Title of Invention	A METHOD FOR THE PREPARATION OF CINACALCET
Abstract	A new method for the preparation of Cinacalcet by treating (R)-1-naphthyl ethylamine with an aromatic aldehyde to form (1R)-1-(2-naphthyl)-N-(aryl methylene)ethanamine derivative which is further treated with 1 -(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) to obtain an iminiunm salt and followed by hydrolysis to obtain Cinacalcet free base. A new compound, (11")- 1-(2-naphthyl)-N-(aryImethyl ene)ethanamine and an iminium salt compound are disclosed.

Title of Invention

A METHOD FOR THE PREPARATION OF CINACALCET

Abstract

A new method for the preparation of Cinacalcet by treating (R)-1-naphthyl ethylamine with an aromatic aldehyde to form (1R)-1-(2-naphthyl)-N-(aryl methylene)ethanamine derivative which is further treated with 1 -(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) to obtain an iminiunm salt and followed by hydrolysis to obtain Cinacalcet free base. A new compound, (11")- 1-(2-naphthyl)-N-(aryImethyl ene)ethanamine and an iminium salt compound are disclosed.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) As amended by the Patents (Amendment) Act, 2005 & The Patents Rules, 2003 As amended by the Patents (Amendment) Rules, 2005 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION A NEW METHOD FOR THE PREPARATION OF CINACALCET AND NEW INTERMEDIATES THEREOF. APPLICANTS Name Nationality 4th Floor. SETHNA. 55. Maharshi Karve Road. M arine Lines. Megafine Pharma (P) Ltd. Indian Company Address Mumbai - 400 002, Maharashtra. India. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the nature of this invention: TECHNICAL FIELD: This invention relates to a new method for the preparation of N-\| l(R)-(l-naphthyl)ethyl\|-N-j3-[j-(triiluoromethyl) phenyl]propyl]-l -amine. Cinacalcet. of the formula (I); Formula 1 This invention also relates to (l^)-l-(2-naphthyl)-yV-(phenylmethylene)ethanamine derivative of the formula (IV); which is used as an intermediate for the preparation of Cinacalcet. This invention also relates to a process for the preparation of (]R)-]-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV). This invention also relates to a iminium salt compound of formula (VI): Formula (VI) which is used as an intermediate for the preparation of Cinacalcet. This invention also relates to a process for the preparation of the iminium salt compound of formula (VJ). BACKGROUND OF THE INVENTION: N-[l(R)-(l-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl) phenyl]propyl]-l-amine (herein "Cinacalcet" or "CNC") has a CAS number of 226256-56-0, a formula of C22H22F3N and the following structure: CH3 Formula (I) This molecule is the free base form of Cinacalcet hydrochloride (herein "CNC-HCl"). having a CAS number of 364782-34-3 and the following structure: .HCI CH3 Formula (VII) CNC-HCl is marketed as SENSIPAR™, and is the first drug in a class ofcompounds known as Calcimimetics to be approved by the FDA. 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 lew 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 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. CNC-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCl lowers serum levels of PTH as vvel] as the calcium/phosphorus ion product, a) measure of the amount of calcium and phosphorus in the blood. US 6,011,068 disclose inorganic ion receptor activity, especially calcium receptor-active molecules, such as those having the general structure of Cinacalcet. US 6,211,244 disclose calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. In accordance with the patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-[3-(trifluoromethyI)phenyl\|propyiamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resoiution of the racemic Cinacalcet base by chiral liquid chromatography, according to Scheme 1: CNC base racemic Scheme 1 Similarly, using the process disclosed in US 6,211,244, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-l-(l- naphthyl)ethylamine with 3-\| 3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanotic sodium cyanoborohydride. according to the following Scheme 2: R - CNC base Scheme 2 US 6,211.244 disclose an additional process for the synthesis of Cinacalcct. This process involves treating 3-trirluoromethylcinnamonitrile. which can be prepared as disclosed in US 4,966,988. with diisobutyl aluminum hydride, followed by treating the intermediate aluminum- imine complex with (R)-I-(l-naphthyI)ethyIamine, and reducing the intermediate imine with ethanolic sodium cyanoborohydride. according, to the following Scheme 3: Scheme 3 These three processes however, require the use of reagents such as titanium isopropoxide which is highly hygroscopic and expensive, as well as toxic, and ethanotic or methanolic sodium cyanoborohydride. which is highly toxic and flammable, and not environmentally friendly, making the processes difficult to apply on industrial scale. Thus, an alternative process for the preparation of cinacalcet base and cinacalcet salt, which is more direct, higher yield, environmental friendly and applicable to industrial scale production is desirable. OBJECTS OF THE PRESENT INVENTION: An object of the present invention is to provide a new method for the preparation of Cinacalcet and / or its salts, wherein the process is economical, simple, efficient, cost-effective and easy to carry out. Another object of the invention is to provide the new method for the preparation of Cinacalcet and /or its salts with high yields and substantially pure and free from impurities and thus making the process efficient. Yet another object of the invention is to provide the new method for the preparation of Cinacalcet and / or its salts in a single pot where in isolation of intermediates by nitrations arc avoided to reduce exposure of the production executive to the chemicals and to reduce the turn around time of the total time cycle per batch. Yet another object of the invention is to provide the new method for the preparation of Cinacalcet and / or its salts in which aromatic aldehyde which is used as a starting material may be easily recovered and recycled from the reaction mixture efficiently; thus reduces the effluents and making the process cost-effective and eco-friendly . Yet another object of the invention is to provide a new compound. (l/?)-l-(2-naphthyl)-N- (phenylmethylene)ethanamine. of formula (IV), which is used as an intermediate for the production of cinacalcet. Yet another object of the invention is to provide process for preparing a new compound. (\R)-\- (2-naphthyl)-//-(phenylmethylene)ethanamine, of formula (IV). which is used as an intermediate for the production of cinacalcet. Yet another object of the invention is to provide a iminium salt compound of formula (VI), which is used as an intermediate for the preparation of Cinacalcet. Yet another object of the invention is to provide a process for the preparation of the iminium salt compound of formula (VI)S which is used as an intermediate for the preparation of Cinacalcet. DETAILED DESCRIPTION OF THE INVENTION: The present invention provides a novel method for efficiently preparing Cinacalcet and/or one of its pharmaceutically acceptable salts. According to the process of present invention, Cinacalcet is obtained by using milder reaction conditions and without tfee need for laborious operations such as chromatographic purifications or solvent distillations, and hazardous chemicals. The process for making the compound (I) involves three steps. While the steps are normally run separately, that is consecutively, the process may nonetheless be conveniently performed in a one pot arrangement as well, e.g. as a one pot process with out isolation of the intermediates. According to the invention, there is provided a new method for the preparation of Cinacalcet of formula (I); Formula 1 the method comprises; a. reacting (R)-1-naphthyl ethylamine of the Formula (II) and aromatic aldehyde of formula (III) to form (l/?)-l-(2-naphlhyl)-A'-(phenylmethylene)ethanamine derivative of formula Wherein, Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alky], aryl. alkoxy. amino, hydroxyl, halogen, and nitro groups. b. treating the reaction mixture comprising (l/R)-l-(2-naphthyl)-N- (phenylmethylene)ethanamine derivative of formula (IV) which is obtained from step (a) with I- (3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) to obtain iminium salt compound ol formula (VI); Wherein; Ar : benzyl-, phenyl- or naphlhyl- which may be mono- or di- or poly substituted with alkyl. aryl. alkoxy. amino, hydroxyl, halogen, and nitro groups. X: Chloro. Bromo or lodo and c. treating the reaction mixture of step (b) comprising iminium salt of formula (VI) with water and /or acid solution to obtain Cinacalcet free base of the compound of formula (1). Formula-(VI) Formula-(I) Step (a) of the above-mentioned method comprises reacting (R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C. In another embodiment of the invention, the Step (a) of the above-mentioned method comprises reacting(R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (HI) ai temperature of 60 to I50°C optionally in the presence of organic solvent. Preferably, step (a) is carried out at temperature of 80 to 120°C, more preferably, 90 to !20°C. Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphlhyl- which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy. amino, hydroxyl. halogen, and nitro groups. The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in step (a) is selected from the group consisting of a hydrocarbons, alcohols. CI-CIO ether, C5-C8 cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide. CI -C8 chlorinated hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as methanol, ethanol, propanoL butanol and the like, hydrocarbons such as toluene, xylene and the like; more preferably, the solvent is toluene or ethanol. The reaction time of step (a) is invariably depends on the lemperature condition used to carry out step (a). The reaction time increases with decrease in temperature. The course of the reaction is monitored by a suitable analytical method, for instance by TLC till the completion of the reaction. Step {a) of the method further/optionally comprises isolating (ltf)-l-(2-naphthyl)-;V- (phenylmethylene)ethanamine derivative of formula (IV) as a white crystalline solid by filtering the reaction mass of step (a). The above mentioned step (b) comprises treating the reaction mixture of step (a) comprising (l/?)-l-(2-naphthyl)-/V-(pheny]methylene)elhanamine derivative of formula (IV) with l-(3- halopropyl)-3-(trifluoromethyl)benzene of formula (V) at lemperature of 80-160°C to obtain iminium salt compound of formula (VI). The halo group. "X" in the compound Formula (V) is either chloro. bromo, or iodo. In another embodiment of the invention, the Step (b) of the above-mentioned method comprises treating the reaction mixture of step (a) comprising (1 /?)-1 -(2-naphlhyl)-/V- (phenylmethylene)ethanamine derivative of formula (IV) with l-(3-halopropyl)-3- (trifluorornethyl)benzene of formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent. In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the reaction mixture of step (a) comprising ((l/f)-l-(2-naphthyl)-A/- (phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3- (trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent under pressure. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (l/?)