4312 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 17
Tahtaoui et al.
The precipitate was filtered, the filtrate was evaporated, and
the desired product was purified by silica gel column chroma-
tography (EtOAc/heptane 7/3) as a colorless oil (6.84 g, 97%).
TLC (EtOAc/heptane 7/3) Rf 0.33. 1H NMR (CDCl3, 300 MHz):
δ 7.24-7.47 (m, 15 H), 4.37 (t, J ) 4.3 Hz, 2 H), 3.67-3.77
(m, 18 H), 3.28 (t, J ) 5.1 Hz, 2 H), 3.06 (s, 3 H). 13C NMR
(CDCl3, 75 MHz): δ 143.9, 128.5, 127.5, 126.7, 86.2, 70.5, 70.4,
70.3, 70.2, 69.1, 68.7, 63.1, 37.3. MS (ESI-TOF, 80 eV) m/z
602.25 (C32H42O9S), 625.20 (M + Na), 361.13 (M + H -
PPh3C)+, 243.09 (PPh3C)+.
1,1,1-Tr ip h en yl-2,5,8,11,14,17,20-h ep ta oxa d ocosa n -22-
ol (29). A solution of EG (0.69 mL, 12.46 mmol) and t-BuOK
(1.4 g, 12.46 mmol) in dry t-BuOH (50 mL) was refluxed for
30 min. Product 28 (2 g, 4.15 mmol) was then added, and the
mixture was refluxed for 4 h. The mixture was then cooled,
washed with brine, extracted with CH2Cl2, dried over MgSO4,
filtered, and evaporated. The crude product was then purified
by silica gel column chromatography (EtOAc) to give 29 as a
colorless oil (2.22 g, 94%). TLC (EtOAc) Rf 0.16. 1H NMR
(CDCl3, 200 MHz): δ 7.14-7.42 (m, 15 H), 3.55-3.69 (m, 26
H), 3.20 (t, J ) 4.9 Hz, 2 H). 13C NMR (CDCl3, 50 MHz): δ
143.9, 128.5, 127.5, 126.7, 86.3, 72.4, 70.3, 70.1, 63.1, 61.3. MS
(ESI-TOF, 80 eV) m/z 568.30 (C33H44O8), 591.33 (M + Na)+,
607.32 (M + K)+.
22-Azid o-1,1,1-t r ip h e n yl-2,5,8,11,14,17,20-h e p t a oxa -
d ocosa n e (30). Compound 29 was mesylated according to the
method used for compound 28. It was purified by silica gel
column chromatography (EtOAc): 81%. TLC (EtOAc Rf 0.28).
1H NMR (CDCl3, 200 MHz): δ 7.19-7.47 (m, 15 H), 4.32 (t, J
) 5.1 Hz, 2 H), 3.60-3.72 (m, 24 H), 3.23 (t, J ) 5.1 Hz, 2 H),
3.00 (s, 3 H). 13C NMR (CDCl3, 50 MHz): δ 143.9, 128.5, 127.5,
126.7, 86.3, 70.4, 69.1, 68.7, 63.1, 37.4. MS (ESI-TOF, 80 eV)
m/z 646.28 (C34H46O10S), 669.27 (M + Na)+, 405.18 (M + H -
PPh3C)+, 243.11 (PPh3C)+. Displacement of the mesyl group
was achieved by adding NaN3 (290 mg, 4.46 mmol) to a
solution of 29 (1.92 g, 2.97 mmol) in CH3CN (100 mL). The
mixture was refluxed overnight and then evaporated. CH2Cl2
(100 mL) was added, and the organic layer was washed with
H2O (50 mL) and brine (50 mL), dried over MgSO4, filtered,
and evaporated. The crude product was chromatographied on
a silica gel column (EtOAc/heptane 5/5) to give product 30
(1.395 g, 80%). TLC (EtOAc/heptane 6/4) Rf 0.15. 1H NMR
(CDCl3, 200 MHz): δ 7.21-7.49 (m, 15 H), 3.64-3.68 (m, 24
H), 3.35 (t, J ) 4.6 Hz, 2 H), 3.24 (t, J ) 4.8 Hz, 2 H). 13C
NMR (CDCl3, 50 MHz): δ 144.0, 128.6, 127.6, 126.8, 86.4, 70.5,
69.8, 63.2, 50.5. MS (ESI-TOF, 80 eV) m/z 593.31 (C33H43N3O7),
616.31 (M + Na)+, 632.28 (M + K)+, 243.12 (PPh3C)+.
