FIELD OF THE INVENTION
The present invention relates to an industrial process for the purification of
cinacalcet hydrochloride of formula I.
HN
F3C
.HCl CH3
Formula I
5
In particular, the present invention relates to an industrial process for the
purification of cinacalcet hydrochloride to reduce the level of genotoxic
impurities.
BACKROUND OF THE INVENTION
10 Cinacalcet hydrochloride of formula I, is a novel calcimimetic agent that
modulate the extra cellular calcium sensing receptor by making it more
sensitive to the calcium suppressive effects on parathyroid hormone and is
chemically known as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)
phenyl]-l-aminopropane hydrochloride and represented by below structure.
HN
F3C
.HCl CH3
Formula I
15 Cinacalcet hydrochloride is used in the treatment of primary and secondary
hyperparathyroidism, which is characterized by high levels of calcium
circulated due to increased secretion of parathyroid hormone by one or more
of the parathyroid glands. Hyperparathyroidism can lead to osteoporosis and
patients with renal failure suffering arising out of secondary
20 hyperparathyroidism have increased risk of renal bone disease, soft-tissue
calcifications and vascular disease.
Calcium receptor-active molecules like cinacalcet and its pharmaceutically
acceptable salts thereof are disclosed in PCT publication WO 1994/018959,
US patents 6,211,244, 6,313,146, 6,031,003, 6,001,068, 6,011,884, 5,962,314,
25 5,858,684, 5,841,368, 5,763,569 and 5,688,938 etc. US patent 6,211,244
3
discloses a process for preparation of calcium receptor-active molecules like
cinacalcet, but do not provide any specific example for preparation of
cinacalcet and its pharmaceutically acceptable salt thereof.
The methods disclosed in the above patents for preparation of these
compounds include reductive amination of 5 an aldehyde or a ketone with a
primary amine in the presence of sodium cyanoborohydride or sodium
triacetoxy borohydride.
Alternatively, some compounds are prepared by condensation of a primary
amine with an aldehyde or a ketone in the presence of titanium (IV)
10 isopropoxide and the resulting imine intermediate is then reduced in situ by
action of sodium cyanoborohydride, sodium borohydride, or sodium
triacetoxyborohydride. The resulting enamines are then catalytically reduced
with hydrogen gas using palladium dihydroxide on carbon. The resulting
imine intermediate is reduced in situ by the action of sodium
15 cyanoborohydride or sodium borohydride. The intermediate alkene is
catalytically reduced with hydrogenolysis in the presence of palladium on
carbon in ethanol. Further, compounds obtained by using above processes are
converted to corresponding hydrochloride salts by treatment of free base with
hydrogen chloride gas in ether or hexane. The processes disclosed above,
20 involve use of expensive reagents and further involve purification by using
column chromatography.
An article, published in Drugs of future 2002, 27(9), 831-836 discloses a
process for preparation of cinacalcet, which is similar to a general process that
has been disclosed in US patent 6,211,244. The process involves reaction of 1-
25 acetylnaphthalene with 3-[3-(trifluoromethyl)phenyl]propyl amine in presence
of titanium isopropoxide to produce an imine, which on treatment with
methanolic sodium borohydride gives racemic base which is then resolved by
chiral chromatography.
US Patent 7,250,533 herein referred as US ‘533 discloses a process for
30 synthesis of cinacalcet by involving use of phenyl propanol derivative,
namely 3-(3-trifluoromethylphenyl)propanol. The process involves conversion
of hydroxyl moiety of phenyl propanol derivative, into a good leaving group
4
and further condensing the resulting derivative with (R)-1-
naphthylethylamine, in presence of a base, in an organic solvent to obtain
cinacalcet, according to following scheme.
OH
F3C
X
F3C
HN
F3C
CH3
H3C NH2
5
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
10 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.
