Pyrimidoquinazoline-Based Antitumor Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 25 5551
2,7-Bis(h yd r oxym eth yl)-3,8-bis(n -p r op yl)p yr im id o[4,5-
g]qu in a zolin e-4,9-(3H,8H)-d ion e (7c). A suspension of 218
mg (0.56 mmol) of 6c in 10 mL of 48% aqueous hydrobromic
acid was refluxed for 12 h. The reaction mixture was then
chilled, and the pH was adjusted to 7 with saturated sodium
bicarbonate. The crystallized product was filtered off, washed
with water, and dried: 151 mg (75%) yield; mp 205-215 °C
(dec); TLC (ethyl acetate), Rf ) 0.36; IR (KBr pellet) 3387,
water. Purification was carried out by precipitating the product
from a concentrated dimethyl solution with water: mp >250
°C (dec); TLC (ethyl acetate/methanol [9:1]), Rf ) 0.50; IR (KBr
pellet) 3035, 2947, 1681, 1616, 1461, 1108, 1093, 798 cm-1
;
1H NMR (dimethyl sulfoxide-d6) δ 8.29 (2Η, s, C(5) and C(10)
aromatic protons), 4.44 (4H, s, C(2) and C(7) bromomethyls);
mass spectrum (EI mode), m/z 398 (M+, 79Br79Br), 400 (M+,
79Br81Br), 402 (M+, 81Br81Br). Anal. (C12H6Br2N4O4‚0.75H2O)
C, H, N.
2964, 2877,1680, 1604, 1467, 1379, 1356, 1261, 1099, 1068,
1
796 cm-1
;
NMR (dimethyl sulfoxide-d6) δ 8.35 (2H, s, C(5)
2,7-Bis(b r om om e t h yl)-2,8-d im e t h ylp yr im id o[4,5-g]-
qu in a zolin e-4,9-(3H,8H)-d ion e (9b). To a solution of 48 mg
(0.14 mmol) of 8b in 10 mL of dimethyl formamide was added
2 mL of 48% aqueous hydrobromic acid. The reaction mixture
was stirred for 24 h, and the crystallized product was filtered
off and dried: 21 mg (35%) yield; TLC (dichloromethane/
methanol [95:5]), Rf ) 0.53; IR (KBr pellet) 3455, 1690, 1595,
and C(10) aromatic protons), 5.80 (2H, brs, hydroxyl protons),
4.65 (4H, s, hydroxymethylmethylenes), 4.075 (4H, t, J ) 5.7
Hz, propylmethylenes adjacent to N0, 1.76 (4H, sextet, J ≈ 6
Hz, other propylmethylenes), 0.96 (6H, t, J ) 7.4 Hz, propy-
lmethyls); mass spectrum (EI mode), m/z 358 (M+), 328 (M+
- CH2), 298 (M+ - 2CH2O), 285 (M+ - CH2O-propyl).
1
2,7-Bis(ch lor om eth yl)p yr im id o[4,5-g]qu in a zolin e-4,9-
(3H,8H)-d ion e (8a ). To an ice bath chilled mixture consisting
of 104 mg (0.379 mmol) of 7a , 960 µL (12 mmol) of pyridine,
and 35 mL of dimethylformamide was added 960 µL (12 mmol)
of methanesulfonyl chloride. The reaction mixture was main-
tained at 5 °C during the addition and for 20 min thereafter.
The reaction mixture was then allowed to warm to room
temperature and stirred for 2.5 h. Water (150 mL) was added
to the reaction mixture after this period of time, and the
resulting mixture was stirred for 2 h. The precipitated product
was filtered off and dried: 61 mg (52%) yield. Purification was
carried out by dissolution of the product in a small volume of
dimethyl sulfoxide followed by precipitation with methanol:
mp >200 °C (dec); TLC (ethyl acetate/methanol [9:1]), Rf )
0.48; IR (KBr pellet) 3112, 3061, 3010, 2947, 1672, 1616, 1493,
1461, 1420, 1278 cm-1; 1H NMR (dimethyl sulfoxide-d6) δ 8.32
(2H, s, C(5) and C(10) aromatic protons), 4.59 (4H, s, C(2) and
C(7) chloromethyls); mass spectrum (EI mode), m/z 310 (M+,
35Cl35Cl), 312 (M+, 35Cl37Cl), 314 (M+, 37Cl37Cl). Anal. (C12H8-
Cl2N4O2) C, H, N.
