1642 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 8
Dumaˆıtre and Dodic
were filtered, washed with water, and dried. Recrystallization
from ethanol provided 46 as white crystals (300 mg, 54%): mp
300 °C; IR (KBr) 3307-3427 (NH, NH2), 1701, 1668 cm-1 (CO);
1H-NMR (DMSO) δ 11.65 (s, 1H, NH), 8.55 (s, 1H, NH), 7.8
(sd, 1H, Ar), 7.55 (dd, 1H, Ar), 7.05 (d, 1H, Ar), 5.8 (s, 2H,
NH2), 4 (t, 2H, OCH2), 3.85 (s, 3H, NCH3), 2.45 (s, 3H, CH3),
1.7 (m, 2H, CH2), 0.95 (t, 3H, CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-th iou r eid op h en yl)-1,5-d i-
h yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (47). A mixture of
potassium thiocyanate (2 g, 20.5 mmol) and 34 (500 mg, 1.5
mmol) in water (5 mL) and acetic acid (5 mL) was heated at
reflux with stirring for 3 h. The mixture was then diluted with
water, and the crystals that formed were filtered, washed with
water and ethanol, and dried. Recrystallization from dimeth-
ylformamide afforded 47 as white crystals (240 mg, 41%): mp
290 °C; 1H-NMR (DMSO) δ 11.7 (s, 1H, NH), 9.65 (s, 1H, NH),
7.65 (d, 1H, Ar), 7.5 (dd, 1H, Ar), 7.1 (d, 1H, Ar), 4H (t, 2H,
OCH2), 3.8 (s, 3H, NCH3), 2.4 (s, 3H, CH3), 1.7 (m, 2H, CH2),
0.95 (t, 3H, CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-((4-flu or op h en yl)u r eid o)-
p h en yl)-1,5-d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (51).
4-Fluorophenyl isocyanate (0.15 mL, 1.3 mmol) was added to
a solution of 34 (330 mg, 1 mmol) in THF (40 mL). Crystal-
lization occurred after a few minutes, and the mixture was
stirred for 30 min at room temperature. The crystals were
collected by filtration, washed with ether, and dried. Recrys-
tallization from THF gave 51 as white crystals (200 mg,
44%): mp 280 °C; IR (KBr) 3301 (NH), 1702, 1668 cm-1 (CO);
1H-NMR (DMSO) δ 11.65 (s, 1H, NH), 8.65 (d, 2H, Ar), 7.85
(sd, 1H, Ar), 7.55 (dd, 1H, Ar), 7.4 (m, 2H, NH), 7.1 (m, 3H,
Ar), 4 (t, 2H, OCH2), 3.8 (s, 3H, NCH3), 2.4 (s, 3H, CH3), 1.7
(m, 2H, CH2), 0.95 (t, 3H, CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-(d im eth yla m in o)p h en yl)-
1,5-d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (36). Form-
aldehyde solution (3 mL, 35%) was added to a solution of 34
(0.5 g, 1.52 mmol) in formic acid (3 mL), and the reaction
mixture was heated overnight at 80 °C. The resultant solution
was then poured into water and neutralized with dilute NaOH
and extracted with CH2Cl2. The organic extract was washed
with water, dried (Na2SO4), and concentrated to give a yellow
oil that was purified by chromatography on silica gel 60 (CH2-
Cl2-MeOH, 95:5). Recrystallization from ethanol gave 36 as
white crystals (125 mg, 24%): mp 180 °C; IR (KBr) 3287 (NH),
1689 cm-1 (CO); 1H-NMR (CDCl3) δ 11.2 (s, 1H, NH), 7.4 (sd,
1H, Ar), 6.95 (m, 2H, Ar), 4.1 (t, 2H, OCH2), 3.95 (s, 3H, NCH3),
3 (s, 6H, N(CH3)2), 2.6 (s, 3H, CH3), 1.95 (m, 2H, CH2), 1.15 (t,
3H, CH3).
1-E t h yl-3-m et h yl-6-(2-p r op oxy-5-(4-m et h ylt h ia zol-2-
yl)ph en yl)-1,5-dih ydr opyr azolo[3,4-d]pyr im idin -4-on e (59).
