1814 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Kalindjian et al.
aqueous sodium hydrogen carbonate solution (5 mL), and brine
(5 mL) and dried. Column chromatography (silica, 5% ethyl
acetate and 95% dichloromethane) afforded a white solid (76
mg, 69%): 1H NMR (DMSO-d6) δ 11.5 (1H, s), 10.3 (1H, s),
8.8 (3H, m), 8.5 (1H, t), 8.3 (1H, s), 7.7 (1H, s), 7.6-7.2 (16H,
m), 7.2 (1H, s), 6.5 (1H, s), 5.4 (4H, s), 4.7 (1H, m), 3.4 (1H,
m), 2.9 (3H, m), 1.8 (3H, s), 1.6-1.3 (12H, m).
Step c. The product of step b (70 mg, 0.08 mmol) was
dissolved in a 1:1 mixture of THF and methanol (3 mL), and
10% palladium on charcoal (10 mg) was added. The reaction
mixture was stirred overnight under an atmosphere of hydro-
gen and then filtered through Celite and evaporated to yield
the title compound (53 mg, 96%): 1H NMR (DMSO-d6) δ 11.5
(1H, s), 10.2 (1H, s), 8.7 (1H, d), 8.6 (2H, s), 8.4 (1H, t), 8.2
(1H, s), 7.7 (1H, s), 7.5 (1H, s), 7.2 (6H, m), 6.5 (1H, s), 4.8
(1H, m), 3.5 (1H, m), 3.0 (3H, m), 1.8 (3H, s), 1.5 (6H, m), 1.4
(6H, s); further characterized as the bis(N-methyl-D-glucamine)
salt. Anal. (C38H38N4O7‚2C7H17NO5‚H2O) C, H, N.
6-[[[1(S)-[[(3,5-Dica r b oxyp h en yl)a m in o]ca r b on yl]-2-
p h en yleth yl]a m in o]ca r bon yl]-5-[[(1-a d a m a n tylm eth yl)-
a m in o]ca r bon yl]in d ole (8). This was made using the
coupling deprotection method B but using the soluble regioi-
somer purified by column chromatography in step a: 1H NMR
(DMSO-d6) δ 11.5 (1H, s), 10.2 (1H, s), 8.8 (1H, d), 8.6 (2H, s),
8.4 (1H, t), 8.2 (1H, s), 7.9 (1H, s), 7.5 (1H, t), 7.2-7.4 (5H,
m), 7.0 (1H, s), 6.6 (1H, s), 4.7 (1H, m), 3.4 and 2.9 (4H, m),
1.8 (3H, s), 1.5 (6H, m), 1.3 (6H, s); further characterized as
5-[[[1(S)-[[(3,5-Dica r b oxyp h en yl)a m in o]ca r b on yl]-2-
p h en yleth yl]a m in o]ca r bon yl]-6-[[(1-a d a m a n tylm eth yl)-
a m in o]ca r bon yl]ben zim id a zole (9): 1H NMR (DMSO-d6) δ
10.2 (1H, m), 8.9 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s),
8.2 (1H, m), 7.9 (1H, br s), 7.3 (7H, m), 4.7 (1H, m), 3.5 (1H,
m), 3.0 (3H, m), 1.8 (3H, s), 1.5 (6H, m), 1.4 (6H, s); further
characterized as the bis(N-methyl-D-glucamine) salt. Anal.
(C37H37N5O7‚2C7H17NO5‚3.25H2O) C, H, N.
5-[[[1(S)-[[(3,5-Dica r boxyp h en yl)a m in o]ca r bon yl]-2-(2-
flu or op h en yl)et h yl]a m in o]ca r b on yl]-6-[[(1-a d a m a n t yl-
m eth yl)am in o]car bon yl]ben zim idazole (13): 1H NMR (DM-
SO-d6) δ 13.0 (3H, br s), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s),
8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, d), 7.4-7.2 (4H,
m), 7.1 (1H, s), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.8 (3H, s), 1.6
(6H, m), 1.3 (6H, m); further characterized as the bis(N-methyl-
D-glucamine) salt. Anal. (C37H36FN5O7‚2C7H17NO5) C, H, N.
