FIELD OF THE INVENTION

The present invention relates to an efficient and industrially advantageous process
for purification of N-methyl-2-chloropyrimidine derivative, namely, N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of formula I,
Formula I
5 which is a key intermediate of pazopanib hydrochloride.
The present invention also provide an improved process for preparation of pure
pazopanib hydrochloride using highly pure N-(2-chloropyrimidin-4-yl)-N,2,3-
trimethyl-2H-indazol-6-amine of formula I.
BACKGROUND OF THE INVENTION
10 Pazopanib hydrochloride of formula II, is a tyrosine kinase indicator, and is
chemically known as 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2-methylbenzenesulfonamide hydrochloride,
Formula II
Pazopanib hydrochloride is marketed as under the trade name VOTRIENT®
and has
been used for the treatment of patients with advanced renal cell carcinoma and
15 treatment of patients with advanced soft tissue sarcoma who have received prior
chemotherapy.
Pazopanib hydrochloride was first disclosed in US patent 7,105,530. The process to
prepare pazopanib hydrochloride has also been disclosed by condensation of 2,3-
dimethyl-2H-indazol-6-amine with 2,4-dichloropyrimidine using sodium
20 bicarbonate, tetrahydrofuran and ethanol to obtain N-(2-chloropyrimidin-4-yl)-2,3-
dimethyl-2H-indazol-6-amine, which on methylation with methyl iodide in the
presence of cesium carbonate in N,N-dimethylformamide form N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine. The resulting compound
3
is then condensed with 5-amino-2-methylbenzenesulfonamide in the presence of
hydrochloric acid in isopropanol to obtain pazopanib hydrochloride which is
depicted as below:
5 In this patent, pazopanib intermediate namely N-(2-chloropyrimidin-4-yl)-N,2,3-
trimethyl-2H-indazol-6-amine is isolated by pouring the reaction mixture after
completion of reaction into the ice water bath and the resulting precipitate was
collected via filtration and washed with water. The precipitate was air dried to obtain
N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine. This patent is
10 silent about the purity of the obtained N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl2H-indazol-6-amine.
Several preparation and purification methods have been reported in literature to
prepare N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine; some of
which have been incorporated here for reference.
15 Another US patent publication 2016/0280689 discloses purification of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine by dissolving crude N-
(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine in refluxing ethyl
acetate to obtain purity of 99.4% and 4-chloro isomeric impurity of below formula
at a level of 0.34%.
20 In another example the 4-chloro isomeric impurity has been found to be at a level of
0.24%. The 4-chloro isomeric impurity is defined as impurity 6 in the specification.
4
This patent publication also discloses several polymorphic forms of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine.
The process disclosed in above patent publication controls the 4-chloro isomeric
impurity to the level of 0.24% to 0.34%. The said impurity is found to be mutagenic
5 and can act as a precursor to formation of new impurities during the conversion of
N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine to pazopanib
hydrochloride via a series of steps. Thus, control of 4-chloro isomeric impurity at
intermediate step is very crucial.
A PCT publication WO2011/050159 discloses preparation of N-(2-chloro pyrimidin10 4-yl)-N,2,3-trimethyl-2H-indazol-6-amine via methylation of N-(2-chloro-4-
pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine with methylating agent in an organic
solvent in the presence of potassium carbonate having a D99 of > 300 μm or < 200
μm at reflux temperature to obtain a N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine having total percentage of 0.05-3.0% of combined impurities of the
15 formulas as shown below:
Impurity-2
Impurity-4
Impurity-3
which are defined as impurity 2, 3 and 4 respectively in the specification. In the
exemplified process N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
amine is isolated having purity of >98% and <2% of combined impurities 2-4.
Process according to above patent publication discloses the use of specific size of
20 potassium carbonate is the key element to control of impurities within the range of
about 0.05-3.0%. The publication is silent about the critical 4-chloro isomeric
impurity, which is found to be mutagenic. It is crucial to control the said 4-chloro
isomeric impurity at this intermediate stage only because it can act as a precursor to
5
formation of new impurities during the conversion of N-(2-chloropyrimidin-4-yl)-
N,2,3-trimethyl-2H-indazol-6-amine to pazopanib hydrochloride.
Another PCT publication WO 2011/069053 discloses preparation of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine by methylation of N-(2-
5 chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine with dimethyl carbonate in
N,N-dimethylformamide in the presence of potassium carbonate. The resulting
product has 99.0% purity. This patent publication is silent about impurity profile of
the isolated N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine and
does not specify regarding 1.0% of related substances present in the desired
10 substance. Since 4-chloro isomeric impurity is found to be mutagenic, so the control
of impurities at intermediate stage is very important to get final pazopanib
hydrochloride in high purity.
Another PCT publication WO 2019/029295 discloses a purification of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine by recrystallization
15 using ethyl acetate. This patent publication is also silent about the purity of the
resulting N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine.
An Indian patent application IN 2505/CHE/2011 discloses purification of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine using isopropanol and
diisopropyl ether. This patent application is also silent about the purity of the
20 isolated N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine. Further
the purification involves two solvents i.e. isopropanol and diisopropyl ether which is
not an attractive option at industrial scale.
Another Indian patent application IN 1535/CHE/2012 discloses preparation of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine by methylation of N-(2-
25 chloro-4-pyrimidinyl)-2,3-dimethyl-2H-indazol-6-amine with methyl iodide in the
presence of alkali metal alkoxide and purification using acetone. This patent
application is also silent about the details of impurities and the resulting N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine have a purity of ~98%.
This indicates that approximately 2% of related compounds may be present in the
6
desired product. Thus, the control of impurities at intermediate stage is very
important to get pazopanib hydrochloride in high purity.
