1112
L.-C. Yang, C.-M. Qi, G.-X. Zhang and N.-Z. Zou
Vol. 40
2H, CH CH CH ), 2.39 (s, 3H, PhCH ), 1.81 (m, 2H,
PhCH ), 2.44 (s, 3H, PhCH ), 1.83 (m, 2H, CH CH CH ), 0.98
3 3 2 2 3
2
2
3
3
-1
(t, J=7.4 Hz, 3H, CH CH ); ir (KBr): 1600, 1559, 1455 cm .
CH CH CH ), 1.06 (t, J=7.4 Hz, 3H, CH CH ); ir (KBr): 3480,
2
3
2
2
3
2
3
-1
2950, 1740, 1670, 1550, 1520 cm .
4'-[[2-n-Propyl-4-methyl-6-(5-methylbenzoxazole-2-yl)-benzim-
idazol-1-yl]methyl]-2-cyanobiphenyl (5).
Methyl4-(n-Butyrylamino)-3-methyl-5-aminoobenzoate (18).
To a solution of 21 (1 g) in dimethoxy ethane (3.5 mL) was
added NaH (0.34 g) at 0 °C, the mixture was stirred for 1 h at
ambient temperature, and 22 (1.5 g) was added. After stirring for
4 h the solid was collected by filtration, washed with petroleum
ether (5 mLx3) and water (5 mLx3), dried to give white solid 5
(1.73 g, 86.5%).
Compound 17 (0.28 g) was reduced with Raney Ni (0.2 g) and
hydrazine in methanol by the same procedure as described for the
preparation of compound 15 to obtain pure product 18 (0.23 g,
-1
92%). Ir (KBr): 3440, 3360, 2975, 1720, 1660, 1517 cm .
2-n-Propyl-4-methyl-6-(methoxycarbonyl)benzimidazole (19).
Compound 18 (1.0 g) was dissolved in the glacial acetic acid
and heated under reflux for 2 h. After evaporation of the acetic
acid water was added and the pH was adjusted to 9 by addition of
concentrated ammonia. This solution was extracted with ethyl
acetate (10 mLx3), and the combined organic layers were washed
4'-[[2-n-Propyl-4-methyl-6-(5-methylbenzoxazole-2-yl)-benzim-
idazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)biphenyl (6).
To a solution of 5 (1 g) in DMF were added sodium azide (1.73
g) and ammonium chloride (1.40 g), and the mixture was heated
at 140 °C for 18 h. After cooling, water (15 mL) was added, and
the precipitated solid was collected by filtration, dried and puri-
fied by recrystallization from methanol to give 6 (0.87 g, 80%).
with aqueous NaHCO solution and dried (MgSO ). After
3
4
removal of the solvent the yellow solid 19 was obtained (0.85 g,
1
90%). mp 139-143 °C; H nmr (DMSO): δ 12.40 (br, 1H, NH),
7.80 (s, 1H, Ar-H), 7.50 (s, 1H, Ar-H), 3.77 (s, 3H, CH O), 2.70
3
4'-[[2-n-Propyl-4-methyl-6-(5-methylbenzoxazole-2-yl)-benzim-
idazol-1-yl]methyl]biphenyl-2-carboxylate (3).
(t, J=7.4 Hz, 2H, CH CH CH ), 2.40 (s, 3H, PhCH ), 1.70 (m,
2
2
3
3
2H, CH CH CH ), 0.90 (t, J=7.3 Hz, 3H, CH CH ); ir (KBr):
2
2
3
2
3
-1
The title compound was prepared from 21 and 23 by the same
procedure described for the preparation of 5 (84.7%).
3400, 1720, 1627 cm .
2-n-Propyl-4-methyl-6-carboxybenzimidazole (20).
4'-[[2-n-Propyl-4-methyl-6-(5-methylbenzoxazole-2-yl)-benzim-
idazol-1-yl]methyl]biphenyl-2-carboxylic Acid (4).
To a solution of 0.69 g of 19 in methanol was added a solution
of 10% NaOH, and the mixture was heated under reflux for 2 h.
After evaporation of methanol, water (3.5 mL) was added to the
residue and the pH was adjusted to 5 by addition of aqueous cit-
ric acid (30%). The precipitated solid was collected by filtration,
washed with water, and dried to yield compound 20 (0.54 g,
To a solution of 3 (1.06 g) in methanol was added 10% NaOH
solution (4 mL) at refluxing. The mixture was stirred for 3 h and
poured on water (6 mL). The pH was adjusted to 5 by addition of
glacial acetic acid, and the solid was collected by filtration and
dried to give 4 (0.86, 83.5%) as a white solid.
1
82.3%). mp 298-300 °C; H nmr (DMSO): δ 12.70 (br, 2H, NH
and COOH), 8.81 (s, 1H, Ar-H), 7.79(s, 1H, Ar-H), 3.04 (t, J=7.3
Compounds 1, 2, and 7-12 were prepared in a similar manner.
Hz, 2H, CH CH CH ), 2.73 (s, 3H, PhCH ), 2.00 (m, 2H,
2
2
3
3
CH CH CH ), 1.20 (t, J=7.1 Hz, 3H, CH CH ); ir (KBr): 3200-
2500, 1680, 1580, 1420-1340 cm .
2
2
3
2
3
REFERENCES AND NOTES
-1
[1] M. B. Vallotton, Sci., 8, 69 (1987).
[2] W. J. Greenlee, Med. Res. Rev., 10, 173 (1990).
2-n-Propyl-4-methyl-6-(5-methylbenzoxazole-2-yl)benzimida-
zole (21).
[3] E. G. Erdos and R. A. Skidgel, Hypertension, 8, I34 (1986).
[4] H. Urata, A. Kinoshita, K. S. Misono, F. M. Bumpus and A.
Husain, J. Biol. Chem., 265, 22348 (1990).
[5] D. J. Carini, J. V. Duncia, P. E. Aldrich, A. T. Chiu, A. L.
Johnson, M. E. Pierce, W. A. Price, J. B. Santella, G. J. Wells, R. R.
Wexler, P. C. Wong and S. E. Yoo, J. Med. Chem., 34, 2525 (1991).
[6] F. M. Bumpus, K. J. Catt, A. T. Chiu, M. DeGasparo, T.
Goodfriend, A. Husain, M. J. Peach, D. G. Jr. Taylor and P. B. M. W. M.
Timmermans, Hypertension, 17, 720 (1991).
Compound 20 (1.13 g) was dissolved in polyphosphoric acid
(9.4 mL) at 120 °C, and p-methyl-o-aminophenol hydrochloride
(0.88 g) was added in small portions. After stirring at 160 °C for
20 h the mixture was allowed to cool and then poured into water.
The pH was adjusted to 9 by addition of concentrated ammonia
(ice cooling). The precipitated solid was collected by filtration,
dried, recrystallized twice with ethyl acetate and ethanol respec-
1
tively to give white solid 21 (1.05 g, 67.1%). mp 208-210 °C; H
[7] U. J. Ries, G. Mihm, B. Narr, K. M. Hasselbach, H.
Wittneben, M. Entzeroth, C. A. Jacobus, V. Meel, W. Wienen and N. H.
Hauel, J. Med. Chem., 35, 4040 (1993).
nmr (DMSO): δ 8.10 (s, 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.63 (d,
J=8.2 Hz, 10H, Ar-H), 7.56 (s, 1H, Ar-H), 7.20 (d, J=8.2 Hz, 1H,
Ar-H), 2.85 (t, J=7.5 Hz, 2H, CH CH CH ), 2.59 (s, 3H,
[8] R. Geigy and W. Konigs, J. Med. Chem., 18, 2400 (1885).
2
2
3