(1 L) was added and hydrogenated over 5% Pd-C (4 g) in
a closed autoclave system at 25-35 °C under 5.5 kg/cm2 of
hydrogen pressure for 4-5 h. The reaction mass was filtered
through hyflow at 25-35 °C, and the catalyst was washed
with methanol (200 mL). The pH of the combined filtrates
was adjusted to 1.0-2.0 with concentrated hydrochloric acid
(60 mL) and stirred for 15 min. The solvent was distilled
off under reduced pressure to obtain crude, and the obtained
crude was crystallized from acetonitrile (500 mL). The
crystalline solid obtained was filtered, washed with chilled
acetonitrile (200 mL), and dried at 50-55 °C for 5-6 h to
obtain the HCl salt of 9 as a white crystalline material. Yield
85 g (74%); mp 170-175 °C; 1H NMR (CDCl3) δ 7.2-7.5
(m, 4H), 6.80 (s, 1H), 6.7 (s, 2H), 3.01 (s, 3H); MS m/z 123
(M+ + H).
(m, 14H), 5.7 (s, 2H), 4.10 (s, 3H), 3.59 (s, 2H), 3.28 (t, J
) 7.8, 2H), 2.88 (s, 3H), 2.01 (q, J ) 7.7, 2H), 1.14 (t, J )
7.4, 3H); 13C NMR (DMSO-d6) δ 13.7, 16.4, 20.6, 28.7, 31.6,
46.0, 51.7, 109.1, 110.2, 118.6, 121.7, 121.9, 123.1, 123.3,
126.4, 127.4, 128.2, 128.5, 129.2, 130.4, 130.6, 131.4, 134.7,
136.1, 136.6, 139.7, 140.7, 142.5, 154.0, 156.1, 168.2.
4′-[(1,4′-Dimethyl-2′-propyl-[2,6′-bi-1H-benzimidazol]-
1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic Acid (1). A mix-
ture of 14 (10 g, 0.017 mol), acetonitrile (150 mL), and KOH
flakes (4.5 g, 0.08 mol) was heated to reflux for about 2 h.
The reaction mass was cooled to 25-35 °C, and the
potassium salt thus obtained was separated by filtration and
washed with acetonitrile (20 mL). The wet solid was
dissolved in a mixture of water (150 mL) and acetonitrile
(50 mL) and then heated to 60-65 °C under stirring. The
pH of the resulting clear solution was adjusted to 5.0-5.5
using 5% acetic acid (4 mL), and stirring continued for 2 h.
The crystalline solid was filtered and washed with water (50
mL). The wet solid obtained was transferred to a closed
autoclave system, methanol (80 mL) was added, and the
system was heated to 80-85 °C until dissolution under
inbuilt pressure (2.0-2.2 kg/cm2). The reaction mass was
allowed to cool to room temperature and then stirred for 1-2
h. The precipitated solid was filtered, washed with chilled
methanol (10 mL), and dried at 70-75 °C for 4-5 h under
a vacuum to obtain Telmisartan (1) as a white crystalline
powder. Yield 7 g (77%); purity by HPLC 99.9%; mp 260-
262 °C; Pd content not detected; Heavy metals <10 ppm;
4′-Bromomethylbiphenyl-2-carboxylic Acid Methyl
Ester (13). A mixture of 4′-methylbiphenyl-2-carboxylic acid
methyl ester (17, 10.0 g, 0.044 mol), 1,3-dibromo-5,5-
dimethylhydantoin (9.0 g, 0.031 mol), and 2,2-azobisisobu-
tyronitrile (0.5 g, 0.003 mol) in chloroform (100 mL) was
heated to reflux (60-65 °C) for 1-2 h. The reaction mixture
was cooled to 25-35 °C, the formed byproduct was filtered,
and the filtrate was washed with water (200 mL). The organic
layer was separated and concentrated under a vacuum. The
obtained residue was triturated with n-hexane (50 mL), and
the obtained solid was filtered and dried under a vacuum:
1
yield 12.5 g, 92.6%; mp 40-42 °C; H NMR (CDCl3) δ
7.2-7.8 (m, 8H), 4.5 (s, 2H), 3.6 (s, 3H); MS m/z 306 (M+
+ H).
1
MS m/z 515 (M+ + H); H NMR (CDCl3) δ 12.8 (s, 1H),
4′-(1,4′-Dimethyl-2′-propyl-1H-[2,5′]bibenzimidazolyl-
3′-ylmethyl)biphenyl-2-carboxylic Acid Methyl Ester (14).
A mixture of 1,4′-Dimethyl-2′-propyl-1H,3′H-2,5′bibenz-
imidazole (10, 10.0 g, 0.032 mol), KOH flakes (2.8 g, 0.05
mol), and 4′-bromomethylbiphenyl-2-carboxylic acid methyl
ester (13, 16.2 g, 0.053 mol) in acetone was stirred at 25-
35 °C for 1.5-2.0 h. The product thus obtained was separated
by filtration, and the filtered solid was washed with 20 mL
of chilled acetone. The wet solid obtained was directly
dissolved in methanol (50 mL), and the pH of the resulting
solution was adjusted to 1-2 using 30% methanolic HCl
(27 mL). Solvent was distilled off under reduced pressure,
and the resulting crude was isolated as a crystalline solid
material from acetonitrile (90 mL). The crystalline solid
obtained was filtered, washed with chilled acetonitrile (20
mL), and dried at 50-55 °C for 3-4 h to obtain 14 as a
white crystalline powder. Yield 14.8 g (85%); mp 170-175
7.05-7.5 (m, 14H), 5.60 (s, 2H), 3.82 (s, 3H), 2.97 (t, J )
7.5, 2H), 2.63 (s, 3H), 1.88 (q, J ) 7.3, 2H), 1.04 (t, J )
7.3, 3H); 13C NMR (DMSO-d6) δ 13.5, 16.7, 20.6, 27.6, 32.7,
47.1, 51.7, 112.0, 112.7, 114.7, 118.6, 125.3, 125.7, 125.8,
127.0, 127.4, 128.6, 129.3, 130.4, 130.6, 131.5, 132.3, 133.1,
133.7, 134.5, 140.2, 140.5, 150.2, 157.3, 168.1. Anal. Calcd
for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89; O, 6.22.
Found: C, 77.0; H, 5.82; N, 10.89; O, 6.20.
Acknowledgment
We thank the management of R&D-IPDO, Dr. Reddy’s
Laboratories Ltd., for supporting this work. Cooperation from
the colleagues from the analytical research development is
highly appreciated.
Received for review September 28, 2006.
OP060200G
1
°C; MS; m/z 529 (M+ + H). H NMR (CDCl3) δ 7.2-7.9
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