PROCESS FOR THE PREPARATION OF PAZOPANIB OR SALTS THEREOF
Field of the Invention
The present invention provides a process for t e preparation of pazopanib of
Formula la or salts, and intermediates thereof.
Background of the Invention
Pazopanib is a tyrosine kinase inhibitor of Formula la.
Formula la
Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4-
[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-
methylbenzenesulfonamide monohydrochloride, having the structure as depicted in
Formula I :
Formula I
U.S. Patent No. 7,105,530 provides aprocess forthe preparation of a
hydrochloride salt of a compound of Formula II
Formula II
involving the reduction of 2,3-dimethyl-6-nitro-2H-indazole with tin (II) chloride in
concentrated hydrochloric acid in t e presence of 2-methoxyethyl ether at 0°C. It also
describes the preparation of a compound of Formula III
Formula III
involving the reaction of a hydrochloride salt of compound of Formula II with 2,4-
dichloropyrimidine in the presence of a base and solvent mixture of
tetrahydrofuran/ethanol followed by stirring for 4 hours at 85°C.
PCT Publication No. WO 2007/064752 provides a process for the preparation of a
compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10%
Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of
ammonium formate at a rate that ensures the reaction temperature is maintained at or
between 25°C and 30°C. It also discloses the preparation of a compound of Formula III
comprising heating the compound of Formula II with sodium bicarbonate in presence of
tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to
25°C.
The present invention provides a process for the preparation of a compound of
Formula II which offers recycling of the Raney nickel catalyst used in the process, and an
easy filtration work-up procedure. Further, the present invention offers selective reduction
under mild conditions that is economical to use at an industrial scale.
The present invention also provides a process for the preparation of compound of
Formula III which avoids the use of two or more solvents, and additionally, also
circumvents heating and cooling procedures during the reaction. The aforesaid advantages
yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3-
dimethyl-2H-indazol-6-amine (CPDMI) impurity.
The compounds of Formula II and Formula III prepared by t e present invention
yield a compound of Formula la or its salts in comparable yield and suitable purity
required for medicinal preparations.
Summary of the Invention
A first aspect of the present invention provides a process for the preparation of
pazopanib of Formula la or its salts
Formula la
comprising:
i) treating 2,3-dimethyl-6-nitro-2H-indazole with Raney nickel to obtain a
compound of Formula II;
Formula II
ii) treating the compound of Formula II at a temperature of about 45°C or below
with 2,4-dichloropyrimidine to obtain a compound of Formula III;
Formula III
converting the compound of Formula III to pazopanib of Formula la or its
salts; and
isolating pazopanib of Formula la or its salts.
A second aspect of t e present invention provides a process for the preparation of
pazopanib of Formula la or its salts
Formula la
comprising:
i) treating 2,3-dimethyl-6-nitro-2H-indazole with Raney nickel to obtain a
compound of Formula II;
Formula II
ii) treating the compound of Formula II with 2,4-dichloropyrimidine to obtain a
compound of Formula III;
Formula III
iii) converting the compound of Formula III to pazopanib of Formula la or its
salts; and
iv) isolating pazopanib of Formula la or its salts
wherein the compound of Formula II is not isolated from the reaction mixture.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described
hereinafter.
The term "about", as used herein, refers to ±5% variation in the values mentioned
herein.
The 2,3-dimethyl-6-nitro-2H-indazole may be prepared by processes known in the
prior art, for example, the process known in PCT Publication No. WO 2007/064752, or
may be prepared by the process provided herein.
The Raney nickel used in the reaction is in t e form of a fine grained solid. Step i)
is carried out in t e presence of an organic solvent and hydrogen gas. The organic solvent
may be an alcoholic solvent. Examples of the alcoholic solvents include methanol,
ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, or mixtures
thereof. The compound of Formula II may be isolated from the reaction mixture or may
be carried as such on to step ii) without isolation. The compound of Formula II may be
isolated from reaction mixture by any method known in the art. The catalyst Raney nickel
is recovered back and recycled.
The compound of Formula II may be further treated with suitable solvents, or
mixtures thereof. The treatment of compound of Formula II with solvents may include
preparing a suspension, stirring, or slurrying. Examples of the solvents to be used include
halogenated solvents, aliphatic hydrocarbon solvents, or mixtures thereof. Examples of
halogenated solvents include dichloromethane, dichloroethane, chloroform, and carbon
tetrachloride. Examples of aliphatic hydrocarbons include n-pentane, n-hexane, nheptane,
and n-octane.