A Chinese patent CN 103373989 discloses preparation of N-(2-chloropyrimidin-4-
yl)-N,2,3-trimethyl-2H-indazol-6-amine via condensation of N,2,3-trimethyl-2H5 indazol-6-amine with 2,4-dichloropyrimidine using sodium bicarbonate in ethanol
and the concentrated mass is then mixed with isopropyl ether and toluene and stirred
for 1 hour at room temperature. The resulting solid was then filtered and dried under
vacuum to obtain N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine
with 99% HPLC purity.
10 This patent is also silent about the impurity profile of isolated N-(2-chloropyrimidin4-yl)-N,2,3-trimethyl-2H-indazol-6-amine and its further conversion to pazopanib
hydrochloride.
An article, namely Drug Design (2014), 83(3), 306-316 discloses purification of N-
(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine by silica gel
15 chromatography.
The main drawback of the purification is that chromatographic technique for
purification is cumbersome, tedious and difficult to utilize on an industrial scale.
Like any synthetic compound, drug intermediates too can contain extraneous
compounds or impurities that can come from many sources which may get carried
20 forward to final active pharmaceutical ingredient (API) i.e. pazopanib hydrochloride
or alternatively the impurities may react to form other new products. These
extraneous compounds in the intermediate may be unreacted starting materials, by
products of the reactions, products of side reactions, or degradation products or
different isomers. Impurities generated due to any reason in any active
25 pharmaceutical ingredient (API) like pazopanib hydrochloride are undesirable and as
they may be harmful to a patient being treated with a dosage form containing the
API.
The American Food and Drug Administration (FDA) as well as European
medicament control offices require, following of Q7A ICH (International
7
Conference on Harmonization) guidelines, according to which Active
Pharmaceutical Ingredient (API) should be free of impurities to the maximum extent
possible. This would results in achieving maximum safety of the drug in the clinical
practice. National inspection and control offices usually require that the content of
5 an individual impurity in an API should not exceed the limit of 0.1%. All the
substances (generally referred to as impurities) contained in an API over the limit of
0.1% should be isolated and characterized in accordance with the ICH
recommendations. Q7A ICH guidance for manufacturers also states that level of
process impurities must be maintained below set limits by specifying the quality of
10 raw materials, controlling process parameters, such as temperature, pressure, time
and stoichiometric ratio of the raw materials, and including purification steps, such
as crystallization, distillation, and liquid-liquid extraction, in the manufacturing
process.
It is always advantageous to use intermediates of high purity which is free from the
15 undesired impurities or such impurities should be present in acceptable amounts.
The purity of the chemical compounds can be tested by chromatographic techniques
such as high pressure liquid chromatography (HPLC). The control of impurities at
intermediate step is always important, since impurities present in the intermediate
stage may carry forward and may react further with reagents and which could result
20 in formation of new impurities along with main product.
As most of the prior art references are silent about the purity of resulting N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine and content of
impurities, there is an urgent need to develop a process which provides highly pure
N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine to ensure the high
25 purity/ potency of the final API i.e. pazopanib hydrochloride, that is free from the
undesired impurities. Thus, the present invention provides a process for the
purification of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of
formula I, which makes the intermediate suitable for synthesizing pazopanib
hydrochloride of high purity.
30
8
OBJECT OF THE INVENTION
The main object of the present invention is to provide an efficient and industrially
advantageous process for the purification of N-(2-chloropyrimidin-4-yl)-N,2,3-
trimethyl-2H-indazol-6-amine of formula I,
Formula I
5 which is a key intermediate of pazopanib hydrochloride.
Another object of present invention is to provide an improved process for
preparation of pure pazopanib hydrochloride using highly pure N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of formula I.
SUMMARY OF THE INVENTION
10 Accordingly, the present invention provides a process for the purification of N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of formula I,
Formula I
comprising the steps of:
a) providing a mixture of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine of formula I, in an aromatic hydrocarbon solvent;
15 b) stirring the reaction mass at temperature 40°C to reflux temperature till
dissolution;
c) adding activated carbon to the reaction mass;
d) filtering the reaction mass;
e) cooling the filtrate to 0°C to 10°C; and
20 f) isolating pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
amine of formula I.
According to one other embodiment, the present invention provides a process for
preparation of pazopanib hydrochloride of formula II,
9
Formula II
comprising the steps of:
a) providing a mixture of crude N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl2H-indazol-6-amine of formula I,
Formula I
in an aromatic hydrocarbon solvent;
5 b) stirring the reaction mass at temperature 40°C to reflux temperature till
dissolution;
c) adding activated carbon to the reaction mass;
d) filtering the reaction mass;
e) cooling the filtrate to 0°C to 10°C;
10 f) isolating pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
amine of formula I; and
g) converting pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
amine of formula I in to pazopanib hydrochloride of formula II.
According to one other embodiment, the present invention provides a process for
15 preparation of Form I of pazopanib hydrochloride consistently.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the X-Ray powder diffraction pattern for pazopanib
hydrochloride Form-1
DETAILED DESCRIPTION OF THE INVENTION
20 The present invention provides a novel, efficient and industrially advantageous
process for the purification of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine, designated as N-methyl 2-chloropyrimidine compound of formula
I, which is an important intermediate for the preparation of pazopanib
hydrochloride.
10
According to one aspect, the present invention provides a novel, efficient and
industrially advantageous process for the purification of N-(2-chloropyrimidin-4-yl)-
N,2,3-trimethyl-2H-indazol-6-amine of formula I, to reduce the amount of process
related impurities and to increase its purity.
