302
Chem. Pharm. Bull.
Vol. 64, No. 4 (2016)
95–97°C, Anal. (%): (C23H30ClNO4), Calcd (Found), C: 65.78 (t, J=8.5Hz, 1H, aromatic C(5′)H), 7.11 (t, J=7.5Hz, 1H, aro-
(65.55), H: 7.20 (6.94), N: 3.34 (3.33). 1H-NMR (500MHz, matic C(4′)H), 7.21 (d, J=8.5Hz, 1H, aromatic C(6′)H), 7.38
CDCl3) δ: 0.87 (d, J=5.8Hz, 6H, CH(CH3)2), 0.90 (d, (d, J=7.5Hz, aromatic 1H, C(3′)H).
J=5.8Hz, 6H, CH(CH3)2), 1.80–1.96 (m, 2H, 2 of CH(CH3)2),
5-Isobutyl 3-Methyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4-
2.32 (s, 6H, C2-CH3 and C6-CH3), 3.83 (d, J=6.0Hz, 4H, 2 of dihydropyridine-3,5-dicarboxylate (6d)
COOCH2), 4.89 (s, 1H, C4-H), 5.79 (s, 1H, NH), 6.99–7.21(m,
Recrystallization from methanol afforded 0.215g (32%), mp:
3H, aromatic C(6′)H, C(5′)H and C(4′)H), 7.28 (s, 1H, aro- 158–160°C, Anal. (%): (C20H24ClNO4), Calcd (Found), C: 63.57
matic C(2′)H).
Bis(2-methoxyethyl) 4-(3-Chlorophenyl)-2,6-dimethyl-1,4- CDCl3) δ: 0.78 (d, J=6.4Hz, 6H, CH(CH3)2), 1.88–1.99 (m,
dihydropyridine-3,5-dicarboxylate (3k) 1H, CH(CH3)2), 2.28 (s, 6H, C2-CH3 and C6-CH3), 3.58 (s,
(63.40), H: 6.40 (6.15), N: 3.71 (3.57). 1H-NMR (500MHz,
Recrystallization from methanol afforded 0.476g (62%), mp: 3H, COOCH3), 3.84 (d, J=7.3Hz, 2H, COOCH2CH), 5.30
118–120°C, Anal. (%): (C21H26ClNO6), Calcd (Found), C: 59.50 (s, 1H, C4-H), 5.68 (s, 1H, NH), 6.97 (t, J=8.5Hz, 1H, aro-
(59.19), H: 6.18 (5.92), N: 3.30 (3.28). 1H-NMR (500MHz, matic C(5′)H), 7.11 (t, J=7.5Hz, 1H, aromatic C(4′)H), 7.23
CDCl3) δ: 2.31 (s, 6H, C2-CH3 and C6-CH3), 3.33 (s, 6H, 2 (d, J=8.5Hz, 1H, aromatic C(6′)H), 7.38 (d, J=7.5Hz, 1H,
of OCH3), 3.49–3.62 (m, 4H, 2 of COOCH2CH2O), 4.06–4.24 aromatic C(3′)H).
(m, 4H, 2 of COOCH2), 4.96 (s, 1H, C4-H), 6.99–7.15 (m, 2H,
3-Ethyl 5-Isobutyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4-
aromatic C(6′)H and C(5′)H); 7.19 (d, J=8.8Hz, 1H, aromatic dihydropyridine-3,5-dicarboxylate (6e)
C(4′)H); 7.26 (s, 1H, aromatic C(2′)H).
