Pazopanib, A VEGFR Inhibitor
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4637
min, maintaining the reaction temperature below 100 °C with an
ice bath. After the addition was complete, the ice bath was removed
and the solution was allowed to stir for an additional 20 min.
Addition of Et2O (70 mL) to the solution resulted in formation of
a yellow precipitate, which was filtered off, washed with Et2O, and
dried to afford 6-amino-3-methylindazole (9) (10.0 g, 92% yield).
1H NMR (400 MHz): δ 9.5 (br s, 1H), 7.79 (d, 1H, J ) 8.6 Hz),
7.44 (s, 1H), 7.02 (d, 1H, J ) 8.6 Hz), 3.5 (br s, 2H), 2.50 (s, 3H).
LCMS (APCI, m/z) 148 (M + H+).
over 3 min at room temperature. After 15 min, iodomethane (1.37
g, 9.6 mmol) was added dropwise and stirring continued for 30
min, the reaction was then quenched with water and extracted with
ether (3 × 30 mL). The combined extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure to yield a yellow
solid. The resulting solid was purified by silica gel column
chromatography eluting with CH2Cl2 to yield tert-butyl 6-[(2-chloro-
4-pyrimidinyl)(methyl)amino]-3-methyl-1H-indazole-1-carboxy-
1
late (3.26 g, 95% yield). H NMR (400 MHz): δ 8.03 (d, J ) 6.1
Hz, 1 H), 7.99 (d, J ) 1.5 Hz, 1 H), 7.38 (dd, J ) 8.3, 1.8 Hz, 1
H), 7.97 (d, J ) 8.3 Hz, 1 H), 6.45 (d, J ) 6.1 Hz, 1 H), 3.47 (s,
3 H), 2.55 (s, 3 H), 1.61 (s, 9 H). LCMS (APCI, m/z) 360 (M +
H+). HPLC (method A): 90% (tR 8.4 min).
To a stirred solution of 9 (2.7 g, 15 mmol) and NaHCO3 (1.3 g,
45 mmol) in THF (15 mL) and EtOH (60 mL) was added 2,4-
dichloropyrimidine (6.7 g, 45 mmol) at room temperature. The
reaction was stirred for 4 h, and the resulting suspension was filtered
and the residue washed thoroughly with EtOH. The filtrate was
concentrated under reduced pressure, and the resulting solid was
washed with Et2O to remove excess 2,4-dichloropyrimidine to
A solution of tert-butyl 6-[(2-chloro-4-pyrimidinyl)(methyl)-
amino]-3-methyl-1H-indazole-1-carboxylate (2.0 g, 5.4 mmol) and
5-(ethylsulfonyl)-2-methoxyaniline (1.28 g, 6.0 mmol) in iPrOH
(11 mL) was stirred for 16 h. The reaction solution was concentrated
in vacuo and the residue was dissolved in a 1:1 mixture of CH2Cl2
and trifluoroacetic (40 mL) and stirred for 30 min. The reaction
was neutralized by addition of saturated aqueous NaHCO3 and the
organic phase separated and the aqueous phase further extracted
with CH2Cl2 (100 mL). The combined organic layers were dried
over anhydrous MgSO4, filtered, and evaporated to give a crude
mixture that was purified by silica gel chromatography eluting with
CH2Cl2/MeOH (95:5 v/v) to give 11a (1.4 g, 57% yield). 1H NMR
(400 MHz): δ 12.74 (s, 1H), 9.10 (s, 1H), 7.85 (d, J ) 6.0 Hz,
1H), 7.81 (s, 1H), 7.79 (d, J ) 8.2 Hz, 1H), 7.46 (d, J ) 8.6 Hz,
1H), 7.41 (s, 1H), 7.25 (d, J ) 8.2 Hz, 1H), 7.05 (d, J ) 8.6 Hz,
1H), 5.78 (d, J ) 6.0 Hz, 1H), 3.99 (s, 3H), 3.51 (s, 3H), 3.18 (q,
J ) 7.4 Hz, 2H), 2.50 (s, 3H), 1.09 (t, J ) 7.4 Hz, 3H). LCMS
(APCI, m/z) 451, 452 (M + H+). Anal. (C22H24N6O3S·0.3H2O)
C, H, N, S.