5 N-(2-Chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of formula I can be
prepared by processes known in the art, such as by the processes described in the US
patent 7,105,530 and an article Bioorganic & Medicinal Chemistry Letters 24 (2014)
1108–1110.
Generally, N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine of
10 formula I can be prepared starting from 1,2-dimethyl-5-nitro-1H-benzimidazole of
formula III.
Formula III
2-Dimethyl-5-nitro-1H-benzimidazole of formula III can be procured from market
or can be prepared by the processes known in the art. The process involves the
reduction of 5-nitro benzimidazole compound of formula III using 10% palladium
15 on carbon and ethanol under hydrogen pressure to obtain 1,2-dimethyl-5-amino-1Hbenzimidazole of formula IV;
Formula IV
The resulting 5-amino benzimidazole compound of the formula IV can be condensed
in-situ or directly with 2,4-dichloropyrimidine of formula V;
Formula V
in the presence of sodium bicarbonate in a suitable solvent to obtain 2-
20 chloropyrimidine compound of the formula VI;
11
Formula VI
followed by methylation of 2-chloropyrimidine compound of formula VI using a
suitable methylating agent in the presence of base in a suitable solvent.
2,4-Dichloropyrimidine of formula V can be procured from market or can be
prepared by the processes known in the art.
5 During process development and reported in literature too, it has been observed that
several side products including isomeric impurities, known and unknown impurities
also formed along with the desired compound, as 2,4-dichloro pyrimidine of formula
V contains two chlorine groups. During condensation reaction of 5-amino
benzimidazole compound of formula IV with 2,4-dichloropyrimidine for preparation
10 of 2-chloropyrimidine compound of the formula VI, the other 4-chloro isomer
designated as impurity A can also form. Thereafter 2-chloropyrimidine compound
of the formula VI and the impurity A can further react with 5-amino benzimidazole
compound of formula IV, to form a dimer impurity designated as impurity B which
is depicted below:
15
During the methylation reaction of 2-chloropyrimidine compound of formula VI to
N-methyl 2-chloropyrimidine compound of formula I, impurity A formed as shown
above, can also be methylated and results in the formation of 4-chloro isomeric
compound designated as impurity C as depicted below:
12
It has been observed that if condensation of 2,4-dichloropyrimidine of formula V
with 5-amino benzimidazole of formula IV is carried out in methanol, then a
methoxy compound also forms which during methylation reaction forms another
5 related substance of following formula designated as impurity D:
Impurity D
In some of the batches it has been observed that if 2-chloropyrimidine compound of
formula VI contains traces amount of the starting material 2,4-dichloropyrimidine of
formula V, during its conversion to N-methyl 2-chloropyrimidine compound of
formula I in presence of base, another related compound designated as impurity E
10 can also form as depicted below:
The known and unknown impurities present in 2-chloropyrimidine compound of
formula VI may further react in the next stage of the process to form new impurities
which may get carried to the final stage. The impurity B too may react along with
15 the desired N-methyl 2-chloropyrimidine compound of formula I to form impurities
at advance stage.
It has been observed that the isolated N-methyl 2-chloropyrimidine compound of
formula I without purification results in to brownish solid and HPLC purity of
around 97.8% and impurity C around 0.30% w/w along with other known and
20 unknown impurities.
13
The resulting N-methyl 2-chloropyrimidine compound of formula I without any
purification can be converted to pazopanib hydrochloride by its condensation with 2-
methyl-5-amino-benzenesulfonamide, designated as sulfonamide compound of
formula VII;
Formula VII
5 During conversion, if impurity C presents in N-methyl 2-chloropyrimidine
compound of formula I may also react with sulfonamide compound of formula VII
to form impurity F as depicted below:
Similarly, if unreacted 2-chloropyrimidine compound of the formula VI present in
10 N-methyl 2-chloropyrimidine compound of formula I may react with sulfonamide
compound of formula VII to form impurity G as depicted below:
The N-methyl 2-chloropyrimidine compound of formula I along with unknown or
identified impurities if carried forward to the next step for the preparation of
15 pazopanib hydrochloride without purification may results in to the formation of
multiple unknown and known impurities like impurity F and impurity G. The
resulting pazopanib hydrochloride have purity of around 98.8% and contain
impurity of formula F in around 0.33% w/w and it is difficult to remove impurity F
at final stage. Thus, to control the impurity F and other unknown impurities at final
20 stage, it is essential to purify N-methyl 2-chloropyrimidine compound of formula I at
intermediate stage itself.
14
Generally, the process of purification of N-methyl 2-chloropyrimidine compound of
formula I have been carried out in any suitable solvent, but best results have been
found in an aromatic hydrocarbon solvent. Particularly, N-methyl 2-
chloropyrimidine compound of formula I can be dissolved in an aromatic
5 hydrocarbon solvent at a suitable temperature of 40°C to reflux temperature of the
solvent used. Preferably the purification can be done at 75°C to 90°C, more
preferably at 85°C to 90°C. The aromatic hydrocarbon solvent can be selected from
benzene, toluene, xylene(s), and the like; preferably, the aromatic hydrocarbon
solvent is toluene. After dissolution of N-methyl 2-chloropyrimidine compound of
10 formula I in a suitable solvent, activated carbon can added to improve the color. The
reaction mixture containing activated carbon can be stirred for 15 minutes to one
hour, preferably for 30 minutes to 45 minutes at temperature 75°C to 90°C,
preferably 85°C to 90°C. Thereafter, reaction mixture can be filtered through hyflo
bed and bed can be washed with same aromatic hydrocarbon solvent, which is used
15 for dissolution. Thereafter, the resulting filtrate can be slowly cooled to 0°C to 20°C,
preferably at 0°C to 10°C, more preferably at 0°C to 5°C and stirred for 1 hour to 3
hours. The resulting solid can be isolated from the reaction mixture by using a
suitable technique such as filtration, centrifugation, decantation and the like. The
resulting wet solid can be dried under vacuum at 45°C to 50°C to obtain purified N20 methyl 2-chloropyrimidine compound of formula I.
