1824 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 12
Rewcastle et al.
Similarly prepared were the following compounds.
6-Am in o-4-[(3-br om op h en yl)a m in o]p yr im id o[5,4-d ]p y-
r im id in e (5b): 72% yield; mp (i-PrOH) 280-282 °C; 1H NMR
[(CD3)2SO] δ 9.59 (s, 1 H, exchangeable with D2O, NH), 9.06
(s, 1 H, H-4), 8.50 (s, 1 H, H-6), 8.42 (br s, 1 H, H-2′), 7.91 (br
d, J ) 8.3 Hz, 1 H, H-6′), 7.35 (t, J ) 7.9 Hz, 1 H, H-5′), 7.29
(d, J ) 7.5 Hz, 1 H, H-4′), 7.22 (br, 2 H, exchangeable with
D2O, NH2). Anal. (C12H9BrClN6) C, H, N.
Diethoxymethyl acetate was obtained from Aldrich Chemical
Co., Inc., and used as received.
5-Am in o-2-ch lor opyr im idin e-4-car boxam ide (8). A sus-
pension of ethyl 5-amino-2-chloropyrimidine-4-carboxylate (7)18
(5.7 g, 28 mmol) in EtOH (150 mL) was saturated with
ammonia gas, and the mixture was heated in a sealed pressure
vessel at 100 °C for 2 days. After cooling, the solid was
collected and dried to give 5-amino-2-chloropyrimidine-4-
1
carboxamide (8) (4.32 g, 89%): mp (EtOH) 247-248.5 °C; H
4-[(3-Br om op h en yl)a m in o]-6-(m eth yla m in o)p yr im id o-
[5,4-d ]p yr im id in e (5c): 68% yield; mp (i-PrOH) 202.5-204
°C; 1H NMR [(CD3)2SO] δ 9.51 (s, 1 H, exchangeable with D2O,
NH), 9.01 (s, 1 H, H-4), 8.47 (s, 1 H, H-6), 8.38 (br s, 1 H, H-2′),
8.04 (br d, J ) 7.0 Hz, 1 H, H-6′), 7.87 (br, 1 H, exchangeable
with D2O, NH), 7.34 (t, J ) 8.0 Hz, 1 H, H-5′), 7.31 (d, J ) 7.8
NMR [(CD3)2SO] δ 8.40 (s, 1 H, H-6), 8.04 and 7.77 (2 br s, 2
H, exchangeable with D2O, CONH2), 7.01 (br s, 2 H, exchange-
able with D2O, NH2); 13C NMR δ 167.6 (s, CO), 151.2 (d, C-6),
143.5 (s), 142.0 (s), 134.5 (s). Anal. (C5H5ClN4O) C, H, N.
6-Ch lor op yr im id o[5,4-d ]p yr im id in -4(3H)-on e (9).
A
suspension of 8 (1.60 g, 9.3 mmol) in diethoxymethyl ace-
tate (12 mL) was heated to 100 °C to give a clear solution
which slowly deposited a white precipitate over time. Heating
was continued for 6 h, and after cooling the solid was col-
lected, washed with petroleum ether, and dried to give
6-chloropyrimido[5,4-d]pyrimidin-4(3H)-one (9) (1.11 g). Dilu-
tion of the mother liquors with petroleum ether gave crude
material which was chromatographed on silica gel, eluting
with CH2Cl2/EtOAc (3:2), to give a further 0.26 g of 9 (total
Hz, 1 H, H-4′), 3.06 (d, J ) 4.4 Hz, 3 H, CH3). Anal. (C13H11-
BrN6) C, H, N.
4-[(3-Br om oph en yl)am in o]-6-(dim eth ylam in o)pyr im ido-
[5,4-d ]p yr im id in e (5d ): 70% yield; mp (i-PrOH) 179-180 °C;
1H NMR [(CD3)2SO] δ 9.56 (s, 1 H, exchangeable with D2O,
NH), 9.09 (s, 1 H, H-4), 8.47 (s, 1 H, H-6), 8.35 (br s, 1 H, H-2′),
8.08 (br d, J ) 7.5 Hz, 1 H, H-6′), 7.37 (t, J ) 8.0 Hz, 1 H,
H-5′), 7.32 (d, J ) 7.8 Hz, 1 H, H-4′), 3.33 (s, 6 H, CH3). Anal.
(C14H13BrN6) C, H, N.
1
yield 1.37 g, 81%): mp (EtOAc) 234 °C dec; H NMR [(CD3)2-
4-[(3-Br om op h en yl)a m in o]-6-m eth oxyp yr im id o[5,4-d ]-
p yr im id in e (5e): by reaction of 5a in MeOH/Et3N under
reflux for 3 h, 100% yield; mp (i-PrOH) 166-167 °C; 1H NMR
[(CD3)2SO] δ 10.00 (s, 1 H, exchangeable with D2O, NH), 9.37
(s, 1 H, H-4), 8.70 (s, 1 H, H-6), 8.33 (br s, 1 H, H-2′), 8.04 (br
d, J ) 7.8 Hz, 1 H, H-6′), 7.40 (t, J ) 7.9 Hz, 1 H, H-5′), 7.36
SO] δ 13.02 (br s, 1 H, exchangeable with D2O, NH), 9.32 (s,
1 H, H-8), 8.31 (s, 1 H, H-2); 13C NMR δ 162.8 (d), 158.0 (s),
156.1 (s), 148.4 (d), 146.2 (s), 141.5 (s). Anal. (C6H3ClN4O)
C, H, N.