5-[[[1(S)-[[(3,5-Dica r boxyp h en yl)a m in o]ca r bon yl]-2-(4-
h yd r oxyp h en yl)et h yl]a m in o]ca r b on yl]-6-[[(1-a d a m a n -
tylm eth yl)a m in o]ca r bon yl]ben zim id a zole (14): 1H NMR
(DMSO-d6) δ 13.0 (3H, br s), 10.2 (1H, s), 9.3 (1H, br s), 8.8
(1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H,
s), 7.2 (1H, s), 7.1 (2H, d), 6.7 (2H, d), 4.6 (1H, m), 3.0-2.3
(4H, m), 1.8 (3H, s), 1.6 (6H, m), 1.4 (6H, m); further
characterized as the bis(N-methyl-D-glucamine) salt. Anal.
(C37H37N5O8‚2C7H17NO5‚0.2H2O) C, H, N.
5-[[[1(S)-[[(3,5-Ditetr a zolylp h en yl)a m in o]ca r bon yl]-2-
p h en yleth yl]a m in o]ca r bon yl]-6-[[(1-a d a m a n tylm eth yl)-
a m in o]ca r bon yl]ben zim id a zole (16): isolated as the bis-
(ammonium) salt; 1H NMR (DMSO-d6) δ 10.2 (1H, s), 8.8 (1H,
d), 8.6 (2H, d), 8.4 (2H, m), 7.9 (1H, s), 7.4-7.2 (7H, m), 4.8
(1H, m), 3.5-3.0 (4H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s).
Anal. (C37H37N13O3‚2NH3‚1.5H2O) C, H, N.
5-[[[1(S)-[[(3,5-Dica r boxyp h en yl)a m in o]ca r bon yl]-2-(2-
flu or op h en yl)et h yl]a m in o]ca r b on yl]-6-[[(cycloh ep t yl-
m eth yl)am in o]car bon yl]ben zim idazole (18): 1H NMR (DM-
SO-d6) δ 3.0 (3H, br s), 10.2 (1H, br s), 8.9 (1H, d), 8.74 (2H,
s), 8.7 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.8 (1H, s), 7.5-7.1 (5H,
m), 4.8 (1H, m), 3.5 (1H, m), 3.3-3.1 (3H, m), 1.6-1.1 (13H,
m); further characterized as the bis(N-methyl-D-glucamine)
salt. Anal. (C34H34FN5O7‚2C7H17NO5) C, H, N.
the bis(N-methyl-D-glucamine) salt. Anal. (C38H38N4O7‚2C7H17
NO5‚H2O) C, H, N.
-
Indole derivatives 12 and 15 were prepared using method
B with the appropriate synthons as described in Scheme 2 and
Table 3. Compound 17, a tetrazole derivative, was prepared
using the (pivaloyloxy)methyl (POM) group protection and
using the coupling methodology described in method B, steps
a and b but with deprotection of the POM group achieved using
a solution of ammonia in methanol. In each case the insoluble
regioisomer isolated in step a was the precursor of interest.
5-[[[1(S)-[[(3,5-Dica r b oxyp h en yl)a m in o]ca r b on yl]-2-(2-
flu or op h en yl)eth yl]a m in o]ca r bon yl]-6-[[(1-a d a m a n tylm -
eth yl)a m in o]ca r bon yl]in d ole (12): 1H NMR (DMSO-d6) δ
13.3 (2H, br s), 11.8 (1H, s), 10.2 (1H, s), 8.74 (1H, d), 8.7 (2H,
s), 8.5 (1H, t), 8.2 (1H, s), 7.8 (1H, s), 7.6-7.2 (6H, m), 6.5 (1H,
s), 4.8 (1H, m), 3.6 (1H, m), 3.0 (3H, m), 1.9 (3H, br s), 1.6
(12H, m); further characterized as the bis(N-methyl-D-glucam-
ine) salt. Anal. (C38H37FN4O7‚2C7H17NO5‚2.8H2O) C, H, N.
