IMPROVED ONE-POT SYNTHESIS OF TELMISARTAN
533
Preparation of Telmisartan (1)
A mixture of 1,40-dimethyl-20-propyl-1H,30H-2,50-dibenzimidazole (10.0 g,
1.0 mol) and 40-bromomethylbiphenyl-2-carboxylic acid methyl ester (10.0 g,
1.0 mol) in acetonitrile (50.0 mL) was stirred for 5–10 min at 25–35ꢀC, then potass-
ium hydroxide (2.8 g, 1.5 mol) was added in lots for 10–15 min. The resultant mixture
was maintained for 2–3 h at 25–35ꢀC. Reaction completion was monitored using
thin-layer chromatography (TLC). After completion of the reaction, potassium
hydroxide (5.0 g) and acetonitrile (100.0 mL) were added to the reaction mass. The
reaction mass was heated to reflux and maintained for 2–3 h at the same tempera-
ture. Then reaction mass was cooled to 30–40ꢀC, and potassium hydroxide (1.0 g)
was added to the reaction mass. The temperature was raised to reflux and main-
tained for 2–3 h at reflux. The reaction completion was monitored using TLC. After
completion of the reaction, the mass was cooled to 25–35ꢀC and stirred for
10–15 min, filtered, and washed with acetonitrile (10.0 mL). The wet solid was
directly dissolved in water (150.0 mL) at 25–35ꢀC, and ethyl acetate (30.0 mL) was
added to the reaction mass. The mass was stirred for 10–15 min, and the ethyl acetate
layer was separated. The aqueous layer was filtered through a celite bed and washed
with water (20.0 mL). The aqueous solution pH was adjusted to 5.0–5.5 using 10%
acetic acid solution and maintained with stirring for 1.0 h. The precipitated product
was filtered and washed with water (20.0 mL), the obtained wet cake was taken into
acetonitrile and water (90:10 mL), and the reaction mass was heated to reflux and
maintained for 30–40 min. The reaction mass was cooled to 25–35ꢀC and maintained
for 30–40 min at the same temperature. The separated solid was filtered and dried for
5–6 h at 60–70ꢀC under vacuum to afford telmisartan (1) as a white solid. Yield: 12 g
(71%); purity by HPLC 99.5%; mp 260–262ꢀC; ROI: <0.1%; heavy metal <10 ppm;
1
mass: m=z 515 (Mþ þ H); H NMR (CDCl3) d 12.6 (s, 1H), 7.05–7.5 (m, 14H), 5.86
(s, 2H), 4.0 (s, 3H), 2.5 (t, 2H), 3.08 (s, 3H), 1.84 (q, 2H), 0.99 (t, 3H).
ACKNOWLEDGMENTS
We thank the management of Srini Pharmaceuticals Ltd., for supporting this
work. Contributions from colleagues in Srini Pharmaceuticals Research and Devel-
opment during the development of this process and cooperation from colleagues of
Analytical Research and Development are greatly appreciated.
REFERENCES
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