FIELD OF THE INVENTION
The present invention relates to processes for the purification of cinacalcet and its salts thereof.
BACKGROUND OF THE INVENTION
Cinacalcet of formula I, is a novel second generation calcimimetic agent that
modulates the extra cellular calcium sensing receptor by making it more sensitive to
the calcium suppressive effects on parathyroid hormone (PTH) and is chemically
known as A^-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-l-
aminopropane.

Formula Removed
It is used in a treatment for 'primary and secondary hyperparathyroidism. Hyperparathyroidism is characterized by high levels of circulating calcium due to an increased secretion of parathyroid hormone by one or more of the parathyroid glands. Hyperparathyroidism can lead to osteoporosis; patients with renal failure suffering from secondary hyperparathyroidism have for example an increased risked of renal bone disease, soft-tissue calcifications and vascular disease. Hydrochloride salt of cinacalcet is marketed as SENSIPAR™, and is the first drug in a class of compounds known as calcimimetics to be approved by the FDA.
Calcium receptor-active molecules like cinacalcet and its salts were first disclosed in US patent 6,011,068. The patent discloses the process for the preparation of calcium receptor-active molecules like cinacalcet, but does not provide any example specifically, for the preparation of cinacalcet or its pharmaceutical acceptable salts. However the compounds prepared in this patent are purified by the column
chromatography and then converted to their hydrochloride salts by using hydrogen chloride gas in ether or hexane in combination with hydrogen chloride gas.
Drug of future 2002, 27(9), 831-836 discloses a process for the preparation of cinacalcet. The process involves the reaction of 1-acetylnaphtahalene with 3-[3-(trifluoromethyl) phenyljpropylamine in presence of titanium isopropoxidc to produce an imine which on treatment with methanolic sodium borohydride gives racemic cinacalcet base which is then resolved by chiral chromatography.
US patent 7,294,735 discloses a process for the preparation of cinacalcet hydrochloride to remove cinacalcet carbamate impurity. The process involves the purification of cinacalcet containing 3 to 6 percent carbamate impurity in a solvent selected from acetone, linear or branched-chain C2-8 ether, and mixture thereof or with water which is then converted to cinacalcet hydrochloride. The patent discloses another method for the removal of cinacalcet carbamate impurity by column chromatography and high pressure liquid chromatography which is not amenable on industrial scale..
US patent 7,294,533 discloses a process for the purification of cinacalcet to remove starting material, (R)-l-naphthylethylamine as impurity. The process disclosed in the patent first involves the salt formation of cinacalcet by the acidification of cinacalcet in a solvent and then neutralization to give cinacalcet which further have to be converted to cinacalcet hydrochloride, as active compound used for the formulation is cinacalcet hydrochloride. This seems to be a lengthy process for obtaining cinacalcet hydrochloride free from (R)-l-naphthylamine impurity. The patent also exemplifies the purification of crude cinacalcet with column chromatography which is very cumbersome techniques and not applicable for the commercial production.
PCT publication WO2008/58236 discloses the purification of cinacalcet hydrochloride by dissolving cinacalcet hydrochloride in nitrile solvent followed by the addition of anti solvent to the above solution.
Most of the prior art processes discloses the purification of cinacalcet and removal of some impurities like carbamate impurity and (R)-l-naphthylamine from cinacalcet with column chromatography. The use of column chromatography at commercial scale is tedious, cumbersome and time consuming process hence industrially not applicable. Cinacalcet obtained from the prior art processes contain identified and unidentified impurities which are not desirable in the final API.
