3614 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
Traxler et al.
line (pH 10), and filtered. The crude product was washed with
methanol/water (1:1). Recrystallization from methanol/water
gave 0.9 g (68% yield) of the title compound 12 as colorless
crystals of mp 223-224 °C dec; ESIMS m/z 367 (M + H)+; 1H
NMR (DMSO-d6) δ 12.75 (s, pyrazole-NH), 9.04 (s, 1H), 8.49
(s, NH), 8.33 (s, pyrimidine H), 7.93 (m, aromat H), 7.66 (d,
aromat H), 7.51 (d, 2 aromat H), 7.41 (t, aromat H), 7.18 (d,
3-(Ben zyla m in o)-4-((3-ch lor op h en yl)a m in o)-1H-p yr a -
zolo[3,4-d ]p yr im id in e (19): from 79.2 g (295 mmol) of 40e
and 60.6 g (369 mmol) of 3-chloroaniline hydrochloride in 700
mL of methanol (reflux/22 h) was obtained crystalline 19 (73%
1
yield): mp 216-217 °C; H NMR (DMSO-d6) δ 8.94 (s, NH),
8.25 (s, pyrimidine H), 7.91 (m, aromat H), 7.65 (d, aromat
H), 7.5-7.3 (m, 5 aromat H), 7.24 (m, aromat H), 7.15 (d,
aromat H), 6.91 (t, NH), 4.50 (d, CH2). Anal. (C18H15ClN6) C,
H, N,Cl.
aromat H), 6.90 (d, 2 aromat H), 3.73 (s, OCH3). Anal. (C18H15
-
ClN6O‚0.35H2O) C, H, N, H2O.
3-((3-Ch lor oben zyl)a m in o)-4-((3-ch lor op h en yl)a m in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (20): from 40f; mp 161-163
°C; FABMS m/z 386 (M + H)+ (C18H14Cl2N6); 1H NMR (DMSO-
d6, 80 °C) δ 12.38 (s, HN-1), 8.92 (s, NH), 8.27 (s, pyrimidine
H), 7.94 (t, aromat H), 7.68 (m, aromat H), 7.50 (s, aromat H),
7.45-7.25 (m, 4 aromat H), 7.17 (m, aromat H), 6.98 (t, NH),
4.53 (d, CH2).
3-((3-Meth oxyben zyl)am in o)-4-((3-ch lor oph en yl)am in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (21): from 40g and 3-chlo-
roaniline hydrochloride (ethanol, reflux/36 h, 70% yield);
colorless crystals of mp 194-195 °C; ESIMS m/z 381 (M + H)+;
1H NMR (DMSO-d6) δ 12.38 (s, pyrazole-NH), 8.95 (s, NH),
8.26 (s, pyrimidine H), 7.92 (m, aromat H), 7.67 (d, aromat
H), 7.41 (t, aromat H), 6.80-7.44 (m, 5 aromat H, NH), 4.49
(d, CH2), 3.75 (s, OCH3). Anal. (C19H17ClN6O) C, H, N.
3-((4-Meth oxyben zyl)am in o)-4-((3-ch lor oph en yl)am in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (22): from 40h and 3-chlo-
roaniline hydrochloride (ethanol, reflux/16 h, 75% yield);
colorless crystals of mp 222-223 °C; ESIMS m/z 381 (M + H)+;
1H NMR (DMSO-d6) δ 12.37 (s, pyrazole-NH), 8.94 (s, NH),
8.26 (s, pyrimidine H), 7.90 (m, aromat H), 7.66 (d, aromat
H), 7.34-7.44 (m, 3 aromat H), 7.16 (d, aromat H), 6.90 (d, 2
aromat H), 6.82 (t, NH), 4.43 (d, CH2), 3.73 (s, OCH3). Anal.
(C19H17ClN6O) C, H, N.
3-((4-Hydr oxyph en yl)am in o)-4-((3-ch lor oph en yl)am in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (13). The methyl ether 12
was cleaved by heating a mixture of 0.5 g (1.36 mmol) of 12
and 0.87 g (6.55 mmol) of anhydrous aluminum chloride in 15
mL of benzene with the exclusion of air and moisture at 80 °C
for 9 h. The benzene phase was removed and the residue
partitioned between ethyl acetate and water. The organic
phase was washed with water and saturated sodium hydrogen
carbonate solution, dried, and evaporated to dryness. The
residue was purified by flash chromatography on silica gel
using methylene chloride/methanol mixtures (50:1 and 20:1).
