An impurity of Cinacalcet or salt thereof
Field of the invention

This invention relates to (R)-N-(1-(5, 6, 7, 8-tetrahydro naphthalen-1-yl) ethyl)-3-(3-(trifluoromethyl) phenyl) propan-1-amine (“Cinacalcet tetrahydro”) of formula (I), an impurity of Cinacalcet or salt thereof,

Formula (I)

Background of the invention

Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. The chemical name of Cinacalcet is N-[1-(R)-(-)-(1-naphthyl) ethyl]-3-[3¬(trifluoromethyl) phenyl]-1-aminopropane and having molecular formula of C22H22F3N and a CAS number of 226256-56-0. Cinacalcet having following structural formula:

Cinacalcet is a free base of Cinacalcet hydrochloride having a CAS number of 364782-34-3 and represented by following structural formula:

Cinacalcet hydrochloride is marketed by Amgen under brand name Sensipar® and is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis and also for the treatment of hypercalcemia in patients with parathyroid carcinoma. Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone (“PTH”) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, 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, Cinacalcet-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with Cinacalcet-HCl lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood.

Inorganic ion receptor active molecules, especially calcium receptor-active molecules, such as those having the general structure of Cinacalcet, are disclosed in US6011068.

US6211244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. Cinacalcet and its enantiomer may be produced by various methods, using the processes disclosed in US 6211244; Drugs of the Future, 27 (9), 831 (2002); US5648541; US4966988; and Tetrahedron Letters (2004) 45: 8355.

US7294735 discloses a process for preparation of Cinacalcet hydrochloride free of 3-(3-(trifluoromethyl) phenyl) propyl(R)-1(naphthalem-1-yl) ethyl carbamate (“Cinacalcet -carbamate”) impurity. The invention also relates to the Cinacalcet impurity, Cinacalcet carbamate and its use as a reference marker or as reference standard.

Several methods for the preparation of Cinacalcet have been described. Like any synthetic compound, Cinacalcet, or a pharmaceutically-acceptable salt thereof can contain process impurities, unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.

It is well known in the art that, for human administration, safety considerations require the establishment, by national and international regulatory authorities, of very low limits for identified, but toxicologically uncharacterized impurities, before an active pharmaceutical ingredient (API) product is commercialized. Typically, these limits are less than about 0.15 percent by weight of each impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.1 percent by weight. Specific standards can be applied to certain drugs where a pharmacopoeia monograph has been established for that drug. Typically, for impurities that are present in an amount of greater than 0.1 percent by weight, the impurity should be fully identified and characterized.

Therefore, in the manufacture of active pharmaceutical ingredients (APIs) knowledge of the purity of the API, such as Cinacalcet, is required before commercialization, as is the purity of the API in the manufactured formulated pharmaceutical product.

Impurities introduced during commercial manufacturing processes must be limited to very small amounts and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

The direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Intermediates and by-products will, in most cases, be present with the API. At certain stages during processing of an API, such as Cinacalcet, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine the presence of any intermediates or by-products. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for human use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 % wt.

Generally, by-products and intermediates (collectively hereinafter defined as "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. [Strobel p. 953, Strobel, H. A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd ed. (Wiley & Sons: New York 1989)]. Thereafter, the impurity can be identified, e.g., by its position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elusion of the particular component through the detector.

The relative position in the chromatogram is known as the "retention time." The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time" ("RRT") to identify impurities. (Strobel p. 922). The RRT of an impurity is its retention time divided by the retention time of "a reference marker". The reference marker can be the API itself, or it may be a compound other than the API that is added to, or present already in the mixture, in an amount sufficiently large to be detectable and sufficiently low so as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.

Those skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard". A reference standard is similar to a "reference marker", which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analysed using the same technique. [Strobel p. 924, Snyder p. 549, Snyder, L.R.; Kirkland, J.J. Introduction to Modern Liquid Chromatography, 2nd ed.(John Wiley &Sons: New York 1979)]. The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See also US 6,333,198, where the passages relating to the techniques for determining response factors are incorporated herein by reference.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor", which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard" (Strobel p. 925, Snyder p. 552).