24 H), 3.27 (t, J ) 4.6 Hz, 2 H), 2.61 (t, J ) 4.3 Hz, 2 H),
2.02-2.19 (m, 4 H), 1.43 (s, 9 H). 13C NMR (CDCl3, 75 MHz):
δ 154.7, 79.5, 70.6, 70.5, 70.4, 70.2, 67.9, 66.1, 57.5, 54.3, 50.3,
44.1, 40.0, 28.4. MS (ESI-TOF, 80 eV) m/z 520.31 (M + H)+.
The obtained Boc intermediate was then submitted to TFA
(10 mL) deprotection for 2 h. The excess TFA was removed
under reduced pressure, and the resulting compound was
triturated in diethyl ether to give the expected product 32 in
a 98% yield. 1H NMR (CDCl3, 200 MHz): δ 5.60 (br s, 1 H),
3.81-3.94 (m, 4 H), 3.42-3.61 (m, 24 H), 3.26 (t, J ) 4.55 Hz,
2 H), 2.64 (t, J ) 4.25 Hz, 2 H), 2.01-2.15 (m, 4 H). 13C NMR
(CDCl3, 50 MHz): δ 79.4, 70.8, 70.5, 70.3, 70.2, 67.8, 66.0, 57.6,
54.7, 49.8, 43.0, 38.8, 28.2. MS (ESI-TOF, 80 eV) m/z 419.27
(C18H37N5O6), 420.21 (M + H)+.
6-Am in o-h exa n oic Acid (4-{4-[2-Oxo-2-(6-oxo-5,6-d ih y-
d r o-ben zo[E]p yr id o[3,2-b][1,4]d ia zep in -11-yl)eth yl]p ip er -
a zin -1-yl}bu tyl)a m id e (33). To a solution of 15 (142.7 mg,
0.28 mmol) in a mixture of dry DMF/DMSO (1/1), compound
6 (40 mg, 0.14 mmol) and DIPEA (0.15 mL, 0.84 mmol) were
added. The mixture was heated at 80 °C for 10 h and then
poured into brine and extracted with EtOAc. The organic layer
was dried over Na2SO4, filtered, and evaporated. The purity
was checked by HPLC (tR ) 31.12 min.). MS (ESI-TOF, 135
eV) m/z 652.30 (M + H)+, 674.30 (M + H)+. The phthalimide
protecting group was removed in an ethanolic solution of
hydrazine (see procedure for compound 11), and compound 33
was obtained in 80% yield as a white solid after purification
1
by HPLC (tR ) 22.96 min). H NMR [(CD3)2SO, 300 MHz]: δ
8.22 (s, 1 H), 8.07 (d, 1 H, J ) 7.8 Hz), 7.87 (m, 1 H), 7.64 (m,
3 H), 7.44 (m, 2 H), 3.64 (m, 2 H), 2.99 (m, 9 H), 2.88 (m, 2 H),
2.74 (t, 2 H, J ) 7.5 Hz), 2.27 (s, 2 H), 2.06 (t, 2 H, J ) 7.2
Hz), 1.16-1.60 (m, 14 H). 13C NMR [(CD3)2SO, 75 MHz]: δ
172.3, 169.7, 166.8, 155.3, 144.4, 140.8, 133.2, 131.6, 131.1,
130.7, 130.0, 127.9, 125.7, 124.6, 61.3, 57.6, 52.5, 45.9, 39.2,
38.9, 35.7, 27.6, 27.3, 26.1, 25.4, 24.1. MS (ESI-TOF, 135 eV)
m/z 521.31 (C28H39N7O3), 522.28 (M + H)+.
6-Am in o-h exa n oic Acid [5-(4-{4-[2-Oxo-2-(6-oxo-5,6-d i-
h ydr o-ben zo[E]pyr ido[3,2-b][1,4]diazepin -11-yl)eth yl]pip-
er azin -1-yl}bu tylcar bam oyl)pen tyl]am ide (34). Compound
34 was obtained according to the experimental conditions for
compound 33 starting from 17 (14.4 mg, 0.028 mmol), 6 (4 mg,
0.014 mmol), and DIPEA (0.015 mL, 0.084 mmol) in a 1/1
mixture of DMF/DMSO. The mixture was heated at 80 °C for
10 h and then poured into brine and extracted with EtOAc.
The organic layer was dried over Na2SO4, filtered, and
evaporated. The purity was checked by HPLC (tR ) 34.4 min).
MS (ESI-TOF, 135 eV) m/z 765.40 (M + H)+,787.41 (M + Na)+.
