WO2016027211A2 - Process for the preparation of cinacalcet and its pharmaceutically acceptable salts - Google Patents

Process for the preparation of cinacalcet and its pharmaceutically acceptable salts Download PDF

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WO2016027211A2
WO2016027211A2 PCT/IB2015/056205 IB2015056205W WO2016027211A2 WO 2016027211 A2 WO2016027211 A2 WO 2016027211A2 IB 2015056205 W IB2015056205 W IB 2015056205W WO 2016027211 A2 WO2016027211 A2 WO 2016027211A2
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Prior art keywords
formula
cinacalcet
reaction
acid
imine
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PCT/IB2015/056205
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French (fr)
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WO2016027211A3 (en
Inventor
Rao Uwais Ahmad KHAN
Rajesh Harshnath PATHAK
Chetan Vinesh PATIL
Sanjay Ramrao GAIKWAD
Shrikrishna Motiram Apar
Govind Udhavrao LINGE
Mohammad Umar SHAIKH
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Mehta Api Pvt. Ltd.
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Publication of WO2016027211A2 publication Critical patent/WO2016027211A2/en
Publication of WO2016027211A3 publication Critical patent/WO2016027211A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers

Definitions

  • the present invention relates to an efficient process for the preparation of Cinacalcet of formula (II) and its pharmaceutically acceptable salts thereof of formula (I), in particular Cinacalcet Hydrochloride of formula (la) in higher yields and purity. More particularly, the present invention is directed to an improved process employing reaction conditions favoring the formation of intermediate cinacalcet imine of formula (III). Furthermore the present invention is directed to an improved process for preparation of Cinacalcet and its pharmaceutically acceptable salts which is industrially scalable avoiding use of toxic and difficult to handle reagents as well as fewer unit operations.
  • Cinacalcet (N-[l-(R)-(-)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- aminopropane) of Formula II, belongs to a category of calcimimetics class of compounds. It is useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed under the trade name of Senipar in United States and under the trade name of Mimpara in Europe.
  • WO2012007954 A 1 discloses process for Cinacalcet by reductive amination in presence of titanium Isopropoxide using NaBH 4 CN, wherein an ether solvent is used instead of ethanol.
  • Indian patent applications 2268/DEL/2008 and 87/MUM/2011 disclose preparation of Cinacalcet wherein reaction of (R)-(I-naphthyl)ethylamine of formula (IV) with 3-[3- (trifluoromethyl)phenyl] propionaldehyde of formula (V) is carried out in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine, which is further reduced to cinacalcet with NaBH 4.
  • Sodiumtriacetoxyborohydride is hygroscopic in nature hence demands anhydrous conditions to be maintained rendering it not suitable for use on industrial scale.
  • WO2012007954 A 1 discloses reaction and work-up in THF followed by salt formation in Di-isopropyl ether and further purification in two solvent system consisting of Water and Methanol or Water and Acetonitrile.
  • US20110124917 discloses reaction in Methanol, Workup in toluene, Salt formation in Ethyl Acetate and purification in Isopropanol.
  • WO2008068625A2 discloses reaction, salt formation and Purification in two solvent system consisting of isobutyl Acetate and n-Heptane.
  • 2268/DEL/2008 discloses reaction in MDC, Salt formation in Ethyl Acetate and Purification in Ethyl Acetate and Di-isopropyl ether.
  • 87/MUM/2011 discloses reaction in THF, work-up in toluene. Salt formation in two solvent system consisting of cyclohexane and MTBE.
  • the present inventors have surprisingly found that when the condensation of [3- (trifluoromethyl)phenyl]propionaldehyde of formula - (V) with (R)-(l- naphthyl)ethylamine formula - (IV) is carried out in the absence of any reagent and water is removed under vacuum by azeotropic distillation at low temperatures in the optional presence of water scavengers, than Cinacalcet.hydrochloride with high purity and yield is obtained. Further the process is also industrially feasible due to the non-usage of hazardous reagents as also due to the reduction in isolation and purification steps.
  • It is yet another object of the present invention is to provide an improved process for the preparation of Cinacalcet or its pharmaceutically acceptable salts in the absence of any reagent. It is yet another object of the present invention to provide a commercially scalable process for preparation of Cinacalcet or its pharmaceutically acceptable salts in high yield.
  • It is yet another object of the invention is to provide a process for the preparation of Cinacalcet or its pharmaceutically acceptable salts which is feasible at commercial scale.
  • Form ula - 1 comprising the steps of:
  • Formula - 1 c) reacting the cinacalcet of formula (II) in-situ with a suitable acid to obtain its pharmaceutically acceptable salts of formula (I) which is optionally purified.
  • Cinacalcet imine of formula (III) characterized in removing the water formed during the reaction by azeotropic distillation or through the usage of desiccants at temperatures ranging from 0 to 40°C so as to favourably form Cinacalcet imine of formula (III),
  • Cinacalcet hydrochloride c) reacting the cinacalcet of formula - (II) in-situ with hydrochloric acid to obtain Cinacalcet hydrochloride.
  • the present invention provides a robust, efficient and economical synthesis of Cinacalcet and its pharmaceutically acceptable salts which is high yielding with high purity and industrially feasible.
  • the synthetic steps comprises:
  • Cinacalcet Imine of formula III Cinacalcet Imine of formula III
  • Cinacalcet imine of formula-(III) in-situ with an industrially suitable reducing agent to obtain Cincalcet of formula - (II) Formula - (II)
  • Cincalcet of formula - (II) Formula - (II)
  • the present invention provides an efficient process for synthesis of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride of Formula - (la) in higher yields and purity by ensuring moisture free conditions through azeotropic distillation alongside maintaining optimum temperatures so as to favour the formation of Cinacalcet imine of formula - (III) during the condensation reaction thereby resulting in much higher yields.
  • the azeotropic distillation is carried out in the temperature range -10 to 40°C, preferably between 0-30°C, more preferably between 10-15°C.
  • the present invention also provides a process for ensuring moisture free conditions during the condensation reaction by removing water through use of desiccants such as calcium chloride and likes or use of neutral desiccants such as molecular sieves, silica gel and likes.
  • desiccants such as calcium chloride and likes or use of neutral desiccants such as molecular sieves, silica gel and likes.
  • a process for the preparation of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride of formula - (la) in higher yields and purity which comprises of:
  • one embodiment provides a process wherein the said reaction is carried out using said compound of formula (IV) and said compound of formula (V) in the ratio ranging from 1.0: 1.06 to 1.06: 1 mole equivalent.
  • one embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium through azeotropic distillation under vacuum at temperatures favouring the formation of Cinacalcet imine - (II).
  • the azeotropic distillation is carried out in the temperature range -10 to 40°C, preferably between 0-30°C, more preferably between 10- 15°C.
  • another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using azeotropic distillation at low temperatures under vacum along with the optional use of desiccants selected from a group comprising of calcium chloride, moleular sieves and the likes.
  • the azeotropic distillation is preferably carried out below 40°C.
  • another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using desiccants selected from a group comprising of calcium chloride and the likes.
  • another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using neutral desiccants selected from a group comprising of molecular sieves, silica gel and the likes.
  • one embodiment provides a process wherein the said reaction is carried out using 0.2 to 2% of desiccants on weight by weight basis of R- Napthylethylamine.
  • the major advantage of the present process being that the removal of water is effected at temperatures below those leading to decomposition of Cinacalcet imine of formula (III) thereby not only shifting the reaction equilibrium towards formation of cinacalcet imine (III) by removal of water, but also avoiding the decomposition of thermally unstable cinacalcet imine (III) by maintaining optimum temperatures throughout the reaction time thereby ensuring significantly higher yields and purity as compared to prior-art.
  • Cinacalcet contaminated with impurities results in formation of sticky lumps in the reaction mass thereby making it difficult to isolate.
  • Another advantage of the present process is the ease of isolation of Cinacalcet salt obtained immediately after treating Cinacalcet of formula (II) with an acid.
  • the present invention ensures conditions favourable for formation of Cinacalcet imine (III), by azeotroping water from reaction at temperatures below those leading to decomposition of Cinacalcet imine, preferably below 40°C, eventually resulting in Cinacalcet salt with better purity profile thereby allowing easier isolation from a suitable solvent.
  • the reaction may be carried out at temperatures ranging from about but not limiting to - 10°C to 50°C, preferably at 0°C to20°C and more preferably at 10 to 20°C.
  • Suitable solvent used for condensation reaction is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroe thane, chloroform ; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions.
  • the suitable solvent is preferably toluene.
  • the reaction time and the temperature should be suitable to bring the reaction to completion, without the production of unwanted side products.
  • reaction mass is further proceeded to reduction as such without isolating the intermediate Cinacalcet imine of formula (III) b) reducing the intermediate Cinacalcet imine - (III) with a suitable reducing agent in a suitable solvent to roduce Cinacalcet of formula (II),
  • the suitable reducing agent is selected from a group of reducing agents comprising of borohydrides like sodium borohydride, calcium borohydride or potassium borohydride
  • one embodiment provides a process wherein the said reaction is carried out using 1.2 to 2.4 mole equivalent of sodium borohydride.
  • the suitable solvent used in reduction reaction is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions.
  • the suitable solvent is preferably toluene.
  • the reaction may be carried out at temperatures ranging from about 20 to 40°C more preferably at about 25°C to 30°C.
  • reaction mass is quenched with acetic acid and the pH adjusted within the range of about pH 4 to pH 7, preferably within the range of about pH 5 to pH 6.
  • the acetic acid used is preferably 50% Aq. Acetic Acid.
  • the organic layer is water washed and proceeded further as such for salt formation.
  • Formula - II suitable acid used as mentioned above is selected from a group comprising of hydrochloric acid, sulfuric acid, phosphoric acid, p - toluenesulphonic acid, methanesulphonic acid, benzenesulphonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid.
  • the suitable solvent used as mentioned above is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions.
  • the suitable solvent is preferably toluene.
  • the pH adjustment is carried out at temperatures ranging from about 20°C to 60°C, preferably at about 50°C.
  • organic layer obtained after pH adjustment is water washed. The pH of the organic layer obtained after water wash is checked. If the pH of the organic layer is above pH
  • the organic layer may be concentrated under vacuum to provide Cinacalcet
  • the Cinacalcet Hydrochloride of formula (la) may be further purified using suitable solvent by stirring at temperatures ranging from about 20°C to 40°C, preferably at about
  • the suitable solvent used as mentioned above is selected from a group of solvents comprising of ethers such as tert-butyl methyl ether; Tetrahydrofuran, Diethylether; hydrocarbons like cyclohexane, xylene; esters such as ethyl acetate, isobutyl acetate in various proportions.
  • the suitable solvent is preferably Methyl tert butyl ether.
  • Cinacalcet hydrochloride of formula (I) may be further purified in suitable solvent.
  • the suitable solvent used as mentioned above is selected from a group of solvents comprising of alcohols like isopropanol, methanol and ethanol.
  • the suitable solvent is preferably Isopropanol.
  • one embodiment provides a process suitable for industrial production of Cinacalcet and its pharmaceutically acceptable salts in particular cinacalcet hydrochloride if formula (la) employing use of industrially suitable reagents instead of using toxic or difficult to handle reagents like sodium cyanoborohydride, Sodium triacetoxy borohydride, titanium isopropoxide as disclosed in prior-art.
  • the reduction reaction comprises reducing the intermediate Cinacalcet imine (III) with a suitable reducing agent capable of being used at industrial scale in a suitable solvent to produce Cinacalcet of formula II),
  • the suitable reducing agent capable of being used on industrial scale is selected from a group of reducing agents comprising of borohydrides like sodium borohydride, potassium borohydride and the likes.
  • the suitable reducing agent is preferably sodium borohydride.
  • the suitable solvent is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichlorome thane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions.
  • the suitable solvent is preferably toluene.
  • Cinacalcet Hydrochloride of formula (la) employing in-situ formation of intermediates and salt through use of same solvent for reaction, work-up as well as salt formation, instead of using different solvents thereby avoiding the need for multiple distillations thus rendering the process much simpler with a reduced time cycle.
  • One embodiment according to this aspect of the invention provides a process for preparing Cinacalcet and its pharmaceutically acceptable salts in particular Cinacalcet hydrochloride of formula (la) comprising of:
  • Suitable solvent as mentioned above is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/or mixtures thereof in various proportions.
  • the suitable solvent is preferably toluene.
  • the present invention provides a process for preparation of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride in significantly higher yields and purity as compared to prior-art making the process cost-effective.
  • the synthetic route involves use of easy to handle reagents instead of toxic or difficult to handle reagents thereby rendering the process environment friendly and scalable on industrial scale.
  • the present invention also provides a simpler process as compared to prior art by avoiding multiple distillations and use of different solvents thereby reducing the time cycle.
  • the present invention provides an improved process with respect to simplified process as well as better yield and quality.
  • Cinacalcet Hydrochloride Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate the layers and treat organic layer with 15% HC1 (150 ml).Stirr Reaction mass is at 40 - 50°C for one hour and separate layers. Water wash toluene layer at same temperature. Adjust pH of toluene layer pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill and degasse under vacuum below 70°C to give Cinacalcet Hydrochloride

Abstract

The present invention relates to an efficient process for the preparation of Cinacalcet of formula (II) and its pharmaceutically acceptable salts thereof of formula (I), in particular Cinacalcet Hydrochloride of formula (Ia) in higher yields and purity.

Description

PROCESS FOR THE PREPARATION OF CINACALCET AND ITS
PHARMACEUTICALLY ACCEPTABLE SALTS
FIELD OF THE INVENTION
The present invention relates to an efficient process for the preparation of Cinacalcet of formula (II) and its pharmaceutically acceptable salts thereof of formula (I), in particular Cinacalcet Hydrochloride of formula (la) in higher yields and purity. More particularly, the present invention is directed to an improved process employing reaction conditions favoring the formation of intermediate cinacalcet imine of formula (III). Furthermore the present invention is directed to an improved process for preparation of Cinacalcet and its pharmaceutically acceptable salts which is industrially scalable avoiding use of toxic and difficult to handle reagents as well as fewer unit operations.
BACKGROUND OF THE INVENTION
Cinacalcet (N-[l-(R)-(-)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l- aminopropane) of Formula II, belongs to a category of calcimimetics class of compounds. It is useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed under the trade name of Senipar in United States and under the trade name of Mimpara in Europe.
US6211244 and Drugs of the future (2002) 27 (9): 831, discloses a synthesis of Cinacalcet by reductive amination which implies the reaction of (R)-(l-naphthyl) ethylamine of formula (IV) with 3 -[3- (trifluoromethyl) phenyl] propionaldehyde of formula (V) in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine of formula (III), which is reduced to cinacalcet of formula (II) with NaBH4CN in ethanol.
WO2012007954 A 1 discloses process for Cinacalcet by reductive amination in presence of titanium Isopropoxide using NaBH4CN, wherein an ether solvent is used instead of ethanol. Indian patent applications 2268/DEL/2008 and 87/MUM/2011 disclose preparation of Cinacalcet wherein reaction of (R)-(I-naphthyl)ethylamine of formula (IV) with 3-[3- (trifluoromethyl)phenyl] propionaldehyde of formula (V) is carried out in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine, which is further reduced to cinacalcet with NaBH4.
The above disclosed processes require the use of reagents such as NaBH4CN, titanium isopropoxide, which are extremely toxic and flammable as well as not being environmentally sound. These reagents therefore make the industrial application of the process difficult.
US20110124917A1 and WO2008068625A2 both disclose preparation of Cinacalcet by reductive amination wherein reduction is performed by using sodiumtriacetoxyborohydride as a selective reducing agent for imines.
Sodiumtriacetoxyborohydride is hygroscopic in nature hence demands anhydrous conditions to be maintained rendering it not suitable for use on industrial scale.
WO2012007954 A 1 discloses reaction and work-up in THF followed by salt formation in Di-isopropyl ether and further purification in two solvent system consisting of Water and Methanol or Water and Acetonitrile. US20110124917 discloses reaction in Methanol, Workup in toluene, Salt formation in Ethyl Acetate and purification in Isopropanol. WO2008068625A2 discloses reaction, salt formation and Purification in two solvent system consisting of isobutyl Acetate and n-Heptane. 2268/DEL/2008 discloses reaction in MDC, Salt formation in Ethyl Acetate and Purification in Ethyl Acetate and Di-isopropyl ether. 87/MUM/2011 discloses reaction in THF, work-up in toluene. Salt formation in two solvent system consisting of cyclohexane and MTBE.
All the above prior-art process employs use of different solvents for each unit operation or a two-solvent system for purification, thereby rendering the processes not easily scalable on industrial scale.
1367/MUM/2009 discloses reductive amination using sodium borohydride with 67.6% yield reported. 3068/MUM/2012 discloses reductive amination using sodium borohydride with 86% yield but with less purity. Further 3068/MUM/2012 requires the usage of sulphuric acid for the reaction of (R)-(I-naphthyl)ethylamine of formula (II) with 3-[3- (trifluoromethyl)phenyl] propionaldehyde of formula (III). Thus the processes disclosed above have one or other drawbacks, ranging from poor yield, purity, use of difficult to handle and toxic reagents or use of different solvents for each unit operation.
In view of the problems occurred in above methods, there remains a need for more economical and efficient industrially scalable process for the preparation of Cinacalcet and its pharmaceutically acceptable salts, which overcomes the drawbacks as disclosed in the prior art.
The present inventors have surprisingly found that when the condensation of [3- (trifluoromethyl)phenyl]propionaldehyde of formula - (V) with (R)-(l- naphthyl)ethylamine formula - (IV) is carried out in the absence of any reagent and water is removed under vacuum by azeotropic distillation at low temperatures in the optional presence of water scavengers, than Cinacalcet.hydrochloride with high purity and yield is obtained. Further the process is also industrially feasible due to the non-usage of hazardous reagents as also due to the reduction in isolation and purification steps.
OBJECT OF THE INVENTION
It is an object of the present invention to provide an improved process for the preparation of cinacalcet from 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula (V) and (R)-(l- naphthyl)ethylamine formula (IV) or its isomers.
It is yet another object of the present invention to provide an improved process for the preparation of cinacalcet or its pharmaceutically acceptable salts from 3-[3- (trifluoromethyl)phenyl]propionaldehyde of formula (V) and (R)-(l- naphthyl) ethylamine formula (IV) or its isomers.
It is yet another object of the present invention to provide an improved process for the preparation of Cinacalcet hydrochloride from 3-[3-(trifluoromethyl)phenyl] propionaldehyde of formula (V) and (R)-(l- naphthyl)ethylamine formula (IV) or its isomers.
It is yet another object of the present invention is to provide an improved process for the preparation of Cinacalcet or its pharmaceutically acceptable salts in the absence of any reagent. It is yet another object of the present invention to provide a commercially scalable process for preparation of Cinacalcet or its pharmaceutically acceptable salts in high yield.
It is yet another object of the present invention to provide an improved process for the synthesis of substantially pure Cinacalcet or its pharmaceutically acceptable salts with the amount of impurities within the industrially acceptable standards.
It is yet another object of the invention is to provide a process for the preparation of Cinacalcet or its pharmaceutically acceptable salts which is feasible at commercial scale.
It is a further object of the invention to provide a process for the synthesis of Cinacalcet or its pharmaceutically acceptable salts which is simple and easy to handle at an industrial scale
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided an improved processes for the preparation of Cinacalcet and its harmaceutically acceptable salts of formula (I),
Figure imgf000005_0001
Form ula - 1 comprising the steps of:
a) condensing 3-[(3-Trifluorometh l)phenyl] propionaldehyde of formula (V)
Figure imgf000005_0002
Formula - (V) with (R)-(l-napthyl)ethylamine of formula (IV) or its isomers
Figure imgf000006_0001
Formula - (IV)
in a suitable solvent to obtain Cinacalcet imine of formula (III)
Figure imgf000006_0002
Cinacalcet Imine.
Form ula - I I I
characterized in removing the water from the reaction medium at temperatures favouring the formation of Cinacalcet imine of formula (III),
b) reducing of the Cinacalcet imine of formula (III) in-situ with an industrially suitable reducing agent to give cinacalcet of formula II)
Figure imgf000006_0003
Formula - 1 c) reacting the cinacalcet of formula (II) in-situ with a suitable acid to obtain its pharmaceutically acceptable salts of formula (I) which is optionally purified.
According to another aspect of the present invention there is provided an improved process for the preparation of Cinacalcet hydrochloride,
Figure imgf000007_0001
Formula - I comprising the steps of:
a) condensing 3-[(3-Trifluoromethyl henyl] propionaldehyde of formula (V)
Figure imgf000007_0002
Formula - (V)
with (lR)-(l-napthyl)ethylamine of formula IV) or its isomers
Figure imgf000007_0003
Formula - (IV)
in a suitable solvent to obtain Cinacalcet imine of formula III)
Figure imgf000007_0004
Cinacalcet Imine.
Formula - III
characterized in removing the water formed during the reaction by azeotropic distillation or through the usage of desiccants at temperatures ranging from 0 to 40°C so as to favourably form Cinacalcet imine of formula (III),
b) reducing of the Cinacalcet imine of formula (III) in-situ with a borohydride selected from sodium borohydride, calcium borohydride or potassium borohydride to give cinacalcet of formula(II)
Figure imgf000008_0001
Cinacalcet
Formula - II
c) reacting the cinacalcet of formula - (II) in-situ with hydrochloric acid to obtain Cinacalcet hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a robust, efficient and economical synthesis of Cinacalcet and its pharmaceutically acceptable salts which is high yielding with high purity and industrially feasible. In accordance with the present invention to provide a process for the preparation of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride of formula-(Ia) the synthetic steps comprises:
a) condensing 3-[(3-Trifluorometh l)phenyl] propionaldehyde of formula-(V),
Figure imgf000008_0002
Formula - (V)
with (R)-(l- naphthyl)ethylamine of formula-(IV) or its isomers
Figure imgf000008_0003
Formula - (IV)
in a solvent to obtain Cinacalcet Imine of formula III)
Figure imgf000008_0004
Cinacalcet Imine.
Formula - III characterized in that the water from the reaction is removed at temperatures favouring the formation of Cinacalcet imine of formula (III),
b) reducing Cinacalcet imine of formula-(III) in-situ with an industrially suitable reducing agent to obtain Cincalcet of formula - (II)
Figure imgf000009_0001
Formula - (II) c) treating Cincalcet of formula - (II) in-situ with a suitable acid to obtain pharmaceutically acceptable salt of Cinacalcet of Formula- (I), which is optionally purified.
Figure imgf000009_0002
Formula - I
None of the Prior-art methods employing reductive amination using sodium borohydride for the preparation of Cinacalcet with ICH quality have reported yields greater than 68% on theoretical basis.
The effect of different parameters on the yield obtained was analyzed by the applicant and found that ensuring moisture free conditions at optimum temperatures during the condensation reaction effected higher yields. This dependence of yield on temperature and moisture is related to the instability of Cinacalcet imine of Formula - (III) in the presence of moisture or higher temperatures thereby resulting in its decomposition which further results in poor yields.
Since the condensation reaction proceeds with formation of water as a by-product it becomes difficult to ensure moisture free conditions in the reaction medium. Removal of water by azeotropic distillation employs higher temperatures which further leads to decomposition of Cinacalcet imine of formula - (III).
The effect of temperature on the yield of Cinacalcet Hydrochloride is studied in detail and can be represented as below in the given Table 1 Table 1:
Figure imgf000010_0001
The present invention provides an efficient process for synthesis of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride of Formula - (la) in higher yields and purity by ensuring moisture free conditions through azeotropic distillation alongside maintaining optimum temperatures so as to favour the formation of Cinacalcet imine of formula - (III) during the condensation reaction thereby resulting in much higher yields. The azeotropic distillation is carried out in the temperature range -10 to 40°C, preferably between 0-30°C, more preferably between 10-15°C.
The present invention also provides a process for ensuring moisture free conditions during the condensation reaction by removing water through use of desiccants such as calcium chloride and likes or use of neutral desiccants such as molecular sieves, silica gel and likes. In accordance with one aspect of the present invention there is provided a process for the preparation of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride of formula - (la) in higher yields and purity which comprises of:
a) condensing 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V), with (R)- (1- naphthyl)ethylamine of formula (IV) or isomers in a suitable solvent to give cinacalcet imine of formula (III),
Figure imgf000011_0001
propionaldehyde (1 R)-(1 -napthyl)ethyl amine Formula - III
Formula - V Formula - IV
characterized in that the water from the reaction medium is removed as the reaction proceeds at temperatures favoring the formation of intermediate Cinacalcet imine of formula-(III).
According to one aspect of the invention one embodiment provides a process wherein the said reaction is carried out using said compound of formula (IV) and said compound of formula (V) in the ratio ranging from 1.0: 1.06 to 1.06: 1 mole equivalent.
According to one aspect of the invention one embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium through azeotropic distillation under vacuum at temperatures favouring the formation of Cinacalcet imine - (II). The azeotropic distillation is carried out in the temperature range -10 to 40°C, preferably between 0-30°C, more preferably between 10- 15°C.
According to the aspect of the invention another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using azeotropic distillation at low temperatures under vacum along with the optional use of desiccants selected from a group comprising of calcium chloride, moleular sieves and the likes. The azeotropic distillation is preferably carried out below 40°C.
According to the aspect of the invention another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using desiccants selected from a group comprising of calcium chloride and the likes.
According to the aspect of the invention another embodiment provides a process employing conditions favourable for the formation of cinacalcet imine of formula (II) by removing water from reaction medium using neutral desiccants selected from a group comprising of molecular sieves, silica gel and the likes. According to one aspect of the invention one embodiment provides a process wherein the said reaction is carried out using 0.2 to 2% of desiccants on weight by weight basis of R- Napthylethylamine.
The major advantage of the present process being that the removal of water is effected at temperatures below those leading to decomposition of Cinacalcet imine of formula (III) thereby not only shifting the reaction equilibrium towards formation of cinacalcet imine (III) by removal of water, but also avoiding the decomposition of thermally unstable cinacalcet imine (III) by maintaining optimum temperatures throughout the reaction time thereby ensuring significantly higher yields and purity as compared to prior-art.
It has been observed that during the salt formation, Cinacalcet contaminated with impurities results in formation of sticky lumps in the reaction mass thereby making it difficult to isolate. Another advantage of the present process is the ease of isolation of Cinacalcet salt obtained immediately after treating Cinacalcet of formula (II) with an acid. The present invention ensures conditions favourable for formation of Cinacalcet imine (III), by azeotroping water from reaction at temperatures below those leading to decomposition of Cinacalcet imine, preferably below 40°C, eventually resulting in Cinacalcet salt with better purity profile thereby allowing easier isolation from a suitable solvent.
The reaction may be carried out at temperatures ranging from about but not limiting to - 10°C to 50°C, preferably at 0°C to20°C and more preferably at 10 to 20°C.
Suitable solvent used for condensation reaction is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroe thane, chloroform ; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions. The suitable solvent is preferably toluene.
The reaction time and the temperature should be suitable to bring the reaction to completion, without the production of unwanted side products.
After the completion of reaction the reaction mass is further proceeded to reduction as such without isolating the intermediate Cinacalcet imine of formula (III) b) reducing the intermediate Cinacalcet imine - (III) with a suitable reducing agent in a suitable solvent to roduce Cinacalcet of formula (II),
Figure imgf000013_0001
The suitable reducing agent is selected from a group of reducing agents comprising of borohydrides like sodium borohydride, calcium borohydride or potassium borohydride
According to one aspect of the invention one embodiment provides a process wherein the said reaction is carried out using 1.2 to 2.4 mole equivalent of sodium borohydride.
The suitable solvent used in reduction reaction, is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions. The suitable solvent is preferably toluene.
The reaction may be carried out at temperatures ranging from about 20 to 40°C more preferably at about 25°C to 30°C.
After the reduction reaction is complete the reaction mass is quenched with acetic acid and the pH adjusted within the range of about pH 4 to pH 7, preferably within the range of about pH 5 to pH 6. The acetic acid used is preferably 50% Aq. Acetic Acid.
After pH adjustment, the organic layer is water washed and proceeded further as such for salt formation.
c) reacting the cinacalcet base of formula (II) in-situ with a suitable acid to provide a pharmaceutically acceptable salt of cinacalcet of formula (la), which is then isolated from a suitable solvent o tionally followed by purification.
Figure imgf000013_0002
Formula - II suitable acid used as mentioned above is selected from a group comprising of hydrochloric acid, sulfuric acid, phosphoric acid, p - toluenesulphonic acid, methanesulphonic acid, benzenesulphonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid or citric acid.
The suitable solvent used as mentioned above is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions. The suitable solvent is preferably toluene.
In accordance with another aspect of the present invention, there is provided a process for preparing Cinacalcet hydroch
Figure imgf000014_0001
wherein the pH of the organic layer, obtained as such after work-up from reduction reaction, is adjusted below pH - 2 by using hydrochloric acid to obtain Cincalcet Hydrochloride of formula - (la).
The pH adjustment is carried out at temperatures ranging from about 20°C to 60°C, preferably at about 50°C.
Optionally organic layer obtained after pH adjustment is water washed. The pH of the organic layer obtained after water wash is checked. If the pH of the organic layer is above pH
2, it may be again adjusted below pH 2 by using Hydrochloric acid.
The organic layer may be concentrated under vacuum to provide Cinacalcet
Hydrochloride of formula (la).
The Cinacalcet Hydrochloride of formula (la) may be further purified using suitable solvent by stirring at temperatures ranging from about 20°C to 40°C, preferably at about
25 °C to 30°C.
The suitable solvent used as mentioned above is selected from a group of solvents comprising of ethers such as tert-butyl methyl ether; Tetrahydrofuran, Diethylether; hydrocarbons like cyclohexane, xylene; esters such as ethyl acetate, isobutyl acetate in various proportions. The suitable solvent is preferably Methyl tert butyl ether.
Furthermore, the Cinacalcet hydrochloride of formula (I) may be further purified in suitable solvent.
The suitable solvent used as mentioned above is selected from a group of solvents comprising of alcohols like isopropanol, methanol and ethanol. The suitable solvent is preferably Isopropanol.
In accordance with another aspect of the present invention, one embodiment provides a process suitable for industrial production of Cinacalcet and its pharmaceutically acceptable salts in particular cinacalcet hydrochloride if formula (la) employing use of industrially suitable reagents instead of using toxic or difficult to handle reagents like sodium cyanoborohydride, Sodium triacetoxy borohydride, titanium isopropoxide as disclosed in prior-art.
In accordance with another aspect of the present invention, the reduction reaction comprises reducing the intermediate Cinacalcet imine (III) with a suitable reducing agent capable of being used at industrial scale in a suitable solvent to produce Cinacalcet of formula II),
Figure imgf000015_0001
The suitable reducing agent capable of being used on industrial scale is selected from a group of reducing agents comprising of borohydrides like sodium borohydride, potassium borohydride and the likes. The suitable reducing agent is preferably sodium borohydride.
The suitable solvent is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichlorome thane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/ or mixtures thereof in various proportions. The suitable solvent is preferably toluene. According to still another aspect of the invention, there is provided a simpler process for preparation of Cinacalcet and its pharmaceutically acceptable salts in particular Cinacalcet Hydrochloride of formula (la) employing in-situ formation of intermediates and salt through use of same solvent for reaction, work-up as well as salt formation, instead of using different solvents thereby avoiding the need for multiple distillations thus rendering the process much simpler with a reduced time cycle.
One embodiment according to this aspect of the invention provides a process for preparing Cinacalcet and its pharmaceutically acceptable salts in particular Cinacalcet hydrochloride of formula (la) comprising of:
a) condensing 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V), with (R)-(l- naphthyl)ethylamine of formula (IV) or its isomers in a suitable solvent to give cinacalcet imine of formula (III),
b) reducing the intermediate Cinacalcet imine (III) with a suitable reducing agent in-situ in the same suitable solvent as mentioned above to produce Cinacalcet free base of formula (II)
c) reacting the cincalcet of formula (II) in-situ in the same suitable solvent as mentioned above with a hydrochloric acid to produce acid addition salt of formula (la).
Suitable solvent as mentioned above is selected from a group of solvents comprising of hydrocarbons like toluene, cyclohexane, xylene; halogenated solvents such as dichloromethane, dichloroethane, chloroform; alcohols; esters such as ethyl acetate, isobutyl acetate; ethers such as Tetrahydrofuran, Diethylether, tert-butyl methyl ether and/or mixtures thereof in various proportions. The suitable solvent is preferably toluene.
The Advantage of this process is that it uses single solvent for reaction, work-up as well as salt formation as against the prior-art disclosed which employ use of different solvents thereby avoiding the need for multiple distillations effectively making the process industrially scalable, cost effective and with reduced time cycle.
Thus the present invention provides a process for preparation of Cinacalcet and its pharmaceutically acceptable salt in particular Cinacalcet Hydrochloride in significantly higher yields and purity as compared to prior-art making the process cost-effective. The synthetic route involves use of easy to handle reagents instead of toxic or difficult to handle reagents thereby rendering the process environment friendly and scalable on industrial scale. The present invention also provides a simpler process as compared to prior art by avoiding multiple distillations and use of different solvents thereby reducing the time cycle. Thus the present invention provides an improved process with respect to simplified process as well as better yield and quality.
All the referenced patents and applications are incorporated herein by reference in their entirety. Furthermore, where a definition or use of a term in a reference, which is incorporated by reference herein, is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
EXAMPLES
The following examples are used to illustrate the invention, but are not intended to limit the invention in any way.
Example I:
Preparation of Cinacalcet Hydrochloride, Formula (la)
To (1000 ml) toluene in a 4Neck Round Bottom flask along with dean-stark apparatus coupled to a condenser, charge (80gms) (R)-(l- naphthyl) ethylamine of formula - (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V). Apply vacuum to the reaction mass through condenser and maintain for 8 hrs simultaneously azeotroping out water generated in the reaction till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. Release vacuum after the reaction complies. Water collected after Azeotropic distillation: 7-7.5 ml. Cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate Layers the organic layer and treat with 15% HC1 (150 ml). Stirr the Reaction mass at 40 - 50°C for one hour and separate the layer. Heat the toluene at same temperature. Adjust pH of toluene layer to below pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs.
Weight: 182 gms
% Yield on theoretical basis: 98.9%
Purity: 97.54%
To (182 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0°C -5°C. Maintain the reaction mass at 0-5°C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.
Wet cake is dried under vacuum at 40°C.
Weight: 163 gms
Yield on theoretical basis: 88.58%
Purity: 99.54%
To (163 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chilled to 0-5 °C. The reaction mass is maintained for 2 hrs at same temperature and filtered under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.
Weight: 157 gms
Yield on theoretical basis: 85.32%
Purity: 99.91% Example II:
Preparation of Crude Cinacalcet Hydrochloride, Formula (la)
To (1000 ml) toluene in a 4Neck Round Bottom flask, is charged (80gms) (R)-(l- naphthyl)ethylamine of formula (IV). Cooled to 10-15°C. Charged (lOOgms) 3-[(3- Trifluoromethyl)phenyl] propionaldehyde of formula (V) slowly. Charged (1 gm) Calcium Chloride and maintained for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, the reaction mass is cooled to 5-10°C. Charged (35 gms) sodium borohydride in two lots to the reaction mass and raised the temperature to 25-30°C.The reaction mass is maintained for 8 hrs to give Cinacalcet Free base of formula (II) in-situ. After the reaction complies by thin layer chromatography pH of the reaction mass is adjusted to about pH 6 using acetic acid. Charged (200 ml) water to the reaction mass and stirred for 30 mins. Layers separated and the organic layer is treated with 15% HC1 (150 ml). Reaction mass is stirred at 40 - 50°C for one hour and layer separated. Toluene layer is water washed at same temperature. pH of toluene layer adjusted to below pH-2 by treating with 15% HC1 (150 ml) at 40-45°C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs
Weight: 178 gms
Yield on theoretical basis: 96.73%
Purity: 94.88%
To (178 gms) of Crude cinacalcet Hydrochloride charged (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Allowed to cool gradually at 25-30°C and further chilled the reaction mass to 0-5°C. Maintained the reaction mass at 0-5°C for 2 hrs and filtered under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether. Wet cake is dried under vacuum at 40°C.
Weight: 159 gms,
% Yield on theoretical basis: 86.40% Purity: 99.77%
To (159 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution. Gradually cool to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass is for 2 hrs at same temperature and filte under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C. Weight: 150 gms
% Yield on theoretical basis: 81.51 %
Purity: 99.91 %
Example III:
Preparation of Cinacalcet Hydrochloride, Formula (la)
To (1000 ml) toluene in a 4Neck Round Bottom flask, charge (80gms) (R)-(l- naphthyl)ethylamine of formula (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3- Trifluoromethyl)phenyl] propionaldehyde of formula (V). Charge ( 1 gm) Molecular Sieves and maintain the reaction mass for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate the layers and treat organic layer with 15% HC1 (150 ml).Stirr Reaction mass is at 40 - 50°C for one hour and separate layers. Water wash toluene layer at same temperature. Adjust pH of toluene layer pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill and degasse under vacuum below 70°C to give Cinacalcet Hydrochloride
Weight: 172 gms
Yield on theoretical basis: 93.47%
Purity: 97.29% To (172 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0-5 °C. Maintain the reaction mass at 0-5 °C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.
Wet cake is dried under vacuum at 40°C.
Weight: 155 gms
% Yield on theoretical basis: 84.23%
Purity: 99.57% To (155 gms) of MTBE pure Cinacalcet Hydrochloride charge (400 ml) Isopropanol and heat to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass i for 2 hrs at same temperature and filter under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.
Weight: 146 gms
% Yield on theoretical basis: 79.34%
Purity: 99.83%

Claims

1. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts of formula (I),
Figure imgf000022_0001
Formula - I comprising the steps of:
a) condensing 3-[(3-Trifluorometh l)phenyl] propionaldehyde of formula (V)
Figure imgf000022_0002
Formula - (V)
with (R)-( 1 -napthyl)ethylamine of formula IV) or its isomers
Figure imgf000022_0003
Formula - (IV)
in a suitable solvent to obtain Cinacalcet imine of formula III)
Figure imgf000022_0004
Cinacalcet Imine.
Formula - III
characterized in removing the water formed during the reaction by azeotropic distillation or through the usage of desiccants at temperatures ranging from 0 to 40°C so as to form Cinacalcet imine of formula (III). b) reducing of the Cinacalcet imine of formula (III) in-situ with a reducing agent selected from sodium borohydride, calcium borohydride or potassium borohydride at temperatures ranging from 20 to 40 °C to ive cinacalcet of formula(II)
Figure imgf000023_0001
Formula - II
c) reacting the cinacalcet of formula - (II) in-situ with a suitable acid to obtain pharmaceutically acceptable salts of formula- (I).
2. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 1 , wherein the desiccants used for removing water formed during the reaction are selected from a group comprising calcium chloride, molecular sieves, silica gel and the likes.
3. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 1, wherein the reaction in step (a) is preferably carried out at reaction temperature ranging from 10°C to 20°C.
4. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 1, wherein the azeotropic distillation in step (a) is preferably carried out at reaction temperature ranging from 10°C to 15°C.
5. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 1, wherein the reaction in step (b) is preferably carried out at reaction temperature ranging from 25 °C to 30°C.
6. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 1 , wherein the acid in step (c) is selected from a group comprising of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluene sulphonic acid, methanesulfonic acid, benzenesulphonic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid or citric acid.
7. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to any one of the preceding claim, wherein the reaction in step (a), step (b) and step (c) is preferably carried out in solvents selected a group of solvents comprising hydrocarbons like toluene, cyclohexane, xylene, halogenated solvents like dichlorome thane, dichloroethane, chloroform, alcohol, esters like ethyl acetate, isobutylacetate, ethers such as Tetrahydrofuran, diethyl ether, t-butyl ether and/or mixtures thereof.
8. An improved process for the preparation of Cinacalcet and its pharmaceutically acceptable salts according to claim 7, wherein the reaction in step (a), step (b) and step (c) is preferably carried out in toluene.
9. An improved process for the reparation of Cinacalcet hydrochloride,
Figure imgf000024_0001
Formula - I comprising the steps of:
a) condensing 3-[(3-Trifluoromethyl henyl] propionaldehyde of formula (V)
Figure imgf000024_0002
Formula - (V)
with (lR)-(l-napthyl)ethylamine of formula (IV) or its isomers
Figure imgf000025_0001
Formula - (IV)
in a suitable solvent to obtain Cinacalcet imine of formula III)
Figure imgf000025_0002
Cinacalcet Imine.
Formula - III
characterized in removing the water formed during the reaction by azeotropic distillation or through the usage of desiccants at temperatures ranging from 0 to 40°C so as to favourably form Cinacalcet imine of formula (III),
b) reducing of the Cinacalcet imine of formula (III) in-situ with a borohydride selected from sodium borohydride, calcium borohydride or potassium borohydride to give cinacalcet of formula(II)
Figure imgf000025_0003
Formula - II
c) reacting the cinacalcet of formula - (II) in-situ with hydrochloric acid to obtain Cinacalcet hydrochloride.
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