The product-containing fractions were combined and concen-
trated to a volume of ca. 10 mL, whereas the product
crystallized. The product was filtered off and washed with
diethyl ether, yielding colorless crystals of 13: mp >260 °C;
1
ESIMS m/z 353 (M + H)+; H NMR (DMSO-d6) δ 12.68 (br s,
pyrazole-NH), 8.94 (br s, NH and OH), 8.36 (s, NH), 8.32 (s,
pyrimidine H), 7.93 (s, aromat H), 7.62 (d, aromat H), 7.34-
7.42 (m, 3 aromat H), 7.16 (d, aromat H), 6.70 (d, 2 aromat
H). Anal. (C17H13Cl N6O) C, H, N.
Using the same method, the following were prepared.
3-((3-Meth oxyph en yl)am in o)-4-((3-ch lor oph en yl)am in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (14). A suspension of 1.38
g (4.85 mmol) of 3-((3-methoxyphenyl)amino)-4-cyano-5-(((di-
methylamino)methylene)amino)pyrazole (40c) and 0.915 g
(5.58 mmol) of 3-chloroaniline hydrochloride in 20 mL of
methanol was heated under reflux for 17 h. The resultant
solution was evaporated to dryness and the residue crystallized
from methanol/water and from methanol to give 0.91 g (51.1%
3-(4-Met h oxyp h en yl)-4-((3-ch lor op h en yl)a m in o)-1H -
p yr a zolo[3,4-d ]p yr im id in e (25): from 48a and 3-chloro-
aniline hydrochloride (methanol, reflux/18 h, 77% yield);
colorless crystals of mp 268-269 °C; FABMS m/z 352 (M +
1
H)+; H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.44 (s, 1H), 7.93 (s,
1
yield) of 14: mp 202-203 °C; ESIMS m/z 367 (M + H)+; H
aromat H), 7.73 (d, 2H), 7.47 (m, aromat H), 7.36 (t, aromat
H), 7.13 (m, 3H), 3.85 (s, CH3). Anal. (C18H14ClN5O) C, H,
N,Cl.
NMR (DMSO-d6) δ 12.94 (s, pyrazole-NH), 9.07 (broad s, NH),
8.72 (s, NH), 8.36 (s, pyrimidine H), 7.95 (m, aromat H), 7.65
(d, aromat H), 7.43 (t, aromat H), 7.07-7.23 (m, 4 aromat H),
6.45-6.51 (m, aromat H), 3.76 (s, OCH3). Anal. (C18H15Cl
N6O) C, H, N.
3-(4-Hyd r oxyp h en yl)-4-((3-ch lor op h en yl)a m in o)p yr a -
zolo[3,4-d ]p yr im id in e (26): from ether cleavage of 25;
1
FABMS m/z 336 (M - H)+ (C17H12ClN5O); H NMR (DMSO-
d6, 80 °C) δ 13.7 (sb, HN), 9.8 (sb, OH), 8.46 (s, pyrimidine H),
8.38 (sb, NH), 7.90 (s, aromat H), 7.57 (d, 2 aromat H), 7.44
(d, aromat H), 7.33 (t, aromat H), 7.190 (d, aromat H), 6.93
(d, 2 aromat H).
3-((3-Hydr oxyph en yl)am in o)-4-((3-ch lor oph en yl)am in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (15). Cleavage of the methyl
ether 14 as described above gave colorless crystals of 15: mp
1
265-266 °C; ESIMS m/z 353 (M + H)+; H NMR (DMSO-d6)
3-(3-Nitr op h en yl)-4-((3-ch lor op h en yl)a m in o)-1H-p yr a -
zolo[3,4-d ]p yr im id in e (27): from 48b and 3-chloroaniline
hydrochloride (methanol, reflux/17 h, 85% yield); colorless
crystals of mp 331-333 °C; FABMS m/z 367 (M + H)+; 1H
NMR (DMSO-d6) δ 14.15 (s, NH), 9.00 (s, NH), 8.52 (s,
pyrimidine H), 8.52 (m, aromat H), 8.29 (ddd, aromat H), 8.19
(ddd, aromat H), 7.80 (t, aromat H), 7.78 (t, aromat H), 7.46
(ddd, aromat H), 7.29 (t, aromat H), 7.07 (ddd, aromat H).