A mixture of 26 (450 mg, 1.2 mmol) and chloroacetone (0.2
mL, 2.4 mmol) in ethanol (30 mL) was heated under reflux
for 16 h. After concentration, the residue was treated with
water and extracted with CH2Cl2. The organic extract was
washed with water, dried (Na2SO4), and concentrated. The
residue was purified by chromatography on silica gel 60 (CH2-
Cl2-MeOH, 95:5). After recrystallization from 2-propanol, 59
was obtained as white crystals (160 mg, 32%): mp 218 °C; IR
1
(KBr) 3103-3314 (NH), 1706 cm-1 (CO); H-NMR (DMSO) δ
11.85 (s, 1H, NH), 8.1 (sd, 1H, Ar), 7.95 (dd, 1H, Ar), 7.25 (s,
1H, Ar), 7.2 (d, 1H, Ar), 4.2 (q, 2H, NCH2), 4 (t, 2H, OCH2),
2.4 (s, 3H, CH3), 2.3 (s, 3H, CH3), 1.65 (m, 2H, CH2), 1.3 (t,
3H, CH3), 0.85 (t, 3H, CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-(th ia zol-2-yl)p h en yl)-1,5-
d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (57). A mixture
of 1,3-dimethyl-6-(2-propoxy-5-thiocarbamoylphenyl)-1,5-dihy-
dropyrazolo[3,4-d]pyrimidin-4-one (350 mg, 0.98 mmol), potas-
sium carbonate (406 mg, 2.94 mmol), and bromoacetaldehyde
(240 mg, 1.96 mmol) in DMF (20 mL) was stirred at room
temperature overnight. After concentration under reduced
pressure, the residue was treated with water and extracted
with CH2Cl2. The organic extract was dried (Na2SO4) and
evaporated to dryness.
A mixture of the above product and trifluoroacetic anhydride
(1 mL) in CH2Cl2 (20 mL) was stirred at room temperature
for 1 h. After dilution with CH2Cl2, the organic phase was
washed with water, dried (Na2SO4), and concentrated to leave
an oil which was purified by chromatography on silica gel 60
(CH2Cl2-MeOH, 95:5). After crystallization from H2O/DMF,
57 was obtained as cream crystals (0.12 g, 32%): mp 209 °C;
IR (KBr) 3520, 3319 (NH), 1697.5 cm-1 (CO); 1H-NMR (DMSO)
δ 11.8 (s, 1H, NH), 8.15 (sd, 1H, Ar), 8 (dd, 1H, Ar), 7.8 (d,
1H, Ar), 7.65 (d, 1H, Ar), 7.2 (d, 1H, Ar), 4 (t 2H, OCH2), 3.75
(s, 3H, NCH3), 2.35 (s, 3H, CH3), 1.65 (m, 2H, CH2), 0.9 (t, 3H,
CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-(2-p h en ylth ia zol-4-yl)p h e-
n yl)-1,5-d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (62). A
mixture of 27 (400 mg, 0.95 mmol) and thiobenzamide (130
mg, 0.95 mmol) in ethanol (50 mL) was heated under reflux
for 1 h. The solution was concentrated, treated with water,
and extracted with CH2Cl2. The organic extract was washed
with water, dried (Na2SO4), and concentrated to give a solid
which was purified by chromatography on silica gel 60 (CH2-
Cl2-MeOH, 95:5). Crystallization from methanol gave 62 as
white crystals (0.12 g, 28%): mp 200 °C; IR (KBr) 3318, 3083
1
(NH), 1700, 1683 cm-1 (CO); H-NMR (DMSO) δ 11.9 (s, 1H,
1-Eth yl-3-m eth yl-6-(5-cya n o-2-p r op oxyp h en yl)-1,5-d i-
h yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (25). A mixture of
24 (350 mg, 0.9 mmol), sodium cyanide (45 mg, 0.9 mmol), 18-
crown-6 (0.24 g, 0.9 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (0.52 g, 0.45 mmol) in THF (20 mL) and EtOH
(20 mL) was heated under reflux for 4 h. The reaction mixture
was evaporated to dryness, and the residue was diluted with
water and extracted with CH2Cl2. The organic extract was
dried (Na2SO4) and concentrated to give a solid that was
purified by chromatography on silica gel 60 (CH2Cl2-MeOH,
98:2). After crystallization from 2-propanol, 25 was obtained
as white crystals (0.14 g, 46%): mp 190 °C; IR (KBr) 3318
NH), 8.35 (sd, 1H, Ar), 8.2 (dd, 1H, Ar), 8.15 (s, 1H, ar), 8 (m,
2H, Ar), 7.5 (m, 3H, Ar), 7.25 (d, 1H, Ar), 4.1 (t, 2H, OCH2),
3.85 (s, 3H, NCH3), 2.4 (s, 3H, CH3), 1.75 (m, 2H, CH2), 0.95
(t, 3H, CH3).