The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the reference standard compound using the technique known as "standard addition". In the "standard addition technique", at least two samples are prepared by adding known and differing amounts of the internal standard (Strobel pp. 391-393, Snyder pp. 571, 572). The proportion of the detector response due to the reference standard present in the mixture without the addition can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero concentration of the reference standard (See, e.g., Strobel, Fig. 11.4, p. 392).

Impurities generally found in pharmaceutically active agents and formulations containing them include residual amounts of synthetic precursors to the active agent, by-products which arise during synthesis of the active agent, residual solvent, isomers of the active agent, contaminants which were present in materials used in the synthesis of the active agent or in the preparation of the pharmaceutical formulation, and unidentified adventitious substances. Other impurities which may appear on storage include substances resulting from degradation of the active agent, for instance by oxidation or hydrolysis. the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

At certain stages during processing of an API, such as Cinacalcet, or a pharmaceutically-acceptable salt thereof, it must be analyzed for purity, typically, by HPLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. In the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines recommend that the amounts of unknown impurities be limited to less than 0.1 percent.

As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

Impurities in Cinacalcet including, but not limited to, unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. Thus, there is a need in the art for a method for determining the level of impurities in Cinacalcet samples and removing the impurities.

While developing a process for the preparation of Cinacalcet HCl, present inventors serendipitously found a new process impurity named as Cinacalcet tetrahydro.

Object of the invention

Therefore, it is an object of the invention to provide Cinacalcet impurity, Cinacalcet tetrahydro, (R)-N-(1-(5, 6, 7, 8-tetrahydro naphthalen-1-yl) ethyl) -3-(3-(trifluoromethyl) phenyl) propan-1-amine, having following formula (I),

Formula (I)

Another object of the invention is to provide a process for preparing and isolating Cinacalcet tetrahydro of formula (I).

Yet another object of the invention is to provide Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC.

Further object the invention is to provide Cinacalcet tetrahydro of formula (I), used as reference marker or reference standard for determining the purity of Cinacalcet salt.

Summary of the invention

In one aspect, present invention provides Cinacalcet impurity, Cinacalcet tetrahydro, (R)-N-(1-(5, 6, 7, 8-tetrahydro naphthalen-1-yl) ethyl)-3-(3-(trifluoromethyl) phenyl) propan-1-amine, of formula (I), having the following formula (I):

Formula (I)

In another aspect, the present invention provides Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC.

In another aspect, the present invention provides a method for preparing Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC, comprising the steps of:
a) treating Crude Cinacalcet salt with mixture of suitable solvent system; and
b) isolating Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC.

In another aspect, the present invention provides a process for preparing Cinacalcet tetrahydro comprising a step of reducing 3-{[(1R)-1-(naphthalen-1-yl) ethyl] amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol in the presence of reducing agent and perchloric acid in alcohol.

In another aspect, the present invention provides a Cinacalcet tetrahydro used as a reference marker or reference standard for determining the purity of Cinacalcet salt.

Brief description of the drawing

FIG. 1 illustrates a typical HPLC chromatogram of Cinacalcet hydrochloride having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is less than 0.15 %.

FIG. 2 illustrates 1 H NMR spectrum of Cinacalcet tetrahydro of formula (I).

Details description of the invention

In one embodiment, the present invention provides a Cinacalcet impurity, Cinacalcet tetrahydro, (R) -N-(1-(5, 6, 7, 8-tetrahydro naphthalen-1-yl) ethyl)-3-(3-(trifluoromethyl) phenyl) propan-1-amine, of formula (I).