Like any synthetic compound, cinacalcet salt may contain process impurities, including 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 may arise from degradation of the API or during the manufacturing process, including the chemical synthesis. In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is a necessary condition for commercialization. Impurities formed during commercial manufacturing processes must be limited to very small amounts, and are preferable if, substantially absent. According to ICH guidelines, impurities are to be maintained below set limits. The guidance specifies the quality of raw materials, and process parameters, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
Chemical purity is important in the field of pharmaceuticals therefore there is need to obtain cinacalcet hydrochloride in high purity. In order to achieve high chemical purity, cinacalcet hydrochloride must be free from known and unknown impurities. Therefore there is an urgent need to develop a simple and efficient process which can be easily implemented in industry and yield the final compound i.e. cinacalcet hydrochloride having impurities in acceptable limit or free from impurities.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide processes for the purification of cinacalcet and its salts.
Another object of the invention is to provide a process for the purification of cinacalcet to remove certain identified and unidentified impurities.
Another object of the present invention is to provide industrially advantageous processes for the purification of cinacalcet hydrochloride that yields cinacalcet hydrochloride having impurities in acceptable limits or preferably free from impurities.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides industrially advantageous processes for the purification of cinacalcet and its salts.
According to one embodiment, the present invention provides a process for purification of cinacalcet hydrochloride, which comprises:
(a) slurrying cinacalcet hydrochloride in a suitable solvent; and
(b) isolating cinacalcet hydrochloride from the reaction mixture.
According to another embodiment, the present invention provides a process for purification of cinacalcet hydrochloride, comprising the steps of:
(a) providing a solution of cinacalcet hydrochloride in a solvent;
(b) washing the solution with water or aqueous solution of a suitable acid;
(c) distilling the solvent;
(d) slurrying the resulting residue in a suitable solvent; and
(e) isolating cinacalcet hydrochloride from the reaction mixture.
According to one another embodiment, the present invention provides a process for the purification of cinacalcet, comprising the steps of:
(a) providing a solution of cinacalcet in a solvent;
(b) adding silica gel to the solution;
(c) removing the solvent from the mixture by distillation or evaporation;
(d) adding a solvent to the residue;
(e) filtrating the solvent from the mixture;
(f) optionally, repeating steps (d) to (e);
(g) recovering pure cinacalcet from the filtrate; and
(h) optionally, converting cinacalcet to cinacalcet hydrochloride.
According to yet another embodiment, the present invention provides a process for purification of cinacalcet hydrochloride, comprising
(a) providing a solution of cinacalcet hydrochloride in a suitable solvent;
(b) neutralizing the solution with a suitable base;
(c) removing the solvent from the solution;
(d) optionally, isolating cinacalcet;
(e) adding solvent to resulting residue;
(f) treating the solution with lithium' aluminium hydride;
(g) quenching the reaction mixture;
(h) removing the solvent to obtain a residue; and
(i) treating the resulting residue in a solvent with a source of hydrogen chloride to form cinacalcet hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides industrially advantageous processes that yield cinacalcet and its salts in high purity.
According to one embodiment, the present invention provides a method for the purification of cinacalcet hydrochloride by employing slurry wash with suitable solvent or solvent mixture.
Generally, the process involves the stirring of slurry of cinacalcet hydrochloride in a suitable solvent at a temperature of -10 to 70 °C for 1 to 5 hours. Preferably, cinacalcet hydrochloride is slurried with suitable solvents at a temperature of 25 to 50 °C for 1 hour. Suitable solvents include but not limited to ester such as ethyl acetate; ethers such as diisopropyl ether, methyl tertiary butyl ether, diethyl ether, hydrocarbon solvents such as n-heptane and the like or mixture thereof in any suitable proportion. The proportion of the solvents in mixture can vary from 1:1 to 1: 100, preferably 1: 9, more preferably 1:1. It is advantageous to employ the slurry wash with 1:9 mixtures of solvents followed by 1:1 mixture of solvents. Preferably a mixture of ethyl acetate and diisopropyl ether is employed. Cinacalcet hydrochloride is isolated from the mixture by the suitable techniques such as filtration, and the like. Process of purification can be repeated to enhance the purity of cinacalcet hydrochloride and reduce the impurities level in cinacalcet hydrochloride.