Step ii) is carried out in the presence of an organic solvent and a base. Examples
of organic solvents include alcoholic solvents like methanol, ethanol, n-propanol, isopropanol,
n-butanol, iso-butanol, sec-butanol, or mixtures thereof. The base may be
selected from organic or inorganic bases. The organic base is selected from the group
comprising N,N-diisopropylethylamine, triethylamine, tri-isopropylamine, N,N-2-
trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di- -
butyl-4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8-
diazabicyclo[5 .4.0]undec-7-ene, or mixtures thereof. The inorganic base is selected from
the group comprising sodium carbonate, potassium carbonate, sodium hydride, sodium
bicarbonate, potassium bicarbonate, or mixtures thereof.
Step ii) is carried out at a temperature of about 45°C or below, for example, at
about 25°C to 30°C. The temperature of about 45°C or below is critical for controlling
the formation of N-(4-chloropyrimidin-2-yl)-2,3-dimethyl-2H-indazol-6-amine impurity
(4-CPDMI as disclosed in PCT Publication No. WO 201 1/069053) during step ii).
Impurity
The compound of Formula III is subjected to sequential treatment with water and
an organic solvent. The treatment of the compound of Formula III with water and an
organic solvent may include preparing a suspension, stirring, or slurrying. The organic
solvent is selected from the group comprising ethyl acetate, n-propyl acetate, butyl
acetate, or mixtures thereof. The compound of Formula III may be isolated from the
reaction mixture or may be carried as such on to step iii) without isolation. The
compound of Formula III may be isolated from the reaction mixture by any method
known in the art.
Step iii) may be carried out as per the embodiments described hereinafter, or by
any other method known in the art.
The isolation of pazopanib or its salts is carried out by any method known in the
art.
The salt of pazopanib is the hydrochloride salt of Formula I .
The compound of Formula I prepared by the process of the present invention may
be further converted to pazopanib hydrochloride thereof by any method known to a
person skilled in the art.
In the following section, preferred embodiments are described by way of examples
to illustrate the process. However, these are not intended in any way to limit the scope of
the invention. Several variants of these examples would be evident to persons ordinarily
skilled in the art.
EXAMPLES
Step 1: Synthesis of 2,3-dimcthyl-6-nitro-2H-indazole
Example 1:
Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred
suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over
a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was
stirred at 25°C to 30°C for 16 hours. The solvent was recovered under reduced pressure.
A saturated sodium bicarbonate solution (3240 mL) was added to t e mixture slowly, and
t e reaction mixture was extracted with 4 :1 mixture of dichloromethane:isopropyl alcohol
(1080 mL x 5). The solvent was recovered under reduced pressure. Methyl -butyl
ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30
minutes at 45°C to 50°C. The reaction mixture was cooled to 25°C to 30°C and was
stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tertbutyl
ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3-
dimethyl-6-nitro-2H-indazole as a yellow solid.
Yield: 82.4% w/w
Step 2 : Synthesis of 2,3-dimethyl-2H-indazol-6-amine
Example 2a:
Raney nickel ( 12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2Hindazole
(50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an
autoclave under hydrogen pressure of 3.5 kg/cm2 - 4.0 kg/cm2 at 25°C to 30°C for 5 hours.
Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed
with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered
completely. «-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue,
and the reaction mixture was stirred for 1 hour at 25°C to 30°C. The solid was collected
by filtration, washed with n-heptane (50 mL x 2), and dried under vacuum at 40°C to 45°C
to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.
Yield: 95% w/w
Example 2b:
Raney nickel (2 1.25 g) was added to a suspension of 2,3-dimethyl-6-nitro-2Hindazole
(85 g, 0.45 mol) in methanol (850 mL). The reaction mixture was stirred in an
autoclave under hydrogen pressure of 3.5 kg/cm2 - 4.0 kg/cm2 at 25°C to 30°C for 5 hours.
Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed
with methanol (85 mL x 3). The filtrates were combined, and the solvent was recovered
up to the volume of 850 mL. The 2,3-dimethyl-2H-indazol-6-amine in methanol was used
as such in the next step.
Step 3 : Synthesis of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine
Example :
Sodium bicarbonate ( 112 g, 1.34 mol) was added to a stirred solution of 2,3-
dimethyl-2H-indazol-6-amine (as obtained from step 2; Examples 2a and 2b) in methanol.
2,4-Dichloropyrimidine (99.35 g, 0.67 mol) was added to t e reaction mixture followed by
stirring of t e reaction mixture for 24 hours at 25°C to 30°C. De-ionized water (850 mL)
was added to the reaction mixture followed by stirring of the reaction mixture at 25°C to
30°C for 1 hour. The solid was filtered. The wet solid was washed with de-ionized water
(170 mL x 2) to obtain a wet material. De-ionized water (850 mL) was added to the wet
material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes. The
solid was filtered, then washed with de-ionized water (170 mL x 2). The wet material
obtained was treated with ethyl acetate (340 mL) to obtain a slurry. The slurry was stirred
at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C. The slurry was further
stirred at 0°C to 5°C for 30 minutes. The solid was collected by filtration, then washed
with cold ethyl acetate (170 mL x 2). The solid was dried in an air oven at 50°C for 16
hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an offwhite
solid.