-l-(2-naphthyl)-yV-(phenylmethyIene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-(trifluoromeihyl)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benz'ylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabulylammonium bromide. tetrabutylammomum chloride, tricaprylmethylammonium chloride, tetrabutylammomum iodide and the like. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (l/^)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyllhiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionallyjn presence of organic solvent. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (l/?)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure. In yet another embodiment of the invention, the above mentioned step (b) comprises treating the (lJff)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-160QC to obtain iminium salt compound of formula (VI). In yet another embodiment of the invention, the above mentioned step (b) further comprises treating the (l^)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethy!)benzene of formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent lo obtain iminium sail compound of formula (VI). In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the (l/?)-l-(2-naphthyl)-A^-(phenylmethyIene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent under pressure. In yet another embodiment of the invention, the step (b) further comprises treating the {\R)-\-{2-naphthyl)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l~(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride. 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like. In yet another embodiment of the invention, the step (b) further comprises treating the (l/r)-l-(2-naphthyl)-yV-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trif!uoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, NaJ or phase transfer catalysts such as n-benzylcinchonidinium chloride. benzyltributylammonium chloride. 3-ethyl-5-(2-hydroxyethy!)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent. In yet another embodiment of the invention, the step (b) further comprises treating the (17()-l-(2-naphthyI)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazotium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure. The step (b) is carried out at reflux temperature of solvent used in the step (b). . The solvent used in step (b) is selected from organic and/or inorganic liquids such as C2-C8 aliphatic amides including but not limited to N.N-dimethylacelamidc. dimethylformamide. hexamethylphosphoramide and the like, cyclic amides including bul not limited to :l,3-dimetbyl- 2-imidazolidinone (DMI), N-methyl-3-pyrolidinone (NMP) and the like; dimethylsullbxides, hydrocarbon solvents including but not limited to benzene, toluene, xylene, and the like; alcoholic solvents including but not limited to methanol, ethanol. propanol, butdnof, and the like. ether solvent including not limited to diglymes; inorganic liquids and mixtures therof. The step (b) further comprises isolation of the iminium salt compound of the formula (VI) by conventional methods like extraction, precipitation, filtration, etc. Step (c) of the above mentioned method comprises treating the reaction mixture of step (b) comprising iminium salt compound of formula (VI) with water and / or acid solution at temperature of 20-60°C to obtain Cinacalcet free base of the compound of the formula (I). In yet another embodiment of the invention, the step (c) of the above mentioned method comprises treating the iminium salt compound of formula (VI) as isolated in step (b) with water and / or acid solution at temperature of 20 -60°C to obtain Cinacalcet free base of the compound of the formula (1). Step (c) is carried out till the completion of hydrolysis which is monitored by simple thin layer chromatography. The isolation of compound of formula (I) from step (c) further comprise; diluting the reaction mass with water and water miscible organic solvent such as alcohol like methanol, ethanol. propanol and the like, ketones such as acetone, methyl isobutyl ketone and the like, nitriles such as acetonitrile, adjusting the pH of the reaction mixture to 1-2 using acid which may be organic or inorganic including but not limited to hydrochloric acid, sulfuric acid, nitric acid, acelic acid. formic acid and the like, extracting the reaction mass with a organic solvent followed by separation of organic layer from the aqueous layer, basifying the aqueous layer to adjust the pll of the reaction mixture to 9-10 using suitable base such as ammonia, sodium hydroxide, potassium hydroxide, and the like, extracting the Cinacalcet base in suitable solvent, washing the organic layer containing Cinacalcet base with water and concentrating the organic layer to give Cinacalcet base of formula (I) as a syrup. The organic solvent used in extracting the reaction mass at acidic pl-l is selected from hydrocarbon including benzene, toluene, xylene, heptane, hexanes. cyclohexanes and the like: esters such as ethylacetate, isobutylacetate, methaylacetate and the like, ethers such as diethylether. dimethylether. ethylmethylether. isobutylether, methyl-tert-butylether and the like. The solvent used to extract the Cinacalcet base is selected from hydrocarbon including benzene. toluene, xylene, heptane, hexanes, cyclohexanes and the like: esters such as ethylacetate, isobutylacetate, methaylacetate and the like, ethers such as diethylether, dimethylether. ethylmethylether, isobutylether, methyl-tert-butylether and the like, chlorinated hydrocarbons such as chloroform, dichloromethane and the like. The compound of the formula (I) is treated with a suitable acid to convert it ink) pharmaceutical!}' acceptable salts in suitable solvents. The suitable solvents selected from hydrocarbon including benzene, toluene, xylene, heptane. hexanes, cyclohexanes and the like; esters such as eihylacetate. isobutylacetatc, methaylacetatc. isoprpylacetate and the like, ethers such as diethytether, cjimethylether, ethylmethylether, isobutylether, methyl-tert-butylether and the like, chlorinated hydrocarbons such as chloroform, dichloromethane and the like: alcoholic solvent including but iiot limited to methanol ethanoL propanoL butanol and the like; ketonic solvent including but not limited to acetone. methylisobutylkeotne, tert-butylketone and the like; water, acetonitril, and mixture thereof. The preferred salt of Cinacalcet base of formula (I) is Cinacalcet hydrochloride of the formula (VII); F?C Formula (VII) According to the invention, there is provided a new compound. (l/R)-l-(2-naphthyl)-A'-(phenylmethylene)ethanamine, of formula (IV); Formula (IV) which is used as intermediate for the production of Cinacalcet. According to the invention, there is provided a process for the preparation of the new compound, (l/R)-l-(2-naphthyl)-N-(phenylmethylene)ethanamines of forniula (IV) which is used as intermediate for the production of Cinacalcet; the method comprises; a. reacting (R)-l-naphthyl ethylamine of the formula (II) and aromatic aldehyde of formula (III) to form (lR)-l-(2-naphthyI)-yV-(phenylmethylcne)ethanamine derivative of formula (IV): Wherein, Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alky!, aryl. alkoxy. amino, hydroxy 1, halogen, and nitro groups, and b. isolating (l/?)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV) as white crystalline solid by filtering the reaction mass of step (a). Step (a) of the above-mentioned method comprises reacting (R)-l-naphthyl ethylamine of the Formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C. In another embodiment of the invention, the Step (a) of the above-mentioned method comprises reacting(R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) ai temperature of 60 to 150°C optionally in the presence of organic solvent. Preferably, step (a) is carried out at temperature of 80 to 120°C, more preferably. 90 to 120°C. Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl. aryl, alkoxy. amino, hydroxyl. halogen, and nitro groups. The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in step (a) is selected from the group consisting of a hydrocarbons, alcohols, C1-C10 ether, C5-C8 cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide. C1-C8 chlorinated hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol and the like, hydrocarbons such as toluene, xylene and die like; more preferably, the solvent is toluene or ethanol. The reaction time of step (a) invariably depends on the temperature condition used to carry out step (a). The reaction time increases with decrease in temperature. The course of the reaction is monitored by a suitable analytical method, for instance by TLC till the completion of the reaction. According to the invention, there is provided an iminium salt compound of formula (VI): Formula-(VI) which is used as an intermediate for the preparation of Cinacalcet. According to the invention, there is provided a process for the preparation of the iminium salt compound of formula (VI), which is used as an intermediate for the preparation of Cinacalcet; the method comprises; a. reacting (R)-l-naphthyl ethylamine of the Formula (II) and aromatic aldehyde of formula (III) to form (l^)-l-(2-naphthyl)-A/-(phenyImethyiene)ethanamine derivative of formula (IV); Wherein. Ar : benzyl-: phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl. aryl. alkoxy, amino, hydroxyl, halogen, and nitro groups. b. treating the reaction mixture comprising (l/?)-l-(2-naphthy])-/V- (phenylmethylene)ethanamine derivative of formula (IV) which is obtained from step (a) with l-(3-halopropyl)-3-(trifiuoromethyl)benzene of formula (V) to obtain iminium salt compound of formula (VI); Wherein; Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl, aryl. alkoxy. amino, hydroxyl, halogen, and nitro groups. X: Chloro, Bromo or lodo c. isolating iminium salt compound of formula (VI) by conventional methods like extraction, precipitation, filtration, etc. Step (a) of the above-mentioned method comprises reacting (R)-]-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C. In another embodiment of the invention, the Step (a) of the above-mentioned method comprises reacting(R)-1 -naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C optionally in the presence of organic solvent. Preferably, step (a) is carried out at temperature of 80 to 120°C. more preferably. 90 to 120°C. Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl. aryl, alkoxy, amino, hydroxyl. halogen, and nitro groups. The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in step (a) is selected from the group consisting of a hydrocarbons, alcohols, C1-C10 ether. C5-C8 cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide, C1-C8 chlorinated hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol and the like, hydrocarbons such as toluene, xylene and the like; more preferably, the solvent is toluene or ethanol. The reaction time of step (a) is invariably depends on the temperature condition used to carry out step (a). The reaction time increases with decrease in temperature. The course of the reaction is monitored by a suitable analytical method, for instance by TLC till the completion of the reaction. Step (a) of the method further/optionally comprises isolating (ltf)-l-(2-naphthyl)-A/- (phenylmethylene)ethanamine derivative of formula (IV) as white crystalline solid by filtering the reaction mass of step (a). The above mentioned step (b) comprises treating the reaction mixture of step (a) comprising (ltf)-l-(2-naphthyl)-A-(pheny!methylene)ethanamine derivative of formula (IV) with l-(3- halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-160°C to obtain iminium salt compound of formula (VI). The halo group, "X" in the compound Formula (V) is either chloro. bromo. or iodo. In another embodiment of the invention, the Step (b) of the above-mentioned method comprises treating the reaction mixture of step (a) comprising (lV?)