2-Substituted Aminopyrido[2,3-d]pyrimidin-7(8H)-ones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17 3289
(two times), dried (K2CO3), and concentrated. Crystallization
of the residue from Et2O gave 0.10 g (47%) of 30: mp 140-
142 °C; 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.38 (m, 6H), 3.42
(m, 2H), 3.59 (m, 7H), 7.42 (t, J ) 8 Hz, 1H), 7.58 (d, J ) 8
Hz, 2H), 7.78 (s, 1H), 7.95 and 8.05 (2m, 1H), 8.64 and 8.70 (2
s, 1H); CIMS m/z 448 (M+). Anal. (C21H23Cl2N4O2) C, H, N.
on e (63). A stirred mixture of 0.155 g (0.40 mmol) of sulfone
14a , 0.167 g (0.80 mmol) of 4-(2-diethylaminoethoxy)aniline,26
and 1 mL of (2-methoxyethyl)ether was heated at 150 °C for
20 min. The resultant solution was cooled to 100 °C and then
treated dropwise with H2O until it was slightly turbid. After
the mixture was allowed to stand, crystallization occurred. The
solids were collected, washed successively with Et2O and H2O,
and dried to leave 0.11 g of crude product that was purified
over SiO2 chromatography eluting with CHCl3, EtOAc, and
finally 10% MeOH-CHCl3. Pure product fractions were
concentrated to give an amorphous solid that was dissolved
in EtOAc. After the mixture was allowed to stand, the
precipitated solids were collected and washed sparingly with
EtOAc and Et2O to leave 0.042 g (21%) of 63: mp 141-143
°C; 1H NMR (DMSO-d6) δ 0.98 (t, J ) 7 Hz, 6H), 2.55 (m, 4H),
2.76 (m, 2H), 3.64 (s, 3H), 4.00 (m, 2H), 6.94 (d, J ) 9 Hz,
2H), 7.45 (t, J ) 8 Hz, 1H), 7.58 (d, J ) 8 Hz, 2H), 7.71 (d, J
) 8 Hz, 2H), 7.88 (s, 1H), 8.80 (s, 1H), 10.11 (s, 1H); CIMS
m/z 512 (M+). Anal. (C26H27Cl2N5O2) C, H, N.
Meth od M. [6-(2,6-Dich lor op h en yl)-7-im in o-8-m eth yl-
7,8-dih ydr opyr ido[2,3-d]pyr im idin -2-yl]-[4-(2-dieth ylam i-
n oeth oxy)p h en yl]a m in e (18). According to Method H, a
solution of 0.50 g (1.9 mmol) of 3-phenyl-2-(phenylsulfonyl)-
oxaziridine25 and 0.54 g (1.5 mmol) of imine 10a in 15 mL of
CHCl3 was kept at room temperature overnight. The solution
was purified by SiO2 column chromatography with successive
elution with CHCl3, EtOAc, and finally with 1:20 MeOH-
CHCl3 to obtain the fractions containing sulfoxide intermediate
17. This sulfoxide (0.4 g; 73%) was used directly in the next
step. A mixture of 0.21 g (0.6 mmol) of sulfoxide 17 and 0.25
g (1.1 mmol) of 4-(2-diethylaminoethoxy)aniline26 was heated
at 160 °C for 5 min. The cooled mixture was dissolved in 1
mL of hot EtOAc. After this mixture was cooled, the precipi-
tated solids were collected and washed with EtOAc and Et2O
to leave 0.05 g (17%) of 18: mp 145-147 °C; 1H NMR (DMSO-
d6) δ 0.98 (t, J ) 7 Hz, 6H), 2.55 (m, 2H), 2.75 (t, J ) 6 Hz,
2H), 3.63 (s, 3H), 4.00 (t, J ) 7 Hz, 2H), 6.62 (br s, 1H), 6.92
(d, J ) 9 Hz, 2H), 7.27 (s, 1H), 7.55 (m, 1H), 7.65 (m, 2H),
8.46 (s, 1H), 9.79 (br s, 1H); CIMS m/z 511 (M+). Anal.
(C26H28Cl2N6O‚0.5H2O) C, H, N.
