Vol. 26, No. 15 (2014)
Identification and Synthesis of Impurities Formed During Preparation of Azelnidipine 4677
3,5-dicarboxylate (2a): To stirred solution of imidinoacetate
(1g, 0.0026 mmol), (Z)-methyl 2-(3-nitrobenzylidene)-3-
oxobutanoate (0.65 g, 0.0026 mmol) and isopropyl alcohol
(25 mL) was added sodium methoxide (140 mg, 0.0026 mmol)
heated reflux for 2 h, filtered and distilled under vacuum results
to get residue was treated with cyclohexane obtained then (1.2
g) yellow colored compound obtained. 1H NMR (DMSO-d6)
δ: 8.03-8.08 (2H, m), 7.55-7.64 (2H, m), 4.84-4.89 (2H, m),
2.89-2.93 (1H, m), 3.43-3.48 (1H, m), 2.42 (1H, t), 3.28-4.25
(2H, m), 7.14-7.39 (10 H, m), 2.28 (3H, m), 3.52 (3H, s), 6.80
(2H, br), 8.95 (1H,s). 13C NMR (DMSO-d6) δ: 121.81, 151.48,
120.77, 129.53, 134.21, 147.28, 38.45, 102.34, 145.81, 151.93,
76.28, 166.91, 61.35, 59.42, 61.35, 77.22, 142.14, 142.24,
Synthesis of 3-(1-benzhydrylazetidin-3-yl)-5-isopropyl-
2-amino-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (4): To stirred solution of imidinoacetate
(1g, 0.0026 mmol), (Z)-isopropyl 2-(4-nitrobenzylidene)-3-
oxobutanoate (0.65 g, 0.0026 mmol) and isopropyl alcohol
(25 mL) was added sodium methoxide (140 mg, 0.0026 mmol)
heated reflux for 2 h, filtered and distilled under vacuum results
to get residue was treated with cyclohexane then 1.1 g of yellow
colored compound obtained. 1H NMR (DMSO-d6) δ: 8.18 (2H,
d), 7.45 (2H, d), 4.75-4.83 (2H, m), 2.91 (1H, t), 3.43 (1H, t),
2.40 (1H, br), 3.26-3.33 (1H, m), 4.27 (1H, s), 7.14-7.40 (10H,
m), 2.26 (3H, s), 4.75-4.83 (1H, m), 1.03,1.18 (6H, d,d), 6.78
(2H, br), 8.86 (1H, s), 8.86 (1H, s). 13C NMR (DMSO-d6) δ:
129, 123.09, 145.44, 157.22, 38.67, 102.59, 145.23, 151.87,
75.99, 165.92, 61.68, 59.32, 59.88, 76.93, 142.20, 142.30,
128.40, 127.01, 126.96, 18.66, 167.23, 66.41, 21.53, 21.82.
IR (KBr, νmax, cm-1): 3437, 3027, 2978, 2927, 2850, 1677,
1646, 1516, 1490, 1452, 1385, 1373, 1345, 1287, 1215, 1106,
1067, 828, 746, 705. Mass m/z = 583 (M + H) +, 581 (M - H)-,
617 (M - H + HCl)–, 695 (M - H + CF3COOH)–.
128.40, 127.01, 128.40, 18.66, 167.12, 50.78. IR (KBr, (νmax
,
cm-1): 3441, 3027, 2926, 2850, 1676, 1648, 1489, 1526, 1452,
1434, 1384, 1348, 1318, 1290, 1217, 1110, 1069, 1029, 745,
705. Mass m/z = 555 (M + H)+, 553 (M-H)-, 589 (M-H +
HCl)-, 667 (M - H + CF3COOH)–.