-[-(2-naphthyl)-A'- (phenylmethylene)ethanamine derivative of formula (IV) with 1-(3-halopropyl)-3- (trifluoromethyl)benzene of formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent. In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the reaction mixture of step (a) comprising (\R)-\-(2-naphthyl)-A/- (phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3- (trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent under pressure. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (17?)-l-(2-naphthyt)-A'-(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyi)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benz.ylcinchonidinium chloride, benzyllribulylammonium chloride. 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride. tetrabutylammonium bromide. tetrabutviammonium chloride. Iricaprylmethylammonium chloride, tetrabutylammonium iodide and the like. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (l/?)-l-(2-naphlhyl)-N-(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzyicinchonidinium chloride, benzyllributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent. In yet another embodiment of the invention, the step (b) further comprises treating the reaction mixture of step (a) comprising (Itf)-l-(2-naphthy!)-N(phenytmethy(ene)ethanamine derivative of the formula (IV) with l-(3-halopropyI)-3-(trifluoromethyl)benzene of the formula (V) in presence of catalyst such as Kl. Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributy [ammonium chloride, 3-ethyI-5-(2-hydroxyethyl)-4~methylthiazolium bromide. phenyltrimethylammonium chloride, tetrabutylammonium bromide. tetrabutylammonium chloride, Iricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure. In yet another embodiment of the invention, the above mentioned step (b) comprises treating the (l^)-l-(2-naphthyl)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with N(3-halopropyI)-3-(trifluoromethyi)benzene of formula (V) at temperature of K0-160°C to obtain iminium salt compound of formula (VI). In yet another embodiment of the invention, the above mentioned step (b) further comprises treating the (lV?)-l-(2-naphthyl)-Af-(phenylmethylene)ethanamine derivative of'formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-l60°C optionally in the presence of a organic solvent to obtain iminium salt compound of formula (VI). In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the (1/R)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-haiopropyl)-3-(trifIuoromethyi)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a orgaftic solvent under pressure. In yet another embodiment of the invention, the step (b) further comprises treating the (ltf)-l-(2-naphthyl)-AA-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like In yet another embodiment of the invention, the step (b) further comprises treating the (1 /R)-1 -(2-naphthy])-A'-(pheny]methylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI. Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methy!lhia'zo!ium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent. In yet another embodiment of the invention, the step (b) further comprises treating Ihe (]fi)-]-(2-naphthyl)-Ar-(phenylmethylene)ethanarnine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyI)-3-(trifluoromelhyl)benzene of the Formula (V) in presenccof catalyst such as Kl. Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride. benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyUhiazolium bromide. phenyltrimethylammonium chloride, tetrabutylammonium bromide, letrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure. The step (b) is carried out at reflux temperature of solvent used in the step (b). The solvent used in step (b) is selected from organic and/or inorganic liquids such as C2-C8 aliphatic amides including but not limited to N.N-dimethylacetamide, dimethylformamidc. hexamethylphosphoramide and the like, cyclic amides including but not limited to 1,3-dimethyl- 2-imidazolidinone (DMI), N-methyl-3-pyrolidinone (NMP) and the like; dimethylsulfoxides. hydrocarbon solvents including but not limited to benzene, toluene, xylene, and the like; alcoholic solvents including but not limited to methanol, ethanol. propanol. butanol, and the like. ether solvent including not limited to diglymes; inorganic liquids and mixtures therof. The aromatic aldehyde which is used as a starting material may be easily recovered and recycled from the reaction mixture by forming adduct with metabisulfite or any other known process: which will reduce the effluents and will making the process cost-effective and eco-friendly. Thus the new method for the preparation of Cinacalcet and/or its salts is economical, simple. efficient, cost-effective and easy to carry out. According to the invention, Cinacalcet and /or its salts are obtained with high yields and substantially pure and free from impurities thus making the process efficient. The new method for the preparation of Cinacalcet and / or its salts can be carried out in a single pot where in isolation of intermediates by filtrations arc avoided to reduce exposure of the production executive to the chemicals and to reduce the turn around time of the total time cycle per batch. This invention provides new compounds. (\R)~\ -(2-naphthyl)-A/- (phenylmethylene)ethanamine, of formula (IV) and a iminium salt compound of formula (VI). which are used as intermediates for the production of cinacalcet. The following experimental example is illustrative of the invention but not limitative of the scope thereof. Example 1 PREPARATION OF (lJ?)-l-(2-NAPHtHVL)-A^-(PHENYLMETHYLENK) ETHAN- AMINE DERIVATIVE OF FORMULA (IV) To a stirred solution of (R)-l-naphthyl ethylamine (5 gm) in ethanol (25 ml), berizaldehyde (3.71 gm) was added with stirring at 25-30°C. The reaction mass was stirred at 55-60°C'for 5-6 hours. Upon completion of this reaction by TLC, the reaction mass was cooled to 25-30°C. and then to 5-10°C. The reaction mixture was maintained for 30 minutes. The precipitated solid was filtered. washed with ethanol (10 ml), and dried under vacuum to yield 7.1 gm (94.67%) compound of formula (IV) as a white crystalline solid. Example 2 STEP 2: PREPARATION OF CINACALCET OF FORMULA (I) The solid compound of formula (IV) (5.0 gm) of step-1 and the l-(bromopropyl)-3- (trifluoromethyl)benzene compound of the formula (V) (5.66 gm) were reacted in presence of potassium iodide (0.2 gm) at 120-130°C till the completion of the reaction which was monitored by TLC (16-18 hours). The reaction mass was cooled to 25-3 5°C, diluted with water (50 ml) and acetonitrile (10 ml); the pH of (he reaction mass was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with n- heplane (50 ml). The aqueous layer was separated, basified with ammonia till pH 9-10 and then extracted with toluene (50 ml), with 10% sodium metabisulphiie solution (50 ml) followed by water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup; 4.9 gm (71.0 %); HPLC purity 99.1%; chiral purity: 99.90%. ; Example 3 STEP 2: PREPARATION OF CINACALCET OF FORMULA (I) The solid compound of formula (IV) (5.0 gm) of siep-1 and the l-(brbmopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 gm) were reacted in presence of potassium iodide (0.2 gm) at 120-130°C till the completion of the reaction which was monitored by TLC (16-18 hours). The reaction mass was cooled to 25-35°C, diluted with water (50 mi), pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with toluene (50 ml) and toluene layer was washed with 10% sodium metabisulphite solution(50 ml) followed by water. The toluene layer was separated and concentrated under vacuum to yield syrup, which is dissolved in the acetonitrile (10ml) and water (50 ml). The pH of the resulting solution was adjusted to 1-2 using concentrated hydrochloric acid, washed the acidic aqueous layer with n-heptane'(25 ml) and separated aqueous layer was basified with ammonia till pH 9-10. The mass was then extracted the toluene (50ml), washed with water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup: Yield 4.9 gm (71.0 %); HPLC purity 99.1%; chiral purity: 99.90%. Example 4 STEP 2: PREPARATION OF CINACALCET OF FORMULA (I) The solid compound of formula (IV) (5.0 gm) of step-1. l-(bfomopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 gm) in N-methyl-2-pyrrolidinone (25 ml) were healed at 130-140°C till the completion of the reaction which was monitored by TLC (12hours). The reaction mass was cooled 25-35°C, diluted with water (50 nil), the pl-l of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting solution was extracted with toluene (50 ml), toluene layer was washed with 10% sodium metabisulphite solution (50 ml) and concentrated under vacuum to yield syrup. The syrup was dissolved in the acetonitrile (10ml) and water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid, and washed the acidic aqueous layer with n-heplane (25 ml). The aqueous layer was then basified with ammonia till pH 9-10 and then extracted the cinacalcet base into toluene (50m\). Toluene layer was washed with water (25 ml )and distilled off the toluene layer to get cinacalcet base as thick syrup Yield.4.45 gm (64.50 %): HPLC purity 98.23%; Chiral purity: 99.89%. Example 5 STEP 2: PREPARATION OF CINACALCET OF FORMULA (l) The solid compound of formula (IV) (5.0 gm) obtained in step-1, l-(bromopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 "gm) in N.N-dimethyl formamide (25 ml) were refluxed at 130-140°C till the completion of the reaction which was ^monitored by TLC (\2hours) and Vne reaction mass was cooled \o 25-35°C. The reaction solution was dihtted with water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with toluene (50 ml), washed with 10% sodium metabisulphite solution (50 ml) and concentrated -under vacuum to yield syrup. The syrup was dissolved in the acetonitrile (10ml) and water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and washed the acidic aqueous layer with n-heptane (25 ml). The aqueous layer was separated, basified with ammonia till pH 9-10. and extracted with toluene (50ml). Toluene layer was washed with water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup. Yield 3.44 gm (50.01 %): HPLC purity 97.01%; Chiral purity: 99.89%. Example 6 PREPARATION OF CINACALCET HYDROCHLORIDE OF FORMULA (VII) : Cinacalcet base Compound of formula (1) (5.0 gm) was dissolved in toluene (25 ml) and n-heptane (75 ml), and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid at 25-30°C and stirred for 30 minutes. The precipitated solid was filtered, washed with 10 ml n-heptane, and dried under vacuum to yield 5.1 gm (92.55%) of cinacalcet hydrochloride; HPLC purity 99.80%; Chiral purity: 99.95%. Example 7 PREPARATION OF CINACALCET HYDROCHLORIDE OF FORMULA (VII): Cinacalcet base Compound of formula (I) (5.0 gm) was dissolved in diisopropylelhcr (50 ml) and the pH of the solution was. adjusted to 1-2 using concentrated hydrochloric acid at 25-30°C. the mass was stirred for 30 minutes, precipitated solid was filtered, washed with diisopropylether (10 ml) and dried under vacuum to yield 4.8 gm (86.48%)) of cinacalcet hydrochloride: HPLC purity 99.67%; Chiral purity: 99.92%.

