786
U. Holzgrabe, E. Heller / Tetrahedron 59 (2003) 781–787
evaporated and the solid was filtered by suction and dried
over P4O10 to obtain a pale yellow solid. The product can be
recrystallised from ethyl acetate, but this is not necessary for
(1H, br, NH–CvO), 8.34 (1H, d, J¼4.8, 1.8 Hz, 2-H), 7.92
(1H, dd, J¼7.8, 1.5 Hz, 7-H), 7.60–7.51 (3H, m, 4-H, 9-H,
10-H), 7.37 (1H, td, J¼7.8, 1.3 Hz, 8-H), 7.27 (1H, dd,
J¼8.1, 4.8 Hz, 3-H), 6.59 (1H, br, N–CO–NH), 3.38–3.29
(2H, m, H2C–NH–CO), 2.84–2.79 (2H, m, N–CH0–CH2–
N), 2.63–2.37 (6H, m, HN–CH2–CH2–N,0 20-H, 6a -H, N–
CH2–CH2–CH3), 2.18–2.14 (1H, m, 6b -H), 1.62–1.33
(9H, m, 30-H, 40-H, 50-H, NH–CH2–CH2–CH3), 0.87 ppm
(3H, t, J¼7.6 Hz, CH3). 13C NMR (CDCl3) d: 168.2 (CvO,
amide), 154.9 (CvO, urea), 147.1 (Cquat.), 144.8 (C-2),
142.1 (Cquat.), 133.3 (C-9), 131.2, 131.1 (C-7, C-4), 130.9
(Cquat.), 129.2 (C-8), 128.9 (Cquat.), 127.5 (C-10), 1230.6
(C-3), 60.0 (C-20), 52.3 (N–CH2–CH2–CH3), 52.1 (C-6 ),
50.7, 50.4 (N–CH2–CH–N, N–CH2–CH2–N–CvO),
37.8 (CH2–N–CvO), 28.8 (N–CH2–CH2–CH3), 24.7,
23.1, 22.9 (C-30, C-40, C-50), 11.8 ppm (CH3). IR (ATR):
3196, 3133, 3097 (NH), 3047, 2932, 2854, 2810, (CH), 1670
(CvO amide), 1657 (CvO urea), 1601, 1564 (CvC,
aromat.), 1456, 1362, 1275, 778, 754 cm21, MS (DCI,
NH3); m/z (%): 437 [(Mþ1)þ, 100]; HRMS (CI/NH3)
437.2655 [(MHþ) calcd for C24H32N6O22 Hþ 437.2655].
1
the next step. Yield: 4.75 g (87%), mp 2528C (dec). H
NMR (DMSO-d6) d: 11.02 (1H, br, 5-H), 8.51 (1H, br, 2-H),
7.86 (1H, d, J¼7.6 Hz, 7-H), 7.77–7.53 ppm (5H, m, 3-H,
4-H, 8-H, 9-H, 10-H). 13C NMR (DMSO-d6) d: 165.7 (C-6),
147.4 (C-11), 145.5 (C-2), 144.2 (Cquat.), 139.5 (Cquat.),
135.1 (Cquat.), 125.1 (Cquat.), 134.1, 131.7, 130.0, 127.2,
126.2, 126.1, 118.9 ppm (C-3, C-4, C-5, C-7, C-8, C-9,
C-10). IR (ATR): 3183, 3075 (NH), 3045 (CH), 1730
(Cl–CvO), 1669 (N–CvO), 1594 (CvC, aromat), 1542,
1341, 779, 739 cm21. MS (EI); m/z (%): 273 (Mþ, 15), 238
(Mþ2Cl, 100), 211 (41), 210 (14), 183 (Mþ2COCl, 11),
182 (13), 120 (14).