According to another embodiment, the present invention provides a method for the purification of cinacalcet hydrochloride by washing with water or aqueous solution of a suitable acid.
Generally, the process involves the dissolution of cinacalcet hydrochloride in a suitable solvent followed by washing with water or aqueous solution of a suitable acid followed by water at a temperature of -10 to 70 °C for few minutes to 7 hours, preferably at a temperature of 40 to 50 °C for 0.5 hours. Suitable solvent include aromatic solvent such as toluene; ester such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; and the like or mixture thereof. Suitable acid is selected from inorganic acid such as hydrochloric acid. After washing process, the aqueous layer is separated out. The solvent is removed from the organic layer by the suitable techniques such as evaporation, distillation and the like. Cinacalcet
hydrochloride is isolated from the reaction mixture by any suitable methods. Preferably, the isolation of cinacalcet hydrochloride can be carried out by the addition of suitable solvent to the resulting residue at a temperature of 0 to 40 °C followed by stirring for few minutes to few hours. Preferably, the mixture is slurried at ambient temperature for 45 minutes. Suitable solvent include but not limited to ester such as ethyl acetate; ethers such as diisopropyl ether, methyl tertiary butyl ether, diethyl ether; hydrocarbon solvents such as n-heptane and the like or mixture thereof in any suitable proportion. The proportion of the solvents in mixture can vary from 1:1 to 1: 100, preferably 1: 9, more preferably 1:1. It is advantageous to employ the slurry wash with 1:9 mixtures of solvents followed by 1:1 mixture of solvents. Mixture of ethyl acetate and diisopropyl ether is preferably employed. Above process of purification remove the unidentified and identified impurities from cinacalcet hydrochloride; preferably the process of purification removes the (R)-naphthylethyl amine as impurity from cinacalcet hydrochloride.
According to one another embodiment, the present invention provides a process for the purification of cinacalcet by gel purification.
Generally, the process involves the addition of silica gel to the solution of cinacalcet in a suitable solvent. The solution of cinacalcet can be prepared by suspending cinacalcet in a suitable solvent or such a solution can be obtained directly from the reaction mixture in which cinacalcet is formed. Suitable solvents can be selected from but not limited to aromatic or aliphatic hydrocarbon, Ci_g ether, halogenated solvents or mixture thereof. Preferably, the solvent is selected from heptane, cyclohexane. hexane, toluene, o-xylene, m-xylene, p-xylene, isopropyl ether, diethyl ether, methyl tertiary butyl ether, dichloromethane, chloroform or mixture thereof. The solution of cinacalcet in a solvent can be optionally heated at a temperature from about 25 to 135 °C depending upon the solvent used. Any other temperature is also acceptable as long as stability of cinacalcet is not compromised and a clear solution is obtained.
To above solution of cinacalcet, silica gel is added and mixture is stirred for few minutes to few hours, preferably till the complete adsorption takes place on silica gel. Thereafter, solvent is removed by distillation, or evaporation to have complete adsorption of cinacalcet along with impurities on the silica gel. After the removal of solvent, fresh solvent (same as described above) is added to the residue and mixture is again stirred for few minutes to few hours at a temperature of-5 to 35 °C, preferably for 30 minutes at room temperature till the complete extraction of cinacalcet from the silica gel. The impurities remain adsorbed on the silica gel. Thereafter, the silica gel is removed from the solution. Silica gel can be removed by suitable technique such as filtration and the like. In order to enhance the yield, product can optionally be extracted from the silica gel by performing one or more extraction with a suitable solvent as described above. Then, cinacalcet is recovered from the filtrate by evaporation of the solvent by distillation.. The impurities present in cinacalcet, remain adsorbed on the silica gel, so cinacalcet obtained after purification is free from the polar impurities.