Full Text

FORM 2 THE PATENTS ACT, 1970
(39 of 1970) As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
A NEW METHOD FOR THE PREPARATION OF CINACALCET AND NEW
INTERMEDIATES THEREOF.
APPLICANTS

Name
Nationality
4th Floor. SETHNA. 55. Maharshi Karve Road. M arine Lines.
Megafine Pharma (P) Ltd. Indian Company Address
Mumbai - 400 002, Maharashtra. India.
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention:

TECHNICAL FIELD:
This invention relates to a new method for the preparation of N-| l(R)-(l-naphthyl)ethyl|-N-j3-[j-(triiluoromethyl) phenyl]propyl]-l -amine. Cinacalcet. of the formula (I);

Formula 1 This invention also relates to (l^)-l-(2-naphthyl)-yV-(phenylmethylene)ethanamine derivative of
the formula (IV);

which is used as an intermediate for the preparation of Cinacalcet.
This invention also relates to a process for the preparation of (]R)-]-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV).
This invention also relates to a iminium salt compound of formula (VI):

Formula (VI)
which is used as an intermediate for the preparation of Cinacalcet.
This invention also relates to a process for the preparation of the iminium salt compound of
formula (VJ).
BACKGROUND OF THE INVENTION:
N-[l(R)-(l-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl) phenyl]propyl]-l-amine (herein
"Cinacalcet" or "CNC") has a CAS number of 226256-56-0, a formula of C22H22F3N and the following structure:

CH3 Formula (I)
This molecule is the free base form of Cinacalcet hydrochloride (herein "CNC-HCl"). having a
CAS number of 364782-34-3 and the following structure:

.HCI CH3
Formula (VII) CNC-HCl is marketed as SENSIPAR™, and is the first drug in a class ofcompounds known as Calcimimetics to be approved by the FDA.
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 lew 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 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. CNC-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCl lowers serum levels of PTH as vvel] as the calcium/phosphorus ion product, a) measure of the amount of calcium and phosphorus in the blood.
US 6,011,068 disclose inorganic ion receptor activity, especially calcium receptor-active molecules, such as those having the general structure of Cinacalcet.
US 6,211,244 disclose calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. In accordance with the patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-[3-(trifluoromethyI)phenyl|propyiamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resoiution of the racemic Cinacalcet base by chiral liquid chromatography, according to Scheme 1:

CNC base racemic Scheme 1
Similarly, using the process disclosed in US 6,211,244, as well as DRUGS OF THE FUTURE (2002)
27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-l-(l-
naphthyl)ethylamine with 3-| 3-(trifluoromethyl)phenyl]propionaldehyde in the presence of
titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment
with ethanotic sodium cyanoborohydride. according to the following Scheme 2:

R - CNC base
Scheme 2
US 6,211.244 disclose an additional process for the synthesis of Cinacalcct. This process
involves treating 3-trirluoromethylcinnamonitrile. which can be prepared as disclosed in US
4,966,988. with diisobutyl aluminum hydride, followed by treating the intermediate aluminum-
imine complex with (R)-I-(l-naphthyI)ethyIamine, and reducing the intermediate imine with
ethanolic sodium cyanoborohydride. according, to the following Scheme 3:

Scheme 3
These three processes however, require the use of reagents such as titanium isopropoxide which
is highly hygroscopic and expensive, as well as toxic, and ethanotic or methanolic sodium
cyanoborohydride. which is highly toxic and flammable, and not environmentally friendly,
making the processes difficult to apply on industrial scale.
Thus, an alternative process for the preparation of cinacalcet base and cinacalcet salt, which is
more direct, higher yield, environmental friendly and applicable to industrial scale production is
desirable.
OBJECTS OF THE PRESENT INVENTION:
An object of the present invention is to provide a new method for the preparation of Cinacalcet
and / or its salts, wherein the process is economical, simple, efficient, cost-effective and easy to
carry out.
Another object of the invention is to provide the new method for the preparation of Cinacalcet
and /or its salts with high yields and substantially pure and free from impurities and thus making
the process efficient.
Yet another object of the invention is to provide the new method for the preparation of
Cinacalcet and / or its salts in a single pot where in isolation of intermediates by nitrations arc
avoided to reduce exposure of the production executive to the chemicals and to reduce the turn
around time of the total time cycle per batch.
Yet another object of the invention is to provide the new method for the preparation of
Cinacalcet and / or its salts in which aromatic aldehyde which is used as a starting material may
be easily recovered and recycled from the reaction mixture efficiently; thus reduces the effluents
and making the process cost-effective and eco-friendly .
Yet another object of the invention is to provide a new compound. (l/?)-l-(2-naphthyl)-N-
(phenylmethylene)ethanamine. of formula (IV), which is used as an intermediate for the
production of cinacalcet.

Yet another object of the invention is to provide process for preparing a new compound. (\R)-\-
(2-naphthyl)-//-(phenylmethylene)ethanamine, of formula (IV). which is used as an intermediate
for the production of cinacalcet.
Yet another object of the invention is to provide a iminium salt compound of formula (VI),
which is used as an intermediate for the preparation of Cinacalcet.
Yet another object of the invention is to provide a process for the preparation of the iminium salt
compound of formula (VI)S which is used as an intermediate for the preparation of Cinacalcet.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a novel method for efficiently preparing Cinacalcet and/or one of its pharmaceutically acceptable salts. According to the process of present invention, Cinacalcet is obtained by using milder reaction conditions and without tfee need for laborious operations such as chromatographic purifications or solvent distillations, and hazardous chemicals. The process for making the compound (I) involves three steps. While the steps are normally run separately, that is consecutively, the process may nonetheless be conveniently performed in a one pot arrangement as well, e.g. as a one pot process with out isolation of the intermediates. According to the invention, there is provided a new method for the preparation of Cinacalcet of formula (I);

Formula 1
the method comprises;
a. reacting (R)-1-naphthyl ethylamine of the Formula (II) and aromatic aldehyde of
formula (III) to form (l/?)-l-(2-naphlhyl)-A'-(phenylmethylene)ethanamine derivative of formula

Wherein,
Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alky], aryl. alkoxy. amino,
hydroxyl, halogen, and nitro groups.
b. treating the reaction mixture comprising (l/R)-l-(2-naphthyl)-N-
(phenylmethylene)ethanamine derivative of formula (IV) which is obtained from step (a) with I-

(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) to obtain iminium salt compound ol formula (VI);
Wherein;
Ar : benzyl-, phenyl- or naphlhyl- which may be mono- or di- or poly substituted with alkyl. aryl. alkoxy. amino,
hydroxyl, halogen, and nitro groups.
X: Chloro. Bromo or lodo
and
c. treating the reaction mixture of step (b) comprising iminium salt of formula (VI) with
water and /or acid solution to obtain Cinacalcet free base of the compound of formula (1).

Formula-(VI) Formula-(I)
Step (a) of the above-mentioned method comprises reacting (R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C.
In another embodiment of the invention, the Step (a) of the above-mentioned method comprises reacting(R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (HI) ai temperature of 60 to I50°C optionally in the presence of organic solvent. Preferably, step (a) is carried out at temperature of 80 to 120°C, more preferably, 90 to !20°C. Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphlhyl- which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy. amino, hydroxyl. halogen, and nitro groups.
The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in step (a) is selected from the group consisting of a hydrocarbons, alcohols. CI-CIO ether, C5-C8 cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide. CI -C8 chlorinated hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as methanol, ethanol, propanoL butanol and the like, hydrocarbons such as toluene, xylene and the like; more preferably, the solvent is toluene or ethanol.

The reaction time of step (a) is invariably depends on the lemperature condition used to carry out
step (a). The reaction time increases with decrease in temperature.
The course of the reaction is monitored by a suitable analytical method, for instance by TLC till
the completion of the reaction.
Step {a) of the method further/optionally comprises isolating (ltf)-l-(2-naphthyl)-;V-
(phenylmethylene)ethanamine derivative of formula (IV) as a white crystalline solid by filtering
the reaction mass of step (a).
The above mentioned step (b) comprises treating the reaction mixture of step (a) comprising
(l/?)-l-(2-naphthyl)-/V-(pheny]methylene)elhanamine derivative of formula (IV) with l-(3-
halopropyl)-3-(trifluoromethyl)benzene of formula (V) at lemperature of 80-160°C to obtain
iminium salt compound of formula (VI).
The halo group. "X" in the compound Formula (V) is either chloro. bromo, or iodo.
In another embodiment of the invention, the Step (b) of the above-mentioned method comprises
treating the reaction mixture of step (a) comprising (1 /?)-1 -(2-naphlhyl)-/V-
(phenylmethylene)ethanamine derivative of formula (IV) with l-(3-halopropyl)-3-
(trifluorornethyl)benzene of formula (V) at temperature of 80-160°C optionally in the presence
of a organic solvent.
In yet another embodiment of the invention, the step (b) of the above-mentioned method
comprises treating the reaction mixture of step (a) comprising ((l/f)-l-(2-naphthyl)-A/-
(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-
(trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the
presence of a organic solvent under pressure.
In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (l/?)-l-(2-naphthyl)-yV-(phenylmethyIene)ethanamine derivative
of the formula (IV) with l-(3-halopropyl)-3-(trifluoromeihyl)benzene of the Formula (V) in
presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benz'ylcinchonidinium
chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide, phenyltrimethylammonium chloride, tetrabulylammonium bromide.
tetrabutylammomum chloride, tricaprylmethylammonium chloride, tetrabutylammomum iodide
and the like.
In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (l/^)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative
of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in
presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzylcinchonidinium
chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyllhiazolium
bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide
and the like and optionallyjn presence of organic solvent.
In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (l/?)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative
of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in

presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium
chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure.
In yet another embodiment of the invention, the above mentioned step (b) comprises treating the (lJff)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-160QC to obtain iminium salt compound of formula (VI).
In yet another embodiment of the invention, the above mentioned step (b) further comprises treating the (l^)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethy!)benzene of formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent lo obtain iminium sail compound of formula (VI).
In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the (l/?)-l-(2-naphthyl)-A^-(phenylmethyIene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a organic solvent under pressure.
In yet another embodiment of the invention, the step (b) further comprises treating the {\R)-\-{2-naphthyl)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l~(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride. 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like. In yet another embodiment of the invention, the step (b) further comprises treating the (l/r)-l-(2-naphthyl)-yV-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trif!uoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, NaJ or phase transfer catalysts such as n-benzylcinchonidinium chloride. benzyltributylammonium chloride. 3-ethyl-5-(2-hydroxyethy!)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent.
In yet another embodiment of the invention, the step (b) further comprises treating the (17()-l-(2-naphthyI)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as Kl, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazotium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium

chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and
optionally in presence of organic solvent under pressure.
The step (b) is carried out at reflux temperature of solvent used in the step (b). .
The solvent used in step (b) is selected from organic and/or inorganic liquids such as C2-C8
aliphatic amides including but not limited to N.N-dimethylacelamidc. dimethylformamide.
hexamethylphosphoramide and the like, cyclic amides including bul not limited to :l,3-dimetbyl-
2-imidazolidinone (DMI), N-methyl-3-pyrolidinone (NMP) and the like; dimethylsullbxides,
hydrocarbon solvents including but not limited to benzene, toluene, xylene, and the like;
alcoholic solvents including but not limited to methanol, ethanol. propanol, butdnof, and the like.
ether solvent including not limited to diglymes; inorganic liquids and mixtures therof.
The step (b) further comprises isolation of the iminium salt compound of the formula (VI) by
conventional methods like extraction, precipitation, filtration, etc.
Step (c) of the above mentioned method comprises treating the reaction mixture of step (b)
comprising iminium salt compound of formula (VI) with water and / or acid solution at
temperature of 20-60°C to obtain Cinacalcet free base of the compound of the formula (I).
In yet another embodiment of the invention, the step (c) of the above mentioned method
comprises treating the iminium salt compound of formula (VI) as isolated in step (b) with water
and / or acid solution at temperature of 20 -60°C to obtain Cinacalcet free base of the compound
of the formula (1).
Step (c) is carried out till the completion of hydrolysis which is monitored by simple thin layer
chromatography.
The isolation of compound of formula (I) from step (c) further comprise; diluting the reaction
mass with water and water miscible organic solvent such as alcohol like methanol, ethanol.
propanol and the like, ketones such as acetone, methyl isobutyl ketone and the like, nitriles such
as acetonitrile, adjusting the pH of the reaction mixture to 1-2 using acid which may be organic
or inorganic including but not limited to hydrochloric acid, sulfuric acid, nitric acid, acelic acid.
formic acid and the like, extracting the reaction mass with a organic solvent followed by
separation of organic layer from the aqueous layer, basifying the aqueous layer to adjust the pll
of the reaction mixture to 9-10 using suitable base such as ammonia, sodium hydroxide,
potassium hydroxide, and the like, extracting the Cinacalcet base in suitable solvent, washing the
organic layer containing Cinacalcet base with water and concentrating the organic layer to give
Cinacalcet base of formula (I) as a syrup.
The organic solvent used in extracting the reaction mass at acidic pl-l is selected from
hydrocarbon including benzene, toluene, xylene, heptane, hexanes. cyclohexanes and the like:
esters such as ethylacetate, isobutylacetate, methaylacetate and the like, ethers such as
diethylether. dimethylether. ethylmethylether. isobutylether, methyl-tert-butylether and the like.
The solvent used to extract the Cinacalcet base is selected from hydrocarbon including benzene.
toluene, xylene, heptane, hexanes, cyclohexanes and the like: esters such as ethylacetate,
isobutylacetate, methaylacetate and the like, ethers such as diethylether, dimethylether.
ethylmethylether, isobutylether, methyl-tert-butylether and the like, chlorinated hydrocarbons
such as chloroform, dichloromethane and the like.

The compound of the formula (I) is treated with a suitable acid to convert it ink)
pharmaceutical!}' acceptable salts in suitable solvents.
The suitable solvents selected from hydrocarbon including benzene, toluene, xylene, heptane.
hexanes, cyclohexanes and the like; esters such as eihylacetate. isobutylacetatc, methaylacetatc.
isoprpylacetate and the like, ethers such as diethytether, cjimethylether, ethylmethylether,
isobutylether, methyl-tert-butylether and the like, chlorinated hydrocarbons such as chloroform,
dichloromethane and the like: alcoholic solvent including but iiot limited to methanol ethanoL
propanoL butanol and the like; ketonic solvent including but not limited to acetone.
methylisobutylkeotne, tert-butylketone and the like; water, acetonitril, and mixture thereof.
The preferred salt of Cinacalcet base of formula (I) is Cinacalcet hydrochloride of the formula
(VII);

F?C

Formula (VII)
According to the invention, there is provided a new compound. (l/R)-l-(2-naphthyl)-A'-(phenylmethylene)ethanamine, of formula (IV);

Formula (IV)
which is used as intermediate for the production of Cinacalcet.
According to the invention, there is provided a process for the preparation of the new compound,
(l/R)-l-(2-naphthyl)-N-(phenylmethylene)ethanamines of forniula (IV) which is used as
intermediate for the production of Cinacalcet;
the method comprises;
a. reacting (R)-l-naphthyl ethylamine of the formula (II) and aromatic aldehyde of formula
(III) to form (lR)-l-(2-naphthyI)-yV-(phenylmethylcne)ethanamine derivative of formula
(IV):

Wherein,
Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alky!, aryl. alkoxy. amino, hydroxy 1, halogen, and nitro groups, and b. isolating (l/?)-l-(2-naphthyl)-/V-(phenylmethylene)ethanamine derivative of formula (IV) as white crystalline solid by filtering the reaction mass of step (a).
Step (a) of the above-mentioned method comprises reacting (R)-l-naphthyl ethylamine of the
Formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C.
In another embodiment of the invention, the Step (a) of the above-mentioned method comprises
reacting(R)-l-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) ai
temperature of 60 to 150°C optionally in the presence of organic solvent.
Preferably, step (a) is carried out at temperature of 80 to 120°C, more preferably. 90 to 120°C.
Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphthyl- which
may be mono- or di- or poly substituted with alkyl. aryl, alkoxy. amino, hydroxyl. halogen, and
nitro groups.
The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in
step (a) is selected from the group consisting of a hydrocarbons, alcohols, C1-C10 ether, C5-C8
cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide. C1-C8 chlorinated
hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as
methanol, ethanol, propanol, butanol and the like, hydrocarbons such as toluene, xylene and die
like; more preferably, the solvent is toluene or ethanol.
The reaction time of step (a) invariably depends on the temperature condition used to carry out
step (a). The reaction time increases with decrease in temperature.
The course of the reaction is monitored by a suitable analytical method, for instance by TLC till
the completion of the reaction.
According to the invention, there is provided an iminium salt compound of formula (VI):

Formula-(VI) which is used as an intermediate for the preparation of Cinacalcet.
According to the invention, there is provided a process for the preparation of the iminium salt compound of formula (VI), which is used as an intermediate for the preparation of Cinacalcet; the method comprises;

a. reacting (R)-l-naphthyl ethylamine of the Formula (II) and aromatic aldehyde of formula (III) to form (l^)-l-(2-naphthyl)-A/-(phenyImethyiene)ethanamine derivative of formula (IV);

Wherein.
Ar : benzyl-: phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl. aryl. alkoxy,
amino, hydroxyl, halogen, and nitro groups.
b. treating the reaction mixture comprising (l/?)-l-(2-naphthy])-/V-
(phenylmethylene)ethanamine derivative of formula (IV) which is obtained from step (a)
with l-(3-halopropyl)-3-(trifiuoromethyl)benzene of formula (V) to obtain iminium salt
compound of formula (VI);

