with brine (100 mL), dried over MgSO4, filtered, and concentrated.
The crude brown oil was purified by Kugelrohr distillation (180
°C/3 × 10-3 mbar) to yield 3c as a clear yellow oil (7.97 g, 85%).
1H NMR (600 MHz, CDCl3): δ 7.80 (d, 3J ) 7.7 Hz, 1H),
7.48-7.50 (m, 2H), 7.43-7.46 (m, 1H), 7.35-7.37 (m, 1H),
7.29-7.33 (m, 3H), 5.83 (s, 1H), 4.96 (h, 3J ) 6.4 Hz, 1H),
4.04-4.10 (m, 2H), 3.95-4.00 (m, 2H), 0.99 (d, 3J ) 6.4 Hz, 6H).
13C NMR (151 MHz, CDCl3): δ 167.9, 142.1, 141.4, 136.7, 131.5,
130.6, 130.2, 129.3, 128.1, 127.0, 125.9, 103.2, 68.2, 64.9, 21.0.
Anal. Calcd for C19H20O4: C, 73.06; H, 6.45. Found: C, 73.01; H,
6.49.
of the crude product from aq MeOH (60%) yielded 4 as its colorless
solid monohydrate (5.56 g, 90%). Mp: 187-189 °C. 1H NMR (600
3
MHz, DMSO-d6): δ 9.08 (s, 1H), 7.65 (d, J ) 7.9 Hz, 1H), 7.55
3
(d, J ) 7.9 Hz, 1H), 7.21-7.27 (m, 1H), 7.08 (s, 1H), 6.91 (s,
1H), 4.99 (s, 2H), 3.85 (s, 3H), 2.36 (t, 3J ) 7.3 Hz, 2H), 2.17 (s,
3
3
3H), 1.66 (sext, J ) 7.2 Hz, 2H), 0.96 (t, J ) 7.4 Hz, 3H). 13C
NMR (151 MHz, DMSO-d6): δ 171.5, 153.6, 144.9, 142.5, 136.6,
136.0, 128.4, 123.3, 122.2, 121.9, 118.9, 118.8, 114.0, 110.5, 37.6,
31.8, 18.9, 18.4, 13.9. Anal. Calcd for C19H24N4O2: C, 67.04; H,
7.11; N, 16.46. Found: C, 66.81; H, 7.42; N, 16.39.
4′-[(2-Butyrylamino-3-methyl-5-(1N-methyl-1H-benzimidazole-
2-yl)phenylamino)methyl]-biphenyl-2-carboxylic Acid Isopro-
pyl Ester (18). 4 (340 mg, 1.00 mmol), 3a (269 mg, 1.00 mmol),
activated palladium on charcoal (10%, 80.1 mg, 0.08 mmol), and
p-TsOH (20.4 mg, 0.12 mmol) were suspended in toluene (40 mL)
under nitrogen. C(OMe)4 (545 mg, 4.00 mmol) was added, and
the mixture was refluxed for 16 h and then concentrated. The residue
4′-Formyl-2-biphenylcarboxylic Acid Isopropyl Ester (3a). A
i
solution of 3c (3.34 g, 10.7 mmol) in PrOH (40 mL) and aq HCl
(2 N, 20 mL) was heated to 80 °C for 3 h. After cooling to room
temperature, the reaction mixture was poured into saturated aq
sodium bicarbonate (150 mL) and extracted with ethyl acetate (100
mL, 2 × 40 mL). The combined organic layers were washed with
brine (50 mL), dried over MgSO4, and concentrated to yield 3a as
a yellow solid (2.82 g, 98%). Mp: 55-57 °C. 1H NMR (600 MHz,
i
was diluted with PrOH (20 mL), transferred to a stainless steel
autoclave, and stirred under H2 pressure (10 bar) for 16 h at 50 °C,
cooled to room temperature, and filtered, and the filter cake was
rinsed with ethyl acetate (3 × 25 mL). The filtrate was washed
with water, and the aqueous layer was basified to pH 10 with
concentrated aq ammonia (1 × 150 mL) and extracted with ethyl
acetate (2 × 50 mL). The combined organic layers were dried over
MgSO4, and concentrated, and the crude solid was purified by
column chromatography (SiO2, ethyl acetate) to yield 18 as a
colorless solid (414 mg, 72%). Mp: 92-94 °C. 1H NMR (600 MHz,
3
CDCl3): δ 10.03 (s, 1H), 7.86-7.89 (m, 3H), 7.51 (td, J ) 7.5
4
Hz, J ) 1.38 Hz, 1H), 7.42-7.45 (m, 3H), 7.30-7.31 (m, 1H),
3
3
4.96 (h, J ) 6.3 Hz, 1H), 1.01 (d, J ) 6.3 Hz, 6H). 13C NMR
(151 MHz, CDCl3): δ 191.8, 167.3, 148.0, 141.0, 135.0, 131.1,
130.2, 129.9, 129.3, 129.1 (2C), 127.8, 68.6, 21.2. Anal. Calcd for
C17H16O3: C, 76.10; H, 6.01. Found: C, 76.12; H, 5.96.