Yield: 86.7% w/w
Step 4 : Synthesis of pazopanib hydrochloride
Example 4a: Synthesis of N-(2-Chloropyrimidin-4-yl)-N.2.3-trimethyl-2H-indazol-6-
amine
Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added
to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine
(lOOg, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25°C to 30°C. The reaction
mixture was further stirred at 25°C to 30°C for 6 hours followed by cooling of the reaction
mixture to 0°C to 5°C. De-ionized water (300 mL) was added drop-wise to the reaction
mixture, then the reaction mixture was stirred at 5°C to 10°C for 30 minutes. The solid
was collected by filtration, and washed with de-ionized water (100 mL x 2). The wet
material so obtained was dried in an air oven at 50°C for 12 hours to obtain the title
compound.
Yield: 90.4% w/w
Example 4b: Synthesis of pazopanib hydrochloride
To a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-
amine (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol)
in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl
alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for
10 hours to 12 hours. The reaction mixture was cooled to 25°C. The reaction mixture was
further stirred at 25°C to 30°C for 30 minutes, then t e solid was filtered. The wet solid
was washed with isopropyl alcohol (180 mL x 2), and then dried under vacuum at 45°C to
50°C for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6-
yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown
solid.
Yield: 97% w/w
RLL-1509RWO
We claim:
1. A process for the preparation of pazopanib of Formula la or salts thereof
Formula la
comprising:
i) treating 2,3-dimethyl-6-nitro-2H-indazole with Raney nickel to obtain a
compound of Formula II;
Formula II
ii) treating t e compound of Formula II at a temperature of about 45°C or below
with 2,4-dichloropyrimidine to obtain a compound of Formula III;
Formula III
iii) converting the compound of Formula III to pazopanib of Formula la or its
salts; and
iv) isolating pazopanib of Formula la or salts thereof.
A process for the preparation of pazopanib of Formula la or salts thereof
Formula la
RLL-1509RWO
comprising:
i) treating 2,3-dimethyl-6-nitro-2H-indazole with Raney nickel to obtain a
compound of Formula II;
Formula II
ii) treating t e compound of Formula II with 2,4-dichloropyrimidine to obtain a
compound of Formula III;
Formula III
iii) converting the compound of Formula III to pazopanib of Formula la or salts
thereof; and
iv) isolating pazopanib of Formula la or salts thereof
wherein the compound of Formula II is not isolated from the reaction mixture.
3. The process according to claim 1 or claim 2, wherein the treatment of 2,3-
dimethyl-6-nitro-2H-indazole with Raney nickel is carried out in the presence of hydrogen
gas and an organic solvent.
4 . The process according to claim 3, wherein the organic solvent is selected from the
group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol,
sec-butanol, or mixtures thereof.
5. The process according to claim 4, wherein the solvent is methanol.
6. The process according to claim 1, wherein the compound of Formula II is isolated
from the reaction mixture.
7. The process according to claim 1, wherein the compound of Formula II is treated
with a suitable solvent selected from the group consisting of halogenated solvents,
aliphatic hydrocarbon solvents, or mixtures thereof.
RLL-1509RWO
8. The process according to claim 7, wherein the halogenated solvent is selected from
t e group consisting of dichloromethane, dichloroethane, chloroform, and carbon
tetrachloride; and t e aliphatic hydrocarbons is selected from the group consisting of npentane,
n-hexane, n-heptane, and n-octane.
9. The process according to claim 1 or 2, wherein the treatment of the compound of
Formula II with 2,4-dichloropyrimidine is carried out in the presence of a base.
10. The process according to claim 9, wherein the base is selected from the group
consisting of an organic base or an inorganic base.
11. The process according to claim 10, wherein the organic base is selected from the
group consisting of N,N-diisopropylethylamine, triethylamine, tri-isopropylamine, N,N-2-
trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di- -
butyl-4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8-
diazabicyclo[5.4.0]undec-7-ene, or mixtures thereof.
12. The process according to claim 10, wherein the inorganic base is selected from the
group consisting of sodium carbonate, potassium carbonate, sodium hydride, sodium
bicarbonate, potassium bicarbonate, or mixtures thereof.
13. The process according to claim 12, wherein the base is sodium bicarbonate.
14. The process according to claim 1 or 2, wherein the treatment of the compound of
Formula II with 2,4-dichloropyrimidine is carried out in the presence of an organic
solvent.
15. The process according to claim 14, wherein the organic solvent is selected from the
group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol,
sec-butanol, or mixtures thereof.
16. The process according to claim 15, wherein the solvent is methanol.
17. The process according to claim 2, wherein step ii) is carried out at a temperature of
about 45°C or below.
18. The process according to claim 1, wherein the compound of Formula II is not
isolated from the reaction mixture.