Process for the preparation of nitrosamine free cinacalcet and salts thereof

Abstract

The present invention relates to a process for preparation of nitrosamine free Cinacalcet (1) and salts thereof. Wherein, Cinacalcet (1) and its salts is substantially free of nitrosamine impurities by using of an antioxidant in the process for synthesis of Cinacalcet (1) and its pharmaceutically acceptable salts.

Description

[0001] TITLE OF THE INVENTION

[0002] PROCESS FOR THE PREPARATION OF NITROSAMINE FREE CINACALCET AND

[0003] SALTS THEREOF

[0004] This application claims priority from Indian patent application no. IN202321075864.

[0005] FIELD OF THE INVENTION:

[0006] The present invention relates to a process for preparation of Nitrosamine free Cinacalcet (1) and salts thereof. Wherein, Cinacalcet (1) and its salts is substantially free of Nitrosamine impurities.

[0007] BACKGROUND OF THE INVENTION:

[0008] N-[l(R)-(l-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-amine (herein

[0009] "Cinacalcet") structurally represented by formula (1), has a CAS number of 226256-56-0, a molecular formula of C22H22F3N and the following structure:

[0010] Cinacalcet Hydrochloride is marketed as SENSIP AR™ and acts as a calcimimetic (i.e., it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. SENSIPAR™ is a calcium-sensing receptor agonist approved for the treatment of Secondary Hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, Hypercalcemia in patients with Parathyroid Carcinoma (PC), Severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy. US 6,011,068 discloses inorganic ion receptor activity, especially calcium receptor-active molecules, such as those having the general structure of Cinacalcet. US 6,211,244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. As per US’144, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-[3- (trifluoromethyl)phenyl|propyiamine 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. Similarly, using the process disclosed in US ’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 isopropoxi de to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride. US ’244 discloses an additional process for the synthesis of Cinacalcet. This process involves use of 3-trifluoromethylcinnamonitrile.

[0011] In recent years, Nitrosamine contamination of drug products has been admitted as a major regulatory issue for the pharmaceutical industry.

[0012] Drug developers are searching for solutions that will help overcome their formulation challenges in mitigating nitrosamine formation.

[0013] Manufacturers are looking to optimize the formulation process of drug products to limit nitrosamine formation. However, optimization of formulation processes may not prevent nitrosamine contamination entirely. For these reasons, manufacturers are looking to block nitrosamine formation in drug products / substances.

[0014] One possible strategy is that the formation of nitrosamines typically occurs under acidic conditions and the risk of contamination is much lower in neutral or basic environments. But this strategy is not always suitable because some of the drug substances are not stable at higher pH levels.

[0015] Another approach is blocking nitrosamines by including antioxidants in drug formulations. A nitrosation inhibitor-antioxidants that can react with many nitrosating agents (like NO+, NCh” and N2O3), converting them into nitric oxide (NO) and effectively blocking nitrosamine formation. Emerging research has found that antioxidants viz. ascorbic acid and a-tocopherol demonstrated greater than 80% inhibition of nitrosation when spiked at 1% levels in solid oral dosage forms.

[0016] Hence, there remains a need for developing new process which can block the nitrosamine formation in Active drug substance.

[0017] There is continuous evolution in the manufacturing operations in the preparation of Cinacalcet (1) and numerous controls as per different guidelines of worldwide drug authorities has been applied to make the drugs suitable for human consumption and subsequently for treatment. In recent years in pharmaceutical industry API manufacturing to have efficient in-process controls in the preparation of active pharmaceutical ingredients mainly free of nitrosamine impurities.

[0018] The prior art processes for preparation of Cinacalcet (1) are not suitable to control unwanted nitrosamine impurities. Hence, there remains a need for providing efficient, safe, industrially feasible and economically viable process for manufacturing of Cinacalcet (1) to substantially eliminate the problems associated with the prior art processes and provide Cinacalcet which is free from nitrosamine impurities with good yield and purity.

[0019] OBJECTS OF THE PRESENT INVENTION:

[0020] The primary object of the present invention is to provide an efficient, economically and an industrially viable process for preparation of Cinacalcet (1) essentially free of nitrosamines impurities.

[0021] Yet, another object of the present invention is to provide process involving the use of antioxidants for preparation of Cinacalcet (1) essentially free of nitrosamines impurities.

[0022] SUMMURY OF THE INVENTION:

[0023] The present invention discloses a process for the synthesis of nitrosamine free Cinacalcet (1) and its pharmaceutically acceptable salts.

[0024] The present invention surprisingly found nitrosamine free Cinacalcet (1) and its pharmaceutically acceptable salts by using of an antioxidant in the process for synthesis of Cinacalcet (1) and its salts. The present invention discloses the three methods for preparation of nitrosamine free Cinacalcet (1) and its pharmaceutically acceptable salts.