Synthesis of 3-(1-benzhydrylazetidin-3-yl)-5-ethyl 2-
amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (2b): To stirred solution of imidinoacetate
(1 g, 0.0026 mmol), (Z)-ethyl-2-(3-nitrobenzylidene)-3-
oxobutanoate (1.16 g, 0.0026 mmol) and isopropyl alcohol
(25 mL) was added sodium methoxide (140 mg, 0.0026 mmol)
heated reflux for 2 h, filtered and distilled under vacuum results
to get residue was treated with cyclohexane then (1 g) yellow
colored compound obtained. 1H NMR (DMSO-d6) δ: 8.04-8.09
(2H, m), 7.55-7.64 (2H, m), 4.84-4.88 (2H, m), 2.87-2.91 (1H,
dd), 3.45 (1H, t), 2.35 (1H, t), 3.28 (1H, t), 4.20 (1H, s), 7.13-
7.38 (10H, m), 2.28 (3H, s), 3.91-4.03 (2H, m), 1.11 (3H, t),
6.77 (2H, br), 8.85 (1H, s). 13C NMR (DMSO-d6) δ: 122.22,
151.63, 120.71, 129.51, 134.40, 147.08, 38.67, 102.53, 145.50,
151.80,76.30, 166.37, 61.36, 59.35, 60.11, 77.25, 142.11, 142.21,
128.39, 126.95, 127.02, 18.64, 167.14,59.20, 14.01. IR (KBr,
νmax, cm-1): 3423, 3313, 3086, 3030, 2982, 2962, 2942, 2900,
2850, 1683, 1660, 1524, 1493, 1455, 1388, 1375, 1363, 1347,
1314, 1291, 1210, 1168, 1130, 1085, 1072, 827, 747, 704. Mass
m/z = 569 (M + H)+, 682 (M - H + CF3COOH)–.
RESULTS AND DISCUSSION
During the condensation of product 1, formation of 0.5-
1 % of the two impurities 2a and 2b are observed, the level is
reduced to less than 0.1 % during its isolation and purification.
It is difficult to remove the impurity 2a and 2b from azelni-
dipine (1). The 2a and 2b was prepared by condensation of
7(b) and 7(c) with 1-benzhydrylazetidin-3-yl-3-amino-3-
iminopropanoate acetate (8) in the presence of base (Scheme-
II). The impurity 3 was prepared by oxidizing of 1 and the
pyridine impurity 3 formed (Scheme-III). The impurity para
nitro impurity 4 was prepared by the condensation of (Z)-
isopropyl-2-(4-nitrobenzylidene)-3-oxobutanoate with 8 in the
presence of base (Scheme-IV).
NO2
O
Synthesis of 3-(1-benzhydrylazetidin-3-yl) 5-isopropyl
2-amino-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicar-
boxylate (3): To stirred solution of 3-(1-benzhy-drylazetidin-
3-yl)-5-isopropyl-2-amino-6-methyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (1 g, 0.0017 mmol) with
dichloromethane (15 mL) was added 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) (0.52 g) at ambient temperature for
5 h then extracted with 10 mL water, washed the organic layer
with 5 % sodium carbonate solution then residue was treated
with cyclohexane then 800 mg of orange colored compound
obtained. 1H NMR (DMSO-d6) δ: 8.08 (1H, t), 8.43-8.46 (1H,
dd), 7.80 (1H, t), 7.67 (1H, d), 4.8-4.87 (1H, m), 2.08 (1H, t),
3.14-3.23 (2H, m), 2.2 (1H, t), 3.99 (1H, s), 7.15-7.29 (10H,
m), 2.36 (3H, s), 4.66-4.74 (1H, m), 0.84,0.91 (6H, dd), 7.15-
7.29 (2H, m). 13C NMR (DMSO-d6) δ: 122.79, 147.77, 122.72,
129.78, 134.82, 140.55, 147.24, 118.63, 158.30, 158.16,
103.04, 165.65, 63.41, 58.36, 58.71, 76.99, 141.84, 128.45,
+
HOAc
NH
O
R
N
H2N
O
O
8
7
a
NO2
O
O
N
R
O
N
H
NH2
126.86, 127.13, 22.94, 166.37, 68.27, 20.82. IR (KBr, νmax
,
2
a) R= OCH3
b) R= OC2H5
cm-1): 3503, 3381, 3054, 3030, 2982, 2964, 2845, 1716, 1694,
1590, 1557, 1522, 1450, 1350, 1306, 1241, 1122, 1103, 1073,
741, 704. Mass m/z = 581 (M + H) +, 580 (M - H)–.
Scheme-II: Reagents, conditions, (a) sodium methoxide, isopropyl alcohol
at 70 °C