4864 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Burnouf et al.
1
durein pyridine(see9b),9fwas finallypurified bychromatography
with a gradient of 2-4% MeOH/CH2Cl2: yellow powder; 23%
yield; mp >250 °C; 1H NMR (400 MHz, CDCl3) δ 1.92 (m, 4H),
3.02 (m, 1H), 3.14 (m, 4H), 3.28 (m, 1H), 3.89 (m, 1H), 4.55
(m, 1H), 5.53 (m, 1H), 6.20 (s, 1H), 6.70 (s, 1H), 7.25-7.45 (m,
3H), 7.57 (m, 2H), 7.72 (m, 2H), 8.08 (m, 1H), 8.73 (m, 2H).
DMSO); H NMR (400 MHz, DMSO) δ 3.15 (dd, J ) 16.3 Hz,
8.7 Hz, 1H), 3.37 (m, 1H), 3.95 (m, 1H), 4.49 (m, 1H), 5.52 (d,
J ) 7.8 Hz, 1H), 6.91 (s, 1H), 7.34 (s, 1H), 7.42-7.58 (m, 5H),
8.10 (d, J ) 6.0 Hz, 2H), 8.90 (d, J ) 6.0 Hz, 2H), 10.13 (d, J
) 7.8 Hz, 1H). Anal. (C23H19N5O2‚3/2H2SO4‚11/10H2O‚1/3EtOH)
C, H, N, S: O: calcd, 26.0; found, 25.33.
N-((R)-4-Oxo-1-ph en yl-3,4,6,7-tetr ah ydr o[1,4]diazepin o-
[6,7,1-h i]in d ol-3-yl)n icotin a m id e (10a ). Starting from 8a ,
a precipitate formed and 10a was filtered and washed with
N-((R)-9-Nit r o-4-oxo-1-p h en yl-3,4,6,7-t et r a h yd r o[1,4]-
d ia zep in o[6,7,1-h i]in d ol-3-yl)n icotin a m id e (10d ). Instead
of pyridine, the amino intermediate 8d (0.7 g, 2.17 mmol) was
dissolved in CH2Cl2 (20 mL) and triethylamine (0.42 mL, 2.4
mmol) was added. The reaction was stirred overnight at room
temperature and concentrated. After purification by chroma-
tography (98:2 CH2Cl2/MeOH), 10d (0.8 g, 95%) was ob-
CH2Cl2: a white solid; 69% yield; mp 253 °C; [R]20 +53° (c )
D
1
1, CH2Cl2); H NMR (400 MHz, DMSO) δ 3.19 (m, 1H), 3.43
(m, 1H), 3.98 (m, 1H), 4.54 (m, 1H), 5.54 (d, J ) 8.0 Hz, 1H),
7.24 (m, 2H), 7.43-7.70 (m, 7H), 8.40 (dt, J ) 8.0 Hz, 1.8 Hz,
1H), 8.78 (dd, J ) 4.8 Hz, 1.8 Hz, 1H), 9.19 (d, J ) 1.8 Hz,
1H), 9.95 (d, J ) 8.0 Hz, 1H). Anal. (C23H18N4O2) C, H, N.
3,5-Dich lor o-N-((R)-4-oxo-1-p h en yl-3,4,6,7-tetr a h yd r o-
[1,4]d ia zep in o[6,7,1-h i]in d ol-3-yl)ison icotin a m id e (11a ).
Starting from 8a , 11a was finally purified by chromatography
with a gradient of 0-2% MeOH/CH2Cl2 followed by recrystal-
lization from diethyl ether/petroleum ether: white powder;
20% yield; mp 182 °C; [R]20D +136.5° (c ) 1, CH2Cl2); 1H NMR
(400 MHz, DMSO) δ 3.15 (dd, J ) 16.4 Hz, 8.2 Hz, 1H), 3.42
(dt, J ) 16.4 Hz, 9.8 Hz, 1H), 3.95 (m, 1H), 4.54 (m, 1H), 5.43
(d, J ) 8.3 Hz, 1H), 7.22 (m, 2H), 7.40-7.58 (m, 6H), 8.72 (s,
2H), 10.26 (d, J ) 8.3 Hz, 1H); MS m/z 451.
1
tained: yellow powder; mp 172-176 °C; H NMR (400 MHz,
CDCl3) δ 3.32 (dd, J ) 16.8 Hz, 9.9 Hz, 1H), 3.50 (dt, J ) 16.8
Hz, 10.0 Hz, 1H), 4.17 (m, 1H), 4.75 (m, 1H), 5.70 (d, J ) 7.6
Hz, 1H), 7.40-7.57 (m, 6H), 7.85 (d, J ) 7.6 Hz, 1H), 8.25 (m,
2H), 8.33 (s, 1H), 8.80 (d, J ) 4.7 Hz, 1H), 9.20 (s, 1H); MS
m/z 427.