[0025] Method - 1: The said method-1 comprises reacting ( l / ?)- l -( l -naphthyl)-ethanamine. acid salt (3A) with l-(3-halopropyl)-3-(trifluoromethyl)benzene (4) in presence of a solvent, a suitable base to provide nitrosamine free Cinacalcet (1) which is optionally isolated and further converted into its pharmaceutically acceptable salts substantially free of nitrosamine impurities. Wherein, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0026] Method - 2: The said method-2 comprising: converting ( 17?)- 1-(1 -naphthyl) ethanamine. acid salt (3A) in presence of a solvent and base to provide (1 / ?)- ! -(1 -naphthyl) ethanamine (3); then reacting (1A)-1-(1 -naphthyl) ethanamine (3) with 3 -[3 -(trifluoromethyl) phenyl] propanal (6) in presence of a suitable reducing agent, solvent to provide nitrosamine free Cinacalcet (1) which is optionally isolated and further converted into its pharmaceutically acceptable salts substantially free of nitrosamine impurities. Wherein, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0027] Method - 3: The said method-3 comprising: reacting ( l / ?)- l -( l -naphthyl) ethanamine (3) with benzaldehyde (7) to provide (lR)-l-(2-naphthyl)-N-[l-phenylmethylene]ethanamine (5) then reacting compound of formula (5) with l-(3-halopropyl)-3-(trifluoromethyl)benzene (4) in presence of a solvent to provide iminium salt (8) which is treated with water and / or acid solution to obtain nitrosamine free Cinacalcet (1) and further converted into its pharmaceutically acceptable salts substantially free of nitrosamine impurities. Wherein, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0028] DETAILED DESCRIPTION OF THE INVENTION:

[0029] Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.

[0030] Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and “the like”, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed in the embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

[0031] As used herein in the present application, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. The term "substantially free of' means that a contaminant substance can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application. The term “Nitrosamine free” means that a nitrosamine impurity can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application.

[0032] One of the embodiments of the present invention provides a process for preparation of nitrosamine free Cinacalcet and pharmaceutically acceptable salts thereof, the said process comprising: a) reacting ( 17?)- 1-(1 -naphthyl) ethanamine. acid salt (3A) with a l-(3-halopropyl)-3- (trifluoromrthyl)benzene (4) in a solvent, in presence of a suitable base to provide Cinacalcet (1); and b) Converting Cinacalcet of formula (1) obtained in step a) into the required acid addition salt;

[0033] According to another embodiment of the present invention, the process of step (b) can be carried out with or without isolating the compounds of formula (1) of step (a).

[0034] According to another embodiment of the present invention, the compound of formula (2), is isolated and purified. Preferably, performed by crystallization using alkyl acetate, aromatic hydrocarbons, nitriles water or mixtures thereof.

[0035] According to another embodiment of the present invention, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0036] The antioxidant is used in step (a) and / or (b) and / or workup and / or isolation and / or purification steps.

[0037] The Antioxidants used is selected from but not limited to the group comprising of Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG), L-Cysteine (CyS), Ascorbic acid (Vitamin C), a-Tocoferol (Vitamin E), Thioglycolic acid, Thioglycerol, Sodium metabisulfite, Sodium ascorbate, Ascorbyl palmitate, Maltol, Resveratrol, Glycine, Arginine, Lysine, Histidine, Urea, Para-aminobenzoic acid (PABA), Sodium sulfite, Ammonium sulfate, Ammonium chloride.

[0038] The solvent used in step (a) and (b) may be either same or different and is selected from the group comprising of esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, and methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol, ethylene glycol, and diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; cyclic amides such as but not limited to A-methyl-2- pyrrolidinone; nitriles such as but not limited to acetonitrile, and propionitrile; water; or mixtures thereof. Preferably, the solvent used in step (a) and (b) is water, alkyl acetate, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, nitriles.

[0039] The base used in step (a) is selected from inorganic bases such as alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal amide such as but not limited to lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide; and mixtures thereof. Preferably, the base used in step (a) is alkali metal carbonates.

[0040] Steps (a), (b) of the embodiment are carried out at a temperature of 0°C to reflux temperature of solvent. Preferably, steps (a), (b) are carried out at a temperature 0-100 °C.

[0041] Acid used in step (b) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid; optionally saturated these acids with alcohols such as methanol, ethanol, and isopropanol. Preferably, acid used in step (b) is Hydrochloric acid. According to the present invention, isolation followed by purification of compound of the formula (2) from step (b) comprises the steps of: i. treating the reaction mass of step (a) with solvent, water, and acid; ii. separating the organic layer and concentrating the organic layer to obtain residue; iii. diluting obtained residue with suitable organic solvent; and iv. filtering and drying the obtained solid of step (iii) to provide compound of formula (2).

[0042] According to another embodiment of the present invention, optionally, the antioxidant is used in one or more of the steps of (i) to (iv).

[0043] The organic solvent used in steps (i), (iii) may be either same or different and is selected from the group comprising of alcohols including but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; nitriles such as but not limited to acetonitrile, and propionitrile; water or mixtures thereof. Preferably,

[0044] • The organic solvent used in step (i) is halogenated aliphatic hydrocarbons, alkyl acetate, aromatic hydrocarbons.