6-Ch lor o-4-(p h en yla m in o)p yr im id o[5,4-d ]p yr im id in e
(4a ). A suspension of 9 (0.37 g, 2 mmol) in 30 mL of SOCl2
containing 1 drop of DMF was heated under reflux for 30 min
to give a clear solution. The excess of SOCl2 was then removed
under reduced pressure, and the residue of crude 4,6-dichlo-
ropyrimido[5,4-d]pyrimidine (10) was treated immediately
with a solution of aniline (0.47 g, 5 mmol) in 2-propanol.
Precipitation of the product hydrochloride occurred rapidly,
and after heating to reflux for 10 min the mixture was diluted
with sufficient Et3N to give a clear solution. After further
dilution with water the solution was concentrated to give a
crude solid which was purified by chromatography on silica
gel, eluting with CH2Cl2/EtOAc (95:5), to give 6-chloro-4-
(phenylamino)pyrimido[5,4-d]pyrimidine (4a ) (0.41 g, 79%):
mp (i-PrOH) 130-131 °C; 1H NMR [(CD3)2SO] δ 10.48 (br s, 1
H, exchangeable with D2O, NH), 9.44 (s, 1 H, H-4), 8.75 (s, 1
H, H-6), 7.96 (d, J ) 7.9 Hz, 2 H, H-2′,6′), 7.42 (dd, J ) 8.1,
7.6 Hz, 2 H, H-3′,5′), 7.19 (t, J ) 7.2 Hz, 1 H, H-4). Anal.
(C12H8ClN5) C, H, N.
(d, J ) 8.1 Hz, 1 H, H-4′), 4.19 (s, 3 H, CH3). Anal. (C13H10
BrN5O) C, H, N.
-
4-[(3-Br om op h e n yl)a m in o]-6-[[2-(d im e t h yla m in o)-
eth yl]a m in o]p yr im id o[5,4-d ]p yr im id in e (5f): 64% yield;
mp (i-PrOH/H2O) 146-147 °C; 1H NMR [(CD3)2SO] δ 9.50 (br
s, 1 H, exchangeable with D2O, NH), 9.02 (s, 1 H, H-4), 8.47
(s, 1 H, H-6), 8.36 (br s, 1 H, H-2′), 7.98 (br d, J ) 8.3 Hz, 1 H,
H-6′), 7.69 (br, 1 H, exchangeable with D2O, NH), 7.37 (t, J )
8.0 Hz, 1 H, H-5′), 7.31 (d, J ) 8.2 Hz, 1 H, H-4′), 3.37 (br, 2
H, CH2), 2.49 (t, J ) 6.6 Hz, 2 H, CH2), 2.23 (s, 6 H, CH3).
Anal. (C16H18BrN7) C, H, N.
4-[(3-Br om op h en yl)a m in o]-6-[[2-(4-m or p h olin o)eth yl]-
a m in o]p yr im id o[5,4-d ]p yr im id in e (5g): 51% yield; mp (i-
1
PrOH/H2O) 160-161 °C; H NMR [(CD3)2SO] δ 9.50 (br s, 1
H, exchangeable with D2O, NH), 9.02 (s, 1 H, H-4), 8.47 (s, 1
H, H-6), 8.32 (br s, 1 H, H-2′), 7.99 (br d, J ) 7.7 Hz, 1 H,
H-6′), 7.73 (br, 1 H, exchangeable with D2O, NH), 7.38 (t, J )
8.0 Hz, 1 H, H-5′), 7.31 (d, J ) 8.5 Hz, 1 H, H-4′), 3.69 (br, 2
H, NCH2), 3.57 (t, J ) 4.5 Hz, 4 H, OCH2), 2.55 (t, J ) 6.5 Hz,
2 H, NCH2), 2.49 (m, 4 H, NCH2). Anal. (C18H20BrN7O) C,
H, N.
Similarly prepared were the following compounds.
4-[(3-Br om op h en yl)a m in o]-6-ch lor op yr im id o[5,4-d ]p y-
r im id in e (5a ): 80% yield; mp (i-PrOH) 197.5-198 °C; 1H
NMR [(CD3)2SO] δ 10.62 (s, 1 H, exchangeable with D2O, NH),
9.48 (s, 1 H, H-4), 8.83 (s, 1 H, H-6), 8.35 (br s, 1 H, H-2′),
8.40-8.00 (m, 1 H, H-6′), 7.41-7.36 (m, 2 H, H-4′,5′). Anal.
(C12H7BrClN5) C, H, N.
