(1E )-5-(Benzyloxy)-2-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-
2,7,8,9-Tetrahydro-6-oxa-2,3,5-triazabenzo[cd]azulen-4-amine 5
5-yl)pentanal oxime 25
Polymer-supported triphenylphosphine (Aldrich, 380 mg, 1.14
mmol) was suspended in anhydrous N,N-dimethylformamide
(10 cm3) under argon at room temp. Diethyl azodicarboxylate
(200 mg, 1.2 mmol) was then added dropwise over a 20 min
period, allowing the colour to disappear after each addition
before continuing. The reaction was left to stir for 30 min before
adding compound 27 (200 mg, 0.96 mmol) dissolved in N,N-
dimethylformamide (2 cm3) dropwise over 20 min. The mixture
was then left to stir overnight. The reaction was then evapor-
ated and the residue adsorbed onto silica gel. Purification by
column chromatography, eluting with a gradient of methanol
(10–20%) in dichloromethane followed by recrystallisation of
the crude product from ethanol gave fine beige needles (60.8
mg, 33%); mp 220 ЊC (decomp); Rf (C) 0.41; Found: C, 55.79;
H, 5.30; N, 28.22. C9H10ON4ؒ1/4H2O requires C, 55.5; H, 5.18;
N, 28.8%; λmax(EtOH)/nm 298.00, 263.00 (log ε/dm3 molϪ1 cmϪ1
3.77, 3.78); λmin(EtOH)/nm 275.00 (log ε/dm3 molϪ1 cmϪ1 3.55);
δH ([2H6]-DMSO) 2.03 (2H, m, CH2), 2.75 (2H, t, J 5.2, CH2),
4.33 (2H, m, CH2O), 5.86 (2H, s, NH2), 6.63 (1H, s, CH-6),
10.86 (1H, s, NH ); δC ([2H6]-DMSO) 26.34, 29.59, 72.16, 97.79,
113.31, 115.60, 155.41, 156.44, 169.25; m/z (EIϩ) 190 [M]ϩ.
Accurate mass measurement 190.0847 C9H10ON4 requires
190.0855 deviation 4.1 ppm.
Benzenethiol (1.62 mL, 15.8 mmol) was added to a solution
of anhydrous SnCl2 (1 g, 5.27 mmol) in anhydrous acetonitrile
(10 mL). Triethylamine (1.60 g, 15.6 mmol) was then added
dropwise and the reaction allowed to stir for 30 min. A solution
of 22 (1.22 g, 3.52 mmol) in anhydrous acetonitrile (14 mL)
was then added. After 1 h, the reaction was evaporated to dry-
ness and adsorbed onto silica gel (∼5 g). Column chromato-
graphy, eluting with a gradient of methanol (5–20%) in di-
chloromethane, afforded the product as a beige solid (0.76 g,
65%); mp 164 ЊC (from MeCN); Rf (C) 0.25; λmax(EtOH)/nm
276.00 (log ε/dm3 molϪ1 cmϪ1 4.20); λmin(MeOH)/nm 258.00
(log ε/dm3 molϪ1 cmϪ1 4.10); Spectral data of E-isomer:
δH ([2H6]-DMSO) 1.45 (2H, m, CH2), 1.71 (2H, m, CH2),
3.38 (3H, m, CH and CH2O), 4.40 (2H, s, OCH2Ph), 5.75
(2H, s, NH2), 6.02 (2H, s, NH2), 7.20–7.36 (5H, m, Ph),
7.55 (1H, d, J 7.0, CH᎐N), 9.81 (1H, s, NH ), 10.14 (1H, s,
᎐
OH ); δC ([2H6]-DMSO) 27.42, 27.85, 35.67, 70.36, 72.22,
87.08, 127.74, 127.84 (2C), 128.68 (2C), 139.22, 152.86,
153.87, 162.24, 162.44; m/z (EIϩ) 332 [M]ϩ Accurate mass
measurement 332.1714, C16H21O3N5 requires 332.1723 devi-
ation 2.6 ppm.
