2512
P. Wang et al. / Tetrahedron 68 (2012) 2509e2512
(200 ml) in autoclave, then the stirred mixture was heated at 90 ꢀC
for 6 h. After cooling, the reaction mixture was poured slowly into
water (600 ml) with stirring. The resultant suspension was filtered
and the collected solid washed with water and dried under vacuum
to give compound 11 (53.6 g, 95%) as brown solid; mp: 164e165 ꢀC;
123.6, 127.1, 127.4, 128.8, 128.9, 129.4, 130.2, 130.4, 133.7, 134.0,
134.6, 135.6, 141.1, 141.8, 142.8, 143.6, 154.0, 156.5, 171.1; MS (þC,
ESI): M¼514, found 515 [MþH]þ; HRMS (ESI): [MþH]þ calcd for
C33H31N4O2: 515.2369, found 515.2452.
1H NMR (400 MHz, DMSO-d6)
d 2.32 (s, 3H, CH3), 3.90 (s, 3H,
Acknowledgements
NCH3), 7.25 (m, 2H, ArH), 7.51 (br s, 2H, NH2), 7.60 (d, J¼3.6 Hz, 1H,
ArH), 7.64 (d, J¼4.0 Hz, 1H, ArH), 7.88 (s, 1H, ArH), 8.37 (s, 1H, ArH);
We are grateful for the financial supports from the National Key
Project for Basic Research (No. 2010CB126102).
13C NMR (100 MHz, DMSO-d6)
d 18.5, 32.2, 110.8, 117.1, 119.2, 122.3,
122.6, 124.7, 127.5, 130.9, 136.4, 137.1, 142.8, 145.6, 152.1; MS (þC,
ESI): M¼282, found 283 [MþH]þ; HRMS (ESI): [MþH]þ calcd for
C15H15N4O2: 283.1117, found 283.1188.
Supplementary data
4.2.6. 1,70-Dimethyl-20-propyl-2,50-bi(1H-benzimidazole)
(4). The
Supplementary data associated with this article can be found in
clude MOL files and InChiKeys of the most important compounds
described in this article.
compound 11 (40 g, 0.14 mol) and sodium dithionite (148 g,
0.84 mol) was suspended in a mixture of methanol (320 ml) and
water (320 ml), butyl aldehyde (256 ml, 0.28 mol) was added, then
the stirred mixture was heated at reflux for 12 h. After cooling, the
reaction mixture was poured slowly into water (2400 ml) with
stirring. The resultant suspension was filtered and the collected
solid washed with water, and crystallized from toluene to give bis-
References and notes
1. World Health Organization; International Society of Hypertension Writing
Group J. Hypertens. 2003, 21, 1983.
2. (a) Berellini, G.; Cruciani, G.; Mannhold, R. J. Med. Chem. 2005, 48, 4389; (b)
Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.; Prendergast, K.; Smith,
R. D.; Timmermans, P. B. M. W. M. J. Med. Chem. 1996, 39, 625; (c) Unger, T. Am. J.
Cardiol. 1999, 84, 9S.
benzimidazole
4 (36.5 g, 85%) as light yellow solid; mp:
138e139 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
0.97 (t, J¼6.8 Hz, 3H,
CH3), 1.83 (m, 2H, CH2), 2.59 (s, 3H, CH3), 2.85 (t, J¼4.5 Hz, 2H, CH2),
3.89 (s, 3H, NCH3), 7.23e7.27 (m, 2H, ArH), 7. 44 (s, br, 1H, ArH), 7.56
(d, J¼6.8 Hz, 1H, ArH), 7.68 (d, J¼6.8 Hz, 1H, ArH), 7.78 (br s, 1H,
3. (a) Matsubara, H. Circ. Res. 1998, 83, 1182; (b) Gasparo, M. D.; Catt, K. J.; Inagami,
T.; Wright, J. W.; Unger, T. Pharmacol. Rev. 2000, 52, 415.