1-(4-N-Butyrylamino-3-methyl-5-nitrophenyl)-3N-methylben-
zimidazole (17). A solution of N-butyryl-4-amino-3-methyl-5-
nitrobenzoic acid (16, 3.99 g, 15.0 mmol) and 1,1′-carbonyldiim-
idazole (3.74 g, 23.0 mmol) in 1,4-dioxane (40 mL) was stirred
under nitrogen at room temperature until gas evolution ceased.
N-Methyl-1,2-phenylenediamine (1.83 g, 15.0 mmol, 1.71 mL) was
added, and the reaction mixture was refluxed for 2 h, cooled, poured
into ice water (200 mL), and basified with concentrated aq ammonia
to pH 9. The light yellow precipitate was filtered, washed with Et2O
(2 × 10 mL), and dried in vacuo (3 × 10-3 mbar) (2.86 g). The
filtrate was extracted with ethyl acetate (3 × 50 mL); the combined
organic layers were washed with brine (1 × 50 mL), dried over
MgSO4, and concentrated, and the residue was dried in vacuo (3
× 10-3 mbar) (1.47 g). The two crops of light yellow solid were
combined to yield the title compound 17 (4.33 g, 82%). Mp:
3
CDCl3): δ 8.66 (s, 1H), 7.76-7.79 (m, 2H), 7.48 (t, J ) 7.5 Hz,
3
1H), 7.30-7.40 (m, 7H), 7.26-7.27 (m, 1H), 7.21 (d, J ) 7.9
Hz, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.92 (h, 3J ) 6.2 Hz, 1H), 4.36
3
(s, 2H), 3.55 (s, 3H), 2.58 (t, J ) 7.5 Hz, 2H), 2.15 (s, 3H), 1.81
(sext, 3J ) 7.4 Hz, 2H), 1.02 (t, 3J ) 7.4 Hz, 3H), 0.98 (d, 3J ) 6.2
Hz, 6H). 13C NMR (151 MHz, CDCl3): δ 172.8, 168.1, 154.8,
143.8, 142.4, 141.9, 140.3, 137.8, 136.3, 135.8, 131.6, 130.9, 130.6,
129.5, 128.7, 128.4, 127.1, 126.7, 123.7, 122.7, 122.4, 120.1, 119.1,
110.5, 109.8, 68.4, 47.4, 38.5, 31.3, 21.3, 19.7, 18.7, 13.9. Anal.
Calcd for C36H38N4O3: C, 75.24; H, 6.66; N, 9.75. Found: C, 75.01;
H, 6.52; N, 9.59.
Telmisartan (5). 18 (575 mg, 1.00 mmol) was diluted with
glacial acetic acid (40 mL), and the resulting solution was refluxed
for 3 h and then concentrated. Ethanol (10 mL) and aq sodium
hydroxide (2 N, 10 mL) were added, and the mixture was refluxed
for 12 h, cooled to 80 °C, and acidified to pH 5-6 with aq HCl (6
N, 2.6 mL). The resulting suspension was stirred in an ice bath for
1 h, and filtered, and the filter cake was rinsed with water (2 × 10
mL) and Et2O (2 × 10 mL) and then dried in vacuo to give 5 as a
colorless solid (473 mg, 92%, mp 261-263 °C, >99 area % HPLC
purity). The analytical data obtained correspond to those reported
for crystal modification A.8
1
151-153 °C (CHCl3/n-hexane). H NMR (400 MHz, DMSO-d6):
3
δ 10.01 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.70 (d, J ) 7.8 Hz,
3
1H), 7.63 (d, J ) 7.8 Hz, 1H), 7.24-7.33 (m, 2H), 3.92 (s, 3H),
3
3
2.41 (s, 3H), 2.35 (t, J ) 7.2 Hz, 2H), 1.63 (sext, J ) 7.4 Hz,
2H), 0.94 (t, J ) 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6):
3
δ 171.2, 150.5, 146.3, 142.3, 137.1, 136.6, 134.7, 129.8, 127.8,
122.7, 122.5, 122.1, 119.0, 110.6, 37.2, 31.6, 18.3, 17.8, 13.4. Anal.
Calcd for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C, 64.54;
H, 5.81; N, 15.93.
1-(4-N-Butyrylamino-3-methyl-5-aminophenyl)-3N-methyl-
benzimidazole (4). Activated palladium on charcoal (10%, 638 mg,
0.60 mmol) and 1-(4-N-butyrylamino-3-methyl-5-nitrophenyl)-3N-
methylbenzimidazole (17, 6.40 g, 18.2 mmol) were suspended in
MeOH (100 mL) in a stainless steel autoclave. The mixture was
stirred under H2 pressure (10 bar) for 12 h at 50 °C. The suspension
Acknowledgment. We thank Saltigo GmbH and NanoKat
for financial support and Umicore AG for metal catalysts.
Supporting Information Available: Experimental proce-
dures and analytical data. This material is available free of
i
was filtered, the filter cake rinsed with hot PrOH (3 × 50 mL),
and the filtrate concentrated to dryness (5.76 g). Recrystallization
JO801937H
8634 J. Org. Chem. Vol. 73, No. 21, 2008