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4.2. General procedure for the preparation of derivatives
of tetrahydro-isoxazolo-[4,5-d]pyrimidine-3,7-dione (5a–g)
OCH3), 4.07 (d, J=4 Hz, 1H, 3a-CH), 4.37 (d, J=4 Hz,
1H, 7a-CH), 5.69 (s, 1H, 5-CH), 7.26 (s, 1H, 6-NH),
7.36–7.39 (d, J=8.5 Hz, 2H, 30/50-ArH), 7.76–7.80 (d,
J=8.5 Hz, 2H, 20/60-ArH), 8.25 (s, 1H, 2-NH). Anal.
calcd (C12H13N3O4): C, 54.75; H, 4.98; N, 15.96.
Found: C, 54.61; H, 5.06; N, 16.12.
To the suspension of compound 4 (4.35 g, 0.03 mol) in
100 mL of dry methanol was added 0.033 mol of the
corresponding aldehyde. The reaction mixture was stir-
red under reflux for 4 h. The mixture was concentrated
to ca. 30 mL. After cooling, the remainder was placed in
a refrigerator for 6 h, and the precipitate was filtered
and washed with methanol. Solids was purified by
recrystallization.
4.2.6. 5-(4-Nitro-phenyl)-tetrahydro-isoxaxolo[4,5-d]pyri-
midine-3,7-dione (5f). Ivory crystals obtained from 4 and
p-nitrobenzaldehyde and recrystallized from ethanol;
yield 72%; mp 206–207 ꢀC; 1H NMR (DMSO-d6) d 3.60
(br s, 1H, 4-NH), 4.19 (d, J=4 Hz, 1H, 3a-CH), 4.45 (d,
J=4 Hz, 1H, 7a-CH), 5.90 (s, 1H, 5-CH), 7.71 (s, 1H, 6-
NH), 8.07 (d, J=9 Hz, 20/60-ArH), 8.27–8.30 (m, 3H, 30/
50-ArH and 2-NH). Anal. calcd (C11H10N4O5): C, 47.49;
H, 3.62; N, 20.14. Found: C, 47.65; H, 3.51; N, 19.97.
4.2.1. 5-Ethyl-tetrahydro-isoxazolo[4,5-d]pyrimidine-3,7-
dione (5a). From 4 and propionyl aldehyde and recrys-
tallized from ethanol; yield 58% of white crystals; mp
ꢀ
1
189–190 C; H NMR (300 MHz, DMSO-d6) d 1.25 (t,
3H, CH3), 3.15 (m, 2H, CH2), 3.16 (br s, 1H, 4-NH),
3.70 (d, J=4 Hz, 1H, 3a-CH), 4.07 (d, J=4 Hz, 1H, 7a-
CH), 5.57 (s, 1H, 5-CH), 7.28 (s, 1H, 6-NH), 8.32 (s,
1H, 2-NH). EJ MS m/z 185 (M+) Anal. calcd
(C7H11N3O3): C, 45.40; H, 5.99; N, 22.69. Found: C,
45.55; H, 6.05; N, 22.75.
4.2.7. 5-(2-Hydroxy-phenyl)-tetrahydro-isoxazolo[4,5-
d]pyrimidine-3,7-dione (5g). Colorless crystals obtained
from 4 and salicylaldehyde and recrystallized from
methanol; yield 61%; mp 165–166 ꢀC; 1H NMR
(DMSO-d6) d 4.03 (br s, 1H, 4-NH), 4.24 (d, J=4 Hz,
1H, 3a-CH), 4.53 (d, J=4 Hz, 1H, 7a-CH), 5.96 (s, 1H,
5-CH), 7.29–7.40 (m, 3H, 40/50/60-ArH), 7.47 (s, 1H,
6-NH), 7.58–7.61 (d, 1H, J=6 Hz, 60-ArH), 7.94 (br s,
1H, OH), 8.39 (s, 1H, 2-NH). EJ MS m/z 249 (M+).
Anal. calcd(C11H11N3O4): C, 53.01;H, 4.45; N, 16.86.
Found: C, 53.18; H, 4.48: N, 16.72.
4.2.2. 5-Phenyl-tetrahydro-isoxazolo[4,5-d]pyrimidine-
3,7-dione (5b). Colorless needles obtained from 4 and
benzaldehyde and recrystallized from methanol; yield
79%; mp 168–169 ꢀC; 1H NMR (DMSO-d6) d 3.18 (br s,
1H, 4-NH), 4.08 (d, J+4 Hz, 1H, 3a-CH), 4.38 (d, J=4
Hz, 1H, 7a-CH), 5.63 (s, 1H, 5-CH), 7.34 (s, 1H, 6-NH),
7.44–7.51 (m, 3H, 30/40/50-PhH), 7.81–7.84 (m, 2H, 20/
60-PhH), 8.22 (s, 1H, 2-NH). EJ MS m/z 233 (M+).
Anal. calcd (C11H11N3O3): C, 56.65; H, 4.75; N, 18.02.