Formula (I)

The Cinacalcet tetrahydro of the present invention may be characterized by data selected from a 1 H NMR spectrum having hydrogen chemical shifts at about 1.65-1.85, 2.15-2.85; 4.45-4.60, 6.95-7.80, 9-11 ppm; a 13 CNMR spectrum having carbon chemical shifts at about 21.0, 22.6, 23.5, 26.4, 27.6, 30.5, 32.9, 45.6, 54.1, 123.4-123.5, 124.02, 125.3-125.4, 127.2, 129.2, 130.3, 132.0, 134.57, 134.9, 138.6, 141.3 ppm.; and by a retention time (“RT”) of about 15.5-16.5 minutes in HPLC analysis or relative retention time (“RRT”) of about 1.2.

In another embodiment, the present invention provides a pharmaceutical composition comprising Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC and at least one pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising combining Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC with at least one pharmaceutically acceptable excipient.

In another embodiment Cinacalcet tetrahydro may form in the synthesis of Cinacalcet for example, by the processes disclosed in Indian provisional Applications 2183/MUM/2009 and 2184/MUM/2009. This process comprises steps of:
a) treating 3-(trifluoromethyl)benzoic acid with thionyl chloride to obtain 3-(trifluoromethyl)benzoyl chloride,
b) condensing 3-(trifluoromethyl)benzoyl chloride with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum''s acid) in the presence of base and solvent to obtain ethyl 5-{hydroxy[3-(trifluoromethyl)phenyl]methylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione,
c) condensing ethyl 5-{hydroxy[3-(trifluoromethyl)phenyl]methylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione with (1R)-1-(naphthalen-1-yl)ethanamine in the presence of base and solvent, optionally in the presence of phase transfer catalyst to obtain N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-oxo-3-[3-(trifluoromethyl) phenyl] propanamide,
d) reducing N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-oxo-3-[3-(trifluoromethyl)phenyl] propanamide in the presence of reducing agent and solvent to obtain 3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol or salt thereof,
e) converting 3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol or salt thereof into 3-halo-N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl) phenyl]propan-1-amine or salt thereof,
f) reducing 3-halo-N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl) phenyl] propan-1-amine or salt thereof in the presence of reducing agent and solvent to obtain Cinacalcet salts.

In another embodiment, the present invention provides a method for preparing a Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC comprising the steps of:
a) treating crude Cinacalcet salt with mixture of suitable solvent system;
b) isolating Cinacalcet salt having purity at least about 99 % wherein the content of Cinacalcet tetrahydro impurity is in the range of about 0.03 % to about 0.15 % as measured by HPLC.

As used herein “suitable solvent system” includes but not limited to ester, ether, alcohol, aromatic solvent, a saturated hydrocarbon, water and the like or mixture thereof. More preferably, the ester is ethyl acetate. More preferably, the ether is diisopropyl ether. The most preferred suitable solvent system is mixture of ethyl acetate, diisopropyl ether and water.

A present invention includes a process for preparing Cinacalcet tetrahydro by reducing 3-{[(1R)-1-(naphthalen-1-yl) ethyl] amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol in presence of reducing agent and perchloric acid in alcohol.

The reduction of the 3-{[(1R)-1-(naphthalen-1-yl) ethyl] amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol is carried out using reducing agents such as platinum on carbon, Raney Nickel or palladium on carbon. The reduction is preferably carried out using palladium on carbon (5 - 10 %) under a hydrogen pressure of 50-70 psi for 14 to 24 hours at a temperature of 20-25°C in alcoholic solvent such as ethanol, methanol, propanol and the like. The preferred alcoholic solvent is methanol.

A present invention also provides isolated Cinacalcet tetrahydro. Cinacalcet tetrahydro formed during the synthesis of Cinacalcet base or salt thereof may be isolated by subjecting the Cinacalcet base or salt thereof that contains the Cinacalcet tetrahydro to column chromatography. The column chromatography comprises using a silica gel, as a stationary phase, and a gradient of eluents that remove Cinacalcet tetrahydro from the column on which it adsorbed, starting from 100 percent n-hexane to 20 percent ethyl acetate/80 percent n-hexane over a period of 10 minutes.