[0045] • The organic solvent used in step (iii) is alkyl acetate, aromatic hydrocarbons, nitriles, water or mixtures thereof.

[0046] Acid used in step (i) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid; optionally saturated these acids with alcohols such as methanol, ethanol, and isopropanol. Preferably, acid used in step (i) is Hydrochloric acid.

[0047] Cinacalcet and its salts obtained from the process of the present invention are substantially free of Nitrosamine impurities, process related impurities, by products, carry over impurities and degradation impurities. Cinacalcet obtained from the process of the present invention has a purity of at least 99.5% by HPLC. Preferably, Cinacalcet and its salts obtained from the process of the present invention is free of nitrosamine impurities with the threshold / limit of not more than (NMT) 1.1 PPM [as per Appendix-1 of EMA guideline EMA / 409815 / 2020 Rev.19, 10 / 2023]; more preferably, less than 0.5 PPM. Cinacalcet or its salts obtained from the process of the present invention is substantially free from antioxidants which is used in the process, and if it is carried over in drug substance then it is additional advantage for formulation process to control nitrosamine, further all disclosed antioxidants are usually used for formulation process.

[0048] Another embodiment of the present invention provides a process for preparation of nitrosamine free Cinacalcet and pharmaceutically acceptable salts thereof, the said process comprising: a) converting (IR)-l-(l -naphthyl) ethanamine. acid salt (3A) to (IR)-l-(l- naphthyl) ethanamine (3) in presence of base in suitable solvent; b) reacting ( l / ?)- l -( l -naphthyl) ethanamine (3) obtained in step a) with 3 -[3 -(trifluoromethyl) phenyl] propanal (6) in presence of a suitable solvent, a metal catalyst as a reducing agent under hydrogen pressure to provide a Cinacalcet (1); and ( ) ( 6 ) c) Converting cinacalcet of formula (1) into pharmaceutically acceptable salts thereof.

[0049] According to another embodiment of the present invention, the process of step (c) can be carried out with or without isolating the compounds of formula (1) of step (b).

[0050] According to another embodiment of the present invention, the compound of formula (2) is isolated and purified. Preferably, performed by crystallization using alkyl acetate, aromatic hydrocarbons, nitriles water or mixtures thereof.

[0051] According to another embodiment of the present invention, the compound of formula (3) is isolated. According to another embodiment of the present invention, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0052] The antioxidant is used in step (b) and / or (c) and / or workup and / or isolation and / or purification steps.

[0053] The Antioxidants used is selected from but not limited to the group comprising of Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG), L-Cysteine (CyS), Ascorbic acid (Vitamin C), a-Tocoferol (Vitamin E), Thioglycolic acid, Thioglycerol, Sodium metabisulfite, Sodium ascorbate, Ascorbyl palmitate, Maltol, Resveratrol, Glycine, Arginine, Lysine, Histidine, Urea, Para-aminobenzoic acid (PABA), Sodium sulfite, Ammonium sulfate, Ammonium chloride.

[0054] The solvent used in steps (a), (b) and (c) may be either same or different and is selected from the group comprising of esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, and methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol, ethylene glycol, and diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; cyclic amides such as but not limited to A-methyl-2- pyrrolidinone; nitriles such as but not limited to acetonitrile, and propionitrile; water; or mixtures thereof. Preferably,

[0055] • The solvent used in step (a), and (c) is alkyl acetate, halogenated aliphatic hydrocarbons, aromatic hydrocarbons.

[0056] • The solvent used in step (b) is alcohols.

[0057] The base used in step (a) is selected from inorganic bases such as alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal amide such as but not limited to lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide; and organic bases such as primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol; secondary amines such as but not limited to N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine,; tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, N,N-dimethyl ethyl amine; ammonium hydroxide; or mixtures thereof. Preferably, the base used in step (a) is ammonium hydroxide, alkali metal hydroxides.

[0058] The metal catalyst used in step (b) is selected from but not limited to Raney-Ni, Pd / C, Pt / C, Rh / C. Preferably, the metal catalyst used in step (b) is Raney-Ni.

[0059] Steps (a), (b) and (c) of the embodiment are carried out at a temperature of 0°C to the reflux temperature of the solvent. Preferably,

[0060] • Step (a) is carried out at a temperature 0-40 °C

[0061] • Step (b) is carried out at a temperature 25-60 °C

[0062] • Step (c) is carried out at a temperature 0-40 °C

[0063] Acid used in step (c) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid; optionally saturated these acids with alcohols such as methanol, ethanol, and isopropanol. Preferably, acid used in step (c) is Hydrochloric acid.

[0064] According to the present invention, isolation followed by purification of compound of the formula (2) from step (c) comprises the steps of: i. treating the reaction mass of step (b) with solvent, water and acid; ii. separating the organic layer and concentrating the organic layer to obtain residue; iii. diluting obtained residue with suitable organic solvent; and iv. filtering and drying the obtained solid of step (iii) to provide compound of formula (2).