1,3-Dim eth yl-6-(2-p r op oxy-5-(5-m eth ylth ien -2-yl)p h e-
n yl)-1,5-d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (56). A
solution of butyllithium in hexane (2.5 M, 21 mL, 52.5 mmol)
was added dropwise to a solution of 2-methylthiophene (5 g,
51 mmol) and TMEDA (5.82 g, 51 mmol) in anhydrous THF
(100 mL) under argon at room temperature, and the mixture
was heated at 80 °C for 2 h. After cooling to -70 °C,
trimethyltin chloride in THF (1 M, 60 mL, 60 mmol) was added
dropwise, and the reaction mixture was stirred at -70 °C for
4 h. After warming to room temperature, diethyl ether was
added and the organic layer washed with water. After drying
(Na2SO4) and concentration, 2-(trimethylstannyl)-5-methylth-
iophene was obtained as an oil (13.9 g) and used without
further purification.
A mixture of the above product (1.7 g), 1,3-dimethyl-6-(2-
propoxy-5-bromophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-
4-one (1 g, 2.65 mmol), and bis(triphenylphosphine)palladium-
(II) chloride (140 mg, 7 mol%) in THF (100 mL) was heated at
reflux with stirring for 16 h. After evaporation of the THF,
the mixture was chromatographed on silica gel 60 (CH2Cl2-
MeOH, 99:1). After crystallization from diisopropyl ether
containing 10% 2-propanol, 56 was obtained as white crystals
(140 mg, 13.5%): mp 178 °C; IR (KBr) 3319 (NH), 1698 cm-1
(CO); 1H-NMR (CDCl3) δ 10.9 (s, 1H, NH), 8.6 (sd, 1H, Ar),
1
(NH), 2232 (CN), 1701 cm-1 (CO); H-NMR (DMSO) δ 11.95
(s, 1H, NH), 8.05 (sd, 1H, Ar), 7.95 (dd, 1H, Ar), 7.3 (d, 1H,
Ar), 4.2 (q, 2H, NCH2), 4.1 (t, 2H, OCH2), 2.4 (s, 3H, CH3), 1.7
(m, 2H, CH2), 1.35 (t, 3H, CH3), 0.9 (t, 3H, CH3).
1-Eth yl-3-m eth yl-6-(2-pr opoxy-5-th iocar bam oylph en yl)-
1,5-d ih yd r op yr a zolo[3,4-d ]p yr im id in -4-on e (26). A mix-
ture of 25 (850 mg, 2.5 mmol), 85% diethyl dithiophosphate
(1 mL, 6 mmol), and water (3 drops) was stirred at room
temperature for 24 h. By this time the mixture was homoge-
neous. It was taken up with water, and the precipitate was
filtered, washed with water, and dried. After crystallization
from methanol, 26 was obtained as yellow crystals (580 mg,
62.5%): mp 256 °C; IR (KBr) 3330, 3184 (NH, NH2), 1662 cm-1
(CO); 1H-NMR (DMSO) δ 11.8 (s, 1H, NH), 9.75, 9.45 (2s, 2H,
NH2), 8.2 (sd, 1H, Ar), 8.1 (dd, 1H, Ar), 7.15 (d, 1H, Ar), 4.25
(q, 2H, NCH2), 4.1 (t, 2H, OCH2), 2.4 (s, 3H, CH3), 1.7 (m, 2H,
CH2), 1.35 (t, 3H, CH3), 0.9 (t, 3H, CH3).