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M. Zink et al. / European Journal of Medicinal Chemistry 39 (2004) 1079–1088
–
–
residue was purified by MPLC (cyclohexane/acetic acid
(8:2)) and following crystallization from ethanol to yield
79% (2.6 g) of 9 as colourless crystals, m.p. 121–122 °C
(ethanol); IR: cm–1 3435 (NH), 3076, 3027 (Ar-H), 2997,
2950 (C-H), 2834 (OCH3), 2230 (CN), 1721 (C=N), 1611,
C-3); MS: 277 (8) [M+ -ClO4 ], 232 (16) [M+ -ClO4
-(CH3)2NH], 188 (100). Anal. C16H25ClN2O6 (C, H, N).
7.1.9. 2-(2,5-Dimethoxybenzyl)acrylaldehyde (18)
To a stirred solution of oxalylchloride (3.1 g, 0.024 mol) in
50 ml dry methylene chloride, that was cooled to –70 °C,
dimethylsulfoxide (3.72 ml, 0.048 mol) in 20 ml dry methyl-
ene chloride was added drop wise. After 10 min, 3-(2,5-
dimethoxy)phenylpropanol (15) (4.28 g, 0.022 mol) was
added in small portions at –60 °C within 5 min. The solution
was stirred for further 15 min. Then triethylamine (12.4 ml,
0.090 mol) was added cautiously. After the solution had
warmed at room temperature N,N-dimethyl(methylene)-
immoniumchloride (“Böhme-Salz”) (16) (4.12 g, 0.044 mol)
was added and the solution was stirred for 15 h. After the
addition of methylenechloride (30 ml), the organic layer was
washed three times with a saturated aqueous solutions of
NaHCO3 and NaCl, then washed with water (20 ml), dried
with Na2SO4 and concentrated under reduced pressure giv-
ing 2.83 g of a yellow oil (18) in 63% yield, that was purified
by vacuum distillation, b.p. 190–210 °C (0.4 kPa), IR: cm–1
3017 (Ar-H), 2955, 2911 (C-H), 2836 (OCH3), 1693 (CHO),
1503 (C=C), 1H-NMR: (CDCl3) d3.53 (2H, dd J1 = 0.5 Hz,
J2 = 0.5 Hz, CH2), 3.75 (6H, s, OCH3), 6.01 (1H, dt, J1
= 1 Hz, J2 = 0.5 Hz, 3-H), 6.03 (1H, dt, J1 = 1 Hz, J2 = 0.5 Hz,
3-H), 6.69–6.82 (3H, m, 3′-H, 4′-H, 6′-H), 9.61 (1H, s,
CHO); 13C-NMR: D 32.67 (CH2), 55.22 (OCH3), 55.68
(OCH3), 147.93 (C-2), 135.71 (C-3), 111.67, 111.72, 116.51,
127.25 (C-l′, C-3′, C-4′, C-6′), 151.21 (C-2′), 152.96 (C-5′),
194.68 (C-1); MS: 206 (90) [M+], 175 (100) [M+ -OCH3].
Anal. C12H14O3 (C, H).
1
1592, 1563, 1545, 1499 (C=C); H-NMR:d 2.40 (3H, s,
CH3), 2.42 (3H, s, CH3), 3.60 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 3.96 (2H, s, CH2), 6.14 (1H, d, J = 3 Hz, 6′-H), 6.79
(1H, dd, J1 = 9 Hz, J2 = 3 Hz, 4′-H), 6.95 (1H, d, J = 9 Hz,
3′-H); MS: 316/318 (100/33) [M+], 301/303 (25/8) [M+
-CH3], 285/287 (25/9) [M+ -OCH3]. Anal. C17H17N2O2Cl
(C, H, N).
7.1.7. 2,5-Dimethoxybenzylmalonic acid (12)
Diethyl 2,5-dimethoxybenzylmalonate (11) (3.9 g,
0.019 mol) and 15 g NaOH in 100 ml H2O/EtOH (1:1) were
heated to 80 °C for 2 h. After cooling, water (100 ml) was
added; the solution was acidified with HClconc and extracted
with ether (20 ml) for three times. The organic layer was
washed with water (20 ml) three times, dried with Na2SO4,
concentrated under reduced pressure and crystallized from
toluol to yield 43% (1.37 g) of colourless crystals, m.p.
