Journal of Medicinal Chemistry
ARTICLE
the pale yellow solid was filtered, washed with water, and recrystallized
from 95% ethanol (2.29 g, 67%). Mp: 247ꢀ248 ꢀC. 1H NMR: δ 3.36ꢀ
3.49 and 3.51ꢀ3.62 (2 m, 8H, 4CH2 morph.), 3.99ꢀ4.25 (m, 2H,
CH2N), 4.90ꢀ5.03 (m, 1H, CHO), 5.50 (d, 1H, OH disappears with
D2O), 7.03ꢀ7.24 (m, 5H Ar), 7.70 (s, 1H, H-3), 10.75 (br s, 1H, NH
disappears with D2O). IR cmꢀ1: 3380, 3168, 3113 (NH þ OH), 1702
(CO). MS: m/z 341 [Mþ1]þ. Anal.(C17H19N5O3) C, H, N.
The yellow crude oil was crystallized as a brown solid by adding absolute
ethanol and standing in a refrigerator (3.29 g, 75%). Mp: 106ꢀ107 ꢀC.
1H NMR: δ 2.81ꢀ3.12 (m, 4H, 2CH2N morph.), 3.18ꢀ3.81 (m, 4H,
CH2S þ CH2CH2S), 3.86ꢀ4.10 (m, 4H, 2CH2O morph.), 4.60ꢀ4.78
and 5.12ꢀ5.30 (2 m, 2H, CH2N), 5.36ꢀ5.50 (m, 1H, CHCl),
7.16ꢀ7.50 (m, 5H Ar), 8.00 (s, 1H, H-3). MS: m/z 438 [Mþ1]þ.
Anal. (C19H21N5Cl2OS) C, H, N, S.
General Procedure for the Synthesis of Compounds
15aꢀd. The appropriate amine (40 mmol) was added to a solution
of the 4-chloro derivative 14 (4.38 g, 10 mmol) in anhydrous toluene
(10 mL), and the mixture was stirred at room temperature for 24 h. The
organic phase was washed with water (2 ꢁ 10 mL), dried (MgSO4), and
concentrated under reduced pressure. The crude oil was crystallized by
adding diethyl ether.
General Procedure for the Synthesis of Compounds 15e,f.
The appropriate aniline (20 mmol) was added to a solution of the 4-chloro
derivative 14 (4.38 g, 10 mmol) in absolute ethanol (5 mL), and the mixture
was refluxed for 3ꢀ5 h. After cooling to room temperature, the solid was
filtered, washed with water, and recrystallized from absolute ethanol.
1-(2-Chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl)thio]-N-pro-
pyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine (15a). White solid (2.77 g,
60%). Mp: 86ꢀ87 ꢀC. 1H NMR: δ 0.95 (t, J = 7.2, 3H, CH3), 1.63 (sx,
J = 7.2, 2H, CH2CH3), 2.52 (t, J = 4.6, 4H, 2CH2N morph.), 2.62ꢀ2.78
(m, 2H, CH2CH2S), 3.10ꢀ3.33 (m, 2H, CH2S), 3.46 (q, J = 7.2, 2H,
CH2NH), 3.67 (t, J = 4.6, 4H, 2CH2O morph.), 4.53ꢀ4.67 and
4.74ꢀ4.80 (2 m, 2H, CH2N), 5.30 (br s, 1H, NH disappears with
D2O), 5.38ꢀ5.51 (m, 1H, CHCl), 7.12ꢀ7.42 (m, 5H Ar), 7.71 (s, 1H,
H-3). IR cmꢀ1: 3281 (NH). MS: m/z 461 [Mþ1]þ. Anal. (C22H29N6-
OClS) C, H, N, S.
Synthesis of 4-Chloro-1-(2-chloro-2-phenylethyl)-6-mor-
pholin-4-yl-1H-pyrazolo[3,4-d]pyrimidine (10). The Vilsmeier
complex, previously prepared from POCl3 (3.07 g, 20 mmol) and
anhydrous DMF (1.46 g, 20 mmol), was added to a suspension of
1-(2-hydroxy-2-phenylethyl)-6-morpholin-4-yl-1,5-dihydro-4H-pyra-
zolo[3,4-d]pyrimidin-4-one 9 (0.34 g, 1 mmol) in CHCl3 (10 mL). The
mixture was refluxed for 12 h. The solution was washed with 4 M NaOH
(2 ꢁ 20 mL), then with water (20 mL), dried (MgSO4), and concen-
trated under reduced pressure. The crude was purified by column
chromatography (Florisil, 100ꢀ200 mesh) using diethyl ether as the
eluant, to afford the pure product as a yellow oil, which was crystallized
as a white solid by adding a mixture of diethyl ether/petroleum ether (bp
40ꢀ60 ꢀC) (1:1) and standing in a refrigerator (0.25 g, 67%). Mp:
117ꢀ118 ꢀC. 1H NMR: δ 3.47ꢀ3.56 and 3.60ꢀ3.68 (2 m, 8H, 4CH2
morph.), 4.53ꢀ4.70 (m, 2H, CH2N), 5.40ꢀ5.50 (m, 1H, CHCl),
7.15ꢀ7.38 (m, 5H Ar), 7.73 (s, 1H, H-3). MS: m/z 378 [Mþ1]þ.