The purification process can be optionally, repeated to achieve desired purity level
of N-methyl 2-chloropyrimidine compound of formula I and having minimum
amount of impurities. All impurities have potential to further react in usual reaction
sequence leading the final API i.e. pazopanib hydrochloride.
25 The purified N-methyl 2-chloropyrimidine compound of formula I has been found to
be highly pure. The resulting pure N-methyl 2-chloropyrimidine compound of
formula I may have purity greater than 99%, preferably greater than 99.3%, more
preferably greater 99.5% by HPLC and contain less than 0.2% of individual known
or unknown impurity as measured by HPLC.
15
It is advantageous to purify N-methyl 2-chloropyrimidine compound of formula I
using aromatic hydrocarbon solvent, since other solvents does not remove the
unknown color impurities and color does not improve. Using aromatic hydrocarbon
solvent N-methyl 2-chloropyrimidine compound of formula I can isolated as white
5 to off white compound having purity of greater than 99.5% w/w by HPLC.
This purification using aromatic hydrocarbon solvent provides highly pure N-methyl
2-chloropyrimidine compound of formula I with controlled level of identified or
unidentified impurities. The chances of carry forward impurities which can form by
reaction in further steps which results in multiple impurity formation in the final API
10 have been minimized. The control of impurity at intermediate stage is very crucial as
it avoids the possibility of generation of multiple impurities in final API pazopanib
hydrochloride.
It is advantageous to proceed further with pure N-methyl 2-chloropyrimidine
compound of formula I, having purity greater than 99% w/w containing less than
15 0.2% w/w of individual known or unknown impurity, in order to obtain pazopanib
hydrochloride in high purity having undesired impurities in acceptable amounts or
free from the impurities.
In one another aspect, pure N-methyl 2-chloropyrimidine compound of formula I is
converted into pure pazopanib hydrochloride.
20 The conversion of a pure N-methyl 2-chloropyrimidine compound of formula I to
pazopanib hydrochloride can be carried out by processes known in the art.
Generally, pazopanib hydrochloride can be prepared by the condensation of pure Nmethyl 2-chloropyrimidine compound of formula I with sulfonamide compound of
formula VII
Formula VII
25 The sulfonamide compound of formula VII can be procured from market or can be
prepared by the known process. Further it can be purified using methanol and
activated carbon, if required to remove suspended particles, before use.
16
Generally pure N-methyl 2-chloropyrimidine compound of formula I can be
dissolved in an alcoholic solvent at temperature 80°C to 90°C to obtain a clear
solution. The resulting clear solution can be filtered through micron filter to remove
suspended particles. The alcohol can be selected from methanol, ethanol, n5 propanol, isopropanol and tert. butyl alcohol and the like, preferably alcohol is
isopropanol. The solution of N-methyl 2-chloropyrimidine compound of formula I
can be treated with sulfonamide compound of formula VII at 70°C to 100°C,
preferably at 75°C to 95°C more preferably 85°C to 90°C and the reaction mixture
can be heated at same temperature for 30 hours to 40 hours. Generally the reaction
10 takes about 35 hours to 36 hours for completion. After completion of reaction,
monitored by HPLC, the reaction mixture can be cooled to 20°C to 30°C and stirred
for 1 hour to 2 hours followed by filtration to isolate pazopanib hydrochloride. The
resulting pazopanib hydrochloride can be treated with hydrochloric acid in the
presence of methanol. The reaction mixture can be heated to 45°C to 65°C,
15 preferably at 60°C to 65°C and stirred for 40 hours to 50 hours. The resulting
mixture can be cooled to 10°C to 30°C, preferably at 20°C to 30°C and can be
further stirred for 1 hour. The resulting mixture can be filtered, washed with
methanol and dried under vacuum at 45°C to 50°C for 12 hours to obtain highly
pure pazopanib hydrochloride. In a specific embodiment, pazopanib hydrochloride
20 can be treated with hydrochloric acid in the presence of methanol. The reaction
mixture can be heated to 45°C to 65°C, preferably at 60°C to 65°C and stirred for 20
hours to 50 hours. After completion of reaction, which can be monitored by HPLC
till N-methyl 2-chloropyrimidine compound of formula I should not be more than
50ppm. Thereafter, the reaction mixture can be diluted with demineralized [DM]
25 water. The reaction mixture can heated at 45°C to 65°C, preferably at 60°C to 65°C
to get a clear solution. In a separate vessel, the seeding material is prepared by
providing pazopanib hydrochloride Form I in isopropanol. Pazopanib hydrochloride
Form I can be taken in an amount of 1% to 4% of the staring material. Isopropanol
can be taken in an amount of about 500 volumes to 1000 volumes of amount of
30 pazopanib hydrochloride Form I used as seed. The seeding material can be prepared
at a temperature of 10°C to 25°C. Thereafter the clear reaction solution is added to
17
seeding material slowly and cooled to 15°C to 25°C and stirred at this temperature
for 1 to 4 hours. The solid thus obtained, can be filtered and washed with
isopropanol and dried under vacuum. The resulting pazopanib hydrochloride have
purity of greater than 99.5% w/w, preferably greater than 98.8% w/w and most
5 preferably greater than 99.9% w/w and impurity of formula F and other impurities
have been controlled at level of less than 0.10% w/w. Pazopanib hydrochloride
obtained above has been characterized as Form I. It is advantageous to use less than
0.20 molar equivalent of hydrochloric acid at the time of nucleation of
crystallization of pazopanib hydrochloride from the reaction solution to prepare
10 stable Form-I of pazopanib hydrochloride consistently.
