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Y. Imaeda et al. / Bioorg. Med. Chem. 16 (2008) 3125–3140
(50 mL). The organic layer was separated, washed with
brine (50 mL), dried over anhydrous MgSO4, and con-
centrated in vacuo. The residue was purified by silica
gel chromatography (EtOAc/EtOH = 5:1) to give 26
(0.88 g, 79%) as a yellow oil. 1H NMR (200 MHz,
CDCl3) d: 1.30 (3H, d, J = 6.2 Hz), 1.51 (9H, s), 2.79
(1H, dd, J = 14.6 and 8.4 Hz), 2.97 (1H, dd, J = 14.6
and 3.4 Hz), 3.05–3.10 (4H, m), 3.67–3.78 (5H, m),
4.14–4.24 (1H, m), 6.29 (1H, d, J = 7.0 Hz), 7.18 (1H,
dd, J = 8.8 and 7.0 Hz), 7.28–7.35 (2H, m).
CDCl3) d: 2.96 (2H, t, J = 7.5 Hz), 3.03 (3H, s), 3.13
(2H, br s), 3.24–3.26 (5H, m), 3.60 (2H, t, J = 7.5 Hz),
3.80 (4H, br s), 4.26 (2H, s), 6.74 (1H, d, J = 7.4 Hz),
7.59–7.66 (1H, m), 7.73 (1H, d, J = 7.4 Hz), 7.85 (1H,
d, J = 8.8 Hz), 7.93–8.00 (5H, m), 8.50 (1H, s). Anal.
Calcd for C28H30ClN5O4SÆHClÆ0.5H2O: C, 54.81; H,
5.26; N, 11.41. Found: C, 54.67; H, 5.18; N, 11.35.
5.1.28. 2-[5-(4-{3-[(6-Chloronaphthalen-2-yl)sulfonyl]pro-
panoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]acetam-
ide (2j). Yield 62%, colorless powder. Mp 159–161 ꢁC.
1H NMR (200 MHz, CDCl3) d: 2.93–3.12 (6H, m),
3.60 (2H, t, J = 7.4 Hz), 3.77–3.81 (6H, m), 5.47 (2H,
br s), 6.31 (1H, dd, J = 7.0 and 1.2 Hz), 7.25 (1H, dd,
J = 8.8 and 7.0 Hz), 7.37 (1H, d, J = 8.8 Hz), 7.45 (1H,
s), 7.61 (1H, dd, J = 8.8 and 2.2 Hz), 7.94–8.00 (4H,
m), 8.50 (1H, s). Anal. Calcd for C26H26ClN5O4SÆH2O:
C, 55.96; H, 5.06; N, 12.55. Found: C, 56.09; H, 4.90;
N, 12.71.
5.1.26. Ethyl [5-(4-{3-[(6-chloronaphthalen-2-yl)sulfonyl]-
propanoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]acetate
hydrochloride (2h). A solution of 21 (1.50 g, 3.86 mmol)
in concentrated HCl (10 mL) was stirred at room tem-
perature for 5 min. The reaction mixture was diluted
with EtOH (50 mL) and concentrated in vacuo to give
ethyl [5-(piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]ace-
tate dihydrochloride (1.40 g, quant.) as a pale yellow
amorphous powder.
5.1.29. 2-[5-(4-{3-[(6-Chloronaphthalen-2-yl)sulfonyl]pro-
panoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]-N-methy-
lacetamide (2k). Yield 74%, colorless powder. Mp 186–
188 ꢁC. H NMR (200 MHz, CDCl3) d: 2.80–2.82 (3H,
m), 2.93–3.15 (8H, m), 3.60 (2H, t, J = 6.4 Hz), 3.75–
3.82 (4H, m), 6.42 (1H, dd, J = 7.0 and 1.2 Hz), 7.32–
7.64 (5H, m), 7.64–8.00 (4H, m), 8.50 (1H, s). Anal. Calcd
for C27H28ClN5O4SÆH2O: C, 56.69; H, 5.29; N, 12.24.
Found: C, 56.59; H, 5.18; N, 12.11.
To a mixture of 15 (0.96 g, 3.21 mmol) and HOBt
(0.74 g, 4.83 mmol) in MeCN (20 mL) was added WSC
(0.92 g, 4.8 mmol) and the mixture was stirred at room
temperature for 20 min. A solution of the ethyl [5-(pip-
erazin-1-yl)imidazo[1,2-a]pyridin-2-yl]acetate dihydro-
chloride (1.40 g, 3.86 mmol), Et3N (1.35 mL,
9.69 mmol), and DBU (1.20 mL, 8.04 mmol) was added
and the resulting mixture was stirred at room tempera-
ture for 3 h. The solvent was evaporated in vacuo and
the residue was partitioned between CHCl3 (50 mL)
and water (50 mL). The organic layer was separated,
washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by silica
gel chromatography (EtOAc/EtOH = 5:1) to give ethyl
[5-(4-{3-[(6-chloronaphthalen-2-yl)sulfonyl]propanoyl}-
piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]acetate (1.20 g,
66%) as a colorless oil.