Wherein;
Ar : benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl, aryl. alkoxy.
amino, hydroxyl, halogen, and nitro groups.
X: Chloro, Bromo or lodo c. isolating iminium salt compound of formula (VI) by conventional methods like
extraction, precipitation, filtration, etc. Step (a) of the above-mentioned method comprises reacting (R)-]-naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C. In another embodiment of the invention, the Step (a) of the above-mentioned method comprises reacting(R)-1 -naphthyl ethylamine of formula (II) and aromatic aldehyde of formula (III) at temperature of 60 to 150°C optionally in the presence of organic solvent. Preferably, step (a) is carried out at temperature of 80 to 120°C. more preferably. 90 to 120°C. Armoatic aldehyde used in step (a) may be selected from benzyl-, phenyl- or naphthyl- which may be mono- or di- or poly substituted with alkyl. aryl, alkoxy, amino, hydroxyl. halogen, and nitro groups.
The solvent used in step (a) is selected from organic or inorganic; the organic solvents used in step (a) is selected from the group consisting of a hydrocarbons, alcohols, C1-C10 ether. C5-C8 cyclic ether, C2-10 aliphatic ester, C2-C8 aliphatic amides, sulfoxide, C1-C8 chlorinated hydrocarbon, and mixtures of thereof; particularly, the solvent is selected from alcohols such as

methanol, ethanol, propanol, butanol and the like, hydrocarbons such as toluene, xylene and the
like; more preferably, the solvent is toluene or ethanol.
The reaction time of step (a) is invariably depends on the temperature condition used to carry out
step (a). The reaction time increases with decrease in temperature.
The course of the reaction is monitored by a suitable analytical method, for instance by TLC till
the completion of the reaction.
Step (a) of the method further/optionally comprises isolating (ltf)-l-(2-naphthyl)-A/-
(phenylmethylene)ethanamine derivative of formula (IV) as white crystalline solid by filtering
the reaction mass of step (a).
The above mentioned step (b) comprises treating the reaction mixture of step (a) comprising
(ltf)-l-(2-naphthyl)-A-(pheny!methylene)ethanamine derivative of formula (IV) with l-(3-
halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-160°C to obtain
iminium salt compound of formula (VI).
The halo group, "X" in the compound Formula (V) is either chloro. bromo. or iodo.
In another embodiment of the invention, the Step (b) of the above-mentioned method comprises
treating the reaction mixture of step (a) comprising (lV?)-[-(2-naphthyl)-A'-
(phenylmethylene)ethanamine derivative of formula (IV) with 1-(3-halopropyl)-3-
(trifluoromethyl)benzene of formula (V) at temperature of 80-160°C optionally in the presence
of a organic solvent.
In yet another embodiment of the invention, the step (b) of the above-mentioned method
comprises treating the reaction mixture of step (a) comprising (\R)-\-(2-naphthyl)-A/-
(phenylmethylene)ethanamine derivative of the formula (IV) with l-(3-halopropyl)-3-
(trifluoromethyl)benzene of the Formula (V) at temperature of 80-160°C optionally in the
presence of a organic solvent under pressure.
In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (17?)-l-(2-naphthyt)-A'-(phenylmethylene)ethanamine derivative
of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyi)benzene of the Formula (V) in
presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benz.ylcinchonidinium
chloride, benzyllribulylammonium chloride. 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide, phenyltrimethylammonium chloride. tetrabutylammonium bromide.
tetrabutviammonium chloride. Iricaprylmethylammonium chloride, tetrabutylammonium iodide
and the like.
In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (l/?)-l-(2-naphlhyl)-N-(phenylmethylene)ethanamine derivative
of the formula (IV) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in
presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzyicinchonidinium
chloride, benzyllributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium
bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide,
tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide
and the like and optionally in presence of organic solvent.

In yet another embodiment of the invention, the step (b) further comprises treating the reaction
mixture of step (a) comprising (Itf)-l-(2-naphthy!)-N(phenytmethy(ene)ethanamine derivative
of the formula (IV) with l-(3-halopropyI)-3-(trifluoromethyl)benzene of the formula (V) in
presence of catalyst such as Kl. Nal or phase transfer catalysts such as n-benzylcinchonidinium
chloride, benzyltributy [ammonium chloride, 3-ethyI-5-(2-hydroxyethyl)-4~methylthiazolium
bromide. phenyltrimethylammonium chloride, tetrabutylammonium bromide.
tetrabutylammonium chloride, Iricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent under pressure.
In yet another embodiment of the invention, the above mentioned step (b) comprises treating the (l^)-l-(2-naphthyl)-A'-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with N(3-halopropyI)-3-(trifluoromethyi)benzene of formula (V) at temperature of K0-160°C to obtain iminium salt compound of formula (VI).
In yet another embodiment of the invention, the above mentioned step (b) further comprises treating the (lV?)-l-(2-naphthyl)-Af-(phenylmethylene)ethanamine derivative of'formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of formula (V) at temperature of 80-l60°C optionally in the presence of a organic solvent to obtain iminium salt compound of formula (VI).
In yet another embodiment of the invention, the step (b) of the above-mentioned method comprises treating the (1/R)-l-(2-naphthyl)-A/-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-haiopropyl)-3-(trifIuoromethyi)benzene of the Formula (V) at temperature of 80-160°C optionally in the presence of a orgaftic solvent under pressure.
In yet another embodiment of the invention, the step (b) further comprises treating the (ltf)-l-(2-naphthyl)-AA-(phenylmethylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI, Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like In yet another embodiment of the invention, the step (b) further comprises treating the (1 /R)-1 -(2-naphthy])-A'-(pheny]methylene)ethanamine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyl)-3-(trifluoromethyl)benzene of the Formula (V) in presence of catalyst such as KI. Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride, benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methy!lhia'zo!ium bromide, phenyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and optionally in presence of organic solvent.
In yet another embodiment of the invention, the step (b) further comprises treating Ihe (]fi)-]-(2-naphthyl)-Ar-(phenylmethylene)ethanarnine derivative of formula (IV) as isolated from step (a) with l-(3-halopropyI)-3-(trifluoromelhyl)benzene of the Formula (V) in presenccof catalyst such as Kl. Nal or phase transfer catalysts such as n-benzylcinchonidinium chloride.

benzyltributylammonium chloride, 3-ethyl-5-(2-hydroxyethyl)-4-methyUhiazolium bromide.
phenyltrimethylammonium chloride, tetrabutylammonium bromide, letrabutylammonium
chloride, tricaprylmethylammonium chloride, tetrabutylammonium iodide and the like and
optionally in presence of organic solvent under pressure.
The step (b) is carried out at reflux temperature of solvent used in the step (b).
The solvent used in step (b) is selected from organic and/or inorganic liquids such as C2-C8
aliphatic amides including but not limited to N.N-dimethylacetamide, dimethylformamidc.
hexamethylphosphoramide and the like, cyclic amides including but not limited to 1,3-dimethyl-
2-imidazolidinone (DMI), N-methyl-3-pyrolidinone (NMP) and the like; dimethylsulfoxides.
hydrocarbon solvents including but not limited to benzene, toluene, xylene, and the like;
alcoholic solvents including but not limited to methanol, ethanol. propanol. butanol, and the like.
ether solvent including not limited to diglymes; inorganic liquids and mixtures therof.
The aromatic aldehyde which is used as a starting material may be easily recovered and recycled
from the reaction mixture by forming adduct with metabisulfite or any other known process:
which will reduce the effluents and will making the process cost-effective and eco-friendly.
Thus the new method for the preparation of Cinacalcet and/or its salts is economical, simple.
efficient, cost-effective and easy to carry out. According to the invention, Cinacalcet and /or its
salts are obtained with high yields and substantially pure and free from impurities thus making
the process efficient. The new method for the preparation of Cinacalcet and / or its salts can be
carried out in a single pot where in isolation of intermediates by filtrations arc avoided to reduce
exposure of the production executive to the chemicals and to reduce the turn around time of the
total time cycle per batch. This invention provides new compounds. (\R)~\ -(2-naphthyl)-A/-
(phenylmethylene)ethanamine, of formula (IV) and a iminium salt compound of formula (VI).
which are used as intermediates for the production of cinacalcet.
The following experimental example is illustrative of the invention but not limitative of the
scope thereof.
Example 1
PREPARATION OF (lJ?)-l-(2-NAPHtHVL)-A^-(PHENYLMETHYLENK) ETHAN-
AMINE DERIVATIVE OF FORMULA (IV)
To a stirred solution of (R)-l-naphthyl ethylamine (5 gm) in ethanol (25 ml), berizaldehyde (3.71
gm) was added with stirring at 25-30°C. The reaction mass was stirred at 55-60°C'for 5-6 hours.
Upon completion of this reaction by TLC, the reaction mass was cooled to 25-30°C. and then to
5-10°C. The reaction mixture was maintained for 30 minutes. The precipitated solid was filtered.
washed with ethanol (10 ml), and dried under vacuum to yield 7.1 gm (94.67%) compound of
formula (IV) as a white crystalline solid.
Example 2
STEP 2: PREPARATION OF CINACALCET OF FORMULA (I)
The solid compound of formula (IV) (5.0 gm) of step-1 and the l-(bromopropyl)-3-
(trifluoromethyl)benzene compound of the formula (V) (5.66 gm) were reacted in presence of
potassium iodide (0.2 gm) at 120-130°C till the completion of the reaction which was monitored
by TLC (16-18 hours). The reaction mass was cooled to 25-3 5°C, diluted with water (50 ml) and

