4-Benzylamino-2,6-dichloro-8-dimethylaminopyrimido[5,4-d]-
pyrimidine 9c. Ethanolic dimethylamine (0.5 ml, 33%) in THF
(2 ml) was added to 4-benzylamino-2,6,8-trichloropyrimido-
[5,4-d]pyrimidine 8 (0.05 g, 0.15 mmol) in THF (2 ml) accord-
ing to standard procedure B. Filtration of the reaction mixture
followed by washing with water and drying gave the title com-
pound as a beige solid (0.04 g, 67%); δH (CDCl3) 3.30–3.90 (6 H,
br d, (CH3)2N), 4.74–4.76 (2 H, d, J 5.9 Hz, ArCH2NH),
7.25–7.60 (5 H, m, Ar-H × 5); m/z 348 (Mϩ, 61%), 304 (20), 106
(77), 91 (100). Calculated for C15H14N6Cl2: m/z 348.1. Found
348.1.
m/z 467 (Mϩ, 100%), 452 (20), 436 (89) (Found: C 56.59;
H 4.62; N 20.93; C22H22ClN7O3 requires: C 56.56; H 4.75;
N 20.98%).
8-Amino-4-benzylamino-2-chloro-6-(2-hydroxyethylamino)-
pyrimido[5,4-d]pyrimidine 10ai and 8-amino-4-benzylamino-6-
chloro-2-(2-hydroxyethylamino)pyrimido[5,4-d]pyrimidine 10aii.
Following standard procedure C; 8-amino-4-benzylamino-2,6-
dichloropyrimido[5,4-d]pyrimidine 9a (0.20 g, 0.63 mmol),
THF (10 ml) and ethanolamine (5 ml) were stirred for 3 h.
Purification of the crude product by column chromatography
using 3% methanol–dichloromethane as eluent, followed by
recrystallisation from ethyl acetate, gave a mixture of the title
compounds as a yellow solid (0.10 g, 47%); mp 164–166 ЊC:
δH 3.46–3.57 (4 H, m, NH(CH2)2OH), 4.70–4.78 (3 H, m,
ArCH2NH, CH2OH), 6.79 (1 H, br s, CH2NH), 7.31–7.48 (6 H,
m, Ar-H, HNH), 8.41 (1 H, br s, HNH), 8.43 (1 H, br s,
ArCH2NH); m/z 345 (Mϩ, 60%), 329 (15), 314 (45), 91 (100)
(Found: C 52.18; H 4.48; N 27.99; C15H16N7ClO requires:
C 52.17; H 4.67; N 28.39%).
4-Benzylamino-2,6-dichloro-8-piperidinopyrimido[5,4-d]-
pyrimidine 9d. 4-Benzylamino-2,6,8-trichloropyrimido[5,4-
d]pyrimidine 8 (0.13 g, 0.37 mmol), THF (5 ml) and piperidine
(0.04 g, 0.44 mmol) in THF (5 ml) were mixed according to
standard procedure B. Extraction with ethyl acetate, drying
(Na2SO4), and removal of the solvent in vacuo gave the title
compound as a crude solid (0.09 g, 63%); δH 1.76 (6 H, br s,
-(CH2)3-), 4.30 (4 H, br s, CH2NCH2), 4.72–4.75 (2 H, d, J 6.4
Hz, ArCH2NH), 7.32–7.44 (5 H, m, Ar-H), 9.35 (1 H, t, J 6.4
Hz, ArCH2NH); m/z 392 (M ϩ 4, 9%), 390 (M ϩ 2, 50), 388
(Mϩ, 75), 297 (8), 106 (20), 91 (90), 84 (100). Calculated for
C18H18N6Cl2: m/z 388.1. Found 388.1.
4-Benzylamino-2-chloro-6-(2-hydroxyethylamino)-4-methyl-
aminopyrimido[5,4-d]pyrimidine 10bi and 4-benzylamino-6-
chloro-2-(2-hydroxyethylamino)-4-methylaminopyrimido[5,4-d]-
pyrimidine 10bii. 4-Benzylamino-2,6-dichloro-8-methylamino-
pyrimido[5,4-d]pyrimidine 9b (0.50 g, 0.15 mmol), THF (5 ml)
and ethanolamine (1.25 ml) were stirred for 75 min according
to standard procedure C. Column chromatography using 65%
ethyl acetate–petrol as eluent gave a mixture of the title com-
pounds as a white solid (0.04 g, 65%); mp 121–122 ЊC: δH 2.97–
2.99 and 3.02–3.05 (3 H, 2 × d, J 4.7 Hz, NHCH3), 3.56–3.62
(4 H, m, NH(CH2)2OH), 4.68–4.70 and 4.71–4.77 (3 H, 2 × m,
ArCH2NH, CH2OH), 6.75 (1 H, m, NHCH3), 7.31–7.48 (5 H,
m, Ar-H), 7.86–8.02 (1 H, br d, CH2CH2NH), 8.38 (1 H, br d,
ArCH2NH); m/z 361 (M ϩ 2, 8%), 359 (Mϩ, 22), 328 (15), 91
(100) (Found: C 53.52; H 4.84; N 26.93; C16H17N7ClO requires:
C 53.48; H 5.05; N 27.28%).
