Synthesis of Irbesartan
1981
2
IR (cm ): 1724 (C 55 O). H NMR (CDC1 , d ppm): 0.7–0.9 (t, 3H,
1
1
3
CH ), 1.1–1.4 (sextet, 2H, CH ), 1.4–1.6 (quintet, 2H, CH ), 1.6–2.0
3
2
2
(
m, 8H, CH ), 2.1–2.3 (t, 2H, CH ), 4.4–4.6 (s, 2H, Ar–CH ), 6.8–7.0
2 2 2
1
d, 2H, Ar–H), 7.3–7.5 (d, 2H, Ar–H). C NMR (CDCl , d ppm): 186.4,
3
(
3
1
2
61.4, 135.4, 131.9, 131.2, 128.3, 121.6, 77.6, 77.0, 76.3, 63.8, 42.9, 37.2,
þ
8.5, 27.5, 25.9, 22.1, 13.5. Mass: 364 (M ). C H N analysis calcd. for
C H BrN O: C, 59.51; H, 6.38; N, 7.71. Found: C, 59.74; H, 6.51; N, 7.89.
8
1
23
2
0 0
-Butyl-3-[[2 -(1H-tetrazol-5-yl)[1,1 -biphenyl]-4-yl]methyl]-1,3-
diazo Spiro[4,4] non-1-en-4-one (5)
2
A mixture of methanol (50 mL), 3-[4-bromobenzyl]-2-butyl-1,3-diazo spiro
[
4,4] non-1-en-4-one (3, 5 g, 0.0137 mol), potassium hydroxide flakes (1.5 g,
0
2
0
0
.027 mol), and Pd(PPh ) (0.4 g) was under reflux for 45 min. A solution of
3 4
-(2-triphenyl methyl-2H-tetrazole-5-yl)-phenyl boronic acid (4, 10.4 g,
.024 mol), methanol (50 mL), and potassium hydroxide flakes (1.5 g,
.027 mol) was added to the reaction mass and refluxed for 10 h. It was
diluted with water (50 mL) and toluene (50 mL). The organic layer was
separated. The aqueous layer was extracted with toluene (25 mL) and then
acidified with acetic acid to pH 4–5 and concentrated below 608C. To the
residue, ethyl acetate (10 mL) was added. The solid was filtered, washed
with water (10 mL), and dried. Recrystallization using methyl isobutyl
ketone afforded butyl-3-[[2-(1H-tetrazol-5-yl) [1,1-biphenyl]-4 yl]methyl]-
1
,3-diazo spiro [4,4] non-1-en-4-one 5, (4.9 g, 84%) as a solid.
2
1
1
IR (cm ): 3446.9 (N–H), 1732.9 (C 55 O). H NMR (DMSO, d ppm):
0
.7–0.9 (t, 3H, CH ), 1.2–1.4 (sextet, 2H, CH ), 1.4–1.6 (quintet, 2H, CH ),
3
2
2
1
.6–2.0 (m, 8H, CH ), 2.2–2.4 (t, 2H, CH ), 3.0–3.6 (br, 1H, N–H), 4.6–4.8
2
2
13
(s, 2H, Ar–CH ), 7.0–7.8 (m, 8H, Ar–H). C NMR (DMSO, d ppm): 155.0,
2
1
40.9, 138.3, 136.2, 130.5, 130.9, 129.2, 127.7, 126.2, 123.5, 161.1, 185.5, 42.2,
þ
75.7, 36.7, 27.4, 26.5, 25.4, 21.4, 13.5. Mass: 429 (M ). C H N analysis calcd.
for C H N O: C, 70.07; H, 6.59; N, 19.61. Found: C, 70.34; H, 6.81; N, 19.88.
25 28 6
ACKNOWLEDGMENT
The authors thank the management of Dr Reddy’s Laboratories Ltd., Bulk
Actives Unit IV, for supporting this work.
REFERENCES
1
. Bernhart, C. A.; Perreaut, P. M.; Ferrari, B. P.; Muneaux, Y. A.; Assens, J. L. A.;
Jacques, C.; Frederique, H.; Muneaux, C. F.; Taillades, J. E.; Marie-Aimee, V.;
Jean, G.; Guiraudou, P. R.; Lacour, C. A.; Alain, R.; Cazaubon, C. F.;
Jean-Claude, B.; Gerard, L. F.; Dino, N. J. Med. Chem. 1993, 36, 3371.