15 US patent 7,294,533 discloses a process for the purification of cinacalcet to
remove starting material, (R)-1-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 has to be converted into cinacalcet hydrochloride, as
20 an active compound used for the preparation of cinacalcet hydrochloride drug
substances. This seems to be a lengthy process for obtaining cinacalcet
hydrochloride free from (R)-1-naphthylamine impurity. The patent also
exemplifies purification of crude cinacalcet with column chromatography
which is a very cumbersome technique and is not applicable for the
25 commercial production.
PCT publication WO2008/58236 discloses the purification of cinacalcet
hydrochloride by dissolving cinacalcet hydrochloride in an allyl nitrile solvent
followed by the addition of anti solvent to the above solution.
5
US patent application 2011/0172455 discloses a process for the preparation of
cinacalcet hydrochloride wherein phenyl propanol derivative is synthesized by
reduction of 3-(3-trifluoromethyl-phenyl)-propanoic acid using borane
dimethylsulfide. Further hydroxyl moiety of phenyl propanol derivative is
converted into a good leaving group 5 of compound of formula II, followed by
condensation with N-nosylate protected naphthylethylamine of formula III to
give N-nosylate protected cinacalcet of formula IV, which on deprotection in
the presence of hydrochloric acid, give cinacalcet hydrochloride of formula I.
10 Cinacalcet hydrochloride is then purified by using toluene, ethylacetate,
isopropylether or a mixture of ethylacetate and isopropylether thereof. An
impurity of formula V has been generated during the conversion of N-nosylate
protected cinacalcet to cinacalcet hydrochloride.
Formula V
6
According to regulatory authorities, such as FDA, EU authorities, and as per
the guidelines issued by ICH (The International Conference on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for Human
Use), a drug manufacturer must submit data demonstrating that the product
intended for marketing complies 5 with regulations with regard to the content of
impurities. The content of an unidentified impurity cannot exceed 0.1% (1000
ppm) by weight, while the amount of a known impurity cannot exceed 0.15%
(1500 ppm). The drug manufacturer usually submits analytical data to the
regulatory authority demonstrating that content of each impurity is in
10 accordance with regulations. The regulatory authority checks the submitted
data in order to ensure that the drug is having acceptable amount of impurities
and is suitable for marketing. But this level of 0.1 % (1000 ppm) or 0.15 %
(1500 ppm) may be even unacceptably high for an impurity if it is genotoxic.
The above impurity has been controlled at a level of NMT 0.15% using
15 purification with a mixture of ethylacetate and isopropylether. Recently the
impurity of formula V has been found to be genotoxic. The control of
impurities bearing a genotoxic potential in pharmaceutical products has
received more and more attention over the past years. As genotoxic impurities
are considered to be harmful for the patient administrating the drug like
20 cinacalcet hydrochloride having impurity of formula V present in it, so these
should be controlled at minimum possible level as per the regulatory
requirement. Therefore synthetic process should be capable of producing
cinacalcet hydrochloride with low amount of the genotoxic impurity of
formula V as an impurity. Therefore as per the current regulatory norms the
25 impurity of formula V has to be controlled at TTC level in cinacalcet
hydrochloride.
Most of the prior art processes disclose the purification of cinacalcet and
removal of some impurities like carbamate impurity and (R)-1-naphthylamine.
Purifications with known methods have been tried and it has been found that
30 these methods are not suitable to reduce the impurity of formula V to the
desired TTC level due to its genotoxic nature. Since the impurity of formula V
is a process related impurity and is formed in molar equivalents during the
7
conversion of N-nosylate protected cinacalcet to cinacalcet hydrochloride, it is
carried forward to final API stage. The inventors of present invention have
observed that the impurity of formula V is formed in the reaction mass at a
level of 38.27% during deprotection of N-nosylate protected cinacalcet with
thiophenol and does not get reduced during the 5 reaction workup and recovery
of solvent. The existing known processes for the purification via
crystallization using toluene, ethylacete and isopropyl ether results in the
reduction of level of impurity of formula V in the range of 0.01-0.03% (100-
300ppm) in cinacalcet hydrochloride samples which is exceedingly higher
10 than the desired TTC levels i.e., less than 8 ppm (on the basis of daily dose).