Found: C, 56.85; H, 4.90; N, 17.90.
4.2.8. 4-(4-Chloro-benzoylamino)-3-oxo-isoxazolidine-5-
carboxylic acid amide (6). To a suspension of 5.8 g
(0.04 mol) compound 4 in 80 mL anhydrous DMF and
4.5 g (0.045 mol) anhydrous TEA was added 7.87 g
(0.045 mol) p-chlorobenzoyl chloride at À5 to 0 ꢀC por-
tion-wise over a period of 30 min. The mixture was
stirred at 0 ꢀC for 2h and then at room temperature for
4.2.3. 5-(4-Fluoro-phenyl)-tetrahydro-isoxazolo[4,5-d]pyr-
imidine-3,7-dione (5c). Colorless needles obtained from
4 and p-fluorobenzaldehyde and recrystallized from
methanol; yield 83%; mp 165–166 ꢀC; 1HNMR
(DMSO-d6) d 3.75 (br s, 1H, 4-NH), 4.08 (d, J=4 Hz,
1H, 3a-CH), 4.39 (d, J=4 Hz, 1H, 7a-CH), 5.72(s, 1H,
5-CH), 7.41 (s, 1H, 6-NH), 7.52–7.54 (d, J=7 Hz, 20/
60-ArH), 7.87–7.92(d, J=7 Hz, 30/50-ArH), 8.21 (s, 1H,
2-NH). EJ MS m/z 251 (M+) Anal. calcd
(C11H10N3O3F): C, 52.59; H, 4.02; N, 16.73. Found: C,
52.73; H, 4.14; N, 16.51.
.
12h. The precipitate of TEA HCl was filtered and
washed with anhydrous DMF. The filtrate was evapo-
rated in vacuo to dryness. The residue was crushed with
30 mL of water and mixed with a solution of NaHCO3
(5%). The precipitate was filtered and washed water and
dried, giving 7.1 g of crude product (6). The product
was recrystallized from methanol giving a pure (TLC)
compound (6), 6.24 g (55% yield); mp 215–216 ꢀC; H
1
NMR (DMSO-d6) d 4.40 (d, J=4 Hz, 1H, 3a-CH), 4.76
(d, J=4 Hz, 1H, 7a-CH), 7.19 (br s, 1H, NH), 7.38 (br
s, 1H, NH), 7.43 (s, 1H, NH), 7.54 (d, J=9 Hz, 2H, 20/
60-ArH), 7.87(d, J=9 Hz, 2H, 30/50-ArH), 8.10 (s, 1H,
2-NH). EJ MS m/z 283 (M+). Anal. calcd
(C11H10N3O4Cl): C, 46.57; H, 3.55; N, 14.81. Found: C,
46.71; H, 3.61; N, 14.92.
4.2.4. 5 - (4 - Chloro - phenyl) - tetrahydro - isoxazolo[4,5 -
d]pyrimidine-3,7-dione (5d). Colorless needles obtained
from 4 and p-chlorobenzaldehyde and recrystallized
from ethanol; yield 92%; mp 176–177 ꢀC; 1H NMR
(DMSO-d6) d 3.81 (br s, 1H, 4-NH), 4.12(d, J=4 Hz,
1H, 3a-CH), 4.45 (d, J=4 Hz, 1H, 7a-CH), 5.80 (s, 1H,
5-CH), 7.40 (s, 1H, 6-NH), 7.51–7.53 (d, J=8 Hz, 2H,
20/60-ArH), 7.81–8.09 (d, J=8 Hz, 2H, 30/50-ArH), 8.30
(s, 1H, 2-NH). EJ MS m/z 267 (M+) Anal. calcd
(C11H10N3O3Cl): C, 49.35; H, 3.76; N, 15.70. Found: C,
49.56; H, 3.88; N, 15.63.
4.2.9. 5 - (4 - Chloro - phenyl) - 3a,7a - dihydro - 6H - isoxa-
zolo[4,5-d]pyrimidine-3,7-dione (7). To a suspension of
4.2g (0.014 mol) 6 in 100 mL anhydrous toluene was
added 20 mL of thionyl chloride, and refluxed for 8 h.
After cooling, the solvent and excess thionyl chloride
were distilled off under reduced pressure to dryness. The
residue was mixed with 50 mL of water and neutralized
with NaHCO3. The precipitate was filtered, washed with
water and dried. Two recrystallizations of the product
from methanol gave a pure compound (7), 2.2 g (59%
4.2.5. 5-(4-Methoxy-phenyl)-tetrahydro-isoxazolo[4,5-
d]pyrimidine-3,7-dione(5e). Colorless needles obtained
from 4 and p-methoxybenzaldehyde and recrystallized
from ethanol; yield 88%; mp. 179–180 ꢀC; 1H NMR
(DMSO-d6) d 3.76 (br s, 1H, 4-NH), 3.86 (s, 3H,
yield); mp 203–204 ꢀC; H NMR (300 MHz, DMSO-d6)
1