The present invention provides a process for using Cinacalcet tetrahydro as a reference marker or reference standard. Cinacalcet tetrahydro is be used as a reference marker for determining the presence of Cinacalcet tetrahydro in a sample of Cinacalcet bas or salt thereof. In addition, Cinacalcet tetrahydro is also used as a reference standard for determining the relative quantity of Cinacalcet tetrahydro as well as purity of Cinacalcet salt.

The present invention provides use of Cinacalcet tetrahydro as a reference marker for determining the presence of Cinacalcet tetrahydro in Cinacalcet base or salt thereof according to process comprising (a) determining the retention time by a column chromatographic method, such as HPLC or TLC, corresponding to the Cinacalcet tetrahydro in a reference marker comprising Cinacalcet tetrahydro; (b) running a sample of Cinacalcet base or salt on a column chromatography method; and (c) using the retention time in step (a) to identify the presence of Cinacalcet tetrahydro in the sample.

As used herein the term “treating” which includes but not limited to reacting, charging, suspending, dissolving, mixing, combining and melting.

As used herein the term “crude Cinacalcet salt” refers crude Cinacalcet salt comprising Cinacalcet tetrahydro in amount of more than about 0.25 % measured by HPLC.

As used herein the term “Cinacalcet tetrahydro” refers to (R)-N-(1-(5, 6, 7, 8-tetrahydro naphthalen-1-yl) ethyl)-3-(3-(trifluoromethyl) phenyl) propan-1-amine.

As used herein, “Cinacalcet salt” may be any organic acids or inorganic acids that includes but not limited to form such salts which include hydrochloride, hydro bromide, sulfuric acid, oxalic acid, tartaric acid, succinic acid and citric acid. More preferably, the Cinacalcet salt is Cinacalcet hydrochloride.

As used herein the term “isolating” which includes but not limited to method such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.

As used herein, the term “reference marker” is used in qualitative analysis to identify components of a mixture based upon their position, e.g., in a chromatogram or on a Thin Layer Chromatography (TLC) plate. See Strobel pp. 921, 922, 953. For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture. A “reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. For example, the HPLC retention time of the compound allows a relative retention time to be determined, thus making qualitative analysis possible. The concentration of the compound in solution before injection into an HPLC column allows the areas under the HPLC peaks to be compared, thus making quantitative analysis possible.

Reference standards are described in general terms above. However, as will be understood by those skilled in the art, a detector response can be, for example, the peak heights or integrated peak areas of a chromatogram obtained, e.g., by UV or refractive index detection, from the eluent of an HPLC system or, e.g., flame ionization detection (“FID”) or thermal conductivity detection, from the eluent of a gas chromatograph, or other detector response, e.g., the UV absorbance of spots on a fluorescent TLC plate. The position of the reference standard may be used to calculate the relative retention time for Cinacalcet salts and impurities of Cinacalcet salts.

A present invention also provides method for determining the amount of Cinacalcet tetrahydro in Cinacalcet salt or a base comprising (a) using a HPLC to measure the area under a peak corresponding to Cinacalcet tetrahydro in a reference standard comprising a known amount of Cinacalcet tetrahydro; and (b) determining the level of Cinacalcet tetrahydro in the sample by comparing the area of step (a) to the area under the peak in a sample comprising a Cinacalcet salt or base contaminated with Cinacalcet tetrahydro.

The present invention provides a process for using Cinacalcet tetrahydro as a reference marker for determining the presence of Cinacalcet tetrahydro in Cinacalcet base or salt comprising the steps of i) dissolving a reference standard of impurities Cinacalcet tetrahydro and Cinacalcet base or salt in a solvent (diluent) to produce a reference solution; ii) dissolving a sample of Cinacalcet base or salt in a solvent (diluent) to produce a sample solution; iii) injecting the diluent, reference solution and sample solution on to an HPLC column, and determining the area of each peak and calculating the purity of Cinacalcet base or salt.

