Molecules 2014, 19
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(200 mL). The organic phase was washed with water (300 mL), dried over anhydrous magnesium
sulfate and concentrated. The residue was purified by flash column chromatography on silica gel,
eluting with ethyl acetate/petroleum ether, 3:2, to yield 4 as a light yellow solid (1.2 g, 55%). HPLC
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purity 99.7%. H-NMR (DMSO-d6) δ: 9.04 (s, 1H), 7.52-8.01 (m, 4H), 4.99 (s, 1H), 3.98–4.03 (m,
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2H), 3.55 (s, 3H), 2.30 (s, 6H), 1.12–1.16 (m, 3H). C-NMR (DMSO-d6) δ: 167.7, 167.1, 150.7,
148.2, 147.2, 147.0, 134.7, 130.3, 122.3, 121.8, 101.7, 101.4, 59.9, 51.4, 41.0, 18.9 (2C), 14.7. MS
(ESI−) m/z: 359.1 (M−H)−.
3-(2-Cyanoethyl) 5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylate (17)
Ethyl 3-aminobut-2-enoate (16, 37.3 g, 0.29 mol) was added to the solution of compound 8 (85 g,
0.295 mol) in ethanol (216 mL), heated to reflux for 2 h. The reaction mixture was concentrated at
60 °C to about 100 mL, and cooled to 0–5 °C. The precipitate was collected by vacuum filtration and
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dried at 60 °C for 10 h to provide 17 (45.4 g, 39%). H-NMR (DMSO-d6) δ: 9.09 (s, 1H), 7.48–7.99
(m, 4H), 4.97(s, 1H), 4.09–4.13 (m, 2H), 3.93–4.0 (m, 2H), 2.77–2.83 (m, 2H), 2.27–2.30 (d, 6H),
1.10–1.15 (m, 3H). 13C-NMR (DMSO-d6) δ: 167.1, 166.6, 150.7(2C), 148.3, 146.8, 134.9, 130.3, 122.6,
121.8, 119.2, 102.2, 100.9, 59.9, 59.2, 41.0, 19.1, 18.8, 18.0, 14.7. MS (ESI−) m/z: 398.2 (M−H)−.
5-(Ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (18)
Compound 17 (45 g, 0.11 mol) was added to the mixture of 3.8% sodium hydroxide solution (350 g)
and 1,2-dimethoxyethane (170 mL) at 30 °C, stirred for 2 h. The reaction mixture was diluted with
water (115 mL), and extracted with dichloromethane (230 mL). The aqueous phase was acidized to
pH 3.0 by 10% hydrochloric acid. The precipitate was filtered and washed with water, and dried at 90 °C
for 2 h to afford 18 (31.8 g, 83.5%). 1H-NMR (DMSO-d6) δ:11.82 (s, 1H), 8.91 (s, 1H), 7.50–7.98 (m,
4H), 4.98 (s, 1H), 3.97–4.01 (m, 2H), 2.28 (s, 6H), 1.11–1.15 (m, 3H). 13C-NMR (DMSO-d6) δ: 169.1,
167.2, 150.9, 148.1, 147.2, 146.4, 134.8, 130.2, 122.4, 121.7, 102.3, 101.3, 59.8, 41.0, 18.9(2C), 14.7.
MS (ESI−) m/z: 345.1 (M−H)−.
(R)-5-(Ethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (19)
Cinchonine (29.4 g, 0.10 mol) was added to the solution of compound 18 (31.0 g, 0.09 mol) in
N,N-dimethylformamide (5.7 mL), and heated 80 °C to get a clear solution. Water (38.4 mL) was
added, and heated to 120 °C. The solution was cooled slowly to 20 °C and stirred for 12 h. The
precipitate was filtered and washed with N,N-dimethylformamide/water (3:2) solution (12 mL). The
filter mass was dissolved in 35% sodium hydroxide solution (92 mL), extracted with dichloromethane
(80 mL). The aqueous phase was acidized to pH 2.0 with concentrated hydrochloric acid. The
precipitate was collected and washed with water, and dried at 100 °C for 10 h to provide 19 (10.4 g,
33%). 1H-NMR (DMSO-d6) δ: 11.82 (s, 1H), 8.91 (s, 1H), 7.50–7.99 (m, 4H), 4.97 (s, 1H), 3.96–4.00
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(m, 2H), 2.27 (s, 6H), 1.10–1.15 (m, 3H); C-NMR (DMSO-d6) δ: 169.1, 167.2, 150.9, 148.1, 147.2,
146.4, 134.8, 130.2, 122.4, 121.7, 102.3, 101.3, 59.8, 41.0, 18.9 (2C), 14.8. MS (ESI−) m/z: 345.1 (M−H)−.
(3'S,4S)-1-Benzyl-3-pyrrolidinyl
ethyl
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-
dicarboxylate (5). Phosphorus pentachloride (3.5 g, 0.036 mol) was added to the solution of compound
19 (4.8 g, 0.014 mol) in dichloromethane (70 mL) below 0 °C, and stirred for 1 h. The reaction mixture
was cooled to −20 °C, and was added the solution of (S)-1-benzylpyrrolidin-3-ol (14, 2.5 g, 0.014 mol)