4
V. L. CHAPALA ET AL.
were submitted for review, as was the HPLC of the Azilsartan derived from
our procedures.
Methyl (Z)- 2-ethoxy-1-((2’-(N’-hydroxycarbamimidoyl)-[1,1’-biphenyl]-4-yl)methyl)-
1
H-benzo[d]imidazole-7-carboxylate (4)
Sodium bicarbonate (4.5 mole, 378.0 g) was added to a solution of hydroxylamine
ꢀ
hydrochloride (3.3 mole, 232.0 g) in dimethyl sulfoxide (1250.0 ml) at 25-30 C.
ꢀ
Thereafter, the temperature was increased to 45-50 C. At this temperature, l-[(2’-cyano-
19
biphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.60 mole, 250.0 g) (5)
was added to the resulting solution and the mixture was heated up to 100 C followed
by stirring at the same temperature for 18 h. After completion (TLC), the reaction mass
was cooled to 15-20 C, then poured into water. The solution was stirred for 15-20 min
at 15-20 C and filtered. The formed product was washed with water and dried to
ꢀ
ꢀ
ꢀ
obtain methyl 2-ethoxy[[2’-(hydroxyamidino) biphenyl-4-yl] methyl]-lH-benzimidazole-
ꢀ
1
7
1
-carboxylate (4). Yield: 260.0 g; 96%; mp 203-206 C; H NMR (DMSO) d ¼ 9.17 (s,
H, OH), 7.70 (d, 1H, Ar), 7.46 (d, 1H,Ar), 7.46 (d, 1H, Ar), 7.29 (d, 1H, Ar), 7.19
(
t,1H, Ar), 6.94 (d, 2H, Ar), 5.55 (bs, 2H, NH ), 5.50 (s, 2H, N-CH -Ar), 4.62 (q, 2H,
2 2
OCH CH ), 3.71 (s, 3H, OCH ), 1.42 (t, 3H, OCH CH ). IR (KBr pellet): 3514, 3407,
2
3
3
2
3
ꢁ
1
3
268, 2985, 1718, 1634, 1612, 1547, 1284, 1257, 1133 cm . Mass: C H N O LCMS:
m/z 446.17 (M þ H) .
25 25 4 4
þ
Methyl 2-ethoxy [[2’-(hydroxy-tertiary-butoxycarbonyl amidino) biphenyl-4-yl]
16
methyl]-lH-benzimidazole-7-carboxylate (3)
Compound 4 (0.55 mole, 260.0 g) in tertiary-butanol (910.0 ml) was taken in a round
bottom flask, then Boc anhydride (0.69 mole, 152.0 g) was added slowly through an add-
ꢀ
ition funnel at 25-30 C. After completion of addition, the temperature was increased to
ꢀ
5
0-55 C and stirring was continued at the same temperature for 12 h. The progress of
the reaction was monitored by TLC. After completion of reaction, the reaction mixture
ꢀ
ꢀ
was cooled to 15-20 C and stirred for 60 min at 15-20 C to obtain the solid. The prod-
uct was filtered, washed with tertiary-butanol (260.0 ml) and dried under vacuum at 55-
ꢀ
6
0 C. This afforded methyl 2-ethoxy [[2’-(hydroxy tertiary-butoxycarbonyl amidino)
1
biphenyl-4-yl] methyl]-lH-benzimidazole-7-carboxylate (3). Yield: 312.0 g; 98%.
H
NMR (DMSO) d ¼ 9.17 (s, 1H, OH), 7.70 (d, 1H, Ar), 7.46 (d, 1H, Ar), 7.46 (d, 1H,
Ar), 7.29 (d, 1H, Ar), 7.19 (t,1H, Ar), 6.94 (d, 2H, Ar), 5.55 (bs, 1H, NH), 5.50 (s, 2H,
N-CH -Ar), 4.62 (q, 2H, OCH CH ), 3.71 (s, 3H, OCH ), 1.42 (t, 3H, OCH CH ) 1.27
2
2
3
3
2
3
(
1
s, 9H, Boc). IR (KBr pellet): 3514, 3407, 3268, 2985, 1718, 1634, 1612, 1547, 1284,
ꢁ
1
þ
257, 1133 cm . Mass: C H N O (M þ H) LCMS: m/z 546.17.
3
0
34 4 6
Methyl l-[[2’-(4,5-dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-2-
16
ethoxy-lH-benzimidazole-7-carboxylate (2)
Compound 3 (312.0 g) was placed in DMF (1248.0 ml) and then the reaction was heated
ꢀ
up to 110-115 C. The resulting solution was stirred at the same temperature for 12 h.