2-Amino-5-[3-(benzyloxy)propyl]-3,7-dihydro-4H-pyrrolo-
[2,3-d]pyrimidin-4-one 26
Acknowledgements
Compound 25 (200 mg, 0.60 mmol) was refluxed overnight in
water (30 cm3) containing a suspension of Dowex-50 (Hϩ-form)
(∼1 cm3). A hot filtration was performed to remove the Dowex
before an extraction with ethyl acetate (100 cm3) was carried
out. The organic layer was dried (MgSO4) and evaporation of
the solvent in vacuo afforded the product as a beige solid (171
mg, 91%); mp 180 ЊC; Rf (C) 0.68; λmax(MeCN)/nm 282.48infl.
260.00 (log ε/dm3 molϪ1 cmϪ1 3.53, 3.65); λmin(MeCN)/nm
251.00 (log ε/dm3 molϪ1 cmϪ1 3.62); δH ([2H6]-DMSO) 1.86 (2H,
quintuplet, J 6.4, CH2), 2.60 (2H, t, J 7.0, CH2CH2CH2O), 3.42
(2H, t, J 6.4, CH2O), 4.43 (2H, s, OCH2Ph), 6.04 (2H, s, NH2),
6.32 (CH-6), 7.28–7.33 (5H, m, Ph), 10.19 (1H, s, NH ),
10.63 (1H, s, NH ); δC ([2H6]-DMSO) 23.21, 30.53, 69.84,
72.16, 99.18, 113.66, 118.43, 127.44, 127.84 (2C), 128.57 (2C),
139.20, 151.78, 152.57, 159.70; m/z (EIϩ) 298 [M]ϩ. Accurate
mass measurement 298.1419, C16H18O2N4 requires 298.14230
deviation 3.5 ppm.
We are grateful to Dr Brian Taylor and Ms Sue Bradshaw for
NMR data, Mr Simon Thorpe for mass spectra and Dr Geoff
Margison, Paterson Institute for Cancer Research, Manchester
for biological testing. We are also grateful to the EPSRC for
financial support.
References
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2-Amino-5-(3-hydroxypropyl)-3,7-dihydro-4H-pyrrolo[2,3-d]-
pyrimidin-4-one 27
A solution of boron trichloride (1 M) in heptane (54 cm3,
54.1 mmol) was added dropwise to a solution of compound 26
(2.0 g, 6.02 mmol) in dichloromethane (100 cm3) at Ϫ78 ЊC
under argon. The reaction was stirred at Ϫ78 ЊC for 6 h. The
reaction was then allowed to warm to room temp. overnight
whilst a solution of ethanol in dichloromethane (1 : 1, 300 cm3)
was added dropwise. The mixture was evaporated to dry-
ness, redissolved in a small amount of ethanol and neutralized
with aqueous sodium hydroxide solution (1 M). The residue
after evaporation was purified by column chromatography,
eluting with 10% methanol in dichloromethane. The product
was isolated as a pale yellow solid (1.0 g, 84%); mp >300 ЊC
(decomp.) Rf (C) 0.28; λmax(EtOH)/nm 282.98infl. 263.00
(log ε/dm3 molϪ1 cmϪ1 3.83, 3.95); λmin(EtOH)/nm 250.00 (log ε/
dm3 molϪ1 cmϪ1 3.84); δH ([2H6]-DMSO) 1.69 (2H, quintuplet,
J 7.0, CH2), 2.56 (2H, t, J 7.3, CH2CH2CH2O), 3.39 (2H, t,
J 6.7, CH2O), 4.45 (1H, t, J 5.5, OH ), 6.05 (2H, s, NH2),
6.32 (1H, s, CH-6), 10.21 (1H, s, NH ), 10.63 (1H, s, NH );
δC ([2H6]-DMSO) 22.72, 34.01, 60.72, 99.30, 113.65, 118.64,
151.68, 152.74, 159.91; m/z (EIϩ) 208 [M]ϩ. Accurate mass
measurement 208.0952, C9H12O2N4 requires 208.0960 deviation
3.9 ppm.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 6 – 4 1 7 2
4171