A. Kamal et al. / Bioorg. Med. Chem. 17 (2009) 1557–1572
1569
filtered through a Celite. The clear yellow organic supernatant was
5.19.2. (2S)-N-[4-(5-Bromobutanoxy)-5-methoxy-2-nitroben-
extracted with ethyl acetate (2 ꢂ 20 mL). The organic layer was
washed with saturated NaHCO3 solution (20 mL) and brine
(20 mL), and the combined organic phase was dried over anhy-
drous Na2SO4. The organic layer was evaporated under vacuum
and the crude product was purified by column chromatography
(95% CHCl3–MeOH) to afford the compound 13a as a pale yellow
solid. This material was repeatedly evaporated from CHCl3 in vac-
uum to generate the imine for.
zoyl]-4-fluoropyrrolidine-2-carboxaldehyde diethylthioacetal
(31b)
The compound 31b was prepared following the method de-
scribed for the compound 31a, by employing (2S)-N-(4-hydroxy-
5-methoxy-2-nitrobenzoyl)-4-fluoropyrrolidine-2-carboxaldehyde
diethylthioacetal 30 (182 mg, 1 mmol) and 1,4-dibromobutane
(605 mg, 3 mmol), and the crude product was purified by column
chromatography (10% EtOAc–hexane) to afford the compound
31b as white solid.
Yield 526 mg, 65%; ½a 2D6
ꢃ
+38.0 (c 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.45–1.92 (m, 4H), 1.99–2.20 (m, 4H), 2.48–2.99 (m, 8H),
3.1–3.88 (m, 10H), 3.96 (s, 6H), 3.98–4.24 (m, 4H), 6.80 (s, 2H), 7.49
(s, 2H), 7.82 (d, J = 3.8 Hz, 2H). ESI MS: m/z 731 [M+1]+. Anal. Calcd
for C36H42F4N6O6: C, 59.17; H, 5.79; N, 11.50. Found: C, 59.10; H,
5.60; N, 11.40.
Yield 260 mg, 86%; 1H NMR (300 MHz, CDCl3): d 1.26–1.43 (m,
6H), 2.01–2.46 (m, 4H), 2.49–2.67 (m, 2H), 2.70–2.95 (m, 6H),
3.58 (m, 2H), 3.99 (s, 3H), 4.25 (t, J = 6.0, 2H), 4.55 (d, J = 6.7, 1H),
4.73–4.79 (m, 1H), 5.0–5.33 (m, 1H), 6.89 (s, 1H), 7.69 (s, 1H) LC
MS: m/z 553 [M]+. Anal. Calcd for C21H30BrFN2O5S2: C, 45.57; H,
5.46; N, 5.06. Found: C, 45.40; H, 5.25; N, 4.95.
5.18.2. 1,10-{[1,4-Di(butane-1,4-diyl)hexahydropiper-azine]
dioxy}-bis[(11aS)-2,2-di-fluoro-7-methoxy-1,2,3,11a-tetrahydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one] (13b)
The compound 13b was prepared following the method de-
scribed for the compound 13a, employing the compound 37b
(955 mg, 1 mmol) to afford the compound 13b as a pale yellow
solid.
5.19.3. (2S)-N-[4-(6-Bromopentanoxy)-5-methoxy-2-nitroben-
zoyl]-4-fluoropyrrolidine-2-carboxaldehyde diethylthioacetal
(31c)
The compound 31c was prepared following the method de-
scribed for the compound 31a, by employing (2S)-N-(4-hydroxy-
5-methoxy-2-nitrobenzoyl)-4-fluoropyrrolidine-2-carboxaldehyde
diethylthioacetal 30 (182 mg, 1 mmol) and 1,5-dibromopentane
(605 mg, 3 mmol), and the crude product was purified by column
chromatography (10% EtOAc–hexane) to afford the compound
31c as white solid.
Yield 599 mg, 60%; ½a 2D6
ꢃ
+52.0 (c 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.56–1.94 (m, 8H), 1.99–2.35 (m, 4H), 2.49–2.99 (m, 8H),
3.29–3.87 (m, 10H), 3.93 (s, 6H), 3.98–4.37 (m, 4H), 6.89 (s, 2H),
7.46 (s, 2H), 7.83 (d, J = 3.67 Hz, 2H). Anal. Calcd for C38H46F4N6O6:
C, 60.15; H, 6.11; N, 11.08. Found: C, 59.95; H, 6.05; N, 11.0.
Yield 220 mg, 80%; 1H NMR (300 MHz, CDCl3): d 1.26–1.41 (m,
6H), 1.74–2.0 (m, 4H), 2.35–2.47 (m, 2H), 2.49–2.65 (m, 2H),
2.70–2.92 (m, 6H), 3.58–3.66 (m, 2H), 3.98 (s, 3H), 4.25 (t,
J = 6.0 Hz, 2H), 4.57 (d, J = 6.7 Hz, 1H), 4.75–4.85 (m, 1H), 5.0–
5.34 (m, 1H), 6.88 (s, 1H). 7.70 (s, 1H) LC MS: m/z 567 [M]+. Anal.
Calcd for C22H32BrFN2O5S2: C, 46.56; H, 5.68; N, 4.94. Found: C,
46.45; H, 5.55; N, 4.75.