4-[(3-Br om op h en yl)a m in o]-6-[[3-(4-m or p h olin o)p r o-
p yl]a m in o]p yr im id o[5,4-d ]p yr im id in e (5h ): 92% yield; mp
(CH2Cl2/hexane) 138-138.5 °C; 1H NMR [(CD3)2SO] δ 9.46 (br
s, 1 H, exchangeable with D2O, NH), 9.01 (s, 1 H, H-4), 8.47
(s, 1 H, H-6), 8.34 (br s, 1 H, H-2′), 8.00 (br d, J ) 7.7 Hz, 1 H,
H-6′), 7.95 (br, 1 H, exchangeable with D2O, NH), 7.37 (t, J )
8.0 Hz, 1 H, H-5′), 7.31 (d, J ) 8.1 Hz, 1 H, H-4′), 3.60 (br, 2
H, NCH2), 3.57 (t, J ) 4.5 Hz, 4 H, OCH2), 2.42 (t, J ) 6.8 Hz,
4-[(3-Meth ylph en yl)a m in o]-6-ch lor op yr im id o[5,4-d]py-
r im id in e (6a ): 71% yield; mp (i-PrOH) 165-166 °C; 1H NMR
[(CD3)2SO] δ 10.37 (s, 1 H, exchangeable with D2O, NH), 9.42
(s, 1 H, H-4), 8.76 (s, 1 H, H-6), 7.79 (br s, 1 H, H-2′), 7.76 (br
d, J ) 8.1 Hz, 1 H, H-6′), 7.30 (t, J ) 7.8 Hz, 1 H, H-5′), 7.01
2 H, NCH2
H, CH2). Anal. (C19H22BrN7O) C, H, N.
), 2.37 (m, 4 H, NCH2), 1.78 (pentet, J ) 6.9 Hz, 2
(d, J ) 7.5 Hz, 1 H, H-4′), 2.35 (s, 3 H, CH3). Anal. (C13H10
ClN5) C, H, N.
-
4-[(3-Br om op h en yl)a m in o]-6-[[2-(4-im id a zolyl)eth yl]-
a m in o]p yr im id o[5,4-d ]p yr im id in e (5i): 59% yield; mp (i-
PrOH) 209-210 °C; 1H NMR [(CD3)2SO] δ 11.87 (br, 1 H,
exchangeable with D2O, NH), 9.59 (br s, 1 H, exchangeable
with D2O, NH), 9.02 (s, 1 H, H-4), 8.48 (s, 1 H, H-6), 8.38 (br
s, 1 H, H-2′), 8.03 (m, 2 H, NH, H-6′), 7.58 (s, 1 H, H-2′′), 7.39
(t, J ) 8.0 Hz, 1 H, H-5′), 7.32 (d, J ) 8.0 Hz, 1 H, H-4′), 6.89
(s, 1 H, H-5′′), 3.75 (q, J ) 6.4 Hz, 2 H, NCH2), 2.86 (t, J ) 7.1
Hz, 2 H, CH2). Anal. (C17H15BrN8) C, H, N.
6-(Meth yla m in o)-4-(p h en yla m in o)p yr im id o[5,4-d ]p yr i-
m id in e (4c). A solution of 4a (0.20 g, 0.78 mmol) and 40%
aqueous MeNH2 (3 mL) in 20 mL of DMSO was heated in a
sealed pressure vessel at 100 °C for 2 h, and after cooling the
mixture was diluted with water and extracted with EtOAc.
Drying and removal of the solvent gave crude material which
was chromatographed on silica gel, eluting with CH2Cl2/EtOAc
(3:2), to give 0.16 g (82% yield) of 6-(methylamino)-4-(phenyl-
amino)pyrimido[5,4-d]pyrimidine (4c): mp (i-PrOH) 195.5-
196.5 °C; 1H NMR [(CD3)2SO] δ 9.38 (br s, 1 H, exchangeable
with D2O, NH), 9.00 (s, 1 H, H-4), 8.42 (s, 1 H, H-6), 7.98 (d,
J ) 7.9 Hz, 2 H, H-2′,6′), 7.80 (br, 1 H, exchangeable with D2O,
NH), 7.41 (dd, J ) 8.1, 7.6 Hz, 1 H, H-5′), 7.13 (t, J ) 7.3 Hz,
1 H, H-4′), 3.04 (d, J ) 4.8 Hz, 3 H, CH3). Anal. (C13H12N6)
C, H, N.
4-[(3-Br om op h en yl)a m in o]-6-[[3-(1-im id a zolyl)p r op yl]-
a m in o]p yr im id o[5,4-d ]p yr im id in e (5j): 93% yield; mp
1
(CH2Cl2/hexane) 192-194 °C; H NMR [(CD3)2SO] δ 9.38 (br
s, 1 H, exchangeable with D2O, NH), 9.04 (s, 1 H, H-4), 8.48
(s, 1 H, H-6), 8.35 (br s, 1 H, H-2′), 8.06 (br, 1 H, exchangeable
with D2O, NH), 8.01 (br d, J ) 7.0 Hz, 1 H, H-6′), 7.71 (s, 1 H,
H-2′′), 7.38 (t, J ) 8.0 Hz, 1 H, H-5′), 7.32 (d, J ) 8.4 Hz, 1 H,