In view of the above, there exists a need for an improved process for preparing
cinacalcet hydrochloride which yields the product containing acceptable levels
of genotoxic impurity of formula V at a level of less than 8 ppm, as required
by the regulatory authorities.
15 Therefore, the present invention fulfills the need in the art and provides a
process for preparation of pure cinacalcet hydrochloride having genotoxic
impurities in the prescribed limit, that circumvents disadvantages associated
with prior art purification methods and proves to be advantageous from
industrial point of view as well as meet the purity criteria’s set by various
20 regulatory authorities for genotoxic impurities.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide processes for the
purification of cinacalcet hydrochloride.
25 The foremost objective of the present invention is to provide an improved and
advantageous process for the preparation of cinacalcet hydrochloride which
fulfills purity criteria set by various regulatory authorities.
Another objective of the present invention is to provide a process for
preparation of highly pure cinacalcet hydrochloride containing genotoxic
30 impurity of formula V at a level of lower than 8 ppm.
8
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an industrially advantageous, cost
effective, operationally safe method for the purification of cinacalcet
5 hydrochloride of formula I,
HN
F3C
.HCl CH3
Formula I
to obtain highly pure cinacalcet hydrochloride of formula I having genotoxic
impurity of formula V at a level of lower than 8 ppm,
Formula V
10 comprises the step of:
(a) providing a solution of cinacalcet hydrochloride having genotoxic
impurity of formula V at a level of greater than 8 ppm, in a suitable
alcoholic solvent;
(b) cooling the reaction mass;
15 (c) adding a second solvent to the reaction mass; and
(d) isolating pure cinacalcet hydrochloride from the reaction mixture.
In a specific embodiment, the present invention provides an industrially
advantageous, cost effective, operationally safe purification method for
obtaining pure cinacalcet hydrochloride having genotoxic impurity of formula
20 V at a level of lower than 8 ppm, by performing a solvent and antisolvent
purification using suitable solvents.
9
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous, cost effective,
operationally safe method for the purification of cinacalcet hydrochloride. The
present invention provides industrially advantageous processes that yield
cinacalcet 5 hydrochloride in high purity.
Compound of formula II, Compound of formula III, N-nosylate protected
cinacalcet of formula IV, Cinacalcet hydrochloride used for purification, have
been prepared by the process as disclosed in Ind Swift earlier patent
application WO2010/004588.
10 Particularly cinacalcet hydrochloride is prepared by condensation of
compound of formula II
X
F3C
Formula II
wherein X is a good leaving group
with a compound of formula III
Formula III
to prepare N-protected cinacalcet of formula IV
Formula IV
15 The N-protected cinacalcet of formula IV is then deprotected to prepare
cinacalcet which on treatment with hydrochloric acid hydrochloride in a
suitable solvent is converted to cinacalcet hydrochloride.
10
The compound of formula II is prepared through the reduction of 3-(3-
triflouromethyl-phenyl)-propionic acid using a suitable reducing agent to
prepare 3-(3-triflouromethyl-phenyl)-propan-1-ol, which on treatment with
suitable sulphonyl chloride forms the corresponding compound of formula II.
The compound of formula III is prepared by the 5 reaction of (R)-1-naphthalen-
1-yl-ethylamine with p-nitrobenzene sulphonyl chloride in the presence of a
suitable base.
Thereafter N-protected cinacalcet of formula IV can be prepared by the
condensation of compound of formula II and compound of formula III in the
10 presence of a suitable base in a suitable solvent. N-protected cinacalcet of
formula IV on deprotection give cinacalcet which is then converted to
cinacalcet hydrochloride.