155–157 °C (toluol), IR: cm–1 3200–2500 (COOH), 3060
(Ar-H), 2956, 2911 (C–H), 2836 (OCH3), 1718, 1713 (C=O),
1506 (C=C) 1293 (O–H); 1H-NMR:d 2.96 (2H, d, J = 7.5 Hz,
CH2), 3.55 (1H, t, J = 7.5 Hz , H-2), 3.66 (3H, s, OCH3), 3.73
(3H, s, OCH3), 6.69 (1H, d, J = 3 Hz, 6′-H), 6.75 (1H dd, J
= 9 Hz, J = 3 Hz, 4′-H) 6.86 (1H, d, J = 9 Hz, 3′-H), 12.64
(2H, br, OH, D2O exchangeable); 13C-NMR:d 29.76 (CH2),
55.66 (OCH3), 56.20 (OCH3), 111.96, 112.15, 117.08,
127.49 (C-l′, C-3′, C-4′, C-6′), 151.77 (C-5′), 153.14 (C-2′),
170.69 (COOH); MS: 254 (34) [M+], 210 (100) [M+ -CO2];
Anal C12H14O6 (C, H).
7.1.10. 5,8-Dihydro-6-(2,5-dimethoxybenzyl)pyrido[2,3-d]
pyrimidine-2,4-diamine (19)
7.1.8. N-[(2E)-2-(2,5-dimethoxybenzyl)-3-dimethylamino)
prop-2-en-1-ylidene]-N-methyl-methanium-perchlorate
(13)
2-(2,5-Dimethoxybenzyl)acrylaldehyde (18) (911 mg,
4.4 mmol) was heated under reflux with pyrimidine-2,4,6-
triamine (14) (428 mg, 3.4 mmol) in a mixture of ethanol
(5 ml) and acetic acid (5 ml) for 5 h.After cooling, the residue
was filtered off and gave 19 as a colourless powder, yield
30% (320 mg), m.p. 262–263 °C; IR: cm–1 3322, 3161 (NH2,
NH), 3058 (Ar-H), 2944 (C-H), 2833 (OCH3), 1700, 1658
N,N-Dimethylformamide (2.1 g, 0.029 mol) was stirred
and cooled in an ice bath. Phosphoroxychloride (2.09 g,
0.014 mol) was added drop wise. To this mixture, 2,5-
dimethoxybenzyl-malonic acid (12) (2.55 g, 0.01 mol) was
added in small portions and stirred for 24 h at room tempera-
ture, then 30 min under reduced pressure. After cooling in an
ice bath, ethanol (4 ml) and a solution of N,N-dimethyl
ammoniumperchlorate (1.45 g, 0.01 mol) in ethanol (4 ml)
were added. The precipitate was separated and crystallized
from ethanol to yield 13, 32% (1.2 g) of colourless crystals,
m.p. 154 °C (ethanol); IR: cm–1 3018 (Ar-H), 2970, 2943
(C-H), 2841 (OCH3), 1597 (C=N), 1495 (C=C); 1H-NMR: D
3.01 (6H, br, NCH3), 3.23 (6H, br, NCH3), 3.70 (3H, s,
OCH3), 3.72 (2H, s, CH2), 3.78 (3H, s, OCH3), 6.52 (1H, d, J
= 2.2 Hz, 6′-H), 6.84 (1H, dd, J1 = 6.0 Hz, J2 = 2.2 Hz, 4′-H),
6.97 (1H, d, J = 6.0 Hz, 3′-H), 7.67 (2H, s, 1-H, 3-H);
13C-NMR:d 24.63 (CH2), 48.66 (CH3), 55.24 (OCH3), 55.74
(OCH3), 98.36 (C-2), 110.90, 111.44, 115.98, 129.65 (C1′,
C-3′, C-4′, C-6′), 150.21, 153.40 (C-2′, C-5′), 166.40 (C-1,
1
(CHO), 1584, 1528, 1498 (C=C); H-NMR:d 2.90 (2H, s,
CH2), 3.09 (2H, s, 5-H), 3.68 (3H, s, OCH3), 3.72 (3H, s,
OCH3), 5.33 (2H, s, NH2, D2O exchangeable), 5.61 (2H, s,
NH2, D2O exchangeable), 5.67 (1H, d, J = 5 Hz, 7-H), 6.73
(1H, d, J = 3.5 Hz, 6′-H), 6.74 (1H, dd, J1 = 9 Hz, J2 = 3.5 Hz,
4′-H), 6.88 (1H, d, J = 9 Hz, 3′-H), 7.51 (1H, d, J = 5 Hz,
8-NH, D2O exchangeable); MS: 313 (59) [M+], 312 (59) [M+
-1], 298 (5) [M+ -CH3], 282 (76) [M+ -OCH3], 162 (100).
Anal. C16H19N5O2 (C, H, N).
7.1.11. Diethyl [2-(2,5-dimethoxyphenyl)ethyl]malonate
(22)
Diethylmalonate (21) (2.72 g, 0.017 mol) was dissolved in
dry tetrahydrofuran (25 ml). To this solution, a 60% dis-
persion of sodium hydride in petroleum (0.72 g, 0.018 mol)