ArH); 13C NMR (100 MHz, DMSO-d6)
d 13.7, 16.8, 21.1, 30.6, 31.7,
4. (a) Griendling, K. K.; Lassegue, B.; Alexander, R. W. Annu. Rev. Pharmacol. Toxicol.
1996, 36, 281; (b) Timmermans, P. B.; Wong, P. C.; Chiu, A. T.; Herblin, W. F.;
Benfield, P.; Carini, D. J.; Lee, R. J.; Wexler, R. R.; Saye, J. A.; Smith, R. D. Phar-
macol. Rev. 1993, 45, 205.
5. (a) Schupp, M.; Janke, J.; Clasen, R.; Unger, T.; Kintscher, U. Circulation 2004, 109,
2054; (b) Benson, S. C.; Pershadsingh, H. A.; Ho, C. I.; Chittiboyina, A.; Desai, P.;
Pravenec, M.; Qi, N.; Wang, J.; Avery, M. A.; Kurtz, T. W. Hypertension 2004, 43,
993; (c) Miura, M.; Satoh, S.; Kagaya, H.; Saito, M.; Inoue, T.; Ohkubo, T.;
Habuchi, T.; Suzuki, T. J. Clin. Pharm. Ther. 2009, 34, 683; (d) Kurtz, T. W. Acta
Diabetol. 2005, 42, S9.
110.3, 118.6, 121.7, 121.9, 122.9, 123.2, 136.6, 142.5, 154.3, 156.2; MS
(þC, ESI): M¼304, found 305 [MþH]þ; HRMS (ESI): [MþH]þ calcd
for C19H21N4: 305.1688, found 305.1754.
4.2.7. 40-[(1,40-Dimethyl-20-propyl[2,60-bi-1H-benzimidazol]-10-yl)
methyl]-[1,10-biphenyl]-2-carboxylic acid (1). To a mixture of so-
dium hydride (60% dispersion in oil, 6.8 g, 0.17 mol) in N,N-
dimethylformamide (100 ml) was added slowly a solution of bis-
benzimidazole 4 (50 g, 0.16 mol) in N,N-dimethylformamide
(300 ml) at 0 ꢀC and stirred for a further 1 h methyl 40-(bromo-
methyl)biphenyl-2-carboxylate 12 (54.7 g, 0.18 mol) was added at
6. Battershill, A. J.; Scott, L. J. Drugs 2006, 66, 51.
8. (a) Kakuta, H.; Sudoh, K.; Sasamata, M.; Yamagishi, S. Int. J. Clin. Pharmacol. Res.
2005, 25, 41; (b) Kirch, W.; Horn, B.; Schweizer, J. Eur. J. Clin. Invest. 2001, 31,
698.
9. (a) Pershadsingh, H. A. Int. J. Biochem. Cell Biol. 2006, 38, 766; (b) Benndorf, R.
A.; Rudolph, T.; Appel, D.; Schwedhelm, E.; Maas, R.; Schulze, F.; Silberhorn, E.;
Boger, R. H. Metabolism 2006, 55, 1159; (c) Nagel, J. M.; Tietz, A. B.; Goke, B.;
Parhofer, K. G. Metabolism 2006, 55, 1149.
10. Mogi, M.; Li, J. M.; Tsukuda, K.; Iwanami, J.; Min, L. J.; Sakata, A.; Fujita, T.; Iwai,
M.; Horiuchi, M. Biochem. Biophys. Res. Commun. 2008, 375, 446.
11. Ries, U. J.; Mihm, G.; Narr, B.; Hasselbach, K. M.; Wittneben, H.; Entzeroth, M.;
van Meel, J. C. A.; Wienen, W.; Hauel, N. H. J. Med. Chem. 1993, 36, 4040.
12. Reddy, K. S.; Srinivasan, N.; Reddy, C. R.; Kolla, N.; Anjaneyulu, Y.; Venkatraman,
S.; Bhattacharya, A.; Mathad, V. T. Org. Process Res. Dev. 2007, 11, 81.
13. (a) Venkataraman, S.; Mathad, V. T.; Kikkuru, S. R.; Neti, S.; Chinta, R. R.;
Arunagiri, M.; Routhu, L. K. U.S. 20070287840 2007; (b) Perlman, N.; Gilboa, E.