1474, 1350, 1101, 795 cm-1; H NMR (CDCl3) δ 8.60 (2Η, s,
Η(5) and H(10) aromatic), 4.51 (4Η, s, C(2) andC(7) bromom-
ethyls), 3.78 (6H, s, N(3) and N(8) methyls); mass spectrum
(EI mode), m/z 426 (M+, 79Br79Br), 428 (M+, 79Br81Br), 430 (M+,
81Br81Br). Anal. (C14H12Br2N4O2) H, N. Low carbon, 39.28%
calculated versus 40.18% due to partial hydrolysis and loss of
bromide.
2,7-Bis(br om om eth yl)-3,8-bis(n -p r op yl)p yr im id o[4,5-g]-
qu in a zolin e-4,9-(3H,8H)-d ion e (9c). To a solution of 16 mg
of 8c in 3 mL of dimethylformamide was added 0.5 mL of 48%
aqueous hydrobromic acid. The reaction mixture was stirred
for 15 h, and the solvent was removed. The resulting solid was
neutralized with saturated NaHCO3 solution and extracted
with 5 × 10 mL of CH2Cl2. Purification was carried out on a
silica gel prep plate employing CH2Cl2/methanol (98/2) as
eluent: 4 mg yield of product; mp >220 °C (dec); TLC
(chloroform/methanol [9:1]), Rf ) 0.70; 1H NMR (CDCl3) δ 8.59
(2H, s, C(5) and C(10) aromatic protons), 4.49 (4H, s, C(2) and
C(7) bromomethyls), 4.16 (4H, q, J ) 5.7 Hz, propylmethylenes
adjacent to N), 1.81 (4H, sextet, J ) 7.7 Hz, other propylm-
ethylenes), 1.04 (6H, t, J ) 7.5 Hz, propylmethyls); mass
2,7-Bis(ch lor om e t h yl)-3,8-d im e t h ylp yr im id o[4,5-g]-
qu in a zolin e-4,9-(3H,8H)-d ion e (8b). 8b was prepared and
isolated in crude form (28% yield) by the procedure described
for the preparation of 8a .
spectrum (EI mode), m/z 483(M+, 79Br79Br), 485 (M+, 79Br81
-
Br), 487 (M+, 81Br81Br). Anal. (C18H20Br2N4O2) C, H, N.
2,7-Bis(a cet oxym et h yl)-3,8-d im et h ylp yr im id o[4,5-g]-
qu in a zolin e-4,9-(3H,8H)-d ion e (10). To a stirred suspension
of 100 mg (0.33 mmol) of 7b in 15 mL of pyridine was added
100 µL of acetic anhydride. After the reaction mixture was
stirred for 2 h at room temperature, the solvent was removed
in vacuo and the solid residue was triturated with 40 mL of
water for 15 min. The solid was filtered off and recrystallized
from chloroform/hexane: 67 mg (52%) yield; mp 263-264 °C;
TLC (chloroform/methanol [9:1]), Rf ) 0.53; IR (KBr pellet)
1744, 1691, 1674, 1609, 1452, 1341, 1248, 1236, 1074, 794
cm-1; 1H NMR (dimethyl sulfoxide-d6) δ 8.31 (2H, s, C(5) and
C(10) aromatic protons), 5.29 (4H, s, C(2) and C(7) acetoxym-
ethyls), 3.56 (6H, s, N(3) and N(8) methyls), 2.21 (6H, s,
acetylmethyls); mass spectrum (EI mode), m/z 386 (M+), 343
(M+ - COCH3). Anal. (C18H18N4O6) C, H, N.
1, 5-Dica r boxy-2,4-bis(ch lor oa ceta m id o)ben zen e (12).
