A novel practical synthesis of pazopanib: An anticancer drug

Article abstract of DOI:10.2174/157017812800233714

Abstract: This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.

Full text of DOI:10.2174/157017812800233714

276
Letters in Organic Chemistry, 2012, 9, 276-279
A Novel Practical Synthesis of Pazopanib: An Anticancer Drug
YiCheng Mei#, BaoWei Yang#, Wei Chen, DanDan Huang, Ying Li, Xin Deng, BaoMing Liu,
JingJie Wang, Hai Qian* and WenLong Huang*
Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, P.R. China
Received October 28, 2011: Revised February 01, 2012: Accepted February 01, 2012
Abstract: This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic
alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2-
position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported
route.
Keywords: Anticancer drug, pazopanib, regioselective methylation, synthesis, trimethyl orthoformate.
INTRODUCTION
N
Angiogenesis, the formation of new blood vessels from
existing vasculature, plays an essential role in tumor
N
N
H2NO2S
N
N
N
progression and metastasis [1-3]. Vascular endothelial
growth factor (VEGF) is key mediator of
H
a
1
neovascularization and research has intensely focused on
interfering with the VEGF receptor (VEGFR) signaling
system in order to modulate angiogenesis. Pazopanib (1) is a
multikinase inhibitor with targets that include vascular
endothelial growth factor receptors. Pazopanib was approved
by the US FDA for the treatment of advanced renal cell
carcinoma [4, 5].
Fig. (1). The structure of pazopanib.
Several other methods are available for the synthesis of
pazopanib. Arundathy et al. [6, 7] used 3-methyl-6-nitro-1H-
indazole sulfuric acid salt refluxing with dimethyl sulfate
within DMSO and methylene chloride obtained the
intermediate 2,3-dimethyl-6-nitro-2H-indazole (4) that could
be used for the next step. Dimethyl sulfate as an alkylating
agent is especially dangerous since this reagent is an
extremely hazardous liquid and vapor (causes delayed burns
to lungs and tissues, may be fatal if inhaled).
Pazopanib (1) was earlier prepared by a route described
in Scheme 1 [5]. The synthesis involves cyclization of 2-
ethyl-5-nitroaniline (2) which was used as a diazotizing
reagent tert-butyl nitrite to give 3-methyl-6-nitro-1H-
indazole (3). Regioselective methylation of 3 provided
intermediate 4 which was used as a methylating reagent
trimethyl oxonium tetraflouroborate. The nitro functionality
of 4 was reduced using tin(II) chloride to produce 6-amino-
2,3-dimethyl-2H-indazole (5) and subsequent attachment of
a 2,4-dichloropyrimidine to the arylamines 5 afforded 6.
RESULTS AND DISCUSSION
On the basis of the above limitations, we devised a safe,
economically competitive and environmentally benign
synthetic route for 1, which was obtained from 2 in five steps
using inexpensive and commercially available raw materials
and reagents (Scheme 1). To the best of our knowledge, this
novel route is environmentally advantageous over the earlier
described methods owing to avoid using the potently
mutagenic alkylating agents such as dimethyl sulfate and
methyl iodide and one step shorter than previously reported.
In addition, this new method is less expensive because of the
much cheaper material used.
Methylation of
6 with methyl iodide yielded N-(2-
chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine
(7). Finally, condensation of N-(2-chloropyrimidin-4-yl)-
N,2,3-trimethyl-2H-indazol-6-amine (7) and 5-amino-2-
methylbenzenesulfonamide in the presence of a catalytic
amount of HCl was carried out to afford pazopanib (1) in six
steps overall.
This process suffers from disadvantages such as (a) The
use of the potently mutagenic alkylating agent methyl iodide;
(b) The use of trimethyl oxonium tetraflouroborate is
expensive; (c) A highly flammable and light sensitive
diazotizing reagent tert-butyl nitrite was used. All of which
on large scale manufacturing process, may have induced
environmental damage.
Process for 3-methyl-6-nitro-1H-indazole (3) without
using tert-butyl nitrite
We opted sodium nitrite as a key raw material because
the diazotizing reagent tert-butyl nitrite is
a highly
*Address correspondence to these authors at the Center of Drug Discovery,
