A. Zarghi et al. / Il Farmaco 58 (2003) 1077Á
/1081
1079
3. Experimental
1H, CHO), 7.8Á/7.2 (m, 6H, H4-imidazole and phenyl),
2.8 (s, 3H, SCH3).
3.1. Chemistry
3.1.4. General procedure for the synthesis of
dihydropyridine derivatives (5aÁh)
/
Melting points were determined using a Mettler FP61
capillary apparatus. Infrared spectra acquired on a
A mixture of compound 4 (100 mg, 0.429 mmol),
appropriate acetoacetate ester (0.858 mmol) and ammo-
nium acetate (33 mg, 0.429 mmol) in 3 ml of methanol
was refluxed for 24 h. The solvent was evaporated and
the residue was purified by preparative thin-layer
chromatography. Silica gel GF254 was used as adsor-
bent and chloroform was used as mobile phase.
PerkinÁElmer 1420 recording spectrometer. A Bruker
/
FT-80 instrument was used to acquire 1H NMR spectra;
with tetramethylsilane as the internal standard. Mass
spectra were acquired with a Finnigan TSQ-70 mass
spectrometer. Electron-impact ionization was performed
at an ionizing energy of 70 eV. Elemental analyses were
carried out with a PerkinÁ
tus. Elemental microanalyses were within 9
theoretical values for C, H and N.
/
Elmer Model 240-C appara-
3.1.5. 3,5-Dimethyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyyridinedicarboxylate (5a)
/
0.4% of the
Mp: 197Á
/
198 8C; IR (KBr): n (cmꢂ1) 3348 (NH),
3.1.1. 5-Hydroxymethyl-2-mercapto-1-
phenylaminoimidazole (2)
1704 (CO); 1H NMR (CDCl3): d 7.60Á
/7.20 (m, 5H,
phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.55 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 3.70 (s, 6H,
To a mixture of dihydroxyacetone (4.26 g, 46 mmol),
potassium thiocyanate (6.9 g, 70 mmol) and phenylhy-
drazine (8.66 g, 60 mmol) in 30 ml of butanol, 5.4 ml of
glacial acetic acid was added. The reaction mixture was
stirred at room temperature for 72 h and the precipitate
was collected. After washing with ether, the precipitate
was dried under reduce pressure to give 12.7 g (65%) of
OCH3), 2.65 (s, 3H, SCH3), 2.30 (s, 6H, CH3Ã
/
C2 and
C6). Mass; m/z (%): 428 (Mꢀ,10), 414 (86), 400
(21), 383 (19), 382 (40), 355 (100), 335 (31), 325 (13), 323
(74), 224 (35).
CH3Ã
/
3.1.6. 3,5-Diethyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5b)
2. Mp 133Á
/
134 8C; 1H NMR (CDCl3): d 8.2 (s, 1H, H4-
8.1 (m, 2H, phenyl), 7.1Á7.5 (m, 3H,
phenyl), 6.0 (s, 1H, SH), 4.6 (s, 2H, CH2O), 3.7 (s, 1H,
imidazole), 7.9Á
/
/
Mp: 142Á
/
143 8C; IR (KBr): n (cmꢂ1) 3343 (NH),
OH).
1692 (CO); 1H NMR (CDCl3): 7.60Á
/7.20 (m, 5H,
phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.55 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 4.20 (q, 4H,
3.1.2. 5-Hydroxymethyl-2-methylthio-1-
phenylaminoimidazole (3)
OCH2), 2.65 (s, 3H, SCH3), 2.25 (s, 6H, CH3Ã
/
C2 and
C6), 1.30 (t, 6H, CH3). MS; m/z (%): 456 (Mꢀ,8),
442 (37), 396 (20), 369 (100), 349.0 (26), 323 (64), 252
(37).
To a stirring solution of compound 2 (2.81 g, 10
mmol) and potassium hydroxide (1.4 g, 25 mmol) in 5
ml of methanol a solution of methyl iodide (2.13 g, 15
mmol) in 2.5 ml of methanol was added drop-wise. After
2 h the mixture was poured into water and the
precipitate was collected, washed with water, and dried.
CH3Ã
/
3.1.7. 3,5-Dipropyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5c)
The residue was recrystallized from acetoneÁ
ether to give 1.58 g (67%) of 3, mp: 92Á93 8C.
1H NMR (CDCl3): d 7.3Á
7.7 (m, 6H, H4-imidazole
/
petroleum
142 8C; IR (KBr): n (cmꢂ1) 3206, 3270
/
Mp: 141Á
/
1
/
(NH), 1694 (CO). H NMR (CDCl3): d 7.60Á
/7.20 (m,
and phenyl), 4.8 (s, 2H, CH2O), 3.2 (bs, 1H, OH), 2.7 (s,
3H, SCH3).
5H, phenyl), 6.90 (s, 1H, H-C4 imidazole), 6.50 (bs, 1H,
NH), 5.40 (s, 1H, H-C4 dihydropyridine), 4.05 (t, 4H,
OCH2), 2.50 (s, 3H, SCH3), 2.10 (s, 6H, CH3Ã
/
C2 and
3.1.3. 2-Methylthio-1-phenylaminoimidazole-5-
carboxaldehyde (4)
CH3Ã
/
C6), 1.65 (m, 4H, CH2), 0.90 (t, 6H, CH3). MS; m/
z (%): 484 (Mꢀ,5), 470 (34), 410 (18), 385 (18), 383
(100), 363 (30), 323 (68), 280 (54), 196 (24).
A mixture of compound 3 (5 g, 21.3 mmol) and
activated magnesium dioxide (7.4 g, 85.2 mmol) in 35 ml
of acetonitrile was refluxed for 9 h. After cooling, the
mixture was filtered on diatomaceous earth and the
solvent removed under reduced pressure. The residue
was crystallized in a mixture of acetone and petroleum
ether to yield 4.2 g (85%) white needle crystals of
3.1.8. 3,5-Diisopropyl-1,4-dihydro-2,6-dimethyl-4-(2-
methylthio-1-phenylamino-5-imidazolyl)-3,5-
pyridinedicarboxylate (5d)
Mp: 186Á
1688 (CO); 1H NMR (CDCl3): d 7.55Á
phenyl), 6.85 (s, 1H, HÃC4 imidazole), 6.50 (bs, 1H,
NH), 5.40 (s, 1H, HÃC4 dihydropyridine), 5.05 (m, 2H,
/
188 8C; IR (KBr): n (cmꢂ1) 3252 (NH),
/7.20 (m, 5H,
compound 4; mp: 84Á
/
85 8C; IR (KBr): n (cmꢂ1) 3300
(NH), 1710 (CO); H NMR (CDCl3): d (ppm) 10.0 (s,
/
1
/