Anal. (C17H11N6ClO2) C, H, N,Cl.
3-(3-Am in oph en yl)-4-((3-ch lor oph en yl)am in o)-1H-pyr a-
zolo[3,4-d ]p yr im id in e (28). Hydrogenation of 3.44 g (9.38
mmol) of 27 in 300 mL of THF and 10 mL of methanol in the
presence of 3 g of Raney nickel, separation of the catalyst,
partial concentration, and precipitation with diethyl ether gave
amorphous 28 (78% yield) as colorless crystals of mp 264-
266 °C: 1H NMR (DMSO-d6) δ 8.51 (s, pyrimidine H), 8.22 (s,
NH), 8.00 (m, aromat H), 7.44 (d, aromat H), 7.37 (t, aromat
H), 7.24 (t, aromat H), 7.13 (d, aromat H), 6.98 (s, aromat H),
6.87 (d, aromat H), 6.71 (d, aromat H), 5.43 (s, NH2); MS m/z
336 (M)+ (C17H13ClN6).
δ 12.92 (s, pyrazole-NH), 9.24 (s, OH), 8.99 (broad s, NH), 8.60
(s, NH), 8.36 (s, pyrimidine H), 7.93 (m, aromat H), 7.62 (d,
aromat H), 7.41 (t, aromat H), 7.18, (d, aromat H), 7.02-7.10
(m, 2 aromat H), 6.89 (d, aromat H) 6.27-6.35 (m, aromat H).
Anal. (C17H13ClN6O) C, H, N.
3-((4-(Dim e t h yla m in o)p h e n yl)a m in o)-4-((3-ch lor o-
p h en yl)a m in o)-1H-p yr a zolo[3,4-d ]p yr im id in e (18): from
5 g (16.8 mmol) of 3-((4-(dimethylamino)phenyl)amino)-4-
cyano-5-(((dimethylamino)methylene)amino)pyrazole (40d ), 3.3
g (20.1 mmol) of 3-chloroaniline hydrochloride, and 40 mL of
DMF (heating for 8 h at 130 °C). The reaction mixture was
then cooled to room temperature, water was added dropwise,
and the reaction mixture was filtered. The residue was
dissolved in ca. 20 mL of DMF. After precipitation with water,
followed by recrystallization from DMF/water, the resulting
crystals were suspended in 10 mL of water. Then 6 mL of 1
N hydrochloric acid was added, and the mixture was heated
briefly to reflux and filtered. A 3 mL portion of 2 N sodium
hydroxide solution was added to the filtrate. The crystalline
precipitate was filtered off, washed with water, and dried,
yielding the title compound 18 (1.87 g, 28.6% yield) as colorless
crystals of mp 250-255 °C dec: ESIMS m/z 380 (M + H)+; 1H
NMR (DMSO-d6) δ 12.69 (s, pyrazole-NH), 8.90 (s, NH), 8.33
(s, NH), 8.31 (s, pyrimidine H), 7.87 (m, aromat H), 7.62 (d,
aromat H), 7.37-7.43 (m, 3 aromat H), 7.16 (d, aromat H),
3-(4-(BOC-a m in o)p h en yl)-4-((3-ch lor op h en yl)a m in o)-
1H-p yr a zolo[3,4-d ]p yr im id in e (29): from 48e and 3-chlo-
roaniline hydrochloride (methanol, reflux/17 h, 63% yield); mp
1
165-168 °C dec; H NMR (DMSO-d6) δ 9.6 (s, NH), 8.50 (s,
pyrimidine H), 8.42 (s, NH), 7.93 (sb, aromat H), 7.67 (AB, 4
aromat H), 7.50 (d, aromat H), 7.37 (t, aromat H), 7.13 (d,
aromat H), 1.51 (s, t-Bu); MS m/z 436 (M)+ (C22H21ClN6O2).
6.74 (d, 2 aromat H), 2.82 (s, N(CH3)2). Anal. (C19H18
-
ClN7‚0.5H2O) C, H, N, H2O.