1
afford 10 (3.5 g, 89% yield). H NMR (400 MHz): δ 12.56 (s, 1
H), 10.14 (s, 1 H), 8.18 (d, J ) 6.1 Hz, 1 H), 8.00 (br s, 1 H), 7.65
(d, J ) 8.6 Hz, 1 H), 7.08 (dd, J ) 8.7, 1.6 Hz, 1 H), 6.81 (d, J )
6.1 Hz, 1 H), 2.46 (s, 3 H). LCMS (APCI, m/z) 260, 262 (M +
H+). HPLC (method A): 96% (tR 6.3 min).
N4-(3-Methyl-1H-indazol-6-yl)-N2-[3,4,5-tris(methyloxy)phenyl]-
2,4-pyrimidinediamine (5a). Prepared from 10 and 3,4,5-tri-
methoxyaniline by the procedure described in the preparation of 3,
and the filtered product was further purified by silica gel chroma-
tography eluting with a hexanes/EtOAc to yield 5a in 83% yield.
1H NMR (400 MHz): δ 12.55 (br s, 1H), 10.89 (br s, 1H), 10.41
(br s, 1H), 7.93 (d, 1H, J ) 6.7 Hz), 7.69 (br s, 1H), 7.63 (br s,
1H), 7.33-7.41 (m, 1H), 6.82 (br s, 2H), 6.48 (d, 1H, J ) 6.7 Hz),
3.65 (s, 3H), 3.58 (s, 6H), 2.47 (s, 3H). LCMS (APCI, m/z) 407
(M + H+).
4-Methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-
pyrimidinyl}amino)benzenesulfonamide (5b). Prepared from 10
and 3-amino-4-methoxybenzenesulfonamide by the procedure
described in the preparation of 3, and the filtered product was further
purified by silica gel chromatography eluting with a hexanes/EtOAc
to yield 5b in 89% yield. 1H NMR (400 MHz): δ 12.28 (br s, 1H),
9.56 (br s, 1H), 8.72 (br s, 1H), 8.02 (d, 1H, J ) 5.7 Hz), 7.87 (br
s, 1H), 7.74 (br s, 1H), 7.55 (d, 1H, J ) 8.7 Hz), 7.43 (d, 1H, J )
8.0 Hz), 7.17 - 7.13 (m, 4H), 6.32 (d, 1H, J ) 5.9 Hz), 3.91 (s,
3H), 2.39 (s, 3H). LCMS (APCI, m/z) 424 (M - H+).
N4-Methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-[3,4,5-tris(methy-
loxy)phenyl]-2,4-pyrimidinediamine (11b). To a solution of
tert-butyl 6-[(2-chloro-4-pyrimidinyl)(methyl)amino]-3-methyl-1H-
indazole-1-carboxylate (0.25 g, 0.67 mmol) and 3,4,5-trimethoxya-
niline (0.14 g, 0.74 mmol) in iPrOH (6 mL) was added 3 drops of
conc HCl and the mixture heated to reflux for 16 h. The mixture
was cooled to room temperature, and the resulting precipitate was
collected via filtration and washed with iPrOH to yield 11b (0.16
1
g, 52% yield) as a white solid. H NMR (400 MHz): δ 12.67 (br
N2-[2-Methoxy-5-(ethylsulfonyl)phenyl]-N4-(3-methyl-1H-inda-
zol-6-yl)-2,4-pyrimidinediamine Hydrochloride (5c). Prepared from
10 and 5-ethylsulfonyl-2-methoxyaniline in 90% yield by the
procedure described in the preparation of 3. 1H NMR (400 MHz):
δ 12.42 (s, 1H), 10.60 (s, 1H), 8.85 (d, J ) 2.2 Hz, 1H), 8.81 (d,
J ) 5.8 Hz, 1H), 7.92 (bs, 1H), 7.82 (s, 1H), 7.60 (d, J ) 8.6 Hz,
1H), 7.55 (dd, J ) 8.5, 2.3 Hz, 1H), 7.28 (d, J ) 8.7 Hz, 1H), 7.21
(d, J ) 8.6 Hz, 1H), 6.39 (d, J ) 5.8 Hz, 1H), 3.96 (s, 3H), 3.07
(q, J ) 7.4 Hz, 2H), 2.50 (s, 3H), 1.03 (t, J ) 7.4 Hz, 3H). LCMS
(EI, m/z) 439 (M + H+).
s, 1 H), 9.04 (br s, 1 H), 7.75 (dd, J ) 7.5 Hz, 2 H), 7.35 (s, 1 H),
7.15 (s, 2 H), 6.96 (d, J ) 8.1 Hz, 1 H), 5.68 (d, J ) 7.1 Hz, 1 H),
3.65 (s, 6 H), 3.55 (s, 3 H), 3.46 (s, 3 H), 3.27 (s, 3 H). LCMS
(APCI, m/z) 421 (M + H). Anal. (C22H24N6O3 ·HCl·0.5H2O) C,
H, N, Cl.