5-[[[1(S)-[[(3,5-Ditetr a zolylp h en yl)a m in o]ca r bon yl]-2-
(2-flu or op h en yl)eth yl]a m in o]ca r bon yl]-6-[[(cycloh ep tyl-
m eth yl)am in o]car bon yl]ben zim idazole (19): 1H NMR (DM-
SO-d6) δ 10.4 (1H, s), 8.9 (1H, d), 8.8 (2H, s), 8.7 (1H, t), 8.5
(1H, s), 8.4 (1H, s), 7.9 (1H, s), 7.4 (1H, m), 7.3 (1H, m), 7.2
(2H, m), 7.1 (1H, m), 4.9 (1H, m), 3.6 (1H, dd), 3.1 (2H, m), 2.9
(1H, dd), 1.6-1.0 (13H, m); further characterized as the bis-
5-[[[1(S)-[[(3,5-Dica r b oxyp h en yl)a m in o]ca r b on yl]-2-
p h en ylet h yl]a m in o]ca r b on yl]-6-[[(cycloh ep t ylm et h yl)-
a m in o]ca r bon yl]in d ole (15): 1H NMR (DMSO-d6) δ 11.5
(1H, s), 10.2 (1H, s), 8.7 (3H, m), 8.5 (1H, t), 8.2 (1H, s), 7.8
(1H, s), 7.5-7.0 (7H, m), 6.5 (1H, s), 4.7 (1H, m), 3.2-2.7
(4H, m), 1.7-1.0 (13H, m); further characterized as the
(N-methyl-D-glucamine) salt. Anal. (C34H34FN13O3‚2C7H17
NO5‚4.0H2O) C, H, N.
-
5,6-Bis(m et h oxyca r b on yl)-2-(t r im et h ylsilyl)b en zofu -
r a n (31). Compound 30 (4.5 g, 13.4 mmol) and (trimethylsilyl)
acetylene (1.71 g, 17.4 mmol) were dissolved in a mixture of
triethylamine (50 mL) and dioxane (80 mL), and the solution
was degassed with argon for 15 min. Copper(I) iodide (152
mg, 0.8 mmol) was added followed by bis(triphenylphosphine)-
palladium dichloride (564 mg, 0.8 mmol). The reaction was
stirred at 60 °C overnight under an atmosphere of argon. The
solvents were removed by evaporation, and the resulting oil
was redissolved in dichloromethane and washed sequentially
with 10% citric acid solution and brine. The organic layer was
dried, filtered, evaporated, and passed through a short silica
column (dichloromethane) to give the title compound (4.0 g,
97%): 1H NMR (CDCl3) δ 7.9 (1H, s), 7.8 (1H, s), 7.0 (1H, s),
3.9 (6H, s), 0.3 (9H, s).
Ben zofu r an -5,6-dicar boxylic Acid An h ydr ide (32). Step
a . Compound 31 (1.2 g, 3.9 mmol) was dissolved in THF (50
mL), and tetrabutylammonium fluoride monohydrate (1.02, 3.9
mmol) was added. The solution immediately turned black and
was allowed to stir at room temperature overnight. The
reaction mixture was evaporated to leave a brown oil which
was purified by column chromatography (silica, 10% ethyl
acetate and 90% dichloromethane) to leave the desilylated
analogue of compound 31 (720 mg, 79%).
bis(N-methyl-D-glucamine) salt. Anal. (C35H36N4O7‚2C7H17
NO5‚4.3H2O) C, H, N.
-
5-[[[1(S)-[[(3,5-Ditetr a zolylp h en yl)a m in o]ca r bon yl]-2-
p h en yleth yl]a m in o]ca r bon yl]-6-[[(1-a d a m a n tylm eth yl)-
a m in o]ca r bon yl]in d ole (17): 1H NMR (DMSO-d6) δ 11.5
(1H, s), 10.4 (1H, s), 8.8 (3H, m), 8.5 (2H, m), 7.7 (1H, s), 7.5
(1H, t), 7.4-7.0 (6H, m), 6.5 (1H, s), 4.8 (1H, m), 3.2-2.9 (4H,
m), 1.8 (3H, s), 1.5 (6H, q), 1.3 (6H, s); further characterized
as the bis(N-methyl-D-glucamine) salt. Anal. (C38H38N12O3‚
2C7H17NO5‚3H2O) C, H, N.
Ben zim id a zole-5,6-d ica r boxylic Acid An h yd r id e (26).
Benzimidazole-5,6-dicarboxylic acid (18.00 g, 87.4 mmol) was
heated strongly with a heat gun under vacuum for 20 min.
The yellow solid was extracted with hot acetone (750 mL) using
a Soxhlet apparatus to give the title compound (13.79 g, 84%):
1H NMR (DMSO-d6) δ 8.7 (1H, s), 8.3 (2H, s).
The following benzimidazoles were made using the coupling
conditions in method B but using the appropriate synthons
shown in Scheme 3 and Table 3. No regioisomers can arise
from the chemistry so the product of step a after work up was
the single desired precursor. Deprotection of benzyl esters was
by hydrogenation as described in method B step c, and POM
groups were removed from tetrazoles using a solution of
ammonia in methanol.
Step b. The saponification and anhydride formation were
carried out in an analogous manner to the preparation of
compound 24.