To a suspension of 50 mg (0.185 mmol) of 1114 in 125 mL of
dry benzene was added 37 µL of chloroacetyl chloride and 63µL
of pyridine. The reaction mixture was stirred for 14 h. The
benzene was removed in vacuo to afford a white residue. This
solid residue was washed with a 1.0 N hydrochloric acid
solution and then rinsed with cold distilled water: 47 mg (72%)
yield. Analytically pure product was prepared by dissolving
150 mg of product in 60 mL of hot acetone and then adding
boiling water dropwise. Product was obtained as ivory
needles: 135 mg (90%) yield; mp >265 °C (dec); TLC (2-
propanol/water/ammonium hydroxide [7:2:1]), Rf ) 0.53; 1H
NMR (dimethyl sulfoxide-d6) δ 9.85 and 8.67 (2H, 2s, aro-
matic), 4.50 (4H, s, chloromethyls); IR (KBr) 3408, 3161, 2958,
1697, 1593, 1531, 1394, 1329, 1232, 1122 cm-1; mass spectrum
(El mode), m/z 348 (M+, 35Cl35Cl), 349 (M+35Cl37Cl), 350 (M+,
37Cl37Cl). Anal. (C12H10Cl2N2O6‚H2O) C, H, N.
The pale-yellow product was flash-chromatographed on a
column of silica gel using chloroform/methanol (99:1) as eluant.
The purified product was recrystallized from chloroform/
hexane: mp >210 °C (dec); TLC (chloroform/methanol [9:1]),
Rf ) 0.66; IR (KBr pellet) 1688, 1669, 1604, 1470, 1454, 1421,
1
1342, 816, 798 cm-1; H NMR (dimethyl sulfoxide-d6) δ 8.34
(2H, s, C(5) and C(10) aromatic protons), 4.95 (4H, s, C(2) and
C(7) chloromethyls), 3.66 (6H, s, N(3) and N(8) methyls); mass
spectrum (EI mode) m/z 338 (M+, 35Cl35Cl), 340 (M+, 37Cl35Cl),
342 (M+, 37Cl37Cl). Anal. (C14H12Cl2N4O2‚0.2H2O) C, H, N.
2,7-Bis(ch lor om eth yl)-3,8-bis(n -p r op yl)p yr im id o[4,5-g]-
qu in a zolin e-4,9-(3H,8H)-d ion e (8c). A mixture consisting
of 56 mg (0.156 mmol) of 7c, 200 µL of methanesulfonyl
chloride, 200 µL of pyridine, and 1 mL of dry dimethyl
formamide was heated at 80 °C until complete dissolution
occurred (about 2 min). The reaction mixture was then cooled
to room temperature, resulting in crystallization of 8c. The
pale product was flash-chromatographed on a silica gel column
employing chloroform/methanol (98:2) as eluent. The purified
product was recrystallized from chloroform/hexane: mp 219
°C (dec); TLC (chloroform/methanol [9:1]), Rf )0.71; IR (KBr
1
pellet) 1686, 1591, 1469, 1377 cm-1; H NMR (CDCl3) δ 8.60
(2H, s, C(5) and C(10) aromatic protons), 4.64 (4H, s, C(2) and
C(7) chloromethyls), 4.16 (4H, q, J ) 5.7 Hz, propylmethylenes
adjacent to N), 1.81 (4H, sextet, J ) 7.7 Hz, other propylm-
ethylenes), 1.04 (6H, t, J ) 7.5 Hz, propylmethyls); mass
spectrum (EI mode), m/z 394(M+, 35Cl35Cl), 396 (M+, 37Cl35Cl),
398 (M+, 37Cl37Cl). Anal. (C18H20Cl2N4O2) C, H, N.
2,7-Bis(br om om eth yl)p yr im id o[4,5-g]qu in a zolin e-4,9-
(3H,8H)-d ion e (9a ). To a stirred suspension of 10 mg (0.032
mmol) of 8a in 2.0 mL of dimethyl sulfoxide was added 270
µL of 48% aqueous hydrobromic acid. After the reaction
mixture was stirred for 40 min, the product was precipitated
as a pale-yellow solid, 4.9 mg (38%) yield, by adding 40 mL of
4,1-Ben zo[1,3-e:6,5-e′]bisoxa zep in e-2,5,7,10-(1H, 3H, 9H,
11H)-tetr on e (13). To 205 mg (0.59 mmol) of 12 in 250 mL of
dry dimethylformamide at 75 °C was added 0.65 mL (4.71