China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu
210009, P.R. China; Tel: +86-25-83271302; Fax: +86-25-83271480;
E-mail: qianhai24@163.com, ydhuangwenlong@126.com
flammable and light sensitive liquid. 2-ethyl-5-nitroaniline
(2) is reacted with sodium nitrite in acetic acid to obtain the
3-methyl-6-nitro-1H-indazole (3) in 93.9% yield [8].
#These authors contributed equally to this work.
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of Pazopanib
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
277
Previously reported route for prepration of pazopanib
b
c
d
N
N
N
N
N
N
N
H
N
N
N
O2N
O2N
Cl
N
H2N
H
4
5
a
3
6
e
N
N
N
O2N
NH2
H2NO2S
N
N
1
N
f
H
2
j
g
i
h
N
1 Pazopanib
N
N
N
N
N
N
N
H
N
N
HN
Cl
N
O2N
O2N
4
7
3
CH3
8
A novel regioselective
methylation
more environmentally benign
economically advantageous
More stable diazoting
reagent was used
number of steps
was reduced
A novel intermediate
Novel route for prepration of pazopanib
Scheme 1. Synthesis of pazopanib. Reagents and conditions: (a) t-BuONO, acetic acid; (b) trimethyl oxonium tetraflouroborate; (c) tin(II)
chloride; (d) 2,4-dichloropyrimidine; (e) MeI, rt; (f) sodium nitrite, acetic acid; (g) trimethyl orthoformate, DMF, sulfuric acid, toluene,
reflux; (h) MeOH, Pd/C, H2, paraformaldehyde, NaH, NaBH4; (i) 2,4-dichloropyrimidine; (j) 5-amino-2-methylbenzenesulfonamide, reflux.
Process for 2,3-dimethyl-6-nitro-2H-indazole (4) via a
methyl group using the Eschweiler-Clarke methylation
novel regioselective methylation method
reaction [12], providing a novel intermediate 7.
A novel method for the preparation of 2,3-dimethyl-6-
nitro-2H-indazole was developed. We have chosen the
trimethyl orthoformate as methylating reagent due to its
commercial availability and low cost, since the indazole ring
has two nitrogen atoms and presents annular tautomerism
with regards to the position of the NH hydrogen atom (Fig.
2). The alkylation of N-H indazoles generally yielded a
mixture of N-alkyl 1H-indazoles and N-alkyl 2H-indazoles
regioisomers [9, 10] (Scheme 2).
EXPERIMENTAL SECTION
All purchased starting materials were used without
further purification. Melting points were determined in open
capillary tubes on a MelTemp II apparatus which were
1
uncorrected. H NMR and 13C NMR were run on a Bruker
300 MHz spectrophotometer using DMSO-d6 as solvent with
tetramethylsilane as internal standard. Chemical shift data
are reported in parts per million (δ in ppm) where s, br, d, dd,
t, and m designate singlet, broad, doublet, doublet of doublet,
triplet, and multiplet, respectively. Coupling constants are in
units of hertz (Hz).
N
NH
N
N
H
1b
1a
3-methyl-6-nitro-1H-indazole (3)
Fig. (2). Tautomeric forms of indazole.
To a solution of 2-ethyl-5-nitroaniline (20.0 g, 120
mmol) in glacial AcOH (500 mL) a solution of sodium
nitrite (11.1g 132 mmol) in water (24 mL) was added all at
once. During this addition, the temperature was not allowed
to rise above 35℃. After the nitrite solution had been added,
stirring was maintained for 30 min. The solution was
evaporated in vacuo. Cold water was added to the orange
residue and the contents of the flask were washed into a
beaker where they were stirred. The product was filtered,
rinsed with saturated aqueous NaHCO3 and dried to afford 3-
methyl-6-nitro-1H-indazole (20.0 g, 93.9% yield); mp 176-
The trimethyl orthoformate was reported as potent
alkylating reagent that has been used to methylate many
different functional groups [11]. We found that in the
presence of sulfuric acid, the trimethyl orthoformate can
regioselect methylate at N-2 position of the 3-methyl-6-
nitro-1H-indazole. The workup is simple and it involves that
once the reaction is completed, the reaction is cooled to room
temperature followed by filtration and washing the product.
Process for N,2,3-trimethyl-2H-indazole-6-amine (7)
1
178℃; H NMR (300 MHz DMSO-d6): δ 13.50 (br, 1H),
The N,2,3-trimethyl-2H-indazol-6-amine (7) was
prepared by hydrogenation, followed by introduction of the
8.38 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.88 (dd, J’ = 8.7 Hz,
J’’ = 1.8 Hz, 1H), 2.56 (s, 3H); MS: m/z 178.1 [M + H]+
Methylating
reagent
R
R
R
+
N
N
N
N
N
N
H
1-Methyl-1H-indazoles
2-Methyl-2H-indazoles
1H-indazoles
Scheme 2. Methylation of 1-H indazoles