1
5.1.30. 1-[5-(4-{3-[(6-Chloronaphthalen-2-yl)sulfonyl]pro-
panoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]-2-meth-
ylpropan-2-ol hydrochloride (2l). Yield 50%, colorless
amorphous powder. 1H NMR (200 MHz, DMSO-d6)
d: 1.20 (6H, s), 2.82 (2H, t, J = 7.3 Hz), 2.94 (2H, s),
3.01 (2H, br s), 3.12 (2H, br s), 3.64–3.68 (6H, m),
6.95 (1H, d, J = 7.6 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.74
(1H, dd, J = 8.4 and 2.2 Hz), 7.88 (1H, dd, J = 8.8 and
7.6 Hz), 7.96 (1H, s), 8.02 (1H, dd, J = 8.4 and
1.4 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.28–8.32 (2H, m),
8.69 (1H, s). Anal. Calcd for C28H31ClN4O4SÆHClÆ2-
H2O: C, 53.59; H, 5.78; N, 8.93. Found: C, 53.72; H,
5.80; N, 8.72.
The product (1.20 g, 2.11 mmol) was dissolved in EtOAc
(30 mL) and 4 M HCl in EtOAc (1.00 mL, 4.00 mmol)
was added and the resulting mixture was stirred at room
temperature for 10 min. The precipitate was collected by
filtration and washed with EtOAc and Et2O to give 2h
(0.68 g, 53%) as a colorless amorphous powder. 1H
NMR (300 MHz, DMSO-d6) d: 1.24 (3H, t,
J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 3.00 (2H, br s),
3.12 (2H, br s), 3.61–3.70 (6H, m), 4.12 (2H, s), 4.17
(2H, q, J = 7.2 Hz), 6.96 (1H, d, J = 7.5 Hz), 7.65 (1H,
d, J = 9.0 Hz), 7.73 (1H, dd, J = 8.7 and 2.1 Hz), 7.90
(1H, dd, J = 8.7 and 7.8 Hz), 8.00 (1H, dd, J = 8.4 and
1.8 Hz), 8.11 (1H, s), 8.19 (1H, d, J = 8.4 Hz), 8.26–
8.30 (2H, m), 8.67 (1H, d, J = 1.8 Hz). Anal. Calcd for
C29H29ClN4O5SÆHClÆ1.5H2O: C, 54.04; H, 5.16; N,
8.69. Found: C, 54.24; H, 5.35; N, 8.31.
5.1.31. 1-[5-(4-{3-[(6-Chloronaphthalen-2-yl)sulfonyl]pro-
panoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]propan-
2-ol (2m). Yield 73%, colorless powder. Mp 108–109 ꢁC.
1H NMR (300 MHz, CDCl3) d: 1.30 (3H, d, J = 6.3 Hz),
2.80 (1H, dd, J = 14.7 and 8.7 Hz), 2.94–2.99 (3H, m),
3.08 (4H, d, J = 26.1 Hz), 3.60 (2H, t, J = 7.2 Hz), 3.73
(4H, br s), 4.17–4.23 (1H, m), 6.26 (1H, d, J = 7.2 Hz),
7.18 (1H, dd, J = 8.7 and 7.2 Hz), 7.33–7.35 (2H, m),
7.59 (1H, dd, J = 8.7 and 2.0 Hz), 7.90–7.96 (4H, m),
8.49 (1H, s). Anal. Calcd for C27H29ClN4O4SÆ0.5H2O:
C, 58.95; H, 5.50; N, 10.19. Found: C, 59.25; H, 5.78;
N, 9.83.
The following compounds 2i–m were prepared in a man-
ner similar to that described for 2h.
5.1.32.
tert-Butyl
4-(3-nitroimidazo[1,2-a]pyridin-5-
yl)piperazine-1-carboxylate (28). A mixture of 27 (9.88 g,
50.0 mmol), 1-Boc-piperazine (14.0 g, 75.2 mmol), and
N,N-diisopropylethylamine (34.8 mL, 200 mmol) in
2-PrOH (300 mL) was refluxed for 4 h. The reaction mix-
ture was concentrated in vacuo. The residue was crystal-
5.1.27. 2-[5-(4-{3-[(6-Chloronaphthalen-2-yl)sulfonyl]pro-
panoyl}piperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]-N,N-
dimethylacetamide hydrochloride (2i). Yield 67%, color-
less powder. Mp 150–152 ꢁC. 1H NMR (200 MHz,