Pazopanib hydrochloride Form-1, encompassed by the present invention may be
characterized by at least one of X-Ray powder diffraction (XRPD), differential
scanning calorimetry (DSC) or fourier transform infrared (FTIR) spectroscopy. The
XRPD pattern of pazopanib hydrochloride Form-1 is measured on PANalytical
15 X'Pert Pro diffractometer with copper radiation and expressed in terms of two-theta,
d-spacing and relative intensities
We have not found any reference wherein N-methyl 2-chloropyrimidine compound
of formula I has been purified using aromatic hydrocarbon to control the impurities.
Therefore, purification of N-methyl 2-chloropyrimidine compound of formula I
20 using aromatic hydrocarbon forms an inventive part of the invention.
Major advantages realized in the present invention is to provide a process for
purification of N-methyl 2-chloropyrimidine compound of formula I using aromatic
hydrocarbon and controlled the impurities to such an extend that results in
pazopanib hydrochloride with purity greater than 99.9% w/w and impurity of
25 formula F and other impurities have been controlled at level of less than 0.10%w/w.
Overall process of present invention is efficient and industrially viable as it provides
highly pure pazopanib hydrochloride Form-1 consistently and controls known or
unknown impurities including genotoxic reaction intermediates at level of less than
0.10%w/w or not detected level [referred as ND]. Although, the following
18
examples illustrate the present invention in more detail, but should not be construed
as limiting the scope of the invention.
Examples:
Example 1: Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H5 indazol-6-amine
To a solution of 1,2-dimethyl-5-nitro-1H-benzimidazole (50 g) in ethanol (650 mL),
10% palladium on carbon (7.5 g) was added and the resulting mixture was stirred
under hydrogen pressure (3.0 to 3.5 Kg/cm2
) at 30°C to 40°C for 4 hours. After
completion of reaction [monitored by HPLC], the catalyst was removed by filtration
10 and washed with ethanol (100 mL). To the combined filtrate, sodium bicarbonate
(54.92 g) and 2,4-dichloropyrimidine (46.75 g) were added and stirred for 36 hours
at 35°C to 40°C. After completion of reaction, the reaction mixture was cooled to
0°C to 5°C and stirred for 2 hours. The resulting solid, was then filtered, washed
with ethanol (100 mL). The resulting solid was taken in demineralized water (1250
15 mL) and stirred for 1 hour at 25°C to 30°C. The solid was then filtrated, washed
with demineralized water (250 mL x 2) and dried under vacuum at 45°C to 50°C for
12 hours to obtain title compound (41.64 g) having purity 99.32% w/w by HPLC;
impurity-A: 0.31%; single highest unknown impurity: 0.24%.
Example 2: Preparation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H20 indazol-6-amine
To a solution of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (5.0
g) in N,N-dimethylformamide (25 mL), cesium carbonate (7.5 g) and methyl iodide
(3.9 g) were added at 15°C to 20°C under nitrogen atmosphere. The reaction mixture
was stirred at 25°C to 30°C for 4 hours. After completion of reaction [monitored on
25 HPLC], demineralized water (125 mL) was added slowly and reaction mixture was
stirred for further 2 hours. The resulting solid was then filtered and washed with
demineralized water (25 mL x 2) followed by drying under vacuum at 45°C to 50°C
for 12 hours to obtain the title compound (4.2 g) having purity 97.81% w/w by
HPLC; 2-chloropyrimidine compound VI: 0.36%; impurity-C: 0.32%; single highest
30 unknown impurity: 0.39%.
19
Example 3: Preparation of pazopanib hydrochloride
To a solution of 5-amino-2-methyl benzene sulfonamide (15.6 g) in methanol (52
mL), activated carbon (0.2 g) was added at 60°C to 65°C. The resulting mixture was
stirred for 30 minutes. The resulting reaction mixture was filtered through hyflo bed
5 and washed with methanol (8 mL). The resulting filtrate was distilled out completely
under vacuum at temperature not more than 55°C to obtain pure 5-amino-2-methyl
benzene sulfonamide.
A mixture of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine (4.0
g) as obtained in example 2 in isopropanol (52 mL) was heated at 85°C to 90°C and
10 stirred to get a clear solution. The reaction mass was filtered through micron filter,
washed with isopropanol (8 mL). The obtained filtrate was added into the above
pure 5-amino-2-methyl benzene sulfonamide. The reaction mixture was then heated
to 85°C to 90°C and stirred for 36 hours. After completion of reaction [monitored by
HPLC], the reaction mixture was cooled to 20°C to 25°C. The reaction mixture was
15 further stirred for 1 hour, filtered and washed with isopropanol (8 mL) and dried
under vacuum.
Methanol (90 mL), conc. hydrochloric acid (0.144 g) was added to resulting wet
material and stirred for 48 hours at 60°C to 65°C. The resulting reaction mass was
then cooled to 25°C to 30°C and stirred for 1 hour. The resulting solid was filtered
20 and washed with methanol (15 mL). The resulting wet material was dried under
vacuum at 45°C to 50°C for 12 hours to obtain pazopanib hydrochloride (4.5 g)
having purity 98.71% w/w by HPLC; 2-chloropyrimidine compound VI: 0.22%; Nmethyl 2-chloropyrimidine compound I: ND; sulfonamide compound VII: 0.06%;
impurity-F: 0.33%; impurity-G: ND; single highest unknown impurity: 0.22%.