[0065] According to another embodiment of the present invention, optionally, the antioxidant is used in one or more of the steps of (i) to (iv).

[0066] The organic solvent used in steps (i), (iii) may be either same or different and is selected from the group comprising of alcohols including but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; nitriles such as but not limited to acetonitrile, and propionitrile; water or mixtures thereof. Preferably,

[0067] • The organic solvent used in step (i) is halogenated aliphatic hydrocarbons, alkyl acetate, aromatic hydrocarbons.

[0068] • The organic solvent used in step (iii) is alkyl acetate, aromatic hydrocarbons, nitriles, water or mixtures thereof.

[0069] Acid used in step (i) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid; optionally saturated these acids with alcohols such as methanol, ethanol, and isopropanol. Preferably, acid used in step (i) is Hydrochloric acid.

[0070] Cinacalcet and its salts obtained from the process of the present invention are substantially free of nitrosamine impurities, process related impurities, by products, carry over impurities and degradation impurities. Cinacalcet obtained from the process of the present invention has purity of at least 99.5% by HPLC. Preferably, Cinacalcet and its salts obtained from the process of the present invention is free of nitrosamine impurities with the threshold / limit of not more than 1.1 PPM [as per Appendix- 1 of EMA guideline EMA / 409815 / 2020 Rev.19, 10 / 2023]; more preferably, less than 0.5 PPM. Cinacalcet or its salts obtained from the process of the present invention is substantially free from antioxidants which is used in the process, and if it is carried over in drug substance then it is additional advantage for formulation process to control nitrosamine, further all disclosed antioxidants are usually used for formulation process.

[0071] Another embodiment of the present invention provides a process for preparation of nitrosamine free Cinacalcet and pharmaceutically acceptable salts thereof, the said process comprising: a) reacting ( l / ?)- l -( l -naphthyl) ethanamine (3) with benzaldehyde (7) to provide Compound of formula (5);

[0072] Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, or nitro group b) reacting compound of formula (5) with l-(3-halopropyl)-3-(trifluoromrthyl)benzene (4) in presence of a solvent to provide iminium salt (8); and

[0073] ( 5 ) c) treating the reaction mixture of step (b) with water and / or acid solution to obtain Cinacalcet (1) or salts thereof.

[0074] According to another embodiment of the present invention, the process of step (c) can be carried out with or without isolating the compounds of formula (8) of step (b).

[0075] According to another embodiment of the present invention, the pharmaceutically acceptable salts of formula (2) is isolated and purified. Preferably, performed by crystallization using alkyl acetate, aromatic hydrocarbons, nitriles water or mixtures thereof.

[0076] According to another embodiment of the present invention, the compound of formula (5) is optionally, isolated and purified.

[0077] According to another embodiment of the present invention, the antioxidant is used in reaction and / or workup and / or isolation and / or purification steps.

[0078] The antioxidant is used in step (a) and / or (b) and / or workup and / or isolation and / or purification steps.

[0079] The Antioxidants used is selected from but not limited to the group comprising of Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG), L-Cysteine (CyS), Ascorbic acid (Vitamin C), a-Tocoferol (Vitamin E), Thioglycolic acid, Thioglycerol, Sodium metabisulfite, Sodium ascorbate, Ascorbyl palmitate, Maltol, Resveratrol, Glycine, Arginine, Lysine, Histidine, Urea, Para-aminobenzoic acid (PABA), Sodium sulfite, Ammonium sulfate, Ammonium chloride.

[0080] The step (a) is carried out with or without solvent.

[0081] The solvent used in step (a), (b) and (c) may be either same or different and is selected from the group comprising of esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, and methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol, ethylene glycol, and diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; cyclic amides such as but not limited to A-methyl-2- pyrrolidinone; nitriles such as but not limited to acetonitrile, and propionitrile; water; or mixtures thereof. Preferably,

[0082] • The solvent used in step (a) is alcohols, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons.

[0083] • The solvent used in step (b) is cyclic amides.

[0084] The base used in step (c) is selected from inorganic bases such as alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates such as but not limited to sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal amide such as but not limited to lithium amide, sodium amide, potassium amide, cesium amide and rubidium amide; ammonium hydroxide and mixtures thereof. Preferably, ammonium hydroxide. Steps (a), (b), and (c) of the embodiment are carried out at a temperature of 0°C to the reflux temperature of the solvent. Preferably,

[0085] • Step (a) is carried out at a temperature 0-40 °C

[0086] • Step (b) is carried out at a temperature 0-150 °C

[0087] • Step (c) is carried out at a temperature 0-40 °C

[0088] Acid used in step (c) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid; optionally saturated these acids with alcohols such as methanol, ethanol, and isopropanol. Preferably, Hydrochloric acid.