2-Cycloh exyla m in o-6-(2,6-d ich lor op h en yl)-8-m et h yl-
8H-p yr id o[2,3-d ]p yr im id in -7-on e (25). A mixture of 0.10
g (0.26 mmol) of sulfone 14a and 0.30 g (3.0 mmol) of
cyclohexylamine was heated at reflux for 2 min and then
concentrated at reduced pressure. The remaining gum was
crystallized from 1:1 EtOAc-petroleum ether to leave 0.09 g
(86%) of crude 25. Recrystallization from EtOAc gave 0.048
g of pure product 25: mp 242-244 °C; 1H NMR (DMSO-d6) δ
1.10-1.40 (m, 5H), 1.55-1.99 (m, 5H), 3.55 and 3.58 (2s, 3H),
3.85 (br m, 1H), 7.45 (t, J ) 8 Hz, 1H), 7.55 (d, J ) 8 Hz, 2H),
7.77 (s, 1H), 7.82 and 7.95 (2 d, J ) 10 Hz, 1H), 8.64 and 8.66
(2s, 1H); CIMS m/z 403 (M+). Anal. (C20H20Cl2N4O) C, H, N.
Meth od N. 6-(2,6-Dich lor op h en yl)-2-[4-(2-d ieth yla m i-
n oet h oxy)p h en yla m in o]-8-m et h yl-8H -p yr id o[2,3-d ]p y-
r im id in -7-on e, Dih yd r och lor id e (63). A stirred mixture
of 25.6 g (0.067 mol) of sulfone 14a , 24.5 g (0.118 mol) of 4-(2-
diethylaminoethoxy)aniline,26 and 125 mL of glacial HOAc was
heated at reflux for 15 min, and then the resultant solution
1
was concentrated to ca. /2 volume. The viscous residue was
diluted with 500 mL of H2O, and then the solution was treated
carefully with excess saturated aqueous NaHCO3 to precipitate
a tacky yellow solid. The suspension was diluted with EtOAc
(150 mL), and then the organic phase was seeded with 63 base
to induce crystallization. The biphasic suspension was filtered,
and the cake was washed well with H2O and then petroleum
ether. The damp cake was stirred in 500 mL of CH2Cl2, and
the resultant suspension was filtered to collect the 2-hydroxy
impurity. The filtrate was dried (K2CO3) and concentrated to
give a gum that was dissolved in 2 L of boiling 2-propanol.
The solution was diluted with 700 mL of saturated 2-propan-
olic HCl. Voluminous yellow crystals of 63 dihydrochloride
slowly separated. The mixture was cooled, and the solids were
collected and washed successively with 200 mL of 2-propanol
and then 100 mL of Et2O to leave 21.2 g (54%) of 63 as the
6-(2,6-Dich lor op h en yl)-8-m et h yl-2-p h en yla m in o-8H -
p yr id o[2,3-d ]p yr im id in -7-on e (38). (a ) F r om Su lfoxid e
13. A solution of 0.11 g (0.3 mmol) of sulfoxide 13 and 0.25 g
(2.7 mmol) of aniline was heated at 184 °C for 3 min. Most of
the excess aniline was evaporated at reduced pressure, and
the remaining gum was dissolved in 1 mL of hot EtOAc. After
the mixture was cooled, the precipitated solids were collected
and washed successively with EtOAc and Et2O to leave 0.07 g
1
dihydrochloride salt: mp 240-245 °C; H NMR (DMSO-d6) δ
1.25 (m, 6H), 3.15-3.25 (m, 4H), 3.50 (m, 2H), 3.65 (s, 3H),
4.35 (m, 2H), 7.05 (d, J ) 9 Hz, 2H), 7.45 (t, 1H), 7.59 (d, J )
8 Hz, 2H), 7.76 (d, J ) 8 Hz, 2H), 7.89 (s, 1H), 8.82 (s, 1H),
10.20 (br d, 2H); CIMS m/z 512 (M+). Anal. (C26H27Cl2N5O2‚
2HCl‚0.5H2O) C, H, N.
1
(57%) of 38: mp 247-249 °C; H NMR (DMSO-d6) δ 3.68 (s,
Meth od O. 6-(2,6-Dich lor oph en yl)-8-2-(4-h ydr oxyph en -
yla m in o)-8-m eth yl-8H-p yr id o[2,3-d ]p yr im id in -7-on e (51).