3.1.8. 6-Oxo-5,6-dihydrobenzo[e]pyrido[3,2-b][1,4]dia-
zepine-11-carboxylic acid (2-{2-[(benzyl-propylamino)-
methyl]piperidin-1-yl}ethyl]amide 12. The diazepine 11
(1.65 g, 6.0 mmol), Hu¨nig’s base (1.8 ml, 10.0 mmol) and
the amine 9 (2.03 g, 7.0 mmol) were dissolved in dry THF in
a sealed tube. The mixture was heated in a microwave oven
(gradient of heating: 2.5 min to 1108C; holding time: 10 min
at 1108C). The solvent was evaporated, the residue was
diluted with 2 M K2CO3 solution (60 ml) and extracted with
dichloromethane (3£60 ml). The combined organic layers
were dried with Na2SO4, filtered and evaporated. The
residue was recrystallised from ethyl acetate and petroleum
ether to obtain a pale yellow solid (yield: 2.22 g, 70%), mp
153–1548C.). 1H NMR (CDCl3) d: 9.64 (1H, br, NH–
CvO), 8.27 (1H, d, J¼6.3 Hz, 2-H), 7.86 (1H, dd, J¼7.8,
1.2 Hz, 7-H), 7.55–7.50 (3H, m, 4-H, 9-H, 10-H), 7.37–
7.16 (7H, m, 3-H, 8-H, phenyl), 6.63 (1H, br, N–CO–NH),
3.55–3.41 (4H, m, H2C–NH–CO, CH2–Ph), 3.19–2.30
(9H, m, HN–CH2–CH2–N, 20-H, 60-H, N–CH–CH2–N,
N–CH2–CH2–CH3), 1.76–1.28 (8H, m, 30-H, 40-H, 50-H,
3.1.10. [3-[1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-
dimethyl-{6-[(1-{2-[(6-oxo-5,6-dihydro-benzo[e]pyr-
ido[3,2-b][1,4]diazepine-11-carbonyl)amino]ethyl}piper-
idin-2-ylmethyl)-propylamino]hexyl}ammonium
bromide 1. The AFDX-384 analogue 2 (0.22 g, 0.5 mmol)
was dissolved in 25 ml chloroform and treated with Hu¨nig’s
base (0.9 ml, 5.0 mmol) and the bromide 3 (0.24 g,
0.5 mmol), which was prepared according to Refs. 13,14
in a sealed tube. The mixture was heated to 608C for 24 h in
an oil bath. A white solid precipitated and the TLC showed
the absence of starting material. The solvent was evaporated
and the oily residue was crystallized from diethyl ether to
obtain a pale yellow solid. Yield: 0.35 g (83%), mp 209–
2118C. 1H NMR (DMSO-d6) d: 9.15 (1H, s, HN–CO), 8.41
(1H, d, J¼6.6 Hz, 2-H), 8.33–8.30 (2H, d, J¼7.3 Hz, 3-H,
6-H (phthalimide)), 7.95–7.82 (6H, m, 4-H, 5-H (phthali-
mide), 4-H, 7-H, 9-H, 10-H), 7.71 (1H, br, HN–CO–N),
7.54 (1H, t, J¼7.4 Hz, 8-H), 7.03 (1H, t, J¼7.3 Hz, 3-H),
3.64–2.52 (25H, m, 20-H, 60-H, Nþ(CH3)2, N–CH–CH2–
N, Nþ–CH2–CH2–CH2–N(CO)2, HN–CH2–CH2–N,
N–CH2–CH2–CH3, Nþ–CH2–(CH2)4–CH2–N), 2.02–
1.20 (18H, m, 30-H, 40-H, 50-H, N–CH2–CH2–CH3, Nþ–
CH2–CH2–CH2–N(CO)2, Nþ–CH2–(CH2)4–CH2–N),