Reaction of abab and abcc substituted-pyrimido[5,4-d]-
pyrimidines with ethanolamine (mono substitution); standard
procedure C
To the appropriate 2,6-dichloro-4,8-disubstituted-pyrimido-
[5,4-d]pyrimidine (0.15–1.13 mmol) in THF (5–12 ml) under
nitrogen was added ethanolamine (1.25–10 ml). The resultant
yellow solution was heated at 65 ЊC for 2–6 h (unless stated
otherwise), over which period a fine precipitate of ethanol-
amine hydrochloride formed. The suspension was cooled and
water (50 ml) was added, precipitating the product and dis-
solving the salt. The resultant mixture was filtered, to give an
off-white solid which was retained. The filtrate was extracted
with ethyl acetate and the organic layer was washed with
water, dried (Na2SO4), filtered and concentrated, producing a
secondary yield of product. Column chromatography and/or
recrystallisation from a suitable solvent afforded the desired
compound.
4-Benzylamino-2-chloro-6-(2-hydroxyethylamino)-8-dimethyl-
aminopyrimido[5,4-d]pyrimidine 10ci and 4-benzylamino-6-
chloro-2-(2-hydroxyethylamino)-8-dimethylaminopyrimido-
[5,4-d]pyrimidine 10cii. Following standard procedure C;
4-benzylamino-2,6-dichloro-8-dimethylaminopyrimido[5,4-d]-
pyrimidine 9c (0.30 g, 0.86 mmol), ethanolamine (10 ml)
and THF (10 ml) were stirred for 3 h. Purification by column
chromatography using 2% methanol–dichloromethane,
4,8-Bis(benzylamino)-6-chloro-2-(2-hydroxyethylamino)-
pyrimido[5,4-d]pyrimidine
6c.
4,8-Bis(benzylamino)-2,6-
dichloropyrimido[5,4-d]pyrimidine 6a (0.31 g, 0.74 mmol), dry
THF (12 ml) and ethanolamine (3.0 ml, 48 mmol) were heated
at 75 ЊC for 6 h following standard procedure C. The product
was obtained by recrystallisation from hot ethyl acetate to yield
the title compound as a fine white powder (0.12 g, 61%);
mp 180–181 ЊC: νmax/cmϪ1 3584 (NH), 3354 (OH), 3029 (CH),
2936 (CH), 1590, 1568, 1534, 1508; δH 3.50 (4 H, m,
NH(CH2)2OH), 4.75 (5 H, m, ArCH2NH × 2, CH2OH), 6.81
(1 H, br s, CH2NH), 7.41 (10 H, m, Ar-H), 8.44 (2 H, br m,
ArCH2NH); m/z 437 (M ϩ 2, 19%), 435 (Mϩ, 60), 91 (100)
(Found: C 60.73; H 4.95; N 22.38; C22H22N7ClO requires: C
60.58; H 5.09; N 22.50%).
followed by 6% methanol–dichloromethane, produced
a
mixture of the title compounds as a white solid (0.08 g,
25%); mp 106–108 ЊC: δH 3.50–3.63 (10 H, m, NH(CH2)2OH,
(CH3)2N), 4.68–4.77 (3 H, m, ArCH2NH, CH2OH), 6.78
(1 H, m, CH2NH), 7.32–7.44 (5 H, m, Ar-H), 8.50 (1 H,
m, ArCH2NH); m/z 373 (Mϩ, 45%), 329 (18), 91 (100) (Found:
C 54.99; H 5.35; N 25.79; C17H20N7ClO requires: C 54.68;
H 5.40; N 26.26%).
4-Benzylamino-2-chloro-6-(2-hydroxyethylamino)-8-piper-
idinopyrimido[5,4-d]pyrimidine 10di and 4-benzylamino-6-
chloro-2-(2-hydroxyethylamino)-8-piperidinopyrimido[5,4-d]-
pyrimidine 10dii. Following standard procedure C; 4-benzyl-
amino-2,6-dichloro-8-piperidinopyrimido[5,4-d]pyrimidine 9d
(0.09 g, 0.23 mmol), THF (6 ml) and ethanolamine (1.50 ml)
were stirred for 5 h. Purification by column chromatography
using 40–50% ethyl acetate–petrol produced a mixture of the
title compound as a crude yellow solid (0.05 g, 56%); δH 1.73
(6 H, br s, -(CH2)3-), 3.36–3.45 (2 H, m, NHCH2), 3.57–3.60
(2 H, m, CH2OH), 4.36 (4 H, br s, CH2NCH2), 4.67–4.75 (3 H,
m, ArCH2NH, CH2OH), 6.85 (1 H, t, CH2NH), 7.31–7.45 (5 H,
m, Ar-H), 8.36 (1 H, br s, ArCH2NH); m/z 413 (Mϩ, 43%), 382
(15), 106 (10), 91 (100), 84 (30).
6-Chloro-2-(2-hydroxyethylamino)-4,8-bis(4-methoxyanilino)-
pyrimido[5,4-d]pyrimidine 7c. 2,6-Dichloro-4,8-bis(4-methoxy-
anilino)pyrimido[5,4-d]pyrimidine 7a (0.50 g, 1.13 mmol), THF
(10 ml) and ethanolamine (10.12 g, 10 ml) were stirred for 2 h
following standard procedure C. Recrystallisation from ethyl
acetate gave the product as a yellow solid (0.48 g, 91%); mp
198–200 ЊC: δH 3.69 (4 H, m, NH(CH2)2OH), 3.87 (3 H, s,
CH3O), 3.89 (3 H, s, CH3O), 4.81 (1 H, br s, CH2OH), 7.01–7.05
(3 H, d, J 8.8 Hz, Ar-H3/5, CH2NH), 7.09–7.14 (2 H, d, J 8.8 Hz,
Ar-H3/5), 7.83–7.87 (2 H, d, J 8.8 Hz, Ar-H2/6), 7.99–8.04
(2 H, d, J 8.8 Hz, Ar-H2/6), 9.50 (2 H, br s, ArCH2NH);
J. Chem. Soc., Perkin Trans. 1, 2002, 108–115
113