C. Zhang et al.
analysis showed that about 20% starting material remained. Further reduced pressure to give a light yellow solid, which was recrystallized from
N-bromosuccinimide (0.39g, 2.19mmol) was added and the mixture was methanol to give (14) as a light yellow solid (2.01g, 82.2%).
stirred for 40min. TLC analysis showed that no starting material remained.
The suspension was cooled at room temperature, followed by filtering the 7.50 (m, 2H), 4.55 (s, 2H).
1H NMR (300MHz, CDCl3): d 7.76 (d, J = 9.0Hz, 1H), 7.65 (t, J = 6.0Hz, 1H),
solid. The filter cake was rinsed thoroughly with CCl4 (20mLꢁ 3) and the
combined organic layers were concentrated under reduced pressure to
give a yellow liquid. The crude products was purified by chromatography
on silica gel column, eluted with hexanes/ethyl acetate (20:1) to afford (9)
as a white solid (7.17g, 59.9%).
Synthesis of [2H4] ethyl 2-(tert-butoxycarbonyl((20-cyanobiphenyl-4-
yl)methyl)amino)-3-nitrobenzoate (15)
A suspension of (14) (1.78 g, 6.4 mmol) and ethyl 2-(tert-butoxycarbonylamino)-
3-nitrobenzoate (2.00 g, 6.4mmol), K2CO3 (0.89 g, 6.4mmol) in CH3CN
(33 mL) was refluxed for 7 h. The reaction solution was diluted with H2O
(35 mL) and extracted with EtOAc (50mLꢁ 3). The combined organic layers
were washed with brine (80 mL), dried over Na2SO4, and concentrated
under reduced pressure to give a yellow liquid. The crude product was
purified by chromatography on silica gel column, eluted with hexanes/ethyl
acetate (8:1) to afford (15) as a light yellow solid (3.2g, 98.1%).
1H NMR (300MHz, CDCl3): d 8.11 (q, J = 3 Hz, 1H), 7.94 (q, 1H), 7.75
(d, J= 12, 21 Hz, 1H), 7.64 (t, J= 3 Hz, 1H), 7.50–7.41 (m, J = 6 Hz, 3H), 4.77
(dd, J= 6 Hz, 1H), 4.63 (t, J= 6 Hz, 1H), 4.24 (q, J= 6 Hz, 2H), 1.36 (s, 9H),
1.26 (t, 3H).
1H NMR (CDCl3, 300MHz): d 7.86 (d, 1H, J= 9.0Hz), 7.44 (m, 3H), 7.22–7.32
(m, 9H), 6.94(d, 6H, J = 8.7Hz), 4.38 (s, 2H).
Synthesis of [2H4] ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-((20-(1-
trithyl-1H- terazol-5-yl)-biphenyl-4-yl)methyl)-1H-imidazole-5-
carboxylate (11)
The solution of ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-
carboxylate (10) (1.82 g, 7.6mmol) in dry DMF (25 mL) was added to a
solution of t-BuOK (0.857g, 7.6mmol) in dry DMF (10 mL) by cooling with
an ice-water bath as necessary, followed by stirring for 20 min to give a
yellow solution. A light yellow solution of (9) (4.24g, 5.1mmol) in dry DMF
(40mL) was added into the aforementioned solution over 10 min. The
mixture was stirred at room temperature for 2.5h. The solution was diluted
with EtOAc (150mL) and H2O (150mL) to give a light pink solution. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc (100 mL ꢁ 3). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure to afford (11) as a white solid
(5.29 g, 96.5%).
Synthesis of [2H4] ethyl 2-((20-cyanobiphenyl-4-yl)methylamino)-3-
nitrobenzoate (16)
A suspension of (15) in HCl/MeOH (11.6%, 10 mL) and HCl/EtOAc (18.9%,
10 mL) was stirred at room temperature for 2 h. The reaction was concen-
trated under reduce pressure. The residue was suspended in MeOH
(15 mL) and basified by saturated NaHCO3 (45mL) solution to pH 8. The
suspension was filtered, and the solid was rinsed with H2O (15mLꢁ 3).
The solid was thoroughly dried in the dessicator to give (16) as a yellow solid
(1.24 g, 98.4%).
1H NMR (CDCl3, 300 MHz): d 7.86 (d, 1H, J= 9.0Hz), 7.44 (m, 2H), 7.28 (m,
10H, J = 7.5Hz), 6.94(d, 6H, J= 8.7Hz), 5.35 (s, 2H), 4.12 (m, 2H), 2.51 (m, 2H),
1.67 (s, 6H), 1.08 (t, 3H, J= 8.4Hz), 0.86 (t, 3H, J = 7.5Hz).
1H NMR (300 MHz, CDCl3): d 8.13 (t, J = 3 Hz, 1H), 8.02 (d, 1H), 7.76
(d, J= 7.5Hz, 1H), 7.65 (t, J= 3 Hz, 1H), 7.53–7.42 (m, J= 6 Hz, 2H), 6.74
(t, J = 6 Hz, 1H), 4.36 (q, J = 6 Hz, 2H), 4.24 (d, J= 6 Hz, 2H), 1.26 (t, 3H).
Synthesis of [2H4] ethyl 1-((20-(1H-tetrazol-5-yl)biphenyl-4-yl)
methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-
carboxylate (12)
Synthesis of [2H4]ethyl 3-amino-2-((20-cyanobiphenyl-4-yl)
methylamino)benzoate (17)
A suspension of (11) (1.4g, 1.9mmol) in 25% AcOH aqueous solution
(38mL) was stirred at 80 ꢂC for 2.5h. The solution was cooled to room
temperature and stirring continued for 2.5h, followed by filtering resulting
salt. The filter cake was rinsed with 50% AcOH aqueous solution. The
combined filtrates were co-evaporated with dry toluene to afford a colorless
liquid. The crude product was purified by chromatography on silica gel
column, eluted with CH2Cl2/MeOH (50:1) to afford (12) as a colorless liquid
(0.61 g, 65.6%).
