May-Jun 2008
A Convenient and Practical Synthesis of Olmesartan Medoxomil Methyl Ether
919
was then cooled to 0°C and water (30 mL) was added carefully
to the mixture and extracted twice with ethyl acetate (2 × 50
mL). The combined organic phase was dried over anhydrous
sodium sulfate, filtered and concentrated at reduced pressure to
give crude 6, which was chromatographed on silica gel using
20% ethyl acetate in hexane to afford pure 6 as a white solid (10
g, 39 %). M.P. 134°C; IR (KBr): 3650, 3053, 2966, 1964, 1902,
1816, 1721, 1599, 1547, 1499, 1472, 1424, 1272, 1145, 760 cm-
1; 1H-NMR (CDCl3): 400 MHz δ 1.02-1.09 (t, J = 14.4 Hz, 3H),
1.35-1.43 (t, J = 14.4 Hz, 3H), 1.70-1.82 (m, 2H), 1.84 (s, 6H),
2.66-2.74 (t, J = 15.2 Hz, 2H), 3.31 (s, 3H), 4.29-4.40 (q, J =
14.4 Hz, 2H), 5.46 (s, 2H), 6.93-6.97 (d, J = 16 Hz, 2H), 7.12-
7.16 (d, J = 14 Hz, 6H), 7.29-7.25 (d, J = 16.4 Hz, 2H), 7.41-
7.56 (m, 12H), 7.63-7.68 (m, 1H). ESI(APCI)-MS: m/z 731
(M+1). Anal Calcd. for C46H46N6O3: C, 75.59; H, 6.34; N, 11.50.
Found: C, 75.41; H, 6.29; N, 11.53.
methyl-2-oxo-1,3-dioxolene [10] in presence of potassium
carbonate in dimethyl acetamide formed 9 in good yield.
Finally, detritylation of
9
with formic acid in
dichloromethane-methanol (1:1) at 40°C gave crude 2,
which was further purified by column chromatography
and followed by recrystallisation in n-pentane to yield 2
as a white solid in 45 % yield.
In summary, a concise and practical route to olmesartan
medoxomil methyl ether 2 was achieved, which will be
helpful in the gram scale synthesis of this important
impurity. In addition, the synthesis and characterization of
compounds 6, 7, 8 and 9 are reported first time and some
of them could be potential impurities of olmesartan
medoxomil.
4-(1-Methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-
yl) phenyl}phenylmethylimidazole-5-carboxylic acid (7). To
a solution of 6 (5 g, 0.011 mole) in methanol (50 mL) was
slowly added a saturated solution of sodium hydroxide (3.6 g,
0.09 mole) at ambient temperature and the mixture was heated at
reflux for 16 hours. It was then cooled to room temperature and
the solvents were removed under reduced pressure. The residue
was dissolved in water (30 mL) and washed twice with ethyl
acetate (2 × 100 mL). The aqueous layer was cooled to 5-10°C,
acidified to pH 3-4 with dilute hydrochloric acid and extracted
with ethyl acetate (2 ×100 mL). The organic layer was
separated, dried over anhydrous sodium sulphate, filtered and
the solvent was evaporated in vacuo to give 7 as a colorless solid
(2.9 g, 92 %). M.P. 183-4°C; IR (KBr): 2975, 1935, 1706, 1624,
EXPERIMENTAL
Proton NMR spectra were obtained on a Bruker spectrometer
with TMS as internal standard. Melting points were determined
with a Buchi B-545 apparatus and are uncorrected. Mass spectra
were obtained using Agilent 1200 series LCMSD/VL. IR spectra
were taken on a Perkin-Elmer FT/IR 100 spectrometer and were
run as KBr dispersion. Elemental analyses were performed on a
Perkin Elmer 2400 series II CHNS/O analyzer. Thin layer
chromatography was conducted on Merck Silica Gel 60 F254
plates. Column chromatography was performed using silica gel
(230-400 mesh) procured from Sd-fine Chemical, India.