[0089] According to the present invention, isolation followed by purification of compound of the pharmaceutically acceptable salts of formula (2) from step (c) comprises the steps of: i. treating the reaction mass of step (b) with solvent, water and acid; ii. separating the organic layer and concentrating the organic layer to obtain residue; iii. diluting obtained residue with suitable organic solvent; and iv. filtering and drying the obtained solid of step (iii) to provide compound of formula (2).

[0090] According to another embodiment of the present invention, optionally, the antioxidant is used in one or more of the steps of (i) to (iv).

[0091] The organic solvent used in steps (i), (iii) may be either same or different and is selected from the group comprising of alcohols including but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; nitriles such as but not limited to acetonitrile, and propionitrile; water or mixtures thereof. Preferably,

[0092] • The organic solvent used in step (i) is halogenated aliphatic hydrocarbons, alkyl acetate, aromatic hydrocarbons.

[0093] • The organic solvent used in step (iii) is alkyl acetate, aromatic hydrocarbons, nitriles, water or mixtures thereof. Acid used in step (i) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid, and hydrochloric acid optionally saturated with alcohols such as methanol, ethanol, and isopropanol. Preferably, acid used in step (i) is Hydrochloric acid.

[0094] Cinacalcet or its salts obtained from the process of the present invention is substantially free of Nitrosamine impurities, process related impurities, by products, carry over impurities and degradation impurities. Cinacalcet obtained from the process of the present invention has a purity of at least 99.5% by HPLC. Preferably, Cinacalcet and its salts obtained from the process of the present invention is free of nitrosamine impurities with the threshold / limit of not more than (NMT) 1.1 PPM [as per Appendix-1 of EMA guideline EMA / 409815 / 2020 Rev.19, 10 / 2023]; more preferably, less than 0.5 PPM. Cinacalcet or its salts obtained from the process of the present invention is substantially free from antioxidants which is used in the process, and if it is carried over in drug substance then it is additional advantage for formulation process to control nitrosamine, further all disclosed antioxidants are usually used for formulation process.

[0095] BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION

[0096] The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.

[0097] Example-01: Preparation of Cinacalcet Hydrochloride [Method - 1]

[0098] Purified water (500 ml) and K2CO3 (213.68 g, 5.0 moles) were added in RBF at 25-30°C. The reaction media was stirred at 25-30°C for 10-15 mins. l-(bromopropyl)-3-(trifhioromethyl) benzene (4) (107.36 g, 1.30 moles) was added, and the reaction temperature was raised to 60-65°C. (1R)-1- (1 -naphthyl) ethanamine tartrate of formula (3 A) (100 g), and butylated hydroxy toluene [BHT] (1.2 g) was added, and the temperature of the reaction was raised to 85-90°C and maintained the reaction for 10-12 hrs. After completion of the reaction, which was monitored by HPLC, the reaction solution was cooled to 25-30°C, ethyl acetate (500 ml) was added to the solution. The mixture was stirred, and ethyl acetate layer was separated. The ethyl acetate layer was washed with water (500 ml x 2). To the ethyl acetate layer was added Purified water (500 ml) and cone. HC1 (89.0 ml) and stirred at 25-30°C and separated the ethyl acetate layer. The ethyl acetate layer was washed with brine solution, and ethyl acetate layer was distilled out under vacuum below 50°C to afford Cinacalcet hydrochloride which was treated with ethyl acetate (300 mL) at 25-35°C. The reaction mass was heated at 65-70°C and maintained for 30 minutes. The reaction mass was cooled to 25- 30°C, chilled to 0-5°C and stirred for 80-90 minutes. The reaction mass was filtered and washed with ethyl acetate (25.0 ml) to afford Cinacalcet hydrochloride. HPLC Purity: 99.85%.

[0099] Purification of Cinacalcet Hydrochloride : Cinacalcet hydrochloride obtained from example 1 was purified to improve chemical purity. The material (80 g) was dissolved in a mixture of acetonitrile (160 ml) purified water (800 ml), stirred, and heated to below 85°C for 20-30 min. Then treated with activated charcoal (2 g). The resulting solution was filtered through Hyflo bed and washed with acetonitrile (16 ml). The reaction mass was then cooled to 25-30°C, chilled at 0-5°C and maintained for 80 to 90 min. The crystalline solid obtained was filtered and dried under vacuum (650-700 mm / Hg to afford Cinacalcet hydrochloride of as white crystalline solid.

[0100] Yield: 70 gm (60.9%); HPLC purity: 99.90% and Chiral purity: 100.0%.