25 Example 4: Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2Hindazol-6-amine
To a solution of 1,2-dimethyl-5-nitro-1H-benzimidazole (50 g) in ethanol (650 mL),
10% palladium carbon (7.5 g) was added and the resulting mixture was stirred under
hydrogen pressure (3.0 to 3.5 Kg/cm2
) at 30°C to 40°C for 4 hours. After completion
30 of reaction [monitored by HPLC], the catalyst was removed by filtration and washed
20
with ethanol (100 mL). To the combined filtrate, sodium bicarbonate (54.92 g) and
2,4-dichloropyrimidine (46.75 g) were added and stirred for 36 hours at 35°C to
40°C. After completion of reaction [monitored by HPLC], the reaction mixture was
cooled to 0°C to 5°C and stirred for 2 hours. The resulting solid was then filtered,
5 washed with ethanol (100 ml) and dried. Demineralized water (1250 mL) was added
to the dried material and stirred for 1 hour at 25°C to 30°C. The resulting solid was
then filtrated and washed with DM water (250 mL x 2) and dried under vacuum at
45°C to 50°C for 12 hours to obtain title compound (54.6 g) having purity 97.89%
w/w by HPLC; impurity-A: 0.59%; single highest unknown impurity: 0.29%.
10 Example 5: Preparation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine
To a solution of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (53.0
g) as obtained in example 4, in N,N-dimethylformamide (265 mL), cesium carbonate
(79.5 g) and methyl iodide (41.34 g) were added at 15°C to 20°C under nitrogen
15 atmosphere. The reaction mixture was stirred at 25°C to 30°C for 4 hours. After
completion of reaction [monitored on HPLC], demineralized water (1325 mL) was
added slowly to reaction mixture and stirred for further 2 hours. The resulting
mixture was then filtered and washed with demineralized water (265 mL x 2)
followed by drying under vacuum at 45°C to 50°C for 12 hours to obtain brown
20 colored N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (49.50 g)
having purity 98.99% w/w by HPLC; 2-chloropyrimidine compound VI: 0.37%;
impurity-C: 0.30%; single highest unknown impurity: 0.05%.
Example 6: Purification of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine
25 The N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (48.0 g)
obtained in example 5 was dissolved in toluene (624 mL) at 85°C to 90°C.
Activated carbon (7.2 g) was added to the resulting solution and stirred for 15
minutes. The resulting mass was then filtered through hyflo bed and washed with
toluene (96 mL). The reaction mass was then slowly cooled to 0°C to 5°C and
30 stirred for 2 hours. The resulting solid was filtered and washed with chilled toluene
21
(48 mL) and dried under vacuum at 45°C to 50°C to obtain title compound (40.80 g)
having purity 99.50% w/w by HPLC; 2-chloropyrimidine compound VI: 0.14%;
impurity-C: 0.18%; single highest unknown impurity: 0.02%.
Example 7: Preparation of pazopanib hydrochloride
5 To a solution of 5-amino-2-methyl benzene sulfonamide (30.03 g) in methanol (500
mL), activated carbon (1.93 g) was added at 60°C to 65°C. The resulting mixture
was stirred for 30 minutes. The resulting reaction mixture was filtered through hyflo
bed and washed with methanol (77.5 mL). The resulting filtrate was distilled out
completely under vacuum at temperature below 55°C to obtain pure 5-amino-2-
10 methyl benzene sulfonamide.
Meanwhile a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol6-amine (38.5g) obtained in example 6 in isopropanol (500 mL) was heated at 85°C
to 90°C and stirred to get a clear solution. The reaction mass was filtered through
micron filter, washed with isopropanol (77.5 mL). The obtained filtrate was added
15 into the above pure 5-amino-2-methyl benzene sulfonamide. The reaction mixture
was then heated to 85°C to 90°C and stirred for 36 hours. After completion of
reaction [monitored by HPLC], the reaction mixture was cooled to 20°C to 25°C.
The reaction mixture was further stirred for 1 hour, filtered and washed with
isopropanol (115.5 mL x 2) and dried to obtain the title compound (63.5 g) with
20 purity 99.52% w/w by HPLC.
Methanol (112.5 mL), conc. hydrochloric acid (0.18 g) was added to the portion of
above obtained wet material (8.0 g) and stirred for 48 hours at 60°C to 65°C. The
resulting reaction mass was then cooled to 25°C to 30°C and stirred for 1 hour. The
resulting solid was filtered and washed with methanol (15 mL). The resulting wet
25 material was dried under vacuum at 45°C to 50°C for 12 hours to obtain pure
pazopanib hydrochloride (6.44 g) with purity 99.91% w/w by HPLC; 2-
chloropyrimidine compound VI: not detected; N-methyl 2-chloropyrimidine
compound I: 0.005%; sulfonamide compound VII: not detected; impurity-F: 0.06%;
impurity-G: not detected; single highest unknown impurity: 0.017%. XRPD
30 matches with Form-1.
22
Example 8: Preparation of pazopanib hydrochloride Form-1
Step 1- Preparation of pazopanib hydrochloride
To a solution of 5-amino-2-methyl benzene sulfonamide (7.8 g) in methanol (130
mL), activated carbon (0.5 g) was added at 60°C to 65°C. The resulting mixture was
5 stirred for 30 minutes. The resulting reaction mixture was filtered through hyflo bed
and washed with methanol (20 mL). The resulting filtrate was distilled out
completely under vacuum at temperature below 55°C to obtain pure 5-amino-2-
methyl benzene sulfonamide.