Specifically, N-protected cinacalcet of formula IV is reacted with thiophenol
in the presence of potassium carbonate, benzyl triethyl ammonium chloride
15 (TEBA) in dimethyl sulfoxide which results in the deprotection of amine
group. Extraction of the reaction mass with isopropyl ether followed by
washing with purified water and recovery of solvents gives cinacalcet
freebase, which is then treated with hydrochloric acid in a suitable solvent like
ethyl acetate to prepare cinacalcet hydrochloride.
20 The impurity of formula V is a process related impurity and formed during the
deprotection of N-protected cinacalcet of formula IV into cinacalcet base at a
level of 30-40%. Its percentage may not get reduced during the reaction
workup and recovery of solvent. Substantial reduction in the level of the
impurity of formula V observed using isopropyl ether washings and reduced
25 upto a level of 0.03% in the isolated cinacalcet hydrochloride. It is observed
that usually the impurity of formula V is detected in the range of 0.01-0.03%
(100-300ppm) in purified cinacalcet hydrochloride which is exceedingly
higher than the desired TTC levels. Further, as the current regulatory
11
requirement of controlling the impurity of formula V to below TTC level is 8
ppm (on the basis of daily dose).
According to one embodiment, the present invention provides a method for the
purification of cinacalcet hydrochloride by employing solvent anti-solvent
5 purification method.
Generally, the process involves the preparation of a solution of cinacalcet
hydrochloride in a suitable alcoholic solvent at a temperature of 60ºC to reflux
temperature of the solvent for 1 to 2 hours.
The suitable alcoholic solvent used in the reaction includes, but is not limited
10 to methanol, ethanol, propanol, isopropyl alcohol, butanol, tertiary butanol or
the like.
The suitable second solvent is used as an antisolvent to induce crystallization
may be selected from an aprotic solvent. The aprotic solvent includes, but
not limited to hexane, heptane, cyclohexane, ethereal solvent such as diethyl
15 ether, isopropyl ether, methyl tertiary butyl ether, dioxane; and the like or
mixture thereof.
Generally, the process involves the stirring of cinacalcet hydrochloride in a
suitable solvent at a temperature of 60ºC to reflux temperature of solvent for 1
to 2 hours till dissolution. Preferably, cinacalcet hydrochloride is heated in a
20 suitable solvent at a temperature of 60-90ºC for 1 hour. The suitable alcoholic
solvent used in the reaction includes, but not limited to methanol, ethanol,
propanol, isopropyl alcohol, butanol, tertiary butanol or the like in any suitable
proportion. The proportion of the solvent in mixture can vary from 1:1.5 to 1:
5 volumes with respect to cinacalcet hydrochloride, preferably 1: 2 to 1:4,
25 more preferably 1: 2 to 1:4. It is advantageous to employ the solvent with 2.5-
3.5 volumes of solvent to avoid yield loss.
After completion of dissolution, the resulting reaction mixture may be cooled
to a temperature of 0ºC to 35ºC, preferably at a temperature of 10ºC to 30 ºC
and more preferably at a temperature of 15ºC to 25 ºC.
30 The suitable second solvent used as an antisolvent to induce crystallization
may be selected from an aprotic solvent and may be added to the reaction
12
mass. The proportion of the second solvent in mixture can vary from 1:5 to
1:15 volumes with respect to cinacalcet hydrochloride, preferably 1: 7 to 1:13,
more preferably 1: 8 to 1:12. It is advantageous to employ the solvent with 8-
11.5 volumes of solvent to avoid yield loss.
The reaction mixture can then be stirred 5 at temperature of 20 to 40ºC for 10
minutes till complete crystallization [2-6 hours]. Preferably, the reaction
mixture is stirred at 20-25ºC for 2-4 hours. Preferably a mixture of ethanol and
isopropyl ether is employed. Cinacalcet hydrochloride is isolated from the
mixture by the suitable techniques such as filtration or centrifugation and the
10 like. Process of purification can be repeated to enhance the purity of isolated
cinacalcet hydrochloride and reduce the levels of impurities in cinacalcet
hydrochloride.