[0101] Example-02: Preparation of Cinacalcet Hydrochloride [Method - 2]

[0102] Purified water (500 ml), (1R)-1-(1 -naphthyl) ethanamine tartrate of formula (3 A) (100 g) and Dichloromethane [DCM] (500 ml) were added in RBF at 25-30°C. The pH of reaction mass was adjusted to 9-11 using aq. ammonia soln., separated the layers. DCM layer was washed with brine soln. DCM layer was distilled out under vacuum below 50°C and residue was cooled to 25-30°C to afford (IR)-l-(l-naphthyl) ethanamine (3) (50 g). 3 -[3 -(trifluoromethyl) phenyl] propanal (6) (70.84 g) (IR)-l-(l-naphthyl) ethanamine (3) (50 g) and butylated hydroxy toluene [BHT] (1.2 g) along with methanol (600 ml) was added and reaction mass was transferred into autoclave. The reaction mass was stirred for 5-10 minutes. Raney-Ni (6 g) was added under Nitrogen. Nitrogen pressure of 2-3 Kg / cm2was applied and released and was repeated twice. The reaction mass was hydrogenated with pressure of 4-5 Kg / cm2at 45°C to 50°C and maintained for 2 to 8 hours. After completion of the reaction, which was monitored by HPLC, Hydrogen pressure was released, Nitrogen pressure of 2-3 Kg / cm2 was applied and released and was repeated twice. The reaction mass was filtered through Hyflo bed under Nitrogen pressure and washed with methanol (50 ml). The methanol was distilled out under vacuum below 50°C. The residue was cooled to 25-30°C, Purified water (600 ml), DCM (800 ml), and cone. HC1 (89.0 ml) was added and stirred at 25-30°C and separated the DCM layer. The DCM layer was washed with brine solution, and DCM layer was distilled out under vacuum below 50°C to afford Cinacalcet hydrochloride which was treated with ethyl acetate (600 mL) at 25-35°C. The reaction mass was heated at 65- 70°C and maintained for 30 minutes. The reaction mass was cooled to 25- 30°C, chilled to 0-5°C and stirred for 80-90 minutes. The reaction mass was filtered and washed with ethyl acetate (32 ml) to afford Cinacalcet hydrochloride. HPLC Purity: 99.65%

[0103] Purification of Cinacalcet Hydrochloride : Cinacalcet hydrochloride obtained from example 2 was purified to improve chemical purity. The material (80 g) was dissolved in a mixture of acetonitrile (160 ml) purified water (800 ml), stirred, and heated to below 85°C for 20-30 min. Then treated with activated charcoal (2 g). The resulting solution was filtered through Hyflo bed and washed with acetonitrile (16 ml). The reaction mass was then cooled to 25-30°C, chilled at 0-5°C and maintained for 80 to 90 min. The crystalline solid obtained was filtered and dried under vacuum (650-700 mm / Hg to afford Cinacalcet hydrochloride of as white crystalline solid.

[0104] Yield: 70 gm (60.0%); HPLC purity: 99.90% and Chiral purity: 100.0%.

[0105] Example-03: Preparation of Cinacalcet Hydrochloride [Method - 3]

[0106] Solution of (1R)-1 -naphthyl ethylamine (3) (100 gm) and benzaldehyde (7) (62.0 gm) was stirred at 25-30°C for 1-2 hours. After completion of the reaction, which was monitored by HPLC, A-methyl- 2-pyrrolidinone (300 ml) was added to the reaction mass and stirred the mixture for 15-20 min. 1- (bromopropyl)-3-(trifhroromethyl) benzene (4) (172 gm) and butylated hydroxy toluene [BHT] (1.2 g) was added to the resulting solution. The reaction mixture was further stirred and heated to 130- 140°C for 12 hrs. After completion of the reaction (by HPLC), the reaction solution was diluted with water (1000 ml) and the pH of the solution was adjusted to 8-9 using aqueous ammonia, toluene (1000 ml) was added to the soln. The mixture was stirred, and toluene layer was separated. The toluene layer was washed with water (1000 ml) followed by soln, of 10 % sodium metabisulphite (1000 ml x 2). The toluene layer was diluted with water (1000 ml), adjusted pH of the solution to 0.5-2.0 using concentrated HC1. The resulting reaction soln, was stirred, separated aqueous layer and organic layer. Organic layer washed with water washed with water (1000 ml x 2). The toluene layer was distilled off completely to obtain the thick syrup, which was further stirred in diisopropylether (600 ml) at 25-30°C for 6 h isolated the solid by filtration. The obtained solid was suspended in ethyl acetate (500 ml), soln, was heated at 55-60°C for 30 min, cooled to 15-20°C, filter the obtained solid. The product was dried to afford Cinacalcet hydrochloride as white crystalline solid. Yield: 120 gm (52.10%); HPLC Purity: 99.85%: Chiral Purity: 99.98%

[0107] 20 MS; mlz 358.79 (M+ + 1). 1H NMR (OMSO-d6): I) 10.12 (s, 1H), 9.43 (s, 1H), 8.26(d, 1H), 8.08 (d, 1H), 7.99-8.03 (m,2H), 7.60-7.63 (m, 3H), 7.53-7.54 (dt, 2H), 7.45-7.48 (dt, 2H). 5.32(q, 1 H), 2.93-2.96 (m, 1 H), 2.69-2.74 (t, 3H), 1.97-2.07 (m, 2H), 1.68-1.71 (d, 3H). Purification of Cinacalcet Hydrochloride : Cinacalcet hydrochloride obtained from example 3 was purified to improve chemical purity. The material (100 g) was dissolved in a mixture of acetonitrile (200 ml) purified water (1000 ml), stirred, and heated to below 85°C for 20-30 min. Then treated with activated charcoal (2.5 g). The resulting solution was filtered through Hyflo bed and washed with acetonitrile (20 ml). The reaction mass was then cooled to 25-30°C, chilled at 0- 5 °C and maintained for 80 to 90 min. The crystalline solid obtained was filtered and dried under vacuum (650-700 mm / Hg to afford Cinacalcet hydrochloride of as white crystalline solid.