Anal. (C17H17N5Cl2O) C, H, N.
Synthesis of N-(3-Chlorophenyl)-1-(2-chloro-2-phenyle-
thyl)-6-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(11). A solution of 4-chloro-1-(2-chloro-2-phenylethyl)-6-morpholin-4-yl-
1H-pyrazolo[3,4-d]pyrimidine 10 (0.38 g, 1 mmol) and 3-chloroaniline
(0.50 g, 4 mmol) in absolute ethanol was refluxed for 5 h. After cooling, the
solvent was evaporated under reduced pressure, and the crude was treated
with water (20 mL), then extracted with CHCl3 (20 mL); the organic phase
was washed with water (20 mL), dried (MgSO4), and concentrated under
reduced pressure. The obtained oil was crystallized by adding a mixture of
diethyl ether/petroleum ether (bp 40ꢀ60 ꢀC) (1:1) and standing in a
refrigerator to afford a white solid, which was recrystallized from absolute
N-Benzyl-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl)-
thio]-1H-pyrazolo[3,4-d] pyrimidin-4-amine (15b). White solid (3.56
1
g, 70%). Mp: 124ꢀ125 ꢀC. H NMR: δ 2.50 (t, J = 4.4, 4H, 2CH2N
morph.), 2.64ꢀ2.81 (m, 2H, CH2CH2S), 3.10ꢀ3.38 (m, 2H, CH2S),
3.58ꢀ3.72 (m, 4H, 2CH2O morph.), 4.53ꢀ4.94 (m, 4H, CH2N þ
CH2Ar), 5.40ꢀ5.52 (m, 1H, CHCl), 7.12ꢀ7.42 (m, 10H Ar), 7.66 (s,
1H, H-3). IR cmꢀ1: 3197 (NH). MS: m/z 509 [Mþ1]þ. Anal.
(C26H29N6OClS) C, H, N, S.
1
ethanol (0.27 g, 57%). Mp: 168ꢀ170 ꢀC. H NMR: δ 3.45ꢀ3.54 and
3.59ꢀ3.66 (2 m, 8H, 4CH2 morph.), 4.51ꢀ4.68 (m, 2H, CH2N),
5.41ꢀ5.55 (m, 1H, CHCl), 7.00ꢀ7.56 (m, 10H, 9 Ar þ H-3). IR cmꢀ1
:
1-(2-Chloro-2-phenylethyl)-N-(4-fluorobenzyl)-6-[(2-morpholin-4-
ylethyl)thio]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15c). White solid
(3.16 g, 60%). Mp: 86ꢀ87 ꢀC. 1H NMR: δ 2.55 (t, J = 4.6, 4H, 2CH2N
morph.), 2.70ꢀ2.83 (m, 2H, CH2CH2S), 3.00ꢀ3.29 (m, 2H, CH2S),
3.55ꢀ3.68 (m, 4H, 2CH2O morph.), 4.55ꢀ5.00 (m, 4H, CH2N þ
CH2Ar), 5.43ꢀ5.54 (m, 1H, CHCl), 7.07ꢀ7.39 (m, 9H Ar), 7.67 (s, 1H,
H-3). IR cmꢀ1: 3280 (NH). MS: m/z 527 [Mþ1]þ. Anal. (C26H28N6-
OClFS) C, H, N, S.
3356 (NH). MS: m/z 469 [Mþ1]þ. Anal. (C23H22N6Cl2O) C, H, N.