Silica gel used for the purification can have mesh size ranges from 50-400 mesh, preferably 230 - 400 mesh, 100 - 230 mesh, 200 - 300 mesh and 50 - 80 mesh. The ratio of crude cinacalcet to silica gel can be from 1:1 to 1:3, preferably 1:3, more preferably 1:2.
Specifically, cinacalcet is dissolved in a suitable non polar solvent followed by addition of silica gel to the solution. The solvent is removed from the mixture to ensure complete adsorption of cinacalcet along with impurities on silica gel. After complete adsorption suitable non polar solvent is added to extract cinacalcet from silica gel and stirred. Silica gel is removed by the filtration and pure cinacalcet is recovered from the solution by suitable techniques such as distillation..
Cinacalcet obtained after the purification as described in the present invention can be optionally converted to its pharmaceutical acceptable salts. Preferably, cinacalcet is converted to cinacalcet hydrochloride.
The conversion of cinacalcet to cinacalcet hydrochloride can be carried out by the any process known in the art.
Specifically, cinacalcet and a solvent are combined at a temperature if 0 to 70 °C in at least an amount of solvent sufficient to obtain a solution followed by the acidification with a source of hydrogen chloride which includes hydrochloric acid, hydrogen chloride gas or mixture thereof with suitable solvent selected from water, alcohol, ester, aromatic hydrocarbon, ether and the like. Preferably, the source of hydrogen chloride includes methanolic hydrochloride, ethyl acetate hydrochloride, toluene hydrochloride, aqueous hydrochloric acid and the like. Solvent used for providing the solution of cinacalcet is preferably ethyl acetate. Cinacalcet hydrochloride is isolated from the reaction mixture by the suitable techniques such as distillation, evaporation, extraction with a suitable solvent and the like.
According to another embodiment, the present invention provides a process for purification of cinacalcet hydrochloride by neutralization of cinacalcet hydrochloride to cinacalcet followed by treatment with lithium aluminium hydride and then further conversion to highly pure cinacalcet hydrochloride.
Generally, the process involves the addition of suitable base to a solution of cinacalcet hydrochloride at a temperature of -20 °C to 40 °C for few minutes to few hours. Preferably, the reaction mixture is stirred at ambient temperature for 1 to 5 hours. The solution of cinacalcet hydrochloride can be prepared by mixing cinacalcet hydrochloride in a suitable solvent or such a solution can be obtained directly from a reaction mixture in which cinacalcet hydrochloride is formed. Suitable solvents can be selected from but not limited to aliphatic or aromatic hydrocarbon such toluene, xylene, n-hexane, cyclohexane, n-heptane; ether such as isopropyl ether, diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran; ester such as ethyl acetate; halogenated solvents such as dichloromethane, chloroform and the like or mixture thereof. Suitable'base can be organic or inorganic. Organic base include trialkylamine such as triethylamine and the like. Inorganic base include alkali
or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide or hydrides thereof. Preferably, the inorganic base is selected sodium hydroxide, sodium carbonate or sodium methoxide. More preferably sodium carbonate is employed in the reaction. After the completion of the reaction, the solvent is removed from the reaction mixture by suitable techniques such as evaporation, distillation and the like. It is optional to isolate cinacalcet from the reaction mixture; residue obtained after solvent removal can be used as such for the further reaction.
