ACCEPTED MANUSCRIPT
(C5''), 129.2 (C4''), 130.3 (C2''), 131.1 (C3''), 135.7 (C3'), 140.6
pyridin-1a(2H)-yl]acetic acid ethyl ester 41 (0.300 g, 0.543
mmol), and neat 3,4-dichlorobenzyl amine (1.5 mL) were
reacted. Compound 43 Colourless solid (0.318 g, 72%) with a
minor presence of 41 (10%): M.p > 320 °C (dec.). FTIR (KBr)
ν: 3326, 3085, 1650, 1585, 1544, 1507, 1193, 747 cm-1. 1H NMR
(400 MHz, DMSO-d6) δ: 4.31 (d, 4H, J = 6.0 Hz, 1-NHCH2, 1f-
CH2CONHCH2), 4.67 (s, 4H, H2, 1f-CH2), 6.25 (dd, 2H, J = 7.0,
7.0 Hz, H5a, H5f), 7.23 (dd, 2H, J = 6.8, 1.6 Hz, H6a, H6f), 7.27-
7.29 (m, 2H, H6b, H6g), 7.34 (s, 4H, H2d, H3d, H5d, H6d), 7.53 (d,
2H, J = 2.0 Hz, H2b, H2g), 7.58 (d, 2H, J = 8.4 Hz, H5b, H5g),
8.07 (dd, 2H, J=7.2, 1.6 Hz, H4a, H4f), 8.49 (s, 2H, H1c, H3e),
8.73 (t, 2H, J = 6.0 Hz, 1-NH, 1f-CH2CONH), 9.41 (2, 2H, H3c,
H1e). 13C NMR (100 MHz, DMSO-d6) δ: 41.8 (1-NHCH2, 1f-
CH2CONHCH2), 52.4 (C2, 1f-CH2), 106.0 (C5a, C5f), 119.3-
119.7 (C4a, C4f, C2d, C3d, C5d, C6d), 128.2 (C6b, C6g), 129.9
(C2b, C2g), 130.0 (C4b, C4g), 130.6 (C6a, C6f), 131.1 (C5b, C5g),
131.3 (C3a, C3f), 131.6 (C3b, C3g), 134.7 (C1d, C4d), 141.2 (C1b,
C1g), 153.1 (C2c, C2e), 157.5 (C2a, C2f), 167.7 (C1, 1f-CH2CO).
ESI-MS m/z 835.0 (M+Na+). HRMS m/z: 833.0929; calc. for
C36H30N8O6Cl4: 833.0935 (M+H+).
(C1''), 141.1 (i-C6H5), 158.4 (C2'), 167.4 (C1). ESI-MS m/z
452.1 (M+Na+). HRMS m/z: 430.1073; calc. for C22H22O2N3Cl2:
430.1084 (M+H+).
8.2.5.3 N-Benzyl-2-oxopiperidine-3-carboxamide 25. Ethyl 2-
oxopiperidine-3-carboxylate 24 (2.00 g, 11.7 mmol), and neat
benzylamine (5.0 mL) were reacted. Compound 25 Colourless
solid (2.71 g, 100%): M.p 121-124 °C. FTIR (KBr) ν: 3256,
1
3081, 2950, 1683, 1634, 1556, 743, 694 cm-1. H NMR (400
MHz, DMSO-d6) δ: 1.55-1.62 (m, 1H, H5), 1.77-1.98 (m, 3H,
H4, H5, H6), 3.13-3.18 (m, 3H, H3, H4, H6), 4.23-4.35 (m, 2H,
3-CONHCH2), 7.19-7.32 (m, 5H, C6H5), 7.67 (brs, 1H, Wh ~ 7
½
Hz, H1) 8.45 (brt, 1H, J = 5.6 Hz, 3-CONH). 13C NMR (100
MHz, DMSO-d6) δ: 20.6 (C5), 24.6 (C4), 41.3 (C6), 42.1 (3-
CONHCH2), 48.1 (C3), 126.6 (p-C6H5), 127.0 (o-C6H5), 128.2
(m-C6H5), 139.4 (i-C6H5), 168.1 (C2), 170.0 (3-CO). ESI-MS m/z
255.0 (M+Na+). Anal. Calc. for C13H16O2N2: C, 67.22; H, 6.94;
N, 12.06%. Found: C, 67.51; H, 6.96; N, 12.11%.
8.2.5.4
N-(3',4'-Dichlorobenzyl)-2-oxopiperidine-3-carbox
amide 26. Ethyl 2-oxopiperidine-3-carboxylate 24 (2.00 g, 11.7
mmol), and neat 3,4-dichlorobenzylamine (5.0 mL) were reacted
Compound 26 Colourless solid (3.52 g, 100%): M.p 171-174 °C
(dec.). FTIR (KBr) ν: 3363, 3179, 3036, 2938, 1675, 1655, 1528,
8.2.6 General procedure for benzoylation: Preparation of
compounds 27-29.