The skilled artisan will have no difficulty performing the chromatographic method. In one example, an HPLC method includes the steps of (a) combining a sample of Cinacalcet HCl with a mixture of buffer : acetonitrile at a ratio of 1:1 to obtain a solution; (b) injecting the solution into a L1 column (150 mm x 4.6 mm, 5.0µm) (or similar) column, which is maintained at room temperature; (c) gradually eluting the sample from the column using a mixture of acetonitrile and THF at a ratio of 95:0.5 by volume, (d) measuring the amount of Cinacalcet tetrahydro in the relevant sample with a UV detector, preferably at a 210 nm wavelength.

Samples of Cinacalcet HCl are prepared by weighing accurately about 50 mg of Cinacalcet HCl into a 50 ml volumetric flask, dissolving and diluting to volume with diluent. Samples are then injected into the HPLC column, continuing the chromatogram up to the end of the gradient. The area of each impurity is determined using a suitable integrator.

HPLC conditions: HPCL method for analyzing Cinacalcet tetrahydro
Column : L1 column (150 mm x 4.6 mm, 5.0µm)
Detection : UV at 210nm
Flow rate : 1.0 mL/min
Injection volume : 10 µL
Column oven temperature : 30°C
Diluent : Buffer (50):Acetonitrile (50

1HNMR spectra were recorded on a Brucker-300 spectrometer. Chemical shifts are reported in delta ??units (ppm) relative to TMS as internal standard.

The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example 1
Preparation of 5, 6, 7, 8-tetrahydro-N-[(1R)-1-(naphthalen-1-yl) ethyl]-3-[3-(trifluoromethyl) phenyl] propan-1-amine (Cinacalcet Tetrahydro impurity)

3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}-1-[3-(trifluoromethyl) phenyl] propan-1-ol (100gm ) dissolved in methanol (500ml) and perchloric acid (100ml, 70% solution in water) was hydrogenated under the hydrogen pressure (60 psi) in presence of 10% palladium on carbon (5gm) for 16-20 hr at room temperature. The catalyst is filtered out and washed with methanol. The residue was than treated with saturated solution of sodium bicarbonate till pH is basic (~8.0), then extracted with dichloromethane. The combined organic layer was washed with water and brine and distilled out under reduced pressure to give viscous oil (80gm). A viscous oil of Cinacalcet tetrahydro is dissolved in ethyl acetate (100ml). Then ethyl acetate: HCl (100ml), diisopropyl ether (1000ml) and water (1000ml) was added sequentially at 50-60oC and allowed the reaction mixture to stir at same temperature for 10-30 min. Then the solid was separated by filtration at room temperature and dried to obtain crude Cinacalcet tetrahydro hydrochloride (60gm) which was purified by taking it into refluxed ethyl acetate followed by dropwise addition of methanol till clear solution was obtained. The reaction mixture was allowed gradually to come down to room temperature and cooled to 0oC to 10oC. The solid was separated by filtration and dried to give 5, 6, 7, 8-tetrahydro-N-[(1R)-1-(naphthalen-1-yl) ethyl]-3-[3-(trifluoromethyl) phenyl] propan-1-amine hydrochloride as a white crystalline powder (36gm). This HCl salt of Cinacalcet tetrahydro was treated with aqueous sodium bicarbonate in methylene dichloride to obtain Cinacalcet tetrahydro free base as oil (20 gm).

Example 2
Preparing a Cinacalcet hydrochloride, comprising less than 0.15 Cinacalcet tetrahydro measured by HPLC

The crude Cinacalcet HCl (obtained by process as disclosed in Indian patent application 2183/MUM/2009 and 2184/MUM/2009) was treated with ethyl acetate and heated to 55°C and then diisopropyl ether was added followed by addition of water. The reaction mixture was gradually cooled 0°C to 30°C. The solid was separated by filtration and dried to give Cinacalcet HCl comprising Cinacalcet tetrahydro impurity in an amount less than 0.15 % measured by HPLC.