Recrystallization from methanol afforded 0.196g (28%), mp:
General Procedure for the Synthesis of Asymmetrical 114–116°C, Anal. (%): (C21H26ClNO4), Calcd (Found), C: 64.36
1
Esters of Dialkyl 4-(Chlorophenyl)-2,6-dimethyl-1,4-dihy- (64. 09), H: 6.69 (6.39), N: 3.57 (3.59). H-NMR (500MHz,
dropyridine-3,5-dicarboxylate (6a–n) To a 50mL round- CDCl3) δ: 0.74 (d, J=6.5Hz, 6H, CH(CH3)2), 1.15 (t, J=6.1Hz,
bottomed flask were added a mixture of 2-chlorobenzaldehyde 3H, CH2CH3), 1.84–1.99 (m, 1H, CH(CH3)2), 2.27 (s, 6H,
or 3-chlorobenzaldehyde (0.250g, 1.78mmol), alkyl aceto- C2-CH3 and C6-CH3), 3.75 (d, J=7.1Hz, 2H, COOCH2CH),
acetate (1.78mmol) and alkyl 3-aminocrotonate (1.78mmol) 3.96–4.21 (m, 2H, COOCH2CH3), 5.34 (s, 1H, C4-H), 5.77
in 10mL methanol or 2-propanol. The reaction mixture was (s, 1H, NH), 6.98 (t, J=8.5Hz, 1H, aromatic C(5′)H), 7.11 (t,
protected from light and heated under reflux for 9–24h. After J=7.5Hz, 1H, aromatic C(4′)H), 7.23 (d, J=8.5Hz, 1H, aro-
cooling, the precipitate was filtered and purified by crystalli- matic C(6′)H), 7.37 (d, J=7.5Hz, 1H, aromatic C(3′)H).
zation from methanol or 2-propanol to afford the correspond-
ing product.
3-Methyl
5-(2-Methoxyethyl)
4-(2-Chlorophenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (6f)
5-Ethyl 3-Methyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (6a)
Recrystallization from methanol afforded 0.347g (51%),
mp: 103–105°C, Anal. (%): (C19H22ClNO5), Calcd (Found),
Recrystallization from methanol afforded 0.189g (30%), C: 60.08 (59.76), H: 5.84 (5.61), N: 3.69 (3.44). 1H-NMR
mp: 113–115°C, Anal. (%): (C18H20ClNO4), Calcd (Found), (500MHz, CDCl3) δ: 2.26 (s, 6H, C2-CH3 and C6-CH3), 3.26
C: 61.80 (62.09), H: 5.76 (5.50), N: 4.00 (4.18). 1H-NMR (s, 3H, OCH3), 3.52–3.58 (m, 2H, COOCH2CH2O), 3.66 (s,
(500MHz, CDCl3) δ: 1.17 (t, J=6.1Hz, 3H, CH2CH3), 2.25 (s, 3H, COOCH3), 4.05–4.26 (m, 2H, COOCH2CH2O), 5.42 (s,
6H, C2-CH3 and C6-CH3), 3.59 (s, 3H, COOCH3), 3.98–4.14 1H, C4-H), 5.77 (s, 1H, NH), 7.02 (t, J=8.5Hz, 1H, aromatic
(m, 2H, COOCH2), 5.40 (s, 1H, C4-H), 5.69 (s, 1H, NH), 7.01 C(5′)H), 7.11 (t, J=7.5Hz, 1H, aromatic C(4′)H), 7.22 (d,
(t, J=8.5Hz, 1H, aromatic C(5′)H), 7.13 (t, J=7.5Hz, 1H, aro- J=8.5Hz, 1H, aromatic C(6′)H), 7.36 (d, J=7.5Hz, 1H, aro-
matic C(4′)H), 7.22 (d, J=8.5Hz, 1H, aromatic C(6′)H), 7.37 matic C(3′)H).
(d, J=7.5Hz, 1H, aromatic C(3′)H).