Benzoyl chloride (2.0 equiv) or 2-chlorobenzoyl chloride (2.0
equiv) and carboxamide (1.0 equiv) were refluxed in dry toluene
for 16 hours. The toluene was removed under reduced pressure.
The crude product was purified by silica gel column
chromatography (ethyl acetate/dichloromethane 5% with 0.5%
Et3N).
1
817 cm-1. H NMR (400 MHz, DMSO-d6) δ: 1.57-1.63 (m, 1H,
H5), 1.76-1.97 (m, 3H, H4, H5, H6), 3.13-3.17 (m, 3H, H3, H4,
H6), 4.20 (dd, 1H, J = 8.0, 4.0 Hz, CH2NH), 4.36 (dd, 1H, J =
8.0, 4.0 Hz, CH2NH), 7.28 (dd, 1H, J = 8.4, 1.6 Hz, H6'), 7.55 (d,
1H, J = 8.4 Hz, H5'), 7.59 (d, 1H, J = 2.0 Hz, H2'), 7.70 (brs, 1H,
Wh ~ 5 Hz, H1) 8.54 (brt, 1H, J = 6.4 Hz, NH). 13C NMR (100
8.2.6.1 1-Benzoyl-N-benzyl-2-oxopiperidine-3-carboxamide
27. Colorless solid (0.597 g, 82%): M.p 145-147.5 °C (dec.);
FTIR (KBr) ν: 3265, 3089, 2942, 1693, 1683, 1283, 731, 702 cm-
½
MHz, DMSO-d6) δ: 20.6 (C5), 24.3 (C4), 41.0 (CH2), 41.3 (C6),
48.2 (C3), 127.3 (C6'), 128.9 (C2'), 129.0 (C4'), 130.3 (C5'),
130.8 (C3'), 140.8 (C1'), 168.0 (C2), 170.2 (3-CO). ESI-MS m/z
301.1 (M+H+). Anal. Calc. for C13H14O2N2Cl2: C, 51.85; H, 4.69;
N, 9.30%. Found: C, 51.93; H, 4.85; N, 9.21%.
1
1. H NMR (400 MHz, DMSO-d6) δ: 1.81-1.92 (m, 1H, H5),
2.02-2.12 (m, 3H, 2xH4, H5), 3.53 (t, 1H, J = 6.8 Hz, H3), 3.66-
3.78 (m, 2H, H6), 4.25-4.35 (m, 2H, CH2), 7.21-7.31 (m, 5H,
CH2C6H5), 7.36-7.39 (m, 2H, m-C6H5), 7.48-7.52 (m, 1H, p-
C6H5), 7.64-7.66 (m, 2H, o-C6H5), 8.60 (brt, 1H, J = 6.0 Hz, NH).
13C NMR (100 MHz, DMSO-d6) δ: 20.3 (C5), 25.6 (C4), 42.2
(CH2), 46.0 (C6), 50.9 (C3), 126.8 (p-CH2C6H5), 127.1 (o-
CH2C6H5), 128.0 (m-C6H5), 128.1 (o-C6H5), 128.3 (m-CH2C6H5),
131.5 (p-C6H5), 135.7 (i-C6H5), 139.1 (i-CH2C6H5), 169.5 (3-
CO), 171.1 (C2), 174.2 (1-CO). ESI-MS m/z 359.2 (M+Na+).
Anal. Calc. for C20H20O3N2: C, 71.41; H, 5.99; N, 8.33%. Found:
C, 71.61; H, 5.90; N, 8.34%.