3-({4-[Methyl(3-methyl-1H-indazol-6-yl)amino]-2-
pyrimidinyl}amino)benzenesulfonamide Hydrochloride (12a). To
a solution of tert-butyl 6-[(2-chloro-4-pyrimidinyl)(methyl)amino]-
3-methyl-1H-indazole-1-carboxylate (0.20 g, 0.54 mmol) and
3-aminobenzenesulfonamide (0.092 g, 0.54 mmol) in iPrOH (6 mL)
was added 4 drops of conc HCl and the mixture heated to reflux
for 16 h. The mixture was cooled to room temperature and diluted
with Et2O (6 mL). The resulting precipitate was collected via
filtration and washed with Et2O to yield 12a (0.21 g, 87% yield)
N2-[5-(Ethylsulfonyl)-2-methoxyphenyl]-N4-methyl-N4-(3-meth-
yl-1H-indazol-6-yl)-2,4-pyrimidinediamine (11a). To a solution of
10 (2.8 g, 11 mmol), triethylamine (1.5 mL, 11 mmol) and
4-dimethylaminopyridine (0.13 g, 1.1 mmol) in a mixture of MeCN
(14 mL) and DMF (50 mL) was added to di-tert-butyl dicarbonate
(2.36 g, 11 mmol) portion wise over 3 min. After stirring for 1 h,
the solution was diluted with water and extracted with Et2O (3 ×
40 mL). The combined extracts were dried over Na2SO4, filtered,
and concentrated in vacuo. The resulting residue was purified by
silica gel column chromatography eluting with CH2Cl2/EtOAc (9:
1) to give tert-butyl 6-[(2-chloro-4-pyrimidinyl)amino]-3-methyl-
1H-indazole-1-carboxylate (3.3 g, 85% yield). 1H NMR (400 MHz):
δ 10.35 (s, 1 H), 8.39 (d, J ) 1.3 Hz, 1 H), 8.23 (d, J ) 5.8 Hz,
1 H), 7.80 (d, J ) 8.6 Hz, 1 H), 7.55 (dd, J ) 8.6, 1.8 Hz, 1 H),
6.85 (d, J ) 5.8 Hz, 1 H), 2.50 (s, 3 H), 1.64 (s, 9 H). LCMS
(APCI, m/z) 374, 376 (M + H+). HPLC (method A): 99% (tR 9.5
min).
1
as an off-white solid. H NMR (300 MHz): δ 12.73 (br s, 1H),
9.54 (s, 1H), 8.55 (s, 1H), 7.86 (d, J ) 6.0 Hz, 1H), 7.78-7.81
(m, 2H), 7.40 (s, 1H), 7.33-7.34 (m, 2H), 7.25 (br s, 2H), 7.02 (d,
J ) 8.4 Hz, 1H), 5.82 (d, J ) 6.0 Hz, 1H), 3.51 (s, 3H), 2.50 (s,
3H). LCMS (APCI, m/z) 410 (M + H+).
3-({4-[(1,3-Dimethyl-1H-indazol-6-yl)(methyl)amino]-2-
pyrimidinyl}amino)benzenesulfonamide (12b) Hydrochloride. NaH
(0.33 g, 14 mmol) was added portion-wise to a solution of 10 (1.2
g, 4.6 mmol) in DMF (12 mL) and the reaction solution stirred at
room temperature for 15 min. Iodomethane (0.67 mL, 11 mmol)
was then added and the mixture was stirred for a further 30 min.
The reaction mixture was then diluted with water (100 mL) and
extracted with Et2O (100 mL). The organic layer was dried over
Na2SO4, filtered, and evaporated to yield a crude product that was
subjected to silica gel chromatography eluting with CH2Cl2/EtOAc
(6:4 v/v) to give N-(2-chloro-4-pyrimidinyl)-N,1,3-trimethyl-1H-
To a stirred solution of tert-butyl 6-[(2-chloro-4-pyrimidinyl)-
amino]-3-methyl-1H-indazole-1-carboxylate (3.3 g, 8.8 mmol) in
DMF (44 mL) was added NaH (0.23 g, 9.6 mmol) portion wise