Meanwhile a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol10 6-amine (10.0 g) in isopropanol (130 mL) was heated at 85°C to 90°C and stirred to
get a clear solution. The reaction mass was filtered through micron filter, washed
with isopropanol (20 mL). The obtained filtrate was added into the above pure 5-
amino-2-methyl benzene sulfonamide. The reaction mixture was then heated to
85°C to 90°C and stirred for 36 hours. After completion of reaction [monitored by
15 HPLC], the reaction mixture was cooled to 20°C to 25°C. The reaction mixture was
further stirred for 1 hour, filtered and washed with isopropanol (30 mL) to obtain
wet material (15.9 g) with purity 99.65% w/w by HPLC; N-methyl 2-
chloropyrimidine compound I: 0.19%; sulfonamide compound VII: 0.02%;
impurity-F: 0.03%; impurity-G: ND; single highest unknown impurity: 0.03%.
20 Step 2- Preparation of pazopanib hydrochloride Form-1
Method A- Methanol (56.5 mL), conc. hydrochloric acid (0.045 g) was added to the
portion of above obtained wet material (3.75 g) and stirred for 48 hours at 60°C to
65°C. The resulting reaction mass was then cooled to 25°C to 30°C and stirred for 1
hour. The resulting solid was filtered and washed with methanol (8 mL). The
25 resulting wet material was dried under vacuum at 45°C to 50°C for 12 hours to
obtain Form-1 of pure pazopanib hydrochloride (2.90 g) with purity 100% w/w by
HPLC; N-methyl 2-chloropyrimidine compound I: ND; sulfonamide compound VII:
not detected; Impurity-F: ND; Single highest unknown impurity: ND..
Method B- Methanol (56.5 mL), conc. hydrochloric acid (0.091 g) was added to the
30 portion of above obtained wet material (3.75 g) and stirred for 48 hours at 60°C to
65°C. The resulting reaction mass was then cooled to 25°C to 30°C and stirred for 1
23
hour. The resulting solid was filtered and washed with methanol (8 mL). The
resulting wet material was dried under vacuum at 45°C to 50°C for 12 hours to
obtain Form-1 of pure pazopanib hydrochloride (2.86 g) with purity 99.974% w/w
by HPLC; N-methyl 2-chloropyrimidine compound I: ND; sulfonamide compound
5 VII: ND; impurity-F: 0.006%; single highest unknown impurity: 0.01%.
Method C- Methanol (56.5 mL), conc. hydrochloric acid (0.14 g) was added to the
portion of above obtained wet material (3.75 g) and stirred for 48 hours at 60°C to
65°C. The resulting reaction mass was then cooled to 25°C to 30°C and stirred for 1
hour. The resulting solid was filtered and washed with methanol (8 mL). The
10 resulting wet material was dried under vacuum at 45°C to 50°C for 12 hours to
obtain Form-1 of pure pazopanib hydrochloride (2.83 g) with purity 99.995% w/w
by HPLC; N-methyl 2-chloropyrimidine compound I: ND; sulfonamide compound
VII: ND; impurity-F: ND; single highest unknown impurity: 0.005%.
Example 9: Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H15 indazol-6-amine
To a solution of 1,2-dimethyl-5-nitro-1H-benzimidazole (100 g) in ethanol (1300
mL), 10% palladium on carbon (12 g) was added and the resulting mixture was
stirred under hydrogen pressure (4.0 to 4.5 Kg/cm2
) at 25°C to 35°C for 4 hours.
After completion of reaction [monitored by HPLC], the catalyst was removed by
20 filtration and washed with ethanol (200 mL). To the combined filtrate, sodium
bicarbonate (110 g) and 2,4-dichloropyrimidine (94 g) were added and stirred for 44
hours at 35°C to 40°C. After completion of reaction, the reaction mixture was
cooled to 0°C to 5°C and stirred for 2 hours. The resulting solid was then filtered,
washed with ethanol (200 mL). The resulting solid was taken in demineralized water
25 (2500 mL) and stirred for 1 hour at 20°C to 30°C. The solid was then filtrated,
washed with demineralized water (500 mL x 2) and dried under vacuum at 50°C to
55°C for 18 hours to obtain title compound (108 g) having purity 98.84% w/w by
HPLC; impurity-A: 0.48%; single highest unknown impurity: 0.36%.
24
Example 10: Preparation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine
To a solution of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (100
g) in N,N-dimethylformamide (550 mL), cesium carbonate (150 g) and methyl
5 iodide (78 g) were added at 15°C to 25°C under nitrogen atmosphere. The reaction
mixture was stirred at 25°C to 30°C for 4 hours. After completion of reaction
[monitored on HPLC], demineralized water (2500 mL) was added slowly and
reaction mixture was stirred for further 2 hours. The resulting solid was then filtered
and washed with demineralized water (500 mL x 2) followed by drying under
10 vacuum at 45°C to 50°C for 12 hours to obtain the title compound (94.10 g) having
purity 99.01% w/w by HPLC; 2-chloropyrimidine compound VI: 0.18%; impurity
C: 0.07%; single highest unknown impurity: 0.28%.
Example 11: Purification of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine
15 N-(2-Chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (90.0 g) obtained
in example 2 was dissolved in toluene (1170 mL) at 80°C to 90°C. Activated
carbon (9 g) was added to the resulting solution and stirred for 20 minutes. The
resulting mass was then filtered through hyflo bed and washed with toluene (180
mL). The reaction mass was then slowly cooled to 0°C to 5°C and stirred for 2
20 hours. The resulting solid was filtered and washed with chilled toluene (90 mL) and
dried under vacuum at 45°C to 50°C to obtain title compound (79.37 g) having
purity 99.64% w/w by HPLC; 2-chloropyrimidine compound VI: 0.08%; impurity
C: 0.04%; single highest unknown impurity: 0.02%.