The resulting residue in a suitable solvent is stirred with lithium aluminium hydride for few minutes to few hours at a temperature of -5 to 5 °C, preferably stirred for 0.5 to 2 hours at 0 °C temperature. Suitable solvents include ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, 1,2-dimethoxy ethane, diethyl ether, isopropyl ether, methyl tertiary butyl ether; aliphatic or aromatic hydrocarbon such as toluene, xylene; and the like or mixture thereof. The solution of cinacalcet in a solvent can be optionally cooled at a temperature of below 0 °C followed by addition of lithium aluminum hydride. The reaction can be quenched by the addition of suitable quenching agent such as ester (ethyl acetate), alcohol (methanol) or mixture thereof. After quenching, , solvents are distilled off to obtain a residue. Above residue is treated with a source of hydrogen chloride in presence of solvent to give highly pure cinacalcet hydrochloride. The source of hydrogen chloride include but not limited to hydrochloric acid, hydrogen chloride gas or mixture thereof with suitable solvent selected from water, alcohol, ester, aromatic hydrocarbon, ether and the like. Preferably, the source of hydrogen chloride includes methanolic hydrochloride, ethyl acetate hydrochloride, toluene hydrochloride, aqueous hydrochloric acid and the like. The solvent for the preparation of hydrochloride can be selected from ether such as isopropylether, methyl tertiary butyl ether, diethyl ether and the like or mixture thereof. Cinacalcet hydrochloride is isolated from the reaction mixture by the suitable techniques such as distillation, evaporation,
extraction with a suitable solvent and the like. Preferably, cinacalcet hydrochloride is isolated from the reaction by the removal of solvent.
Cinacalcet hydrochloride thus prepared can be optionally purified with a suitable solvent. Suitable solvent include but not limited to halogenated solvent such as dichloromethane; ester such as ethyl acetate; ethers such as diisopropyl ether, methyl tertiary butyl ether, diethyl ether, dioxane; nitrile such as acetonitrile and the like or mixture thereof.
The processes of the present invention can be performed separately or in combination with each other. The processes of purification can be repeated twice or a number of times to obtain cinacalcet or cinacalcet hydrochloride in desired purity.
Purification of cinacalcet or pharmaceutically acceptable salts thereof with the processes of the present invention is quite advantageous to remove some identified and unidentified impurities. The impurities can be identified by several spectroscopic techniques such as Nuclear magnetic resonance spectroscopy, Mass spectrometry, and High pressure liquid chromatography, preferably by the High pressure liquid chromatography. Preferably, the processes of the present invention are efficient for the removal of cinacalcet bromo impurity, cinacalcet hydroxyl impurity, (R)-napthylethyl amine or salt thereof from cinacalcet and pharmaceutical acceptable salts thereof.
Cinacalcet hydrochloride obtained by the processes of present invention has high degree of chemical purity and optical purity, according to HPLC (high pressure liquid chromatography). In one aspect, the invention provides, cinacalcet hydrochloride having purity not less than 97% area-by HPLC, preferably not less than 99% area by HPLC, and more preferably not less than 99.5% area by HPLC and contains total impurities like identified and unidentified in the amount of less than about 0.5 %, or individual impurities less than about 0.15%o by weight, more preferably free from the impurities.
Cinacalcet used in the present invention can be prepared by any methods already known in the literature. Similarly cinacalcet hydrochloride used in the process of present invention can be obtained by the process as described above or prepared by any method known in art or by the reference as described above..
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the methods of preparation of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example- 1: Purification of Cinacalcet hydrochloride
Cinacalcet hydrochloride (3.5 g, having purity 99.0% by HPLC) was stirred in diisopropyl ether: ethyl acetate mixture (1:1) for 1 hour and filtered to obtain 3 g of title compound having purity 99.8% by HPLC.
Example -2: Purification of Cinacalcet hydrochloride
Cinacalcet hydrochloride (5 g, having purity 96.5% and R-NEA 2.9% by HPLC) was dissolved in toluene (25 ml) and wash with aqueous hydrochloric acid (15 ml) followed by washing with water (15 ml x 2) at a temperature of 40 °C. Toluene was distilled off followed by addition of diisopropyl ether: ethyl acetate mixture (9:1). The mixture was stirred and filtered to obtain 4.5 g of title compound having purity 99% and R-NEA 0.03% by HPLC.
Example- 3: Purification of Cinacalcet hydrochloride
Cinacalcet hydrochloride (5 g, having purity 97.5% and R-NEA 2.0 % by HPLC) was dissolved in toluene (25 ml) and wash with water (15 ml x 2) at a temperature of 40 °C. Toluene was distilled off followed by addition of diisopropyl ether: ethyl acetate
mixture (9:1). The mixture was stirred and filtered to obtain 4.5g of title compound having purity 99.6% and R-NEA 0.02 % by HPLC.
Example -4: Purification of cinacalcet
To a solution of cinacalcet (4.2 g, having purity 85.0% by HPLC) in n-heptane (10 ml), silica gel (8.4 g) was added and the solvent was distilled off. n-l leptane (40 ml) was added to above residue and stirred for 30 minutes. The mixture was filtered and the solvent was distilled off to obtain 2.52 g of title compound having purity 97.50 % by HPLC.
Example -5: Purification of cinacalcet
Cinacalcet hydrochloride (2.5 g, having purity 97.5 % by HPLC) was treated with diisopropyl ether: ethyl acetate mixture (12 ml, 9:1). The mixture was stirred and filtered to obtain 2.0g of title compound having purity 99.7 % by HPLC.
Example-6: Purification of cinacalcet hydrochloride
To a solution of cinacalcet hydrochloride (5 g, having purity 98.0 % by HPLC) in isopropylether (25 ml), was added 10% aqueous sodium carbonate solution (40 ml) and stirred for 1 hour. The organic layer was separated and washed with water (10 ml x 2). Solvent was distilled off to obtain 4.2 g of cinacalcet.
To a solution of above prepared cinacalcet (2.52 g) in tetrahydrofuran (13 ml) under nitrogen atmosphere, was added lithium aluminium hydride (54 mg) at 0 to -5 °C and stirred for 30 minutes. Ethyl acetate (3 ml) and methanol (3 ml) were added to reaction mixture and stirred for 30 minutes. The reaction mixture was filtered over celite and the solvents were distilled off. Isopropylether (10 ml) and 5N hydrochloric acid (4 ml) were added to above residue. The reaction mixture was stirred for 30 minutes, filtered, washed with water and dried to obtain 2.5 g of title compound having purity 98.59% by HPLC.
The resulting product (2.0 g, having purity 98.59%) was stirred in diisopropyl ether: ethyl acetate (10 ml, 9:1). The mixture was filtered to obtain 1.7 g of the title compound having purity 99.8 % by HPLC.
Example -7: Purification of cinacalcet hydrochloride
To a solution of cinacalcet hydrochloride (250g, having purity 99.3 % by HPLC) in isopropyl ether (1.25 L) at 25 °C was added 15 % aqueous sodium carbonate solution and stirred for 2.0 hours. The organic layer was washed with water (250 ml x2), dried over sodium sulfate. The solvent was distilled off followed by addition of tetrahydrofuran (1.1 L) and cooled to 0 °C. Lithium aluminium hydride (4.67 g) was added to the reaction mixture and stirred for 2 hours at 0 °C, followed by addition of ethyl acetate (100 ml) and methanol (100 ml) at 0 °C. Stirring was continued for 30 minutes and the reaction contents was filtered through hyflo bed and washed with methanol followed by distillation of the solvent. Isopropyl ether (1.1 L) and 5N hydrochloric acid (1.1 L) were added and stirred at 20-25 °C for 1.0 hour. The solid was filtered, washed with water (220 ml) and dried. The wet cake was dissolved in dichloromethane (1.1 L) and the aqueous layer was discarded. Active carbon (12 g) was added to dichloromethane layer and stirred at 40 °C for 30 minutes. The dichloromethane solution was filtered through hyflo bed and distilled in vacuum. Acetonitrile (1.1 1) was added and heated to 90 °C till complete dissolution followed by stirring for 3 hours at 20-25 °C. The product was filtered, washed with acetonitrile and suck dried. The product was further dried at 45 - 50 °C in vacuum to obtain 216 g of title compound having purity 99.6% by HPLC.

WE CLAIM:
1). A process for the purification of cinacalcet hydrochloride, comprising
(a) slurrying cinacalcet hydrochloride in a suitable solvent; and
(b) isolating cinacalcet hydrochloride from the reaction mixture.
2). The process according to claim 1, wherein a suitable solvent include ester such as ethyl acetate; ethers such as diisopropyl ether, methyl tertiary butyl ether, diethyl ether, hydrocarbon solvents such as n-heptane and the like or mixture thereof in any suitable proportion;
3). A process for the purification of cinacalcet hydrochloride, comprising
(a) providing a solution of cinacalcet hydrochloride in a solvent;
(b) washing the solution with water or aqueous solution of a suitable acid;
(c) distilling the solvent;
(d) slurring the resulting residue in a suitable solvent; and
(e) Isolating cenacle hydrochloride from the reaction mixture.
4). The process according to claim 3, wherein in step a) solvent include aromatic solvent such as toluene; ester such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; and the like or mixture thereof; in step b) a suitable acid include inorganic acid such as hydrochloric acid and in step d) a suitable solvent include ester such as ethyl acetate; ethers such as isopropyl ether, methyl tertiary butyl ether, diethyl ether; hydrocarbon solvents such as n-heptanes and the like or mixture thereof in any suitable proportion.
5). A process for the purification of cenacle hydrochloride, comprising
(a) providing a solution of cenacle hydrochloride in a suitable solvent;
(b) neutralizing the solution with a suitable base;
(c) removing the solvent from the solution;
(d) optionally, isolating cenacle;
(e) adding solvent to resulting residue;
(f) treating the solution with lithium aluminums hydride;
(g) quenching the reaction mixture;
(h) Removing the solvent to obtain a residue; and(i) treating the resulting residue in a solvent with a source of hydrogen chloride to form cinacalcet hydrochloride.
6). The process according to claim 5, wherein in step a) a suitable solvent include aliphatic or aromatic hydrocarbon such toluene, xylene, n-hexane, cyclohexane, n-heptane; ether such as isopropyl ether, diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran; ester such as ethyl acetate; halogenated solvents such as dichloromethane, chloroform and the like or mixture thereof and in step b) suitable base is organic base that include trialkylamine such as triethylamine; or inorganic base that include alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide or hydrides thereof such as sodium hydroxide, sodium carbonate or sodium methoxide.
7). The process according to claim 5, wherein in step e) solvent include ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, 1,2-dimethoxy ethane, diethyl ether, isopropyl ether, methyl tertiary butyl ether; aliphatic or Aromatic hydrocarbons such as toluene, xylene; and the like or mixture thereof and in step g) quenching is carried out by adding solvent which include ester such as ethyl acetate; alcohol such as methanol or mixture thereof.
8). The process according to claim 5, wherein in step i) solvent include ether such as isopropylether, methyl tertiary butyl ether, diethyl ether and the like or mixture thereof; and a source of hydrogen chloride include hydrochloric acid, hydrogen chloride gas or mixture thereof with suitable solvent selected from water, alcohol,
ester, aromatic hydrocarbon, ether such as methanolic hydrochloride, ethyl acetate hydrochloride, toluene hydrochloride, aqueous hydrochloric acid and the like.
9). A process for the purification of cinacalcet, comprising
(a) providing a solution of cinacalcet in a solvent;
(b) adding silica gel to the solution;
(c) removing the solvent from the mixture by distillation or evaporation;
(d) adding a solvent to the residue;
(e) filtrating the solvent from the mixture;
(f) optionally, repeating steps (d) to (e); and
(g) recovering pure cinacalcet from the filtrate.
10). The process according to claim 9, wherein in steps a) and d) a suitable solvent include aromatic or aliphatic hydrocarbon such as heptane, cyclohexane, hexane, oluene, o-xylene, m-xylene, p-xylene; C1-8 ether such as isopropyl ether, diethyl ether, methyl tertiary butyl ether; halogenated solvents such as dichloromethane. chloroform; or mixture thereof.