(CD3)2SO] for 4a: 8.34 (1H, s), 8.62 (1H, s), 12.58 (1H, br s), 13.60 (1H, br
s); for 4b: 2.40 (3H, s), 8.54 (1H, s), 12.46 (1H, br s), 13.57 (1H, br s).
∑ All new compounds 9c–i exhibited satisfactory elemental combustion
analyses and mass and 1H NMR spectral data consistent with structures
indicated, and showed mps over 300 °C except for 9c (mp 150 °C).
** Typical procedure: A solution of 9c (0.3 g, 1.02 mmol) with thiourea (93
mg, 1.22 mmol) in BusOH (15 ml) was heated under reflux for 1 h. After the
reaction was complete, the solution was concentrated to dryness in vacuo
and treated with EtOH to afford crystals of 10c (mp 260–261 °C, 65%),
which were collected by filtration and recrystallized from a mixture of DMF
and water. Other derivatives 10d (81%), 10e (71%), 10f (71%), 10g (74%),
10h (91%) and 10i (77%) were prepared in a similar manner to 10c and
recrystallized from a mixture of DMF and EtOH or water. The compounds
10d–i showed mps above 300 °C. It is noteworthy that the compounds 4, 9
and 10 were reasonably stable in acid or alkali solution due to the
substituents at the 5-position on the rings. dH[60 or 200 MHz, (CD3)2SO]
for 10c: 0.90 (3H, t, J 6.30), 1.31 (8H, br s), 1.55–2.10 (2H, m), 2.64–3.08
(2H, m), 8.63 (1H, s), 14.0 (1H, br), 14.38 (1H, br); for 10d: 7.50–7.64 (3H,
m), 8.10–8.30 (2H, m), 8.84 (1H, s), 14.0 (1H, br s), 14.35 (1H, br s); for
10e: 7.40 (2H, dd, J 8.84, 8.90), 8.25 (2H, dd, J 8.84, 5.54), 8.75 (1H, s),
14.01 (1H, br), 14.37 (1H, br); for 10f: 7.63 (2H, d, J 8.57), 8.20 (2H, d, J
8.57), 8.81 (1H, s), 14.01 (1H, br), 14.38 (1H, br); for 10g: 2.40 (3H, s), 7.35
(2H, d, J 7.92), 8.10 (2H, d, J 7.92), 8.75 (1H, s), 13.90 (1H, br), 14.40 (1H,
br); for 10h: 3.85 (3H, s), 7.09 (2H, d, J 8.82), 8.14 (2H, d, J 8.82), 8.75 (1H,
s), 14.0 (1H, br), 14.55 (1H, br); for 10i: 8.41 (4H, br s), 8.77 (1H, s), 13.75
(1H, br), 14.25 (1H, br).
oxidation using 70% nitric acid (ca. 1.2 equiv.) in 60–91%
yields in a similar manner as above (Method C).
In addition, we tried to prepare the 5-thioxo derivatives 10c–
i. Thus the key starting materials, 5-chloro derivatives 9c–i,
were readily prepared by refluxing the appropriate 5-oxo
derivatives 4c–i with phosphoryl chloride (100 parts) in
64–92% yields.∑ Then, thiation by reaction of 9c–i with thiourea
(1.2 equiv.) in butan-2-ol under reflux afforded the correspond-
ing 5-thioxo derivatives 10c–i in 65–91% yields.**
In conclusion, we accomplished the facile and general
syntheses of not only oxypurinol 5 and 3- and/or 5-substituted
7H-pyrazolo[4,3-e]-1,2,4-triazolo[4,3-c]pyrimidines (4 and 10)
as a new class of potential XO inhibitors but also 6-chloro-
4-hydrazino-1H-pyrazolo[3,4-d]pyrimidine (2), which was an
useful intermediate. The compounds (4 and 10) exhibited
100–760 fold more potent bovine milk XO inhibitory activities
than that of allopurinol† and did not show any appreciable
inhibition against the proliferation of T-cell acute lymphoblastic
leukemia (CCRF-HSB-2). Further investigation of the present
synthetic and XO inhibitory study is in progress and will be
reported in detail shortly.
We are grateful to the SC-NMR Laboratory of Okayama
University for 200 MHz 1H NMR experiments. This work was
partly supported by Grant-in-Aid for Scientific Research (C)
(No. 09680570) from the Ministry of Education, Science,
Sports and Culture, Japan.
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Notes and references
‡ All new compounds 2, 3c–i, 7 and 8b–i exhibited satisfactory elemental
combustion analyses and mass and H NMR spectral data consistent with
structures indicated, and showed mps over 300 °C except for 3c (mp
250 °C).
1
§ Typical procedure: A solution of 3c (0.3 g, 1.02 mmol) with 70% nitric
acid (0.5 ml, 5.55 mmol) in DMF (30 ml) was heated at 100 °C for 1 h. After
the reaction was complete, the solution was concentrated to dryness in
vacuo and treated with MeOH to afford the crystals 4c (75%), which were
collected by filtration and recrystallized from a mixture of DMF and EtOH.
Other derivatives 4d (85%), 4e (72%), 4f (71%), 4g (67%), 4h (61%) and
4i (60%) were prepared in a similar manner to 4c and recrystallized from a
mixture of DMF and EtOH or water. The compounds 4c–i showed mps
above 300 °C, respectively. dH[60 or 200 MHz, (CD3)2SO] for 4c: 0.86 (3H,
t, J 6.54), 1.30 (8H, br s), 1.50–1.80 (2H, m), 2.50–2.95 (2H, m), 8.53 (1H,
s), 12.41 (1H, br s), 13.50 (1H, br); for 4d: 7.40–7.70 (3H, m), 7.90–8.35
(2H, m), 8.68 (1H, s), 12.60 (1H, br s), 13.60 (1H, br); for 4e: 7.37 (2H, dd,
J 8.82, 9.06), 8.22 (2H, dd, J 8.82, 5.88), 8.66 (1H, s), 12.59 (1H, br s), 13.65
(1H, br); for 4f: 7.62 (2H, d, J 8.60), 8.17 (2H, d, J 8.60), 8.70 (1H, s), 12.62
(1H, br s), 13.66 (1H, br s); for 4g (CF3CO2D): 2.54 (3H, s), 7.51 (2H, d, J
8.76), 8.03 (2H, d, J 8.76 Hz), 8.94 (1H, s); for 4h: 3.85 (3H, s), 7.10 (2H,
d, J 8.76), 8.12 (2H, d, J 8.76), 8.64 (1H, s), 12.60 (1H, br s), 13.50 (1H, br);
for 4i: 8.39 (4H, br s), 8.69 (1H, s), 12.70 (1H, br s), 13.60 (1H, br).
¶ General procedure: A solution of 7 (0.2 g, 1.2 mmol) with an appropriate
triethyl orthoester (6 mmol) in trifluoroacetic acid (3 ml) was stirred at room
temperature for 1 h. After the reaction was complete, the deposit was
collected by filtration and recrystallized from DMF to yield the correspond-
ing 4a (mp > 300 °C, 66%) and 4b (mp > 300 °C, 83%). dH[200 MHz,
15 R. K. Robins, J. Am. Chem. Soc., 1956, 78, 784.
Communication 9/03676H
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Chem. Commun., 1999, 1461–1462