U.S. Patent 20060094883 2006.
0
ꢀC, the mixture was allowed to warm to room temperature and
stirred for 12 h. The mixture was diluted with water and extracted
with ethyl acetate (500 mlꢂ2). The combined organic layer was
washed with water and brine, dried over MgSO4, filtered, and
evaporated in vacuo. The residue was crystallized from ethyl ac-
etate and petroleum ether to afford the telmisartan ester (69.5 g,
80%), which was dissolved in methanol (1000 ml), then 2.7 m/l
aqueous sodium hydroxide solution (195 ml) was added and the
mixture was heated at reflux for 3 h. After cooling, the resultant
mixture was adjusted to pH¼5 with acetic acid, leading to the
precipitation of crude telmisartan 1 (64.2 g, 95%, HPLC: 97.5%),
which was filtered and the collected solid washed with water. The
crude telmisartan was suspended in ethanol (650 ml) and dis-
solved completely via adjusted to pH¼8 with ammonia solution,
Activated carbon (4 g) was added, the mixture was heated at
reflux for 1 h. After filtering, filtrate was cooled and adjusted to
pH¼5 with acetic acid to obtain qualified telmisartan 1 (54.8 g,
81%, HPLC: 99.7%) as white solid; mp: 261e262 ꢀC; 1H NMR
14. (a) Hauel, N.; Dach, R.; Heitger, H.; Meyer, O. U.S. Patent 20040236113, 2004; (b)
Brand, M.; Salman, A.; Gafni, Y.; Noiman, M.; Weisman, A.; Kaspi, J. U.S. Patent
20060264491 2006.
15. Goossen, L. J.; Knauber, T. J. Org. Chem. 2008, 73, 8631.
16. (a) Dubey, P. K.; Ratnam, C. V. Indian J. Chem., Sect. B 1979, 18, 428; (b) Vanden,
E. J. J.; Delfosse, L. F.; Haverbeke, Y. V. Tetrahedron 1995, 51, 5813; (c) Bhatnagar,
I.; George, M. V. Tetrahedron 1968, 24, 1293; (d) Beaulieu, P. L.; Hache, B.; von
Moos, E. Synthesis 2003, 1683; (e) Bahrami, K.; Khodaei, M. M.; Kavianinia, I.
Synthesis 2007, 417; (f) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.;
Fraga-Spano, S.; Macielag, M. J.; Werblood, H. M.; Foleno, B. D.; Webb, G. C.;
Barrett, J. F.; Hlasta, D. J. Bioorg. Med. Chem. Lett. 2001, 11, 1545; (g) Lombardy, R.
L.; Tanious, F. A.; Ramachandran, K.; Tidwell, R. R.; Wilson, W. D. J. Med. Chem.
1996, 39, 1452.
(DMSO-d6, 400 MHz)
d
1.15 (t, J¼7.2 Hz, 3H, CH3), 1.94e2.03 (m,
2H, CH2), 2.69 (s, 3H, ArCH3), 3.12 (t, J¼8 Hz, 2H, CH2), 3.37 (s, 3H,
CH3), 5.40 (s, 2H, CH2N), 6.97 (s, 1H, ArH), 7.05 (s, 1H, ArH),
7.16e7.18 (m, 2H, ArH), 7.33e7.50 (m, 8H, ArH), 8.01e8.03 (m, 1H,
17. (a) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977; (b) Bahrami, K.
Tetrahedron Lett. 2006, 47, 2009.
18. Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993, 34, 7445.
19. (a) Yang, D.; Fokas, D.; Li, L.; Yu, J.; Baldino, M. C. Synthesis 2005, 1, 47; (b)
Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth. Commun. 2007, 37,
1375.
ArH), 8.37e8.38 (m, 1H, ArH); 13C NMR (DMSO-d6, 100MHz)
d
14.1,
17.0, 22.4, 30.0, 31.8, 48.8, 109.4, 111.3, 119.8, 121.8, 123.1, 123.2,