Ethyl-4-(1-hydroxymethylethyl)-2-propyl-1-{4-(2-trityl-
tetrazol-5-yl)phenyl}phenylmethylimidazole-5-carboxylate
(5). To a solution of 4-(1-hydroxy-1-methylethyl)-2-propylimi-
dazole-5-ethylcarboxylate (3) [7] (50 g, 0.208 mole) in acetone
(500 mL) was added 4-((2-trityltetrazol-5-yl)-phenyl)-benzyl
bromide (4) [8] (115.9 g, 0.208 mole), potassium carbonate (57
g, 0.413 mole) and tetrabutylammonium bromide (cat) at
ambient temperature. The resulting mixture was heated at reflux
for 16 hours. The reaction was cooled to room temperature,
filtered and washed with acetone (100 mL). The combined
filtrate and washings were concentrated under reduced pressure
and the residue partitioned between ethyl acetate (2 × 200 mL)
and water (2 × 200 mL). The combined ethyl acetate layer was
dried over anhydrous sodium sulfate and recovered at reduced
pressure. To the residue 500 mL isopropyl alcohol was added
and the resulting solution was stirred at ambient temperature for
12 hours. The solids were filtered, washed with isopropyl
alcohol (100 mL) and dried in air at 40-45°C for 12 hours to
afford 5 [9] as a white powder (126 g, 85 %). M.P. 161°C; IR
(KBr): 3407, 3056, 2977, 2935, 1961, 1702, 1666, 1603, 1470,
1
1460, 1365, 1154, 760 cm-1; H-NMR (CDCl3): 400 MHz δ
0.90-0.97 (t, J = 14.4 Hz, 3H), 1.60 (s, 6H), 1.65-1.73 (m, 2H),
2.64-2.70 (m, 2H), 2.58 (s, 3H), 5.66 (s, 2H), 6.92-6.96 (d, J =
16 Hz, 2H), 7.07-7.11 (d, J = 16.4 Hz, 6H), 7.45-7.60 (m, 2H),
7.67-7.70 (m, 1H). ESI (APCI)-MS: m/z 459 (M-1). Anal Calcd.
for C25H28N6O3: C, 65.20; H, 6.13; N, 18.25. Found: C, 65.43; H,
6.12; N, 18.27.
4-(1-Methoxy-1-methylethyl)-2-propyl-1-{4-(2-trityltetraz-
ol-5-yl)phenyl}phenylmethylimidazole-5-carboxylic acid (8).
To a stirred solution of 7 (26 g, 0.056 mole) in dichloromethane
(200 mL), triethylamine (11.3 g, 0.111 mole) was added at room
temperature. To this solution was added slowly drop wise a
solution of trityl chloride (28.2 g, 0.101 mole) in
dichloromethane (60 mL) and the resulting mixture was stirred
for 5 hours at the room temperature. Water (520 mL) was added
to the reaction mixture and the organic layer was separated,
dried over anhydrous sodium sulphate, filtered and the solvent
evaporated in vacuo to give crude 8. Purification by column
chromatography on silica gel using 35 % ethyl acetate in hexane
afforded 8 as an off-white solid (16g, 40 %). M.P. 139 °C; IR
(KBr): 2971, 1630, 1495, 1448, 1362, 1188, 1005, 759, 698
1
1290, 1177, 1033, 881, 756, 699 cm-1; H-NMR (CDCl3): 400
MHz δ 0.84-0.91 (t, J = 13.6 Hz, 3H), 1.04-1.11 (t, J = 13.6 Hz,
3H), 1.64 (s, 6H), 1.70-1.82 (m, 2H), 2.48-2.55 (t, J = 14.4 Hz,
2H), 4.07-4.17 (q, J = 13.6 Hz, 2H), 5.35 (s, 2H), 6.07-6.74 (m,
2H), 6.94-6.97 (m, 6H), 7.08-7.11 (m, 2H), 7.26-7.47 (m, 12H),
7.85-7.88 (m, 1H). ESI (APCI)-MS: m/z 717 (M+1).
Ethyl-4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-trityl-
tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carbox-ylate
(6). To a stirred suspension of sodium hydride (3.0 g, 0.075
mole) in THF (100 mL) was slowly added drop wise a solution
of 5 (25 g, 0.034 mole) and methyl iodide (6.5 mL, 0.104 mole)
in THF (100 mL) at 0°C. The reaction was slowly warmed to
room temperature and stirred for further 6 hours. The reaction
1
cm-1; H-NMR (CDCl3): 400 MHz δ 0.83-0.90 (t, J = 14.4 Hz,
3H), 1.45-1.53 (m, 2H), 1.56 (s, 6H), 2.35-2.42 (m, 2H), 3.35 (s,
3H), 5.57 (s, 2H), 6.80-6.84 (d, J = 14.8 Hz, 2H), 6.91-6.95 (d, J
= 14 Hz, 6H), 7.04-7.08 (d, J = 15.2 Hz, 2H), 7.28-7.45 (m,
12H), 7.85-7.89 (m, 1H). ESI (APCI)-MS: m/z 703 (M+1).
Anal Calcd. for C44H42N6O3: C, 75.19; H, 6.02; N, 11.96. Found:
C, 75.22; H, 6.03; N, 11.93.
4-(1-Methoxy-1-methylethyl)-2-propyl-1-{4-(2-trityltetra-
zol-5-yl)phenyl}phenylmethylimidazole-5-carboxylic acid-5-
methyl-2-oxo-[1, 3]-dioxolene-4-yl-methyl ester (9). To a
stirred solution of 8 (17.5 g, 0.025 mole) in dimethyl acetamide