0.80 ppm (3H, t, J¼7.3 Hz, CH3). 13C NMR (DMSO-d6)
d: 168.2 (CvO, amide), 158.2 (CvO, imide), 154.9 (CvO,
urea), 146.6 (Cquat.), 140.2 (Cquat.), 135.0 (C-9), 134.4
(C-3, C-4 phthalimide), 132.9 (C-1 phthalimide), 131.7
(Cquat.), 126.9, 126.5, 125.2 (C-4, C-8, C-10), 123.0 (C-2,
C-5 phthalimide), 117.4 (C-2), 115.6 (Cquat.), 114.4 (C-7),
113.3 (C-3), 63.1 (N–CH2–0CH2–N–CvO, br), 60.7, 60.4
(H2C–Nþ–CH2), 54.6 (C-2 ), 52.2 (C-60), 49.9 (N–CH2–
CH2–CH3), 48.9 (Nþ(CH3)2), 46.7 (Nþ–CH2–(CH2)4–
CH2–N), 46.5 (N–CH2–CH–N), 37.2 (CH2–N–CvO),
34.6 (CH2–N(CO)2), 32.1 (Nþ–CH2–CH2–CH2–N(CO)2)
25.6, 25.0, 23.7 (C-30, C-40, C-50), 18.8 (N–CH2–CH2–
CH3), 10.8 ppm (CH3). IR (ATR): 3264 (NH), 3017, 2936
(CH), 1701 (CvO imide), 1679 (CvO amide), 1641 (CvO
urea), 1609 (CvC aromat), 1510, 1454, 1373, 753, 721,
691 cm21. MS (FAB); m/z (%): 831, 83 (Mþ, 0.4, 0.5), 751
(Mþ2Br, 7.0), 437 (52), 238 (58), 185 (74), 93 (100),
C43H59BrN8O4 requires 831.93.
N–CH2–CH2–CH3), 0.82 ppm (3H, t, J¼7.4 Hz, CH3). 13
C
NMR (CDCl3) d: 167.9 (CvO, amide), 154.9 (CvO, urea),
146.5 (Cquat.), 145.4 (C-2), 141.8 (Cquat.), 139.4 (C-100-
phenyl), 133.3 (C-9), 131.2, 131.1 (C-7, C-4), 130.9
(Cquat.), 129.4 (Cquat.), 129.0 (C-300-phenyl), 128.9 (C-8),
128.2 (C-200-phenyl), 127.6 (C-400-phenyl), 126.9 (C-10),
123.6 (C-3), 59.4 (C-20), 56.9 (CH2Ph), 55.1, 55.0 (C-60,
N–CH2–CH2–CH3), 52.0, 51.8 (N–CH2–CH–N,
N–CH2–CH2–N–CvO), 37.3 (CH2–N–CvO), 280.7
(N–CH2–CH2–CH3), 23.7, 21.7, 20.1 (C-30, C-40, C-5 ),
11.8 ppm (CH3). IR (ATR): 3189, 3130 (NH), 3047, 2953,
2933, 2872, 2803 (CH), 1672 (CvO amide), 1655 (CvO
urea), 1564 (CvC, aromat.), 1493, 1457, 1361, 779, 755,
734 cm21. MS (DCI, NH3); m/z (%): 527 [(Mþ1)þ, 42].
Anal. calcd. for C31H38N6O2: C, 70.70; H, 7.27; N, 15.96;
found C, 70.43; H, 7.07; N, 16.16.
3.1.9. 6-Oxo-5,6-dihydrobenzo[e]pyrido[3,2-b][1,4]dia-
zepine-11-carboxylic acid [2-(2-propyl-aminomethyl-
piperidin-1-yl)ethyl]amide 2. Compound 12 (3.40 g,
6.5 mmol) was dissolved in EtOH (150 ml), treated with
200 mg Pd/C (10%) and hydrogenated (50 bar, 608C) for
18 h (monitoring by TLC, Al2O3 (bas.)/CHCl3/MeOH,
20:1). The catalyst was filtered off and the solvent was
evaporated in vacuo. The residue was recrystallised from
ethyl acetate and diethyl ether. Yield: 2.80 g, 99%, pale
yellow solid, mp 1508C. 1H NMR (CDCl3) d: 11.0–10.4 2