[0108] Yield: 90 gm (90.0%); HPLC purity: 99.95% and Chiral purity: 100.0%.

[0109] Example-04: Preparation of Cinacalcet Hydrochloride [Method - 2]

[0110] Purified water (500 ml), (1R)-1-(1 -naphthyl) ethanamine tartrate of formula (3 A) (100 g) and Dichloromethane (500 ml) were added in RBF at 25-30°C. The pH of reaction mass was adjusted to 9-11 using ammonium hydroxide [aq. ammonia solution] and separated the layers. Dichloromethane layer was washed with brine solution. Dichloromethane layer was distilled out under vacuum below 50°C and residue was cooled to 25-30°C to afford (IR)-l-(l-naphthyl) ethanamine (3) (50 g). 3-[3- (trifluoromethyl) phenyl] propanal (6) (70.84 g) (IR)-l-(l-naphthyl) ethanamine (3) (50 g) along with methanol (600 ml) was added and reaction mass was transferred into autoclave. The reaction mass was stirred for 5-10 minutes. Raney-Ni (6 g) was added under Nitrogen. Nitrogen pressure of 2-3 Kg / cm2was applied and released and was repeated twice. The reaction mass was hydrogenated with pressure of 4-5 Kg / cm2at 45°C to 50°C and maintained for 2 to 8 hours. After completion of the reaction, which was monitored by HPLC, Hydrogen pressure was released, Nitrogen pressure of 2-3 Kg / cm2 was applied and released and was repeated twice. The reaction mass was filtered through Hyflo bed under Nitrogen pressure and washed with methanol (50 ml). Antioxidant: butylated hydroxy toluene [BHT] (0.6 to 1.2 g) was added to the reaction mass filtrate and the methanol was distilled out under vacuum below 50°C. The residue was cooled to 25-30°C, Purified water (600 ml), Dichloromethane (800 ml), and cone. HC1 (89.0 ml) was added and stirred at 25- 30°C and separated the Dichloromethane layer. The di chloromethane layer was washed with brine solution, and di chloromethane layer was distilled out under vacuum below 50°C to afford Cinacalcet hydrochloride which was treated with ethyl acetate (600 mL) at 25-35°C. The reaction mass was heated at 65-70°C and maintained for 30 min. The reaction mass was cooled to 25- 30°C, chilled to 0-5°C and stirred for 80-90 min. The reaction mass was filtered and washed with ethyl acetate (32 ml) to afford Cinacalcet hydrochloride . HPLC Purity: 99.65% Purification of Cinacalcet hydrochloride: Cinacalcet hydrochloride obtained from examples 1 or 2 or 3, or 4 was purified to improve chemical purity - Cinacalcet hydrochloride (80 g) was dissolved in a mixture of acetonitrile (160 ml) purified water (800 ml), and antioxidant: butylated hydroxy toluene [BHT] (0.6 g to 1.2 g) was added to the reaction mass. The reaction mass was stirred, and heated to below 85°C for 20-30 min and then treated with activated charcoal (2 g). The resulting solution was filtered through Hyflo bed and washed with acetonitrile (16 ml). The reaction mass was then cooled to 25-30°C, chilled at 0-5°C and maintained for 80 to 90 min. The crystalline solid obtained was filtered and dried under vacuum (650-700 mm / Hg to afford Cinacalcet hydrochloride of as white crystalline solid. Yield: 70 gm (60.0%); HPLC purity: 99.90% and Chiral purity: 100.0%, N-Nitroso-Cinacalcet content (PPM) [analyzed as per LCMS / MS]: Not detected to BDL / BQL range.

[0111] The following examples: 05 to 16 are performed in similar manner to Example 04 and the process performed in these examples resemble with example 04 [Method - 2], * LOD - limit of detection; LOQ - limit of Quantification; BDL - Below limit of detection; BQL - Below limit of Quantification; LCMS - Liquid chromatography mass spectrometry; MS - Mass spectrometry.