acetonitrile (10 ml); the pH of (he reaction mass was adjusted to 1-2 using concentrated
hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with n-
heplane (50 ml). The aqueous layer was separated, basified with ammonia till pH 9-10 and then
extracted with toluene (50 ml), with 10% sodium metabisulphiie solution (50 ml) followed by
water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup; 4.9 gm
(71.0 %); HPLC purity 99.1%; chiral purity: 99.90%. ;
Example 3
STEP 2: PREPARATION OF CINACALCET OF FORMULA (I)
The solid compound of formula (IV) (5.0 gm) of siep-1 and the l-(brbmopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 gm) were reacted in presence of potassium iodide (0.2 gm) at 120-130°C till the completion of the reaction which was monitored by TLC (16-18 hours). The reaction mass was cooled to 25-35°C, diluted with water (50 mi), pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with toluene (50 ml) and toluene layer was washed with 10% sodium metabisulphite solution(50 ml) followed by water. The toluene layer was separated and concentrated under vacuum to yield syrup, which is dissolved in the acetonitrile (10ml) and water (50 ml). The pH of the resulting solution was adjusted to 1-2 using concentrated hydrochloric acid, washed the acidic aqueous layer with n-heptane'(25 ml) and separated aqueous layer was basified with ammonia till pH 9-10. The mass was then extracted the toluene (50ml), washed with water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup: Yield 4.9 gm (71.0 %); HPLC purity 99.1%; chiral purity: 99.90%.
Example 4
STEP 2: PREPARATION OF CINACALCET OF FORMULA (I)
The solid compound of formula (IV) (5.0 gm) of step-1. l-(bfomopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 gm) in N-methyl-2-pyrrolidinone (25 ml) were healed at 130-140°C till the completion of the reaction which was monitored by TLC (12hours). The reaction mass was cooled 25-35°C, diluted with water (50 nil), the pl-l of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting solution was extracted with toluene (50 ml), toluene layer was washed with 10% sodium metabisulphite solution (50 ml) and concentrated under vacuum to yield syrup. The syrup was dissolved in the acetonitrile (10ml) and water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid, and washed the acidic aqueous layer with n-heplane (25 ml). The aqueous layer was then basified with ammonia till pH 9-10 and then extracted the cinacalcet base into toluene (50m\). Toluene layer was washed with water (25 ml )and distilled off the toluene layer to get cinacalcet base as thick syrup Yield.4.45 gm (64.50 %): HPLC purity 98.23%; Chiral purity: 99.89%.

Example 5
STEP 2: PREPARATION OF CINACALCET OF FORMULA (l)
The solid compound of formula (IV) (5.0 gm) obtained in step-1, l-(bromopropyl) -3-(trifluoromethyl)benzene compound of the formula (V) (5.66 "gm) in N.N-dimethyl formamide (25 ml) were refluxed at 130-140°C till the completion of the reaction which was ^monitored by TLC (\2hours) and Vne reaction mass was cooled \o 25-35°C. The reaction solution was dihtted with water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and stirred for 60 min. The resulting reaction solution was extracted with toluene (50 ml), washed with 10% sodium metabisulphite solution (50 ml) and concentrated -under vacuum to yield syrup. The syrup was dissolved in the acetonitrile (10ml) and water (50 ml), the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid and washed the acidic aqueous layer with n-heptane (25 ml). The aqueous layer was separated, basified with ammonia till pH 9-10. and extracted with toluene (50ml). Toluene layer was washed with water (25 ml) and distilled off the toluene layer to get cinacalcet base as thick syrup. Yield 3.44 gm (50.01 %): HPLC purity 97.01%; Chiral purity: 99.89%.
Example 6
PREPARATION OF CINACALCET HYDROCHLORIDE OF FORMULA (VII) :
Cinacalcet base Compound of formula (1) (5.0 gm) was dissolved in toluene (25 ml) and n-heptane (75 ml), and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid at 25-30°C and stirred for 30 minutes. The precipitated solid was filtered, washed with 10 ml n-heptane, and dried under vacuum to yield 5.1 gm (92.55%) of cinacalcet hydrochloride; HPLC purity 99.80%; Chiral purity: 99.95%.
Example 7
PREPARATION OF CINACALCET HYDROCHLORIDE OF FORMULA (VII):
Cinacalcet base Compound of formula (I) (5.0 gm) was dissolved in diisopropylelhcr (50 ml) and the pH of the solution was. adjusted to 1-2 using concentrated hydrochloric acid at 25-30°C. the mass was stirred for 30 minutes, precipitated solid was filtered, washed with diisopropylether (10 ml) and dried under vacuum to yield 4.8 gm (86.48%)) of cinacalcet hydrochloride: HPLC purity 99.67%; Chiral purity: 99.92%.

Documents:

516-MUM-2009-ABSTRACT(26-02-2010).pdf

516-MUM-2009-CLAIMS(26-02-2010).pdf

516-MUM-2009-CLAIMS(AMENDED)-(1-10-2013).pdf

516-MUM-2009-CLAIMS(AMENDED)-(23-1-2014).pdf

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516-MUM-2009-CORRESPONDENCE(26-02-2010).pdf

516-MUM-2009-CORRESPONDENCE(3-4-2009).pdf

516-MUM-2009-CORRESPONDENCE(9-3-2009).pdf

516-MUM-2009-CORRESPONDENCE(IPO)-(17-8-2009).pdf

516-mum-2009-correspondence.pdf

516-MUM-2009-DESCRIPTION(COMPLETE)-(26-02-2010).pdf

516-mum-2009-description(provisional).doc

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516-MUM-2009-FORM 1(1-10-2013).pdf

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Patent Number

259898

Indian Patent Application Number

516/MUM/2009

PG Journal Number

14/2014

Publication Date

04-Apr-2014

Grant Date

28-Mar-2014

Date of Filing

09-Mar-2009

Name of Patentee

MEGAFINE PHARMA (PVT) LTD

Applicant Address

4TH FLOOR, SETHNA, 55, MAHARSHI KARVE ROAD, MARINE LINES, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	MATHAD VIJAYAVITTHAL THIPPANNACHAR	FLAT NO. 6, RACHIT CLASSIC KULKARNI COLONY, OFF COLLEGE ROAD, NASHIK-422009,
2	NIPHADE NAVNATH CHINTAMAN	FLAT NO. 4, ELDORA APPARTMENTS, SAWARKAR NAGAR, GANGAPUR ROAD, NASHIK-422013,
3	P RAGHVENDRA KUMAR	3-A, VATSLYAKUNJ APARTMENTS, RAJPAL COLONY, MAKHMALABAD NAKA, PANCHAVATI, NASHIK-422003,
4	SHINDE GORAKSHANATH BALASAHEB	AT POST-KHADAK-MALEGAON, TAL. NIPHAD, DIST. NASHIK-422304,
5	IPPAR SHARAD SUBHASH	06, LAXMI PUJA COOP, SOCIETY, KAMATWADA, NASHIK-422008,
6	DESHMUKH SHRIKANT PANDHARINATH	413A, SHIMPILANE, LAL CHOWK, SINNAR, NASHIK-422103,

PCT International Classification Number

C07C209/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA