FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"NOVEL PROCESS FOR THE PREPARATION OF
CINACALCET HYDROCHLORIDE AND THE
INTERMEDIATE THEREOF"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA

TECHNICAL FIELD OF THE INVENTION:
The present invention provides a novel process for the preparation of Cinacalcet Hydrochloride and the intermediate thereof which is industrially feasible and commercially viable.
BACKGROUND OF THE INVENTION:
(R)-a-methyl-N-[3-[3-(trifluromethyl) phenyl]propyi]-l-naphthalenemethylamine commonly known as Cinacalcet (CAS number: 226256-56-0) is the base and has the following structure:

Cinacalcet hydrochloride (CAS number: 364782-34-3) which is a hydrochloride salt of Cinacalcet base, has the following structure:

Cinacalcet hydrochloride is known to be useful for the treatment of hyperparathyroidism (elevated parathyroid hormone levels) and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. Cinacalcet hydrochloride acts as an oral calcimimetic drug (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing

receptor. In the United States, it is marketed under the name Sensipar® and, in Europe, it is marketed under the name Mimpara® and Parareg®.
U.S. patent 6,011,068 discloses a class of arylalkylamines comprising Cinacalcet (CNC) genericaily and salts thereof, namely sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. (See e.g., supra. PCT/US92/03736.) Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric.acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. U.S. patent 6,211,244 describes specifically Cinacalcet or pharmaceutically acceptable acid addition salts, which include organic acid salts namely acetate, citrate, lactate, titrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate, meleate, quinate and inorganic acid salts such as sulfate, hydrochloride, phosphate, but it does not provide any specific examples for the preparation and/or isolation of any of these salts. It neither envisages existence of these salts in different crystal forms of polymorphs, their attributes or their abilities to interact and perform in chemical reactions.
WO2008/058236 described a process for making Cinacalcet hydrochloride from Cinacalcet base that includes the steps of: providing a solution of Cinacalcet in an

alcohol or alkyl acetate; treating the solution of the free base with an hydrochloric acid to convert the free base to the hydrochloride salt; adding an anti-solvent to solution containing the hydrochloride salt, to precipitate it in the form of a solid; and isolating the precipitated solid to obtain the Cinacalcet hydrochloride with 92.9% purity as stated in example 22. In Example 23 it further describes that a purification process improves the % purity to 99.8%.
WO2008/058235 disclosed a process for making Cinacalcet hydrochloride from Cinacalcet acetate & Cinacalcet oxalate salts by treating said salts with an amount of hydrochloric acid sufficient to convert the acid addition salt to said hydrochloride salt; and isolating said Cinacalcet hydrochloride. The process is tedious as it involved charcoal treatment, vacuum distillation, separation of organic layers and distillation. The publication is silent about the aspects of the purity of Cinacalcet hydrochloride prepared by the acetate process whereas in cse of oxalate route, purity is stated to be 98.9%. Impurity profile of oxalate process is described to contain Desfluro Impurity: 0.14% and specified unknown imp. 0.83%.
WO2009/039241 described a process for making Cinacalcet hydrochloride from Cinacalcet base by providing a Cinacalcet carboxylate salt and converting said cinacalcet carboxylate salt into cinacalcet hydrochloride via an anion exchange reaction. Assay or % Purity of Cinacalcet acetate obtained by this process is 94.4% as stated in example 1.

Other applications which describe processes for the preparation of Cinacalcet hydrochloride, its polymorphs and intermediates include WO2006/I27932, WO2006/127933, WO2006/127941, WO2007/062147, and US Patent No. 6,342.636. None of these disclose either preparation or use of phosphate salt and the preparation of Cinacalcet hydrochloride therefrom.
Most prior art processes for preparing the hydrochloride salt of Cinacalcet typically comprise: providing a solution of Cinacalcet base/salt other than hydrochloride in a solvent; treating said solution with an amount of hydrochloric acid sufficient to convert Cinacalcet moiety to its hydrochloride salt; precipitating said hydrochloride salt and recovering said salt.
Albeit prior art processes teach preparation of Cinacalcet Hydrochloride from base or from other salt, these demand purer inputs and there remains a scope to invent a process that would deliver better yields and improved quality. There is a need for more cost effective process. Impurity profiles of Cinacalcet Hydrochloride prepared from these processes emphasize the need for a better process to prepare Cinacalcet Hydrochloride which has better impurity profile.
Even though many prior art processes report method for the preparation of Cinacalcet hydrochloride from cinacalcet free base, each process has some limitations with respect to yield, purity WO2008/058236, plant feasibility WO2008/058235 etc. Hence in view of the commercial importance of Cinacalcet

hydrochloride, industry and society needs an improved process for preparation of Cinacalcet Hydrochloride, For regulatory convenience and for assured bioequivalent formulation it is always better to have API having identical physical and chemical attributes. The Cinacalcet Hydrochloride prepared by the process as depicted in this application results into Cinacalcet Hydrochloride having identical XRD as that exhibited by Cinacalcet Hydrochloride present in the innovator formulation currently marketed as SENSIPAR™
SUMMARY OF THE INVENTION:
The present invention provides a novel, simple & improved process for the preparation of Cinacalcet hydrochloride from Cinacalcet hydrogen phosphate. In a further aspect, the present invention provides a process for preparation of Cinacalcet hydrogen phosphate from Cinacalcet free base.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Represents powder X-ray diffraction pattern (PXRD) of Cinacalcet Hydrochloride currently marketed as SENSIPAR™
Figure 2: Represents powder X-ray diffraction pattern (PXRD) of Cinacalcet Hydrochloride obtained according to present invention.

DETAILED DESCROPTION OF THE INVENTION:
The invention provides a novel, simple and efficient process for preparing Cinacalcet hydrochloride from Cinacalcet Hydrogen phosphate which is suitable for industrial production.
In particular, the invention provides a process for producing Cinacalcet hydrochloride comprising:
(i) Preparing Cinacalcet hydrogen phosphate salt from Cinacalcet free
base in a solvent using phosphate ion source, (ii) Optionally isolating Cinacalcet hydrogen phosphate salt and optionally converting to its free base in presence of a solvent using organic or inorganic base, (iii) Converting the said Cinacalcet hydrogen phosphate salt or aforementioned Cinacalcet free base in presence of solvent using hydrochloric acid into Cinacalcet hydrochloride.
Phosphate salt of Cinacalcet is mentioned in the prior art (US6011068, US6211244, WO2009/025792, WO2010/094674) with many other salts without providing any specific teaching or without teaching any specific advantage of it. Prior art is also silent about physical attributes or reaction specifics. Prior art does not teach and/or motivates a person skilled in the art, to prepare Cinacalcet hydrogen phosphate & to convert it into Cinacalcet hydrochloride.

It was surprisingly found that preparing and using Cinacalcet Phosphate for the preparation of Cinacalcet Hydrochloride has exceptional advantages not envisaged by prior art.
There are several instances in the ion exchange reactions where salt formation does not take place by mere contact of base and acid ion for some reasons. Salt formation takes place when certain acid ion sources are used and it does not take place with same acid ion present in some other source. Therefore exchange of counter ion is possible in some cases and is not possible in some cases. The novelty and inventive step of this invention resides in the unique process to prepare an inorganic acid addition salt of Cinacalcet from another inorganic acid addition salt. It was surprisingly found that preparing Phosphate salt and further preparing Hydrochloride salt of Cinacalcet therefrom unexpectedly improves purity. The process produces Cinacalcet Hydrochloride which is devoid of some impurities normally found to be present in it. The process provides flexibility to use Cinacalcet base with purity of about 85%. The process as described by the invention herein produces Cinacalcet Phosphate of approximate purity of 99.0% to 99.5% and the Cinacalcet Hydrochloride having purity of approximately 99.9% with total impurity of about 0.1%. Inventive step of the present invention resides in ability to produce Cinacalcet of excellent purity and remarkably less impurities.
The solvent used for preparing Cinacalcet hydrogen phosphate salt from Cinacalcet free base is selected from alcohol selected from methanol, ethanol, 2-propanol; ether selected from diisopropyl ether, diethyl ether, methyl isobutyl

ether; ester selected from ethyl acetate, methyl acetate, isobutyl acetate; halogenated solvent selected from dichloromethane, dichloroethane, chloroform; or aromatic solvent selected from toluene, xylene; or aqueous solvent or mixture thereof., preferably solvent of choice include alcohol and more preferably 2-propanol.
The phosphate ion source includes sources having pKa lower than Cinacalcet base or orthophosphoric acid or poly phosphoric acid or aqueous solution thereof or mixture(s) thereof. Although the reaction can be carried out at room temperature of 25°C to 40°C, it is better to carry it out at elevated temperature. The reaction is carried out at temperature range of about 50°c to about 90°C. Preferred range of temperatures is 75-80°C. The reaction is carried out for about 2 to 5 hours. However, good results are also obtained by heating for 3 hours. The Cinacalcet hydrogen phosphate salt is optionally isolated and purified. The reaction mixture was cooled to 0°C to room temperature. Good results are obtained at lower temperature ranges. In one embodiment, cooling to 0°C -5°C provided good results. It is then stirred for suitable time. Stirring for 1.5 hrs provided good results. The bulk is then filtered and the solid Cinacalcet hydrogen phosphate was dried at 60°C -65°C. The product gave excellent HPLC purity of 99.0%.
This Cinacalcet hydrogen phosphate salt is then converted to Cinacalcet hydrochloride directly or via its conversion to Cinacalcet free base. The solvent system used for optional conversion of Cinacalcet hydrogen phosphate to its free base is either monophasic or biphasic and is selected from

ether, ester, alcohol, halogenated solvent like dichloromethane, chloro benzene etc. or aromatic solvent like toluene, xylene etc. or aqueous solvent or mixture thereof. Preferred reaction media is biphasic media of halogenated solvent, esters, toluene and water, preferable being the mixture of dichloromethane and water. Monophasic solvent system is to be interpreted as use of single solvent where as biphasic solvent system is to be interpreted as a mixture of two solvents. Organic base used for preparation of base from Cinacalcet Hydrogen Phosphate in the reaction is selected from triethyl amine, diisopropyl amine, ethyl methyl amine and inorganic base includes calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, Calcium Carbonate preferably sodium hydroxide and or potassium hydroxide. Above reaction is successfully carried out at pH range of about 9-12. Preferred range being 10-12 and the most preferred being 10-11 and isolated Cinacalcet base. When a biphasic system is used, separation of organic layer is carried out and is then processed at about distilling temperature of solvent to obtain Cinacalcet base.
The solvent used for conversion of Cinacalcet hydrogen phosphate salt or Cinacalcet free base to cinacalcet hydrochloride is selected from saturated cyclic system like cyclopentane, cyclohexane, cycloheptane; ethers like dimethyl ether, diethyl ether, methyl tertiary butyl ether; esters like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, isopropanol; halogenated solvents like methylene chloride, ethylene dichloride, chloroform, chlorobenzene;

aromatic solvent like toluene, xylene; or aqueous solution or mixture thereof, preferably mixture of cyclohexane and methyl tertiary butyl ether. The reaction is carried out at room temperature to about 90°C. Reaction mixture is stirred for about 2-6 hours and the product is obtained by separation of solid phase form liquid phase. The product of purity of more than 99% is obtained. In one aspect, the invention provides a process for preparation of Cinacalcet hydrogen phosphate comprising:
(i) Providing a solution of Cinacalcet free base in a solvent; (ii) Treating said solution with a phosphate ion source having pKa lower than Cinacalcet base to convert Cinacalcet free base to Cinacalcet hydrogen phosphate salt.. The phosphate ion source includes sources having pKa lower than Cinacalcet
base or orthophosphoric acid or poly phosphoric acid or aqueous solution thereof
or mixture(s) thereof.
The solvent used in this process is selected from alcohol selected from methanol,
ethanol, 2-propanol; ether selected from diisopropyl ether, diethyl ether, methyl
isobutyl ether; ester selected from ethyl acetate, methyl acetate, isobutyl acetate;
halogenated solvent selected from dichloromethane, dichloroethane, chloroform;
or aromatic solvent selected from toluene, xylene; or aqueous solvent or mixture
thereof, preferably an alcohol and more preferably 2-propanol.
In another aspect, the invention provides a process for preparation of Cinacalcet
hydrochloride comprising:

a) Optionally converting Cinacaicet hydrogen phosphate to its free base in presence of a solvent and organic or inorganic base,
b) Converting cinacaicet hydrogen phosphate or aforementioned free base to cinacaicet hydrochloride in presence of a solvent and hydrochloric acid.
The solvent used for conversion of Cinacaicet hydrogen phosphate to its free base is selected from ether, ester, alcohol, halogenated like dichloromethane, chloro benzene or aromatic solvent like toluene, xylene or aqueous solvent or mixture thereof. Preferred reaction media is biphasic media of halogenated solvent, esters, toluene and water. More preferred media being the mixture of dichloromethane and water.
Organic base includes triethyl amine, diisopropyl amine and inorganic base includes calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, Calcium Carbonate preferably sodium hydroxide and or potassium hydroxide.
The solvent used for conversion of cinacaicet hydrogen phosphate or cinacaicet free base to cinacaicet hydrochloride is selected from saturated cyclic system like cyclopentane, cyclohexane, cycloheptane; ethers like dimethyl ether, diethyl ether, methyl tertiary butyl ether; esters like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, isopropanol; halogenated solvents like methylene chloride, ethylene.dichloride, chloroform, chlorobenzene; aromatic solvent like toluene, xylene; or aqueous solution or mixture thereof, preferably mixture of cyclohexane and methyl tertiary butyl ether.

The cinacalcet hydrochloride obtained according to present invention has XRD
peaks similar to XRD peaks observed in the currently marketed SENSIPAR™.
Cinacalcet hydrochloride of the present invention is characterized by powder
XRD peaks at about 13.9, 15.0, 15.5, 16.0, 17.9, 19.0,21.3,23.7,24.3 and 25.7
(±0.2) degrees 20 as depicted in FIG. 2.
The cinacalcet hydrochloride obtained according to present invention has purity
99.85-99.95%.
The following examples are for illustrative purposes only and are not intended
nor should they be interpreted to, limit the scope of the invention.
EXAMPLES:
Example 1: Preparation of Cinacalcet hydrogen phosphate from Cinacalcet
base
150 gm of Cinacalcet free base was stirred with 600 mL of 2-propanol. To the stirred solution, 63 gm of orthophosphoric acid dissolved in 300 mL of 2-propanol was added. The reaction mixture was then heated to 75°C -80°C for 3 hrs. After that the reaction mixture was cooled to 0°C -5°C and then stirred at 0°C -5°C for 1.5 hrs. Filtered off the product and the solid powder was dried at 60°C -65°C to obtain 140 gm of product. HPLC purity is 99.0%.
Example 2: Purification of Cinacalcet hydrogen phosphate
5 gm of Cinacalcet hydrogen phosphate was stirred in 60 mL of methanol to get clear solution. Ethyl acetate (180 mL) was charged to the clear solution and the

reaction mixture was stirred for an hour. Filtered off the product and the solid powder was dried at 60°C -65°C to give 4.75 gm of product. HPLC purity is 99.5%.
Example 3: Preparation of Cinacalcet Hydrochloride from Cinacalcet hydrogen phosphate via Cinacalcet base.
140 gm of Cinacalcet hydrogen phosphate was stirred with 700 mL of dichloromethane and 980 mL of water. pH of the solution was adjusted to 10-11 using 10% aqueous sodium hydroxide solution. Organic layer was then separated and distilled off at 40°C -45°C. Obtained Cinacalcet free base was dissolved in 420 mL of cyclohexane, and 168.5 mL of 10% methyl tertiary butyl ether. Hydrochloric acid was added drop wise to give cinacalcet hydrochloride (115 gm) with HPLC Purity 99.3%.
115 gm of Cinacalcet hydrochloride was stirred with 345 mL of 2-propanol at 78°C -80°C for 15-20 min. After that the reaction mass was gradually cooled to 28°C -30°C. The reaction mixture was then stirred at 28°C -30°C for 1-2 h. Filtered off the product and the solid was dried in air oven at 55°C -60°C to get 105 gm pure Cinacalcet Hydrochloride, HPLC purity 99.8%.
Example 4: Preparation of Cinacalcet Hydrochloride from Cinacalcet hydrogen phosphate
50 gm of Cinacalcet hydrogen phosphate was stirred in 250 mL toluene. Hydrochloric acid (50 ml 5N) was then added to the reaction mixture. After that

the reaction mass was stirred at 60 C for 4 h and then the organic layer was separated out followed by distillation to get crude Cinacalcet hydrochloride. Crystallization of crude Cinacalcet hydrochloride from 2-propanol to obtain 34 gm product. HPLC Purity is 99.9%
Example 5: Preparation of Cinacalcet Hydrochloride from Cinacalcet hydrogen phosphate
50 gm of Cinacalcet hydrogen phosphate was stirred with 250 mL of 20% IPA-HC1 (hydrochloric acid in isopropyl alcohol) for 6 hours at 60°C. The reaction mixture was then gradually cool to 28°C -30°C and then to 10°C -15°C. Solid was filtered off and then dried at 55°C -60°C to obtain 26 gm product. HPLC Purity is 99.92%.
Example 6: Preparation of Cinacalcet Hydrochloride from Cinacalcet hydrogen phosphate
50 gm of Cinacalcet hydrogen phosphate was stirred in 500 mL of toluene and 200 mL of 10% hydrochloric acid. The reaction mixture was then stirred at 60°C for 6 h. The organic layer was then separated and distilled off the toluene. To the slurry 250 mL of tert-butyl methyl ether was added and stirred for 1 h and then filter off to obtain the product. The product was then re-crystallized from 2-propanol to get 41 gm of the title product. HPLC purity is 99.9%.

CLAIMS:
We claim,
1. A process for the preparation of Cinacaicet hydrochloride comprising:
(i) Preparing Cinacaicet hydrogen phosphate salt from Cinacaicet free base in a solvent using phosphate ion source,
(ii) Optionally isolating Cinacaicet hydrogen phosphate salt and optionally converting to free base in presence of a monophasic or biphasic solvent system in presence of organic or inorganic base,
(iii) Converting the Cinacaicet hydrogen phosphate salt obtained in step (i) or (ii) or Cinacaicet free base obtained in Step (ii) in presence of solvent and hydrochloric acid into Cinacaicet hydrochloride.
2. The process for the preparation of Cinacaicet hydrochloride as claimed in
claim 1, wherein solvent for step (i) and step (ii) is selected from alcohol
selected from methanol, ethanol, 2-propanol; ether selected from
diisopropyl ether, diethyl ether, methyl isobutyl ether; ester selected from
ethyl acetate, methyl acetate, isobutyl acetate; halogenated solvent selected
from dichloromethane, dichloroethane, chloroform; or aromatic solvent
selected from toluene, xylene; or aqueous solvent or mixture thereof.
3. The process for the preparation of Cinacaicet hydrochloride as claimed in
claim 2, wherein the solvent used in step (i) is 2-propanol.

4. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 1, wherein phosphate ion source is selected from orthophosphoric acid, poly phosphoric acid or aqueous solution thereof or mixture thereof.
5. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 2, wherein the solvent system for step (ii) is preferably the biphasic solvent system of dichloromethane and water.
6. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 1 step (ii), wherein organic base is selected form triethyl amine, diisopropyl amine and inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate.

7. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 6, wherein base is sodium hydroxide or potassium hydroxide.
8. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 1, wherein solvent for step (iii) is selected from saturated cyclic system selected from cyclopentane, cyclohexane, cycloheptane; ether selected from diisopropyl ether, diethyl ether, methyl isobutyl ether; ester selected from ethyl acetate, methyl acetate, isobutyl acetate; alcohols; halogenated solvents, aromatic solvent or aqueous solution or mixture thereof.
9. The process for the preparation of Cinacalcet hydrochloride as claimed in claim 1, wherein solvent for step (iii) is mixture of cyclohexane and methyl tertiary butyl ether.

10. A process for the preparation of Cinacalcet hydrogen phosphate comprising:
a) Providing a solution of Cinacalcet free base in a solvent;
b) Treating said solution with at least one phosphate ion source having pKa lower than Cinacalcet base to convert Cinacalcet free base to Cinacalcet hydrogen phosphate.

11. The process as claimed in claim 10 step a), wherein solvent is selected from alcohol selected from methanol, ethanol, 2-propanol; ether selected from diisopropyl ether, diethyl ether, methyl isobutyl ether; ester selected from ethyl acetate, methyl acetate, isobutyl acetate; halogenated solvent selected from dichloromethane, dichloroethane, chloroform; or aromatic solvent selected from toluene, xylene; or aqueous solvent or mixture thereof.
12. The process for the preparation of Cinacalcet hydrogen phosphate as claimed in claim 10 step b), wherein phosphate ion source is selected from orthophosphoric acid, poly phosphoric acid or aqueous solution thereof or mixture thereof, preferred source being orthophosphoric acid.
13. The process of claim 11, wherein said solvent is 2-propanol.
14. Cinacalcet hydrogen phosphate as an intermediate for preparation of Cinacalcet hydrochloride.