The resulting cinacalcet hydrochloride has purity of greater than 99.90 % and
the genotoxic impurity of formula V is less than 8 ppm, preferably less than 5
15 ppm, more preferably less than 1 ppm.
The content of the impurity of formula has been analyzed by high performance
liquid chromatography [HPLC] having octadecylsilane bonded silica gradient
elution chromatography column using acetonitrile and potassium dihydrogen
phosphate buffer as mobile phase.
20 Although, the following examples illustrate the present invention in more
detail, but should not be construed as limiting the scope of the invention.
Examples
Example 1: Process for preparation of cinacalcet hydrochloride
To a suspension of potassium carbonate (76.0g), benzyl triethyl ammonium
25 chloride (TEBA) (4.2g) and thiophenol (30.0g) in dimethylformamide
(300ml), N-protected cinacalcet of formula IV (100 g) was added. The
reaction mixture was heated to 30-35°C and stirred for 24 hour till completion
of reaction [TLC]. Thereafter, DM water (600 ml) and isopropyl ether (500
ml) were charged in reaction mass and layers were separated after stirring of
30 15 min. The aqueous layer was extracted with isopropyl ether (200 ml) and
combined organic layers were washed with DM water (160 ml) and the
organic layer was treated with 10% (w/v) aqueous sodium chloride (160 ml)
13
and layers were separated. The organic layer was filtered through hyflo bed
and distilled off completely and degased. The resulting residue was cooled to
0-5oC, treated with ethylaceate hygrogen chloride (82.0ml) slowly and stirred
for 2.0 hours at 25-30oC. Thereafter toluene (1000 ml) and DM Water (330
ml) were added and the reaction 5 mixture was stirred for 1 hour. After
separating the layers, organic layer was filtered through hyflo bed and washed
with toluene (80 ml), and distilled under vacuum at 50-55oC. To the resulting
mass, isopropyl ether (100 ml) was added and distilled off under vacuum
below 65oC. To the resulting reaction mass isopropyl ether (800 ml) was
added at 50-65oC, stirred for further 24 hours at 65-70oC, cooled to 20-25o10 C
and stirred for 3.0 h at 20-25oC. The reaction Mixture was filtered and slurry
washed twice with isopropyl ether (100 ml each). The resulting product
displayed HPLC purity of 99.92% and impurity of formula V at a level of
2861.26 ppm.
15 Example 2: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride as obtained above (10.0 g) in
ethanol (30 ml) was heated to 65-70oC and stirred till a clear solution obtained.
The reaction solution was then cooled to 20-25oC and isopropyl ether (50 ml)
was added and stirred for 3.0 h at same temperature. The reaction mass was
20 filtered and slurry washed twice with isopropyl ether (10 ml each). The
resulting product displayed HPLC purity of 99.99 % and impurity of formula
V at a level of 4.44 ppm.
Example 3: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride as obtained above (32.33 g) in
ethanol (100 ml) was heated to 65-70o25 C and stirred till a clear solution
obtained. The reaction solution was then cooled to 20-25oC and isopropyl
ether (325 ml) was added and stirred for 3.0 h at 20-25oC. The reaction mass
was filtered and slurry washed twice with isopropyl ether (50 ml each). The
resulting product displayed HPLC purity of 100 % and impurity of formula V
30 at a level of 2.8 ppm.
14
Example 4: Process for preparation of cinacalcet hydrochloride
To a suspension of potassium carbonate (190.0g; 1.38 moles), benzyl triethyl
ammonium chloride (TEBA) (10.5g; 0.046 moles) and thiophenol (75.0g; 0.68
moles) in dimethylformamide (750 ml), N-5 protected cinacalcet of formula IV
(250 g; 0.46 moles) was added. The reaction mixture was heated to 30-35°C
and stirred for 24 hour till completion of reaction. Thereafter, DM water (1500
ml) and isopropyl ether (1250 ml) were added to the reaction mass and layers
were separated after stirring of 15 minutes. The aqueous layer was extracted
10 with isopropyl ether (500 ml) and finally combined organic layers were
washed with DM water (400 ml) and the organic layer was treated with 10%
(w/v) aqueous sodium chloride. The layers were separated after stirring of 15
minutes, filtered through hyflo bed and distilled off completely under vacuum.