A stirred mixture of 0.50 g (1.17 mmol) of 49, 5 mL of
concentrated (48%) HBr, and 10 mL of propanoic acid was
heated at reflux for 3 h. After the mixture was cooled, crystals
formed, and these were collected to give 0.51 g of the hydro-
bromide salt. The salt was dissolved in 40 mL of MeOH, and
the solution was neutralized with 3 mL of saturated aqueous
NaHCO3 and then treated with H2O until it was slightly
turbid. After the mixture was allowed to stand, a precipitate
formed that was collected and washed well with H2O to leave
0.38 g (92%) of the product. Dissolution of this in 30% MeOH-
CH2Cl2 and concentration until crystallization commenced
gave pure 51: mp 289-291 °C; 1H NMR (DMSO-d6) δ 3.62 (s,
3H), 6.75 (d, J ) 9 Hz, 2H), 7.45 (t, J ) 8 Hz, 1H), 7.59 (d, J
) 8 Hz, 4H), 7.86 (s, 1H), 8.77 (s, 1H), 9.23 (s, 1H), 9.99 (br s,
1H); CIMS m/z 413 (M+). Anal. (C20H14Cl2N4O2) C, H, N.
Meth od P . 6-(2,6-Dich lor oph en yl)-2-[3-(2-dieth ylam in o-
eth oxy)p h en yla m in o]-8-m eth yl-8H-p yr id o[2,3-d ]p yr im -
id in -7-on e, Dih yd r och lor id e (62). To a mixture of 5.60 g
(13.6 mmol) of 50, 1.90 g (16.3 mmol) of N,N-diethylethanol-
amine, and 4.26 g (16.3 mmol) of triphenylphosphine in 200
mL of THF at 5 °C was added dropwise 2.83 g (16.3 mmol) of
diethyl azodicarboxylate. The reaction mixture was stirred
for 30 min at 5 °C and then warmed to room temperature and
stirred overnight. The mixture was diluted with 95:5 CH2-
Cl2-MeOH and adsorbed onto 60 g of SiO2. The solvent was
3H), 7.05 (t, J ) 7 Hz, 1H), 7.35 (t, J ) 8 Hz, 2H), 7.45 (t, J )
7 Hz, 1H), 7.59 (d, J ) 8 Hz, 2H), 7.85 (d, J ) 8 Hz, 2H), 7.91
(s, 1H), 8.85 (s, 1H), 10.26 (br s, 1H); CIMS m/z 397 (M+). Anal.
(C20H14Cl2N4O) C, H, N.
(b) F r om Su lfon e 14a . A solution of 0.11 g (0.29 mmol) of
the sulfone 14a and 1.0 g (10.7 mmol) of aniline was refluxed
for 3 min. Further workup as described above gave a crude
solid that was purified by SiO2 chromatography, eluting with
CHCl3 and then 50% hexane-EtOAc to afford 0.046 g (40%)
of 38: mp 247 °C; The TLC and NMR for this compound were
identical to those of 3 isolated from the sulfoxide method above.
6-(2,6-Dich lor op h en yl)-2-(4-m et h oxyp h en yla m in o)-8-
m eth yl-8H-p yr id o[2,3-d ]p yr im id in -7-on e (49). A stirred
mixture of 1.13 g (2.9 mmol) of 14a and 3.0 g (24.4 mmol) of
4-methoxyaniline was heated at 160-165 °C for 10 min and
then cooled and treated with glacial HOAc to dissolve the gum.
The solution was diluted with 4 mL of H2O to precipitate solids
that were collected and then washed successively with H2O,
2-propanol, and ether to leave 1.2 g (97%) of crude product.
Recrystallization from EtOAc gave a pure sample of 49: mp
1
221-223 °C; H NMR (DMSO-d6) δ 3.64 (s, 3H), 3.75 (s, 3H),
6.95 (d, J ) 9 Hz, 2H), 7.47 (t, J ) 8 Hz, 1H), 7.59 (d, J ) 8
Hz, 2H), 7.72 (d, 2H), 7.88 (s, 1H), 8.80 (s, 1H), 10.11 (s, 1H);
CIMS m/z 427 (M+). Anal. (C21H16Cl2N4O2) C, H, N.
6-(2,6-Dich lor op h en yl)-2-[4-(2-d iet h yla m in oet h oxy)-
p h e n yla m in o]-8-m e t h yl-8H -p yr id o[2,3-d ]p yr im id in -7-