Example 12: Preparation of pazopanib hydrochloride Form-1
25 Step 1- Preparation of pazopanib hydrochloride
To a solution of 5-amino-2-methyl benzene sulfonamide (58.5 g) in methanol (975
mL), activated carbon (7.5 g) was added at 55°C to 65°C. The resulting mixture was
stirred for 20 minutes. The resulting reaction mixture was filtered through hyflo bed
and washed with methanol (150 mL). The resulting filtrate was distilled out
30 completely under vacuum at temperature below 50°C to obtain pure 5-amino-2-
methyl benzene sulfonamide.
25
Meanwhile a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol6-amine (75.0 g) in isopropanol ( 975 mL) was heated at 75°C to 85°C and stirred to
get a clear solution. The reaction mass was filtered through micron filter, washed
with isopropanol (150 mL). The obtained filtrate was added into the above pure 5-
5 amino-2-methyl benzene sulfonamide. The reaction mixture was then heated to
75°C to 85°C and stirred for 36 hours. After completion of reaction [monitored by
HPLC], the reaction mixture was cooled to 20°C to 25°C. The reaction mixture was
further stirred for 2 hour, filtered and washed with isopropanol (225 mL) to obtain
wet material (120 g) having purity 99.77% w/w by HPLC; 2-chloropyrimidine
10 compound VI: not detected; N-methyl 2-chloropyrimidine compound: 0.13%;
sulfonamide compound VII: not detected; single highest unknown impurity: 0.03%.
Step 2- Preparation of pazopanib hydrochloride Form-1
Methanol (750 mL), conc. hydrochloric acid (17.5 g) was added to the portion of
above obtained wet material (80 g) and stirred for 24 hours at 60°C to 65°C. After
15 completion of reaction [N-methyl 2-chloropyrimidine compound I less than 50 ppm,
monitored by HPLC], demineralized water (225 mL) was added and stirred to get a
clear solution at 60°C to 65°C. Meanwhile to isopropyl alcohol (750 mL), seeding
material i.e. pazopanib hydrochloride (1.0g) was added and the suspension was
cooled 15oC to 20oC. To this suspension above clear methanol reaction mass was
20 added slowly and the resulting reaction mass was then cooled to 20°C to 25°C and
stirred for 2 hour. The resulting solid was filtered and washed with Isopropyl alcohol
(150 mL). The resulting wet material was dried under vacuum at 70°C to 75°C for
15 hours to obtain Form-1 of pure pazopanib hydrochloride (65.3 g) with purity
99.96% w/w by HPLC; N-methyl 2-chloropyrimidine compound of formula I: 22.2
25 ppm; sulfonamide compound VII: not detected; impurity F: 0.01%; single highest
unknown impurity: 0.02%. XRPD matches with Form-1.
Having described the invention with reference to certain preferred aspects, other
aspects will become apparent to one skilled in the art from consideration of the
specification. It will be apparent to those skilled in the art that many modifications,
30 both to materials and methods, may be practiced without departing from the scope of
the invention.

WE CLAIM:

1. A process for the purification of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl5 2H-indazol-6-amine of formula I,
Formula I
comprising the steps of:
a) providing a mixture of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2Hindazol-6-amine of formula I, in an aromatic hydrocarbon solvent;
b) stirring the reaction mass at temperature 40°C to reflux temperature till
10 dissolution;
c) adding activated carbon to the reaction mass;
d) filtering the reaction mass;
e) cooling the filtrate to 0°C to 10°C; and
f) isolating pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
15 amine of formula I.
2. The process as claimed in claim 1, wherein in step a) the aromatic
hydrocarbon solvent is benzene, toluene or xylene.
20 3. The process as claimed in claim 1, wherein in step b) the reaction mixture is
stirred at 75°C to 90°C.
4. A process for preparation of pazopanib hydrochloride of formula II,
Formula II
comprising the steps of:
25 a) providing a mixture of crude N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl2H-indazol-6-amine of formula I,
27
Formula I
in an aromatic hydrocarbon solvent;
b) stirring the reaction mass at temperature 40°C to reflux temperature till
dissolution;
c) adding activated carbon to the reaction mass;
5 d) filtering the reaction mass;
e) cooling the filtrate to 0°C to 10°C;
f) isolating pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
amine of formula I; and
g) converting pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-
10 amine of formula I in to pazopanib hydrochloride of formula II.
5. The process as claimed in claim 4, wherein in step a) the aromatic
hydrocarbon solvent is benzene, toluene or xylene.
15 6. The process as claimed in claim 4, wherein in step b) the reaction mixture is
stirred at 75°C to 90°C.
7. A process for preparation of pazopanib hydrochloride Form I comprises the
steps of :
20 a) providing a suspension of pazopanib hydrochloride in methanol and
hydrochloric acid,
b) stirred the reaction mixture at temperature of 45°C to 65°C for 20-50
hours,
c) diluting the reaction mass with demineralized water,
25 d) heating the reaction mixture at 45°C to 65°C to obtain a clear solution,
e) adding the clear solution obtained in step d) to seeding material prepared
by adding pazopanib hydrochloride Form I in isopropanol,
f) stirred the reaction mixture at 15°C to 25°C for 1-4 hours, and
g) isolating pazopanib hydrochloride Form I.
28
8. The process as claimed in claim 7, wherein in step b) the reaction mixture is
stirred at 60°C to 65°C.
9. The process as claimed in claim 7, wherein in step d) the reaction mixture is
5 stirred at 60°C to 65°C.
10. The process as claimed in claim 7, wherein in step f) the reaction mixture is
stirred at 15°C to 25°C.