed by addition with methanol (35 ml) at 2±3°C within 1 hour. The reaction mass was stirred for 2 hours at about 2±3°C followed by addition with water (230 ml) and stirred for 10 minutes at about 25°C-35°C. The organic layer was separated and washed thrice with aqueous hydrochloride solution (18 ml cone. HC1 + 252 m! water). The organic layer then washed with 5% sodium carbonate solution (270 ml) and organic layer was distilled off under a vacuum at 50°C to get the title compound (weight = 30.5 gm).
Exampfe-7:
Preparation of Cinacalcet Hydrochloride
A solution of cinacalcet base (38 gm) in ethyl acetate (230 ml) was added with 30% aqueous hydrochloride solution (27 ml) followed by stirring for about 15 minutes. The reaction mass was distilled off under a vacuum at 65°C. The resulting residue was added with ethyl acetate (230 ml) followed by distillation of the ethyl acetate under a vacuum at 65°C. The resulting residue was dissolved in ethyl acetate (184 ml) and cooled to 0°C-5°C followed by stirring for about 1 hour. The separated solid was filtered and washed with chilled ethyl acetate (23 ml). The wet solid was dried in hot air oven at 60°C to afford the 30 gm of the title compound (HPLC purity = 99.90%).
Examplc-8:
Preparation of Cinacalcet Hydrochloride
A solution of cinacalcet base (8.2 gm) in sulfolane (40 ml) was added with 30% aqueous hydrochloride solution (5 ml) followed by stirring for about 1 hour. Then water (120 ml) was added slowly to the resulting reaction mass followed by stirring for about 1 hour.
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The separated solid was filtered and washed with water (20 ml). The wet solid was dried in hot air oven at 50°C to afford the 7 gm of the title compound (HPLC purity = 99.30%).
Example-9:
Preparation of Cinacalcet Hydrochloride
A solution of cinacalcet base (8.1 gm) in ethylene glycol (40 ml) was added with 30% aqueous hydrochloride solution (5 ml) followed by stirring for about I hour. The separated solid was filtered and washed with water (20 ml). The wet solid was dried in hot air oven at 50°C to afford the 5.5 gm of the title compound (HPLC purity = 99.09%).
Exam pie-10:
Preparation of Cinacalcet Hydrochloride
A solution of cinacalcet base (8.3 gm) dimethoxyethane (40 ml) was added with 30%o aqueous hydrochloride solution (5 ml) followed by stirring for about 1 hour. Then water (120 ml) was added slowly to the resulting reaction mass followed by stirring for about 1 hour. The separated solid was filtered and washed with water (20 ml). The wet solid was dried in hot air oven at 50°C to afford the 7.4 gm of the title compound (HPLC purity = 99.31%).
Example-11:
Preparation of Cinacalcet Hydrochloride
Cinacalcet base (8.1 gm) was added with 30% aqueous hydrochloride solution (5 ml) followed by stirring for about 30 minutes at 25°C-30°C. The resulting reaction mass was then heated to 60°C-70°C. The resulting slurry was then cooled to 25°C-30°C followed by stirring for about 1 hour. The slurry was filtered and washed with water (20 ml). The separated solid was filtered and washed with water (20 ml). The wet solid was dried in hot air oven at 50°C to afford the 7.0 gm of the title compound.
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Example-12:
Preparation of Cinacalcet Hydrochloride
A solution of cinacalcet base (8.6 gm) in ethyl acetate (50 ml) was added with methanolic HC1 (11.3 ml) followed by stirring for about 30 minutes. The reaction mass was added with charcoal (0.5 gm) and stirred for 15 minutes. The resulting mass was filtered through hyflow bed and washed with ethyl acetate (15 ml). The filtrate was distilled out under vacuum at 60°C-65°C and residual mass was added with ethyl acetate (25 ml). The ethyl acetate was again distilled off under vacuum at 60°C-65°C and residual mass was dissolved in ethyl acetate (50 ml) and cooled it to about 25°C-30°C. The reaction mass was cooled to about 0°C-5°C and stirred for 1 hour. The separated solid was filtered and washed with chilled ethyl acetate (10 ml). The wet solid was dried in hot air oven at 60°C to afford the 7.0 gm of the title compound. (HPLC purity = 99.90%).
Dated this 01st June, 2009
for Torrent Pharmaceuticals Limited, Praveen Chand Gandhi
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