8.2.5.5
N-(3b,4b-Dichlorobenzyl)-2-(3a-{[5c-({1d-[(3e,4e-di
chlorobenzylcarbamoyl) methyl] -2d-oxo-1d,2d-dihydropyridin-3d-
ylamino}methyl)thiophen-2c-ylmethyl]amino}-2a-oxo-pyridin-
1a(2H)-yl)acetamide 39. [3-({5'-[(1''-Ethoxycarbonylmethyl-2''-
oxo-1',2''-dihydro-pyridin-3''-ylamino)-methyl]-thiophen-2'-
ylmethyl}-amino)-2-oxo-pyridin-1(2H)-yl]-acetic acid ethyl ester
38 (0.300 g, 0.599 mmol), and neat 3,4-dichlorobenzyl amine
(1.5 mL) were reacted. Compound 39 Colourless solid (0.418 g,
92%): M.p 233-236 °C (dec.). FTIR (KBr) ν: 3395, 3269, 3068,
2925, 1679, 1650, 1605, 1577, 1556, 1475, 1262, 870, 805, 727
cm-1. 1H NMR (400 MHz, DMSO-d6) δ: 4.29 (d, 4H, J = 6.0 Hz,
2xCONHCH2), 4.36-4.38 (m, 4H, 3a-NHCH2, 3d-NHCH2), 4.57
(s, 4H, 1a-CH2, 1d-CH2), 5.87 (t, 2H, J = 6.4 Hz, 3a-NH, 3d-NH),
6.05 (dd, 2H, J = 7.0, 7.0 Hz, H5a, H5d), 6.25 (dd, 2H, J = 7.4, 1.6
Hz, H4a, H4d), 6.84-6.86 (m, 4H, H6a, H6d, H3c, H4c), 7.27 (dd,
2H, J = 8.4, 2.0 Hz, H6b, H6e), 7.53 (d, 2H, J = 2.0 Hz, H2b, H2e),
7.57 (d, 2H, J = 8.0 Hz, H5b, H5e), 8.66 (t, 2H, J = 6.4 Hz,
2xCONH). 13C NMR (100 MHz, DMSO-d6) δ: 41.1
(2xCONHCH2), 41.6 (3a-NHCH2, 3d-NHCH2), 51.5 (1a-CH2, 1d-
CH2), 105.7 (C5a, C5d), 106.9 (C4a, C4d), 124.5 (C3c, C4c), 125.2
(C6a, C6d), 127.5 (C6b, C6e), 129.1 (C2b, C2e), 129.2 (C4b, C4e),
130.4 (C5b, C5e), 130.9 (C3b, C3e), 137.5 (C3a, C3d), 140.5 (C1b,
C1e), 141.9 (C2c, C5c), 157.0 (C2a, C2d) 167.3 (2xCO). ESI-MS
m/z 783.1 (M+Na+). HRMS m/z: 759.0846; calc. for
C34H31O4N6Cl4S: 759.0876 (M+H+).
8.2.6.2 1-Benzoyl-N-(3',4'-dichlorobenzyl)-2-oxopiperidine-3-
carboxamide 28. Colourless solid (0.599 g, 89%): M.p 144-146
°C (dec.). FTIR (KBr) ν: 3269, 3072, 1687, 1655, 1287, 719 cm-
1
1. H NMR (400 MHz, DMSO-d6) δ: 1.83-1.90 (m, 1H, H5),
2.01-2.12 (m, 3H, H5, 2xH4), 3.54 (t, 1H, J = 6.8 Hz, H3), 3.64-
3.77 (m, 2H, H6), 4.24-4.35 (m, 2H, CH2), 7.23 (dd, 1H, J = 8.4,
2.0 Hz, H6'), 7.35-7.38 (m, 2H, m-C6H5), 7.48-7.51 (m, 2H, p-
C6H5, H2'), 7.54 (d, 1H, J = 8.4 Hz, H5'), 7.62-7.64 (m, 2H, o-
C6H5), 8.67 (t, 1H, J = 6.0 Hz, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 20.3 (C5), 25.4 (C4), 41.1 (CH2), 46.0 (C6), 50.9
(C3), 127.4 (C6'), 127.9 (m-C6H5), 128.0 (o-C6H5), 129.1 (C2'),
129.2 (C4'), 130.4 (C5'), 130.8 (C3'), 131.5 (p-C6H5), 135.7 (i-
C6H5), 140.4 (C1'), 169.6 (3-CO), 171.0 (C2), 174.2 (1-CO). ESI-
MS m/z 427.1 (M+Na+). HRMS m/z: 405.0777; calc. for
C20H19O3N2Cl2: 405.0767 (M+H+).
8.2.6.3
N-Benzyl-1-(2'-chlorobenzoyl)-2-oxopiperidine-3-
8.2.5.6 N-(3b, 4b-Dichlorobenzyl)-2-(3a-{3c-[4d-(3e-{1f-[(3g, 4g-
dichlorobenzylcarbamoyl) methyl]-2f-oxo-1f, 2f-dihydropyridin-
3f-yl}ureido)phenyl]ureido}-2a-oxopyridin-1a (2H)-yl)acetamide
43. 2-[3a-(3b-{4c-[3d-(1e-Ethoxy carbonyl methyl-2e-oxo-1e,2e-
dihydropyridin-3e-yl)ureido]phenyl}ureido)-2a-oxo-dihydro
carboxamide 29. Colorless solid (0.597 g, 75%): M.p 102-105
°C. FTIR (KBr) ν: 3314, 3072, 2946, 1704, 1687, 1642, 1160,
1
751, 719 cm-1. H NMR (400 MHz, DMSO-d6) δ: 1.81-1.88 (m,
1H, H5), 2.02-2.09 (m, 3H, H4, H5, H6), 3.53 (t, 1H, J = 7.2 Hz,
H3), 3.73-3.88 (m, 2H, H4, H6), 4.25 (d, 2H, J = 6.0 Hz, 3-