2-Me t h oxy-N -((R )-9-m e t h yl-4-oxo-1-p h e n yl-3,4,6,7-
t e t r a h y d r o [1,4]d ia ze p in o [6,7,1-h i ]in d o l-3-y l)b e n za -
m id e (13b). Instead of pyridine, the amino intermediate 8b
was treated in CH2Cl2 and triethylamine (see synthesis of
10d ). 13b was purified by chromatography (97:3 CH2Cl2/
MeOH): white powder; 80% yield; mp 123-125 °C; [R]20D +34°
(c ) 1, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H),
3.10 (dd, J ) 16.0 Hz, 9.6 Hz, 1H), 3.33 (dt, J ) 16.0 Hz, 10.1
Hz, 1H), 3.98 (m, 1H), 4.07 (s, 3H), 4.68 (m, 1H), 5.67 (d, J )
7.5 Hz, 1H), 7.00-7.13 (m, 3H), 7.28 (s, 1H), 7.32-7.60 (m,
6H), 8.25 (dd, J ) 7.8 Hz, 1.8 Hz, 1H), 9.80 (d, J ) 7.5 Hz,
1H). Anal. (C26H23N3O3‚1/2H2O) C, H, N.
Gen er a l P r oced u r e J : Cou p lin g Rea ction w ith Ca r -
boxylic Acid Der iva tives a n d TOTU. N-((R)-9-Am in o-4-
oxo-1-p h en yl-3,4,6,7-tetr a h yd r o[1,4]d ia zep in o[6,7,1-h i]-
in d ol-3-yl)n icotin a m id e (10e). To a stirred solution of 8e
(35 g, 0.119 mol) in CH2Cl2 (1.3 L), were introduced acid
isonicotinic (16.2 g, 0.131 mol) and O-[(ethoxycarbonyl)cyano-
methyleneamino)-N,N,N′,N′-tetramethyluronium tetrafluoro-
borate (TOTU) (39.3 g, 0.119 mol). The suspension was cooled
to 0 °C and diisopropylethylamine (41.7 mL, 0.239 mol) was
added. The reaction mixture was stirred for 15 min and
allowed to warm to room temperature. After being stirred
overnight, the mixture was filtered, washed twice with H2O
(500 mL), HCl and H2O (250 mL). After neutralization with
concentrated NaOH, the aqueous phase was extracted by CH2-
Cl2. The combined organic layers were washed by H2O, dried
and filtered. The solvent was removed in vacuo and the crude
material was purified by chromatography eluting with a
MeOH gradient in CH2Cl2 to afford 10e: yellow powder; 24.1
3,5-Dich lor o-N-((R)-9-m et h yl-4-oxo-1-p h en yl-3,4,6,7-
tetr a h yd r o[1,4]d ia zep in o[6,7,1-h i]in d ol-3-yl)ison icotin a -
m id e (11b). Starting from 8b, 11b was finally purified by
chromatography with a gradient of 0-5% acetone/CH2Cl2
followed by recrystallization from diethyl ether/hexane: white
powder; 22% yield; mp 147-198 °C; [R]20 +166° (c ) 1, CH2-
D
Cl2); 1H NMR (400 MHz, DMSO) δ 2.53 (s, 3H), 3.10 (dd, J )
16.0 Hz, 8.4 Hz, 1H), 3.40 (m, 1H), 3.93 (m, 1H), 4.52 (m, 1H),
5.42 (d, J ) 8.3 Hz, 1H), 7.05 (s, 1H), 7.40-7.60 (m, 6H), 8.70
(s, 2H), 10.23 (d, J ) 8.3 Hz, 1H). Anal. (C24H18Cl2N4O2‚1/
10C6H12‚1/10H2O) C, H, N, O, Cl.
N-((R)-9-Am in o-4-oxo-1-p h en yl-3,4,6,7-tetr a h yd r o[1,4]-
d ia zep in o[6,7,1-h i]in d ol-3-yl)-3,5-d ich lor oison icot in a -
m id e (11e). Starting from 8e, 11e was finally purified by
chromatography with
a gradient of 0-2% MeOH/CH2Cl2
followed by recrystallization from ethyl acetate/hexane: yellow
powder; 33% yield; mp 166-220 °C; [R]20 +175° (c ) 1, CH2-
D
1
Cl2); H NMR (400 MHz, DMSO) δ 3.00 (dd, J ) 16.0 Hz, 8.9
Hz, 1H), 3.30 (m, 1H), 3.82 (m, 1H), 4.45 (m, 1H), 5.28 (bs,
2H), 5.39 (d, J ) 8.3 Hz, 1H), 6.38 (s, 1H), 6.88 (s, 1H), 7.40-
7.60 (m, 5H), 8.71 (s, 2H), 10.18 (s, 1H). Anal. (C23H17Cl2N3O2‚
2/5C4H8O2‚1/10C6H12) C, H, O, Cl; N: calcd, 13.73; found, 14.60.
N-((R)-9-Am in o-4-oxo-1-p h en yl-3,4,6,7-tetr a h yd r o[1,4]-
diazepin o[6,7,1-h i]in dol-3-yl)-2-m eth oxyben zam ide (13e).