5-Isopropyl 3-Methyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4- methyl-1,4-dihydropyridine-3,5-dicarboxylate (6g)
dihydropyridine-3,5-dicarboxylate (6b) Recrystallization from methanol afforded 0.394g (56%), mp:
3-Ethyl 5-(2-Methoxyethyl) 4-(2-Chlorophenyl)-2,6-di-
Recrystallization from methanol afforded 0.166g (25%), mp: 70–72°C, Anal. (%): (C20H24ClNO5), Calcd (Found), C: 60.99
151–153°C, Anal. (%): (C19H22ClNO4), Calcd (Found), C: 62.72 (61.31), H: 6.14 (5.80), N: 3.56 (3.53). 1H-NMR (500MHz,
(62.42), H: 6.09 (5.84), N: 3.85 (3.89). 1H-NMR (500MHz, CDCl3) δ: 1.17 (t, J=6.1Hz, 3H, CH2CH3), 2.30 (s, 6H, C2-
CDCl3) δ: 1.00 (d, J=5.9Hz, 3H, CH(CH3)2), 1.19 (d, J=5.9Hz, CH3 and C6-CH3), 3.29 (s, 3H, OCH3), 3.44 (t, J=5.3Hz, 2H,
3H, CH(CH3)2), 2.22 (s, 3H, C2-CH3), 2.32 (s, 3H, C6-CH3), COOCH2CH2O), 3.51–3.61 (m, 2H, COOCH2CH3), 4.00–4.10
3.55 (s, 3H, COOCH3), 4.85–5.05 (m, 1H, CH(CH3)2), 5.31 (m, 2H, COOCH2CH2O), 4.41 (s, 1H, C4-H), 4.85 (s, 1H, NH),
(s, 1H, C4-H), 5.71 (s, 1H, NH), 7.00 (t, J=8.5Hz, 1H, aro- 7.02 (t, J=8.5Hz, 1H, aromatic C(5′)H), 7.11 (t, J=7.5Hz, 1H,
matic C(5′)H), 7.11 (t, J=7.5Hz, 1H, aromatic C(4′)H), 7.21 aromatic C(4′)H), 7.21 (d, J=8.5Hz, 1H, aromatic C(6′)H),
(d, J=8.5Hz, 1H, aromatic C(6′)H), 7.35 (d, J=7.5Hz, 1H, 7.37 (d, J=7.5Hz, 1H, aromatic C(3′)H).
aromatic C(3′)H).
5-Benzyl 3-Methyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4-
3-Ethyl 5-Isopropyl 4-(2-Chlorophenyl)-2,6-dimethyl-1,4- dihydropyridine-3,5-dicarboxylate (6h)
dihydropyridine-3,5-dicarboxylate (6c)
TLC purification afforded 0.601g (81% yield), pure oil,
Recrystallization from methanol afforded 0.483g (71%), mp: Anal. (%): (C23H22ClNO4), Calcd (Found), C: 67.07 (66.89),
1
115–117°C, Anal. (%): (C20H24ClNO4), Calcd (Found), C: 63.57 H: 5.38 (5.47), N: 3.40 (3.36). H-NMR (500MHz, CDCl3) δ:
(63.38), H: 6.40 (6.09), N: 3.71 (3.57). 1H-NMR (500MHz, 2.27 (s, 3H, COOCH3), 3.47 (s, 6H, C2-CH3 and C6-CH3), 3.60
CDCl3) δ: 1.44 (t, J=6.1Hz, 3H, CH2CH3), 1.18 (d, J=6.0Hz, (s, 2H, COOCH2), 4.98 (s, 1H, C4-H), 5.44 (s, 1H, NH), 7.01
3H, CH(CH3)2), 1.24 (d, J=6.0Hz, 3H, CH(CH3)2), 2.21 (s, 6H, (t, J=8.5Hz, 1H, C(5′)H), 7.08–7.15 (m, 8H, aromatic C(4′)H,
C2-CH3 and C6-CH3), 3.82–4.20 (m, 2H, COOCH2), 4.70–5.01 C(6′)H, C(3′)H and OCH2C6H5).
(m, 1H, CH(CH3)2), 5.28 (s, 1H, C4-H), 5.72 (s, 1H, NH), 6.98