Synthesis of 1-(2-Hydroxy-2-phenylethyl)-6-[(2-morpho-
lin-4-ylethyl)thio]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-
4-one (13). NaOH (0.4 g, 10 mmol) dissolved in absolute ethanol
(5 mL) and 4-(2-chloroethyl)morpholine (2.24 g, 15 mmol) were added
to a solution of 1-(2-hydroxy-2-phenylethyl)-6-thioxo-1,5,6,7-tetrahydro-
4H-pyrazolo[3,4-d]pyrimidin-4-one 12 (2.88 g, 10 mmol) in anhydrous
DMF (5 mL). The solution was refluxed for 6 h. After cooling, the solvent
was evaporated under reduced pressure, and the crude was poured into
cold water. The white solid was filtered, washed with water, and
recrystallized from absolute ethanol (2.53 g, 63%). Mp: 201ꢀ202 ꢀC.
1H NMR: δ 2.36ꢀ2.50 (m, 4H, 2CH2N morph.), 3.10ꢀ3.40 (m, 4H,
CH2S þ CH2CH2S), 3.45ꢀ3.56 (m, 4H, 2CH2O morph.), 4.13ꢀ4.40
(m, 2H, CH2N), 4.83ꢀ5.06 (m, 1H, CHO), 5.55 (d, 1H, OH disappears
1-(2-Chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl)thio]-N-(2-
phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15d). White so-
lid (3.40 g, 65%). Mp: 122ꢀ123 ꢀC. 1H NMR: δ 2.51 (t, J = 4.6, 4H,
2CH2N morph.), 2.72 (t, J = 7.6, 2H, CH2CH2S), 2.91 (t, J = 6.4, 2H,
CH2Ar), 3.10ꢀ3.36 (m, 2H, CH2S), 3.66 (t, J = 4.6, 4H, 2CH2O
morph.), 3.79 (q, J = 6.4, 2H, CH2NH), 4.54ꢀ4.70 and 4.75ꢀ4.90 (2 m,
2H, CH2N), 5.30 (br s, 1H, NH disappears with D2O), 5.40ꢀ5.52 (m,
1H, CHCl), 7.10ꢀ7.41 (m, 10H Ar), 7.63 (s, 1H, H-3). IR cmꢀ1: 3251
(NH). MS: m/z 523 [Mþ1]þ. Anal. (C27H31N6OClS) C, H, N, S.
N-(3-Chlorophenyl)-1-(2-chloro-2-phenylethyl)-6-[(2-morpholin-
4-ylethyl)thio]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (15e). White so-
lid (3.70 g, 70%). Mp: 223ꢀ224 ꢀC. 1H NMR: δ 2.88ꢀ4.00 (m, 12H,
4CH2 morph. þ CH2CH2S þ CH2S), 4.65ꢀ4.83 and 5.00ꢀ5.18 (2 m,
2H, CH2N), 5.53ꢀ5.68 (m, 1H, CHCl), 7.00ꢀ8.40 (m, 10H, 9Ar þH-
3), 11.50 (br s, 1H, NH disappears with D2O). IR cmꢀ1: 3262 (NH).
MS: m/z 529 [Mþ1]þ. Anal. (C25H26N6OCl2S) C, H, N, S.
1-(2-Chloro-2-phenylethyl)-6-[(2-morpholin-4-ylethyl)thio]-N-
phenyl-1H-pyrazolo[3,4-d] pyrimidin-4-amine (15f). White solid (3.37
with D2O), 7.10ꢀ7.28 (m, 5H Ar), 7.89 (s, 1H, H-3). IR cmꢀ1
:
3100ꢀ2850 (NH þ OH), 1664 (CO). MS: m/z 401 [Mþ1]þ. Anal.
(C19H23N5O3S) C, H, N, S.
Synthesis of 4-Chloro-1-(2-chloro-2-phenylethyl)-6-[(2-
morpholin-4-ylethyl)thio]-1H-pyrazolo[3,4-d]pyrimidine
(14). The Vilsmeier complex, previously prepared from POCl3 (12.27 g,
80 mmol) and anhydrous DMF (5.85 g, 80 mmol) was added to a
suspension of 1-(2-hydroxy-2-phenylethyl)-6-[(2-morpholin-4-ylethyl)-
thio]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 13 (4.01 g,
10 mmol) in CHCl3 (50 mL). The mixture was refluxed for 8 h. The
solution was washed with 4 M NaOH (2ꢁ 20 mL), then with water
(20 mL), dried (MgSO4), and concentrated under reduced pressure.
1
g, 68%). Mp: 227ꢀ228 ꢀC. H NMR: δ 2.85ꢀ4.00 (m, 12H, 4CH2
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dx.doi.org/10.1021/jm1012819 |J. Med. Chem. 2011, 54, 2610–2626