The residue was cooled to 0-5oC and ethylaceate hygrogen chloride (205 ml;
12-16% w/w) was added slowly, stirred for 2.0 hours at 25-30o15 C. Thereafter,
toluene (2500 ml) and DM Water (525 ml) were added and the reaction
mixture was stirred for 1 hour. The layers were separated, organic layer was
filtered through hyflo bed, hyflo bed was washed with toluene (200 ml) and
the resulting organic layer was distilled under vacuum at 50-55oC. To the
20 degased mass isopropyl ether (250 ml) was added and distilled off under
vacuum below 65oC. To the degased mass, again isopropyl ether (2000 ml)
was added at 50-65oC, stirred for 24 hours at 65-70oC and then cooled to 20-
25oC and stirred for 3.0 hours. The reaction mixture was filtered and slurry
washed twice with isopropyl ether (250 ml each). The resulting product
25 displayed HPLC purity of 99.91% and impurity of formula V at a level of
310 ppm.
Example 5: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (158.4g) as obtained above, in
ethanol (500 ml) was heated to 65-70oC and stirred till a clear solution
obtained. The reaction solution was then cooled to 20-25o30 C. Isopropyl ether
(1625 ml) was added and stirred for further 3.0 hours at 20-25oC. The reaction
mass was filtered and slurry washed twice with isopropyl ether (250 ml each).
15
The isolated product displayed HPLC purity of 99.99 % and impurity of
formula V at a level of 0.11 ppm.
Example 6: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (6.0 g, having impurity of formula
V at a level of 247 ppm) in ethanol (20 ml) 5 was heated to 65-70oC and stirred
till a clear solution obtained. The reaction mass was then slowly cooled to 20-
25oC, methyl tertiary butyl ether (65 ml) was added, stirred for further 3 hours.
The resulting solid was filtered and washed with methyl tertiary butyl ether.
The isolated product displayed HPLC purity of 99.99 % and impurity of
10 formula V at a level of 2.43 ppm
Example 7: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (6.0 g having impurity of formula
V at a level of 247 ppm) in isopropyl alcohol (20 ml) was heated to 65-70oC
and stirred till a clear solution obtained. The reaction mass was then slowly
cooled to 20-25o15 C, isopropyl ether (65 ml) was added and stirred for further 3
hours. The resulting solid was filtered and washed with isopropyl ether. The
isolated product displayed HPLC purity of 99.99 % and impurity of formula V
at a level of 0.97 ppm.
Example 8: Process for purification of cinacalcet hydrochloride
20 The suspension of cinacalcet hydrochloride (4.6 g, having impurity of formula
V at a level of 247 ppm) in ethanol (20 ml) was heated to 65-70oC and stirred
till a clear solution obtained. The reaction mass was then slowly cooled to 20-
25oC, n-heptane (65 ml) was added and stirred for further 3 hours. The
resulting solid was filtered and washed with n-heptane. The isolated product
25 displayed HPLC purity of 99.94 % and impurity of formula V has not been
detected.
Example 9: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (5.0 g, having impurity of formula
V at a level of 500 ppm) in ethanol (15 ml) was heated to 65-70oC and stirred
30 till a clear solution obtained. The reaction mass was then slowly cooled to 20-
25oC, isopropyl ether (50 ml) was added and stirred for further 3 hours. The
resulting solid was filtered and washed with isopropyl ether. The isolated
16
product displayed HPLC purity of 99.99 % and impurity of formula V has not
been detected.