278 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Mei et al.
2,3-dimethyl-6-nitro-2H-indazole (4)
Pazopanib (Free Base). (1)
To solution of N-(2-chloropyrimidin-4-yl)-N,2,3-
a
Concentrated sulfuric acid (1.5 g, 14.9 mmol) was added
to a solution of 3-methyl-6-nitroindazole (3) (2.6 g, 14.7
mmol) in trimethyl orthoformate (10 mL)，toluene (10 mL)
and DMF (1 mL) at room temperature. The solution was
refluxed for 3 hr. The solution was cooled and filtration gave
a yellow solid, which was washed with petroleum ether and
saturated aqueous NaHCO3 to yield the crude product. The
crude product was recrystallized from the ethanol to give
2,3-dimethyl-6-nitro-2H-indazole (4) (1.77 g, 63.0% yield).
trimethyl-2H-indazol-6-amine (2.0 g, 6.9 mmol) and 5-
amino-2-methylbenzenesulfonamide (1.2 g 6.9 mmol) in i-
PrOH (45 mL) was added 3 drops of conc HCl and the
mixture heated to reflux for 5 hr. The mixture was cooled at
room temperature. The resulting precipitate was collected via
filtration and washed with diethyl ether to yield pazopanib
hydrochloride. The salt was suspended in water, triethyl
amine was added to adjust the pH to 9, the precipitate was
filtered and dried resulting a white solid. (2.5 g, 76.0% yield)
1H NMR (300 MHz DMSO-d6 free base) δ 9.37 (s, 1H), 8.60
(d, J = 2.1 Hz, 1H), 7.92 (d, J = 5.7 Hz, 1H), 7.71-7.84 (m,
2H), 7.45 (s, 1H), 7.23 (s, 2H), 7.15 (d, J = 8.7 Hz, 1H), 6.87
(dd, J’ = 8.71 Hz, J’’ = 1.5 Hz, 1H), 5.75 (d, J = 6.0 Hz, 1H),
4.06 (s, 3H), 3.50 (s, 3H), 2.63 (s, 3H), 2.45 (s, 3H); 13C
NMR (75 MHz DMSO-d6 free base) 9.86, 19.59, 37.82,
38.50, 97.11, 114.39, 117.77, 119.95, 120.08, 121.90,
122.30, 127.59, 132.50, 132.64, 139.68, 142.29, 142.38,
147.45, 156.17, 159.87, 162.88; MS: m/z 438.2 [M + H]+.
1
mp 183-184℃; H NMR (300 MHz DMSO-d6): δ 8.49 (d, J
= 1.8 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H ), 7.70 (dd, J’ = 9.0
Hz, J’’ = 1.8 Hz 1H), 4.15 (s, 3H), 2.67 (s, 3H); MS: m/z
192.1 [M + H]+.
N,2,3-trimethyl-2H-indazole-6-amine (7)
Methanol (20 mL) and THF (60 mL) was added to a flask
containing 10% Pd/C (0.3 g, 0.27 mmol). The 2,3-dimethyl-
6-nitro-2H-indazole (4) (2.0 g, 10.5 mmol) was added, and
the reaction mixture was stirred in an H2 atmosphere until
the hydrogen was no longer absorbed. After completion of
the reaction, the Pd/C catalyst was filtered off on celite and
the solvent was removed by rotary evaporation, the residue
was dissolved in methanol (30.0 mL); paraformaldehyde (1.6
g, 53.3 mmol) was added to the solution and stirred at room
temperature. NaH (0.5 g, 22.1 mmol) was added carefully.
The reaction solution was stirred at room temperature
overnight. Then NaBH4 (1.6 g, 42.3 mmol) was added. And
the reaction solution was stirred at room temperature for 3
hours. the solvent was removed by rotary evaporation. The
residue was diluted with EtOAc and washed with water. The
organic phase was dried with anhydrous NaSO4, and then
concentrated by rotary evaporation. Yield N,2,3-trimethyl-
2H-indazole-6-amine (7) as a pink solid (1.6 g, 85.8% yield).
1H NMR (300 MHz DMSO-d6): δ 7.27 (d, J = 8.7 Hz, 1H),
6.43 (d, J’ = 8.7 Hz 1H), 6.14 (s, 1H), 5.61 (br, 1H), 3.87 (s,
3H), 2.67 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz DMSO-
d6): 9.70, 30.38, 36.89, 89.96, 114.95, 115.16, 120.24,
131.23, 148.47, 149.38; MS: m/z 176.1 [M + H]+.
CONFLICT OF INTEREST
Declared none.
ACKNOWLEDGEMENTS
The work was supported by the National Natural Science
Foundation of China (No. 81172932), the special major
science and technology project of "Creation of major new
drugs" (No. 2009ZX09102-033) and the Fundamental
Research Funds for the Central Universities of China
(No.2J10023).
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trimethyl-2H-indazole-6-amine (0.6 g, 3.4 mmol), NaCO3
(0.6 g, 5.7 mmol), 2,4-dichloropyrimidine (0.6 g, 4.03
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chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine
(8) as a pale yellow solid (0.9 g, 88.4% yield). mp 164-
[6]
[7]
[8]
1
165℃; H NMR (300 MHz DMSO-d6): δ 8.14 (d, J = 6.3
[9]
Hz, 1H), 7.93 (d, J = 6.3 Hz 1H), 7.64 (s, 1H), 6.86 (dd, J’ =
8.7 Hz, J’’ = 0.9 Hz 1H), 6.24 (d, J = 6.0 Hz 1H), 4.07 (s,
3H), 3.43 (s, 3H), 2.63 (s, 3H); MS: m/z 288.1 [M + H]+.
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Synthesis of Pazopanib
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
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1