[0112] Following table shows content of N-Nitroso Cinacalcet in Cinacalcet.HCl which is purified in similar manner to above purification procedure of example 04, wherein crude Cincalcet.HCl is obtained as per Examples 1, 2, 3 respectively;

[0113] Analytical Method of analysis applicable for all example:

[0114] System: LC / MS-MS MS parameter for MRM mode of analysis

[0115] Column: SB C8, 150 mm X 4.6 mm, 5 pm, Instrument: API 5500+ (AB Sciex) or equivalent Scan Type: MRM

[0116] Column Oven Temperature: 30°C Ion Mode: EXI (Turbo Spray)

[0117] Auto-sampler Temperature: 25°C Polarity: Positive mode

[0118] Mobile Phase A: 10mm Ammonium QI Mass: 387.3 acetate in Water Q3 Mass: 155.2

[0119] Mobile Phase B: 100% Acetonitrile

Claims

We claim,1. The process for isolation followed by purification to obtain nitrosamine free pharmaceutically acceptable salts of Cinacalcet of formula (2) comprises the steps of:

1. treating the reaction mass of step in which Cinacalcet (1) is formed, with the solvent, water, and suitable acid; ii. separating the organic layer and concentrating the organic layer to obtain residue; iii. diluting obtained residue with suitable organic solvent; and iv. filtering and drying the obtained solid of step (iii) to provide compound of formula (2).Wherein, the antioxidant is used in one or more of the steps of (i) to (iv), selected from Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG), L- Cysteine (CyS), Ascorbic acid (Vitamin C), a-Tocoferol (Vitamin E), Thioglycolic acid, Thioglycerol, Sodium metabisulfite, Sodium ascorbate, Ascorbyl palmitate, Maltol, Resveratrol, Glycine, Arginine, Lysine, Histidine, Urea, Para-aminobenzoic acid, Sodium sulfite, Ammonium sulfate, Ammonium chloride.

2. The process as claimed in claim 1, wherein the organic solvent used in steps (i), (iii) may be either same or different and is selected from the group comprising of alcohols including but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, diethyl ether and di-methyl ether, methyl butyl ether; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; nitriles such as but not limited to acetonitrile, and propionitrile; water or mixtures thereof.

3. The process as claimed in claim 1, wherein Acid used in step (i) is an inorganic acid, selected from Sulfuric acid, Hydrobromic acid, Hydrochloric acid, and hydrochloric acid optionally saturated with alcohols such as methanol, ethanol, and isopropanol.

4. The process as claimed in claim 1, wherein a process for preparation of nitrosamine free Cinacalcet or pharmaceutically acceptable salts thereof, the said process comprising: a) converting (IR)-l-(l -naphthyl) ethanamine. acid salt (3A) to (IR)-l-(l- naphthyl) ethanamine (3) in presence of base in suitable solvent;b) reacting ( I / ?)- ! -( I -naphthyl) ethanamine (3) obtained in step a) with 3 -[3 -(trifluoromethyl) phenyl] propanal (6) in presence of a suitable solvent, a metal catalyst as a reducing agent under hydrogen pressure to provide a Cinacalcet (1); andc) Converting cinacalcet of formula (1) into pharmaceutically acceptable salts thereof.( 2 )Wherein, the antioxidant is used in step (b) and / or (c) and / or workup and / or isolation and / or purification steps.

5. The process as claimed in claim 1, wherein a process for preparation of nitrosamine free Cinacalcet and pharmaceutically acceptable salts thereof, the said process comprising: a) reacting ( 17?)- 1-(1 -naphthyl) ethanamine. acid salt (3A) with a l-(3-halopropyl)-3- (trifluoromrthyl)benzene (4) in a solvent, in presence of a suitable base to provide Cinacalcet (1); andb) Converting Cinacalcet of formula (1) obtained in step a) into the required acid addition salt; with or without isolating the compounds of formula (1).Wherein, the antioxidant is used in step (a) and / or (b) and / or workup and / or isolation and / or purification steps.

6. The process as claimed in claim 1, wherein a process for preparation of nitrosamine free Cinacalcet and pharmaceutically acceptable salts thereof, the said process comprising: a) reacting ( l / )- l -( l -naphthyl) ethanamine (3) with benzaldehyde (7) to provide Compound of formula (5);Ar is benzyl-, phenyl- or naphthyl-, which may be mono- or di- or poly substituted with alkyl, aryl, alkoxy, amino, hydroxyl, halogen, or nitro group b) reacting compound of formula (5) with l-(3-halopropyl)-3-(trifluoromrthyl)benzene (4) in presence of a solvent to provide iminium salt (8); andc) treating the reaction mixture of step (b) with water and / or acid solution to obtain Cinacalcet (1) or salts thereof.Wherein, the antioxidant is used in step (a) and / or (b) and / or workup and / or isolation and / or purification steps.

7. The process as claimed in preceding claims, wherein the antioxidant used is selected fromButylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG), L-Cysteine (CyS), Ascorbic acid (Vitamin C), a-Tocoferol (Vitamin E), Thioglycolic acid, Thioglycerol, Sodium metabisulfite, Sodium ascorbate, Ascorbyl palmitate, Maltol, Resveratrol, Glycine, Arginine, Lysine, Histidine, Urea, Para-aminobenzoic acid, Sodium sulfite, Ammonium sulfate, Ammonium chloride.

8. The process as claimed in preceding claims, wherein compound of formula (2) obtained is substantially free of Nitrosamine impurities, process related impurities, by products, carry over impurities and degradation impurities.

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