Starting from 8e, 13e was finally purified by chromatography
with a gradient of 0-2% MeOH/CH2Cl2: yellow powder; 65%
g, 50%; ee >99%; mp >250 °C; Rf 0.7 (95:5 CH2Cl2/MeOH);
1
[R]20 +61° (c ) 1, H2O); H NMR (400 MHz, DMSO) δ 3.02
D
yield; mp 234 °C; [R]20 +39.5° (c ) 1, CH2Cl2); 1H NMR (400
(dd, J ) 16.1, 8.5 Hz, 1H), 3.25 (m, 1H), 3.85 (m, 1H), 4.42 (m,
1 H), 5.27 (bs, 2H), 5.48 (d, J ) 8.0 Hz, 1H), 6.40 (s, 1H), 6.95
(s, 1H), 7.45-7.65 (m, 6H), 8.37 (dt, J ) 8.0 Hz, 1.8 Hz, 1H),
8.75 (dd, J ) 4.8 Hz, 1.6 Hz, 1H), 9.20 (d, J ) 2.1 Hz, 1H),
9.82 (d, J ) 8.0 Hz, 1H). Anal. (C23H19N5O2) C, H, N, O.
D
MHz, CDCl3) δ 3.00 (dd, J ) 16.2 Hz, 9.5 Hz, 1H), 3.25 (dt, J
) 16.2 Hz, 9.9 Hz, 1H), 3.70 (bs, 2H), 3.90 (m, 1H), 4.05 (s,
3H), 4.60 (m, 1H), 5.65 (d, J ) 7.3 Hz, 1H), 6.45 (d, J ) 2.1
Hz, 1H), 6.80 (s, 1H), 6.95-7.10 (m, 2H), 7.30-7.50 (m, 4H),
7.56 (dd, J ) 7.0 Hz, 1.4 Hz, 2H), 8.23 (dd, J ) 7.9 Hz, 1.9 Hz,
1H), 9.81 (d, J ) 7.3 Hz, 1H). Anal. (C25H22N4O3) C, H, N, O.
4-Am in o-3,5-d ich lor o-N-((R)-9-m et h yl-4-oxo-1-p h en -
yl-3,4,6,7-t et r a h yd r o[1,4]d ia zep in o[6,7,1-h i]in d ol-3-yl)-
ben za m id e (14b). Starting from 8b, 14b was finally purified
by chromatography (98:2 CH2Cl2/MeOH) followed by recrys-
tallization from Et2O: white powder; 56.3% yield; mp 244 °C;
1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 3.10 (dd, J ) 16.2
Hz, 7.9 Hz, 1H), 3.35 (dt, J ) 16.2 Hz, 9.9 Hz, 1H), 3.97 (m,
1H), 4.65 (m, 1H), 4.80 (bs, 2H), 5.55 (d, J ) 7.6 Hz, 1H), 7.04
(s, 1H), 7.28 (s, 1H), 7.34-7.57 (m, 5H), 7.77 (d, J ) 7.6 Hz,
1H), 7.84 (s, 2H). Anal. (C25H20Cl2N4O2‚H2O) C, H; N: calcd,
11.27; found, 10.85.
N-((R)-9-Am in o-4-oxo-1-p h en yl-3,4,6,7-tetr a h yd r o[1,4]-
d ia zep in o[6,7,1-h i]in d ol-3-yl)ison icotin a m id e (9e). Start-
ing from 8e, 9e was finally purified by chromatography, first
eluting with CH2Cl2 then eluting with 98:2 CH2Cl2/MeOH. The
pure residue was dissolved in hot 25:75 CH2Cl2/MeOH, CH2-
Cl2 was removed in vacuo and a yellow precipitate formed
within 1 h at 0 °C (19 g, 52%). To the yellow precipitate (13.9
g, 34.8 mmol) dissolved in MeOH (415 mL) at room temper-
ature was added dropwise concentrated sulfuric acid (5.5 mL).
A red coloration and a slight exotherm were observed. After
stirring for 10 min, absolute EtOH (690 mL) was added
stepwise while MeOH was evaporated in vacuo. The mixture
allowed to cool at 0 °C. Maintaining the temperature 1 h, a
red precipitate formed. The precipitate was filtered and dried
at 50 °C for 2 h and then triturated in hot MeOH (50 mL).
EtOH (550 mL) was slowly added and the mixture was stirred
at 50 °C for 15 min and at 0 °C for 1 h providing 9e: 22.5 g,
4-Am in o-N-((R)-9-a m in o-4-oxo-1-p h en yl-3,4,6,7-t et r a -
h ydr o[1,4]diazepin o[6,7,1-h i]in dol-3-yl)-3,5-dich lor oben z-
a m id e (14e). Starting from 8e, 14e was finally purified by
chromatography (98:2 CH2Cl2/MeOH) followed by recrystalli-
zation from EtOAc: yellow powder; 43% yield; mp >280 °C;
100%; pale beige powder; mp 220-225 °C; [R]20 +94° (c ) 1,
D