5.18.3. 1,10-{[1,4-Di(pentane-1,5-diyl)hexahydropiperazine]
dioxy}-bis[(11aS)-2,2-di-fluoro-7-methoxy-1,2,3,11a-tetrahydro-
5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one] (13c)
The compound 13c was prepared following the method de-
scribed for the compound 13a, employing the compound 37c
(967 mg, 1 mmol) to afford the compound 13c as a pale yellow
solid.
5.20. General procedure for the synthesis of compounds
(38a–c)
Yield 618mg, 64%; ½a 2D6
ꢃ
+51.0 (c 0.5, CHCl3); 1H NMR (200 MHz,
CDCl3): d 1.54–2.03 (m, 12H), 2.22–2.47 (m, 4H), 2.50–2.73 (m,
8H), 3.35–3.85 (m, 10H), 3.94 (s, 6H), 3.97–4.26 (m, 4H), 6.71 (s,
2H), 7.47 (s, 2H), 7.79 (d, J = 3.6, 2H) ESI MS: m/z 787 [M+1]+. Anal.
Calcd for C40H50F4N6O6: C, 61.06; H, 6.40; N, 10.68. Found: C, 60.89;
H, 6.25; N, 10.57.
5.20.1. 1,10-{[1,4-Di(propane-1,3-diyl)hexahydro-piperazine]
dioxy}-bis[(11aS)-7-methoxy-2-nitro-benzoyl-(4-fluoropyrroli-
din-2-carboxaldehyde diethylthioacetal)] (38a)
To
a solution of (2S)-N-[4-(4-bromopropoxy)-5-methoxy-2-
nitrobenzoyl]-4-fluoro pyrrolidine-2-carboxaldehyde diethylthioac-
etal (31a) (507 mg, 1 mmol) in dry acetonitril (30 mL) were added
anhydrous K2CO3 (552 mg, 4 mmol) and the piperazine (43 mg,
0.5 mmol). The reaction mixture was refluxed for 48 h. The
reaction was monitored by TLC using (95% CHCl3/CH3OH) as a
solvent system. The potassium carbonate was removed by suction
filtration and the solvent was evaporated under vacuum. The crude
product was purified by column chromatography (90% CHCl3/
CH3OH) to afford the compound 38a as a pale yellow solid.
Yield 845 mg, 80%; 1H NMR (200 MHz, CDCl3): d 1.29–1.36 (m,
12H), 2.02–2.11 (m, 4H), 2.46–2.69 (m, 8H), 2.73–2.89 (m, 12H),
3.39–3.62 (m, 4H), 3.98 (s, 6H), 4.12–4.25 (t, 4H), 4.52 (d,
J = 6.79 Hz, 2H), 4.72 (q, J = 6.79 Hz, 2H), 5.02–5.15 (t, 4H), 5.20–
5.29 (m, 2H), 6.84 (s, 2H), 7.65 (s, 2H) ESI MS: m/z 1003 [M]+. Anal.
Calcd for C44H64F2N6O10S4: C, 52.67; H, 6.43; N, 8.38. Found: C,
52.50; H, 6.35; N, 8.25.
5.19. General procedure for the synthesis of compounds
(31a–c)
5.19.1. (2S)-N-[4-(4-Bromopropoxy)-5-methoxy-2-nitro-ben-
zoyl]-4-fluoropyrrolidine-2-carboxaldehyde diet-hylthioacetal
(31a)
To a solution of (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)-
4-fluoropyrrolidine-2-carboxaldehyde diethylthioacetal 30 (182 mg,
1 mmol) in acetone (30 mL) were added, anhydrous K2CO3 (553 mg,
4 mmol) and 1,3-dibromopropane (561 mg, 3 mmol) and the mix-
ture was refluxed for 48 h. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, potassium
carbonate was removed by filtration and the solvent was evaporated
under vacuum to get the crude product. This was further purified by
column chromatography (10% EtOAc–hexane) to afford the com-
pound 31a as a white solid.
Yield 236 mg, 82%; 1H NMR (200 MHz, CDCl3): d 1.31–1.40 (m,
6H), 2.28–2.48 (m, 2H), 2.49–2.64 (m, 2H), 2.68–2.91 (m, 6H),
3.64 (m, 2H), 3.99 (s, 3H), 4.25 (t, J = 6.0 Hz, 2H), 4.56 (d,
J = 6.7 Hz, 1H), 4.76 (m, 1H), 5.0–5.33 (m, 1H), 6.88 (s, 1H), 7.68
(s, 1H) LC MS: m/z 539.4 [M]+. Anal. Calcd for C20H28BrFN2O5S2:
C, 44.53; H, 5.23; N, 5.19. Found: C, 44.43; H, 5.15; N, 5.10.
5.20.2. 1,10-{[1,4-Di(butane-1,4-diyl)hexahydropiperazine]
dioxy}-bis[(11aS)-7-methoxy-2-nitro-benzoyl-(4-fluoropyrroli-
din-2-carboxaldehyde diethylthioacetal)] (38b)
The compound 38b was prepared following the method de-
scribed for the compound 38a, employing piperazine and (2S)-N-
[4-(5-bromobutanoxy)-5-methoxy-2-nitrobenzoyl]-4-fluoropyrroli-