Scheme 5 Preparation and functionalization of xanthine prodrug conjugates.
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Representative experimental procedure
Synthesis of 8-(5-bromo-2-hydroxyphenyl)1,3-diethyl-1H-purine-
2,6(3H,7H)-dione
(Bromodimethyl)sulfonium bromide (0.879 g, 4.0 mmol) was
added (in two portions) to a mixture of p-methoxybenzaldehyde
(0.3053 g, 2.5 mmol) and 1,3,-diethyl-5,6-diaminouracil (0.495 g
2.5 mmol) in acetonitrile (5 mL). The reaction mixture was stirred
at room temperature for 14 h. The precipitate formed was collected
by vacuum filtration, washed with ethyl acetate and dried in vacuo.
The crude solid was purified by recrystallization from DMSO
and water to yield the title compound (0.66 g, 73%) as a white
solid m.p. 315–317 ◦C; TLC (dichloromethane–methanol = 19 : 1):
Rf 0.30; 1H NMR (500 MHz, d6-DMSO): d 13.80–14.20 (brs, 1H),
11.75–12.10 (brs, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.5,
2.5 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.08 (q, J = 7.5 Hz, 2H), 3.96
(q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, d6-DMSO): d 156.6, 154.4, 150.7,
150.6, 148.1, 135.1, 129.7, 120.2, 118.0, 115.3, 111.3, 55.6, 39.2,
36.7, 13.9; HRMS (ESI) m/z calcd for C15H16BrN4O3 (M+H)+:
379.0406, found, 379.0401.
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