A suspension of (16) (2.0g, 4.9mmol) and SnCl2ꢀH2O (4.00 g, 22.2 mmol) in
concentrated HCl (36%, 40mL) was stirred under an ice-water bath cooling
for 2.5h. The reaction mixture was basified by saturated Na2CO3 solution
(150 mL) to pH 8–9 and extracted with EtOAc (40mLꢁ 3). The combined
organic layers were washed with brine (60mL), dried over Na2SO4, and
concentrated under reduced pressure to give (17) as a semi-solid
(0.42 g, 90.2%).
1H NMR (CDCl3, 300 MHz): d 7.76 (d, 2H, J = 7.5Hz), 7.65 (m, 1H), 7.47
(d, 1H, J = 7.5Hz), 7.41 (d, 1H, J= 7.5Hz), 7.37 (m, 1H), 6.90(m, 2H), 6.43
(bs, 1H), 4.25(m, 3H),3.96 (s, 2H), 1.31 (t, 3H, J= 6.0Hz), 1.26 (t, 1H, J= 6.0Hz).
1H NMR (CDCl3, 300 MHz): d 7.94 (d, 1H, J = 9.0 Hz), 7.67 (m, 2H), 7.94
(d, 1H, J = 7.5 Hz), 5.43 (s, 2H), 4.22 (m, 2H), 2.47 (m, 2H), 1.71 (m, 2H),
1.49 (s, 6H), 1.16 (t, 3H, J = 8.4 Hz), 0.94 (t, 3H, J = 7.5 Hz).
Synthesis of [2H4] ethyl 1-((20-cyanobiphenyl-4-yl)methyl)-2-ethoxy-
1H-benzo[d] imidazole-7-carboxylate (18)
Synthesis of [2H4] olmesartan (13)
A suspension of (12) (0.878 g, 1.83 mmol), LiOHꢀH2O (0.46 g, 11.0mmol),
dioxane (8.8mL) and H2O (8.8 mL) was stirred at room temperature for
4.5h. The solution was evaporated to dryness. The residue was diluted with
H2O (10 mL) and acidified by 1M HCl (11.5mL) to pH 3 to give an off-white
solid. The solid was collected and recrystallized from EtOAc to afford (13) as
an off-white solid (0.66g, 79.5%).
A
solution of (17) (1.26g, 3.4mmol), tetraethoxymethane (0.97g,
5.03mmol) and acetic acid (0.21g, 3.4mmol) in MeOH (5.0mL) was stirred
at 80 ꢂC for 2 h. The reaction was diluted with MeOH (5mL), H2O (11 mL)
and basified with 6 M NaOH solution (0.55 mL) to pH 8. The resulting
precipitate was filtered, washed with H2O (6mLꢁ 3) to give a yellow
residue. The crude product was purified by chromatography on silica gel
column, eluted with hexanes/ethyl acetate (5:2) to afford (18) as a white
solid (1.17 g, 81.1%).
1H NMR (DMSO-d6, 300 MHz): d 7.76 (dd, 2H, J= 8.1, 6.0Hz), 7.67
(dd, 2H, J= 6.9, 8.4Hz), 5.73 (s, 2H), 2.67 (t, 2H, J = 7.5Hz), 1.62–1.65
(m, 2H), 1.58 (s, 6H), 0.88 (t, 3H, J= 7.5Hz). MS-EI, (m/z): 449.2(100), 450.2
(M, 28%). HPLC (XDB-C18, wavelength= 254 nm, CH3OH/10 mmol/L
NaH2PO4 + 0.05% H3PO4 = 50/50, 1.0mL/min): tR = 6.65min (98.8%). Isotopic
enrichment determined by MS was over 98%.
1H NMR (CDCl3, 300 MHz): d 7.74 (d, 2H, J = 9.0 Hz), 7.63 (m, 2H), 7.43
(m, 2H), 7.20 (d, 1H, J = 7.5 Hz), 5.74 (s, 2H), 4.70 (m, 2H), 4.25 (m, 2H),
1.49 (t, 3H, J = 6.0 Hz), 1.26 (t, 3H, J = 6.0 Hz).
Synthesis of [2H4] ethyl 1-((20-(1H-tetrazol-5-yl)biphenyl-4-yl)
methyl)-2-ethoxy-1H-benzo [d]imidazole-7-carboxylate (19)
Synthesis of [2H4] 40-(bromomethyl)biphenyl-2-carbonitrile (14)
A
suspension of (4) (1.75 g, 8.87 mmol) and benzoyl peroxide
(0.15 g, 0.621 mmol), N-bromosuccinimide (0.75g, 4.43 mmol) in CCl4 A suspension of (18) (1.04g, 2.4mmol) and (6) (4.03g, 12.1mmol) in dry
(21mL) was refluxed for 1 h. Additional N-bromosuccinimide (0.75 g, toluene (10.4mL) was refluxed for 20h. TLC showed some starting material.
4.43 mmol) was added and the mixture was stirred for a further 1h. The Another portion of (6) (2.01g, 6.06mmol) was added and the mixture was
suspension was filtered, and the solid residue was rinsed thoroughly with stirred for 5h. TLC showed no starting material. The reaction solution was
CCl4 (4mLꢁ 3). The combined organic layers were concentrated under evaporated to remove toluene to give a yellow residue, which was diluted
Copyright © 2012 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2012