The phthalimide protecting group was removed in an ethanolic
solution of hydrazine (see procedure for compound 11), and
the expected product 34 was purified by HPLC (tR ) 23.56
20-Azid o-3,6,9,12,15,18-h exa oxa icos-1-yl-m eth a n e Su l-
fon a te (31). To the compound 30 (1.35 g, 2.28 mmol) in MeOH
(50 mL) was added TsOH (0.43 g, 2.88 mmol). The mixture
was refluxed for 2 h, then Na2CO3 (2 eq) was added, and
stirring was continued for 5 min. The solvent was evaporated
under reduced pressure, and EtOAc (50 mL) was added to the
crude product. The precipitate was filtered off, and the filtrate
concentrated under reduced pressure. CH2Cl2 (50 mL) and
Et3N (0.35 mL, 2.50 mmol) were added to the crude product
followed by MsCl (0.2 mL, 2.50 mmol) at 0 °C. Stirring was
carried on for 2 h at 0 °C and then overnight at room
temperature. The precipitate was filtered off, and the crude
product was purified by silica gel column chromatography
(EtOAc) to give 31 as a colorless oil (0.82 g, 84%). TLC (EtOAc)
1
min). Yield: 40%. H NMR [(CD3)2SO, 200 MHz]: δ 8.26 (s, 1
H), 8.02 (d, 1H, J ) 7.7 Hz), 7.86 (m, 1 H), 7.61 (m, 3 H), 7.44
(m, 2 H), 3.65 (m, 2 H), 2.92 (m, 8 H), 2.89 (m, 2 H), 2.74 (t, 2
H, J ) 7.5 Hz), 2.26 (s, 2 H), 2.01 (t, 2 H, J ) 7.1 Hz), 1.14-
1.51 (m, 24 H). 13C NMR [(CD3)2SO, 50 MHz]: δ 172.3, 169.5,
168.2, 166.9, 155.1, 143.9, 140.6, 132.8, 131.3, 131.0, 130.8,
130.5, 128.5, 125.2, 122.9, 65.3, 58.6, 53.2, 45.8, 44.2, 41.6, 39.1,
38.2, 35.7, 28.0, 27.1, 26.5, 26.0, 24.2. MS (ESI-TOF, 135 eV)
m/z 634.40 (C34H50N8O4), 635.39 (M + H)+.
11-{[4-(2-Am in oeth yl)p ip er a zin -1-yl]a cetyl}-5,11-d ih y-
d r o-6H-p yr id o[2,3b][1,4]ben zod ia zep in -6-on e (35). Com-
pound 21 (304 mg, 1.96 mmol) was dissolved in CH3CN (20
mL), and Et3N (0.41 mL, 2.94 mmol) and 6 (650 mg, 1.96
mmol) were added. The mixture was refluxed for 3 h. The
solvents was evaporated, and the crude product was purified
by silica gel column chromatography (EtOAc/MeOH 9/1, Rf
1
Rf 0.19. H NMR (CDCl3, 200 MHz): δ 4.20 (t, J ) 4.4 Hz, 2
H), 3.47-3.67 (m, 24 H), 3.22 (t, J ) 4.5 Hz, 2 H), 2.92 (s,
3H). 13C NMR (CDCl3, 50 MHz): δ 69.9, 69.4, 69.0, 50.1, 37.1.
MS (ESI-TOF, 80 eV) m/z 429.18 (C15H31N3O9S), 430.16 (M +
H)+, 452.14 (M + Na)+.
1
0.12), giving a colorless solid (397 mg, 50%). H NMR (CDCl3,
N -(20-Azid o-3,6,9,12,15,18-h e xa oxa icos-1-yl)p ip e r a -
zin e, TF A Sa lt (32). To a solution of 31 (400 mg, 0.93 mmol)
in CH3CN (20 mL), Et3N (0.26 mL, 1.86 mmol) and N-Boc
piperazine 8 (0.21 mmol, 1.12 mmol) were added. The mixture
was refluxed for 24 h. The precipitate was filtered off, and the
filtrate was evaporated and chromatographied on a silica gel
column (EtOAc/MeOH 95/5). TLC (EtOAc/MeOH) Rf 0.2. 1H
NMR (CDCl3, 300 MHz): δ 3.80-3.96 (m, 4 H), 3.46-3.60 (m,
200 MHz): δ 10.87 (br s, 1 H), 8.25 (s, 1 H), 7.93 (d, J ) 7.1
Hz, 1 H), 7.59-7.68 (m, 3 H), 7.25-7.31 (m, 2 H), 3.31-3.62
(m, 4 H), 1.97-2.81 (m, 10 H). 13C NMR (CDCl3, 50 MHz): δ
169.6, 168.7, 147.3, 144.7, 140.8, 133.4, 131.0, 130.7, 130.1,
128.7, 128.3, 127.9, 123.8, 60.9, 56.9, 56.7, 52.8, 52.6, 52.4, 48.0,
47.7, 29.5, 29.1. MS (ESI-TOF, 135 eV) m/z 407.19 (C20H23N8O2),
407.23 (M + H)+, 813,41 (2M + H)+.