Example 10: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (4.5 g, having impurity of formula
V at a level of 2190 ppm) in ethanol (15 ml) 5 was heated to 65-70oC and stirred
till a clear solution obtained. The reaction mass was then slowly cooled to 20-
25oC, isopropyl ether (49 ml) was added and stirred the reaction mass for 3.0
hours at 20-25oC. The resulting solid was filtered and washed with isopropyl
ether (15.0 ml each). The isolated product displayed that impurity of formula
10 V has been detected at a level of 2.88ppm
Comparative Example:
Example 1: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (5.0 gm) having impurity of
formula V at a level of 500 ppm, in ethyl acetate (5 ml) was heated to 70oC
15 and stirred till a clear solution obtained. The reaction mass slowly cooled to
20-25oC, isopropyl ether (40 ml) was added and stirred for further 3hours. The
resulting solid was filtered and washed with isopropyl ether. The isolated
product displayed HPLC purity of 99.92 % and the impurity of formula V at a
level of 300 ppm by HPLC
20 Example 2: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (5.5 g) having impurity of
formula V at a level of 1000 ppm, in a mixture of toluene (11 ml) and
isopropyl ether (44.0 ml) was heated to 70oC and stirred till a clear solution
obtained. The reaction mass slowly cooled to 20-25oC and stirred for further 3
25 hours. The resulting solid was filtered and washed with isopropyl ether. The
isolated product displayed HPLC purity of 99.10 % and the impurity of
formula V at a level of 1000 ppm by HPLC
Example 3: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride (13.0 g) having impurity of
30 formula V at a level of 1500 ppm in isopropyl ether (108 ml) was heated to
70oC and stirred for 1.0 hour. The reaction mass slowly cooled to 20-25oC,
17
and stirred for further 3 hours. The resulting solid was filtered and washed
with isopropyl ether. The isolated product displayed HPLC purity of 99.56%
and the impurity of formula V at a level of 1250 ppm.
Example 4: Process for purification of cinacalcet hydrochloride
The suspension of cinacalcet hydrochloride 5 (5.0 g) having impurity of formula
V at a level of 1000 ppm in a mixture of ethanol (5ml) and isopropyl ether (40
ml) was heated to 70oC and stirred for 1.0 hour. The reaction mass slowly
cooled to 20-25oC, and stirred for further 3 hours. The resulting solid was
filtered and washed with isopropyl ether. The isolated product displayed
10 HPLC detecting the impurity of formula V at a level of 500 ppm.

WE CLAIM:
1. A process for the purification of cinacalcet hydrochloride of formula I,
HN
F3C
.HCl CH3
Formula I
for preparing highly pure cinacalcet hydrochloride of formula I, containing
5 genotoxic impurity of formula V at a level of lower than 8 ppm,
Formula V
comprises the step of:
(a) providing a solution of cinacalcet hydrochloride having genotoxic
impurity of formula V at a level of greater than 8 ppm in a suitable
10 alcoholic solvent;
(b) cooling the reaction mass;
(c) adding a second solvent to the reaction mass; and
(d) isolating pure cinacalcet hydrochloride from the reaction mixture.
2. The process as claimed in claim 1, wherein in step a) the suitable alcoholic
15 solvent is selected from methanol, ethanol, propanol, isopropyl alcohol,
butanol, tertiary butanol.
3. The process as claimed in claim 1, wherein in step a) solution is prepared at
temperature of 60oC to reflux temperature of the solvent used.
4. The process as claimed in claim 1, wherein in step a) solution is prepared at
temperature of 60oC to 90 o20 C.
5. The process as claimed in claim 1, wherein in step b) the reaction mass is
19
cooled to a temperature 20-40oC.
6. The process as claimed in claim 1, wherein in step c) second solvent is
hexane, heptane, cyclohexane, ethereal solvent such as diethyl ether,
isopropyl ether, methyl tert-butyl ether.
7. The process as claimed 5 in claim 1, wherein in step d) pure cinacalcet
hydrochloride is isolated by filtration from reaction mixture.
8. The process as claimed in claim 1, wherein isolated cinacalcet is pure
having purity of greater than 99.9% and the genotoxic impurity of formula
V at a level of lower than 8 ppm.