1454 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7
ChegaeV et al.
mmol). Stirring was continued for 1 h, and then the reaction mixture
was concentrated under reduced pressure. The oil thus obtained
was treated with cold water (5 mL), and the resulting white solid
was filtered off, washed with a small amount of cold water, and
dried. This product was used without any additional purification
for further reaction. Yield 87%. Mp 294-295 °C (MeCN); 1H NMR
(DMSO-d6) δ: 2.92 (s, 3H, CH3), 3.15 (s, 3H, CH3), 6.73-7.05
(m, 3H, C6H3), 7.38 (d, 2H, C6H4), 7.82 (d, 2H, C6H4), 8.23 (s,
1H), 8.44 (s, 1H) (NdCHNIm, CHIm), 10.2 (br s, 1H, OH); 13C
NMR (DMSO-d6) δ: 35.0, 40.9, 117.4, 117.6, 117.8, 117.9, 125.5,
125.8, 126.4, 127.1, 127.5, 136.6, 138.1, 142.6, 145.2, 145.4, 148.8,
152.0, 159.9; MS (EI) 422/424 (M)+.
126.9, 127.1, 128.4, 129.1, 137.5, 139.8, 145.1, 148.1, 148.2, 151.4,
154.7; MS (EI) 470/472 (M)+. Anal. (C18H16ClFN4O6S) C, H, N.
4-{4-Chloro-1-[4-(methylsulfonyl)phenyl]-1H-imidazol-5-yl}-
2-fluorophenol (10). The product was synthesized starting from 5
following a procedure similar to the one described for the
preparation of 6 from 4. Yield 83%. Mp 243-244 °C dec; 1H NMR
(DMSO-d6) δ: 3.29 (s, 3H, CH3), 6.82-7.09 (m, 3H, C6H3), 7.54
(d, 2H, C6H4), 8.02 (d, 2H, C6H4), 8.13 (s, 1H, CH Im), 10.29 (br
s, 1H, OH); 13C NMR (DMSO-d6) δ: 43.2, 117.5, 117.7, 117.8,
117.9, 125.6, 126.1, 126.5, 127.8, 128.3, 136.7, 139.7, 140.3, 145.3,
148.9, 152.1; MS (EI) 366/368 (M)+. Anal. (C16H12ClFN2O3S) C,
H, N.
2-{4-[4-Chloro-1-(4-(methylsulfonyl)phenyl)-1H-imidazol-5-
yl]-2-fluorophenoxy}ethanol (11a). The title product was synthe-
sized starting from 10 following a procedure similar to that used
to prepare 8a from 7, but without the final treatment with 20%
HCl. The oil obtained after removing the solvent under reduced
pressure was treated with water and extracted with EtOAc. The
organic layer was washed with water and brine, dried, and
evaporated under reduced pressure. The oily residue was triturated
with diethyl ether to give a solid that was collected by filtration.
Finally, the product was recrystallized from i-PrOH. Yield 83%.
4-{4-Chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-imi-
dazol-1-yl}benzenesulfonamide (8a). To a stirred mixture of 7
(0.34 g, 0.80 mmol) and K2CO3 (0.33 g, 2.40 mmol) in acetonitrile
(10 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (0.30
mL, 1.40 mmol) in one portion. The reaction mixture was heated
at 70-75 °C for 8 h, it was concentrated under reduced pressure,
and sequentially MeOH (5 mL) and 2 N NaOH (2 mL) were added.
The resulting mixture was heated at 40 °C for 2 h and then acidified
to pH 1 with 20% HCl. The solvent was removed under reduced
pressure, and the residue was treated with water (10 mL) to give a
sticky precipitate that afforded a powder after a 2-h refrigeration.
The powder was filtered off, washed with water, and dried. An
analytically pure sample was obtained by recrystallization from
1
Mp 142-143 °C (i-PrOH); H NMR (CDCl3) δ: 2.75 (br s, 1H,
OH), 3.10 (s, 3H, CH3), 4.00 (m, 2H), 4.16 (m, 2H) (CH2CH2),
6.87-7.00 (m, 3H, C6H3), 7.34 (d, 2H, C6H4), 7.67 (s, 1H, CH
Im), 7.99 (d, 2H, C6H4); 13C NMR (CDCl3) δ: 44.4, 61.0, 70.7,
114.9, 117.4, 117.7, 119.8, 119.9, 125.7, 126.1, 129.2, 129.9, 135.6,
140.4, 147.1, 147.3, 150.5, 153.8; MS (EI) 410/412 (M)+. Anal.
(C18H16ClFN2O4S) H, N. C: calcd, 52.62; found, 53.23.
1
EtOH. Yield 98%. Mp 190-191 °C (EtOH); H NMR (CD3OD)
δ: 3.89 (t, 2H, CH2), 4.12 (t, 2H, CH2), 6.94-7.13 (m, 3H, C6H3),
7.43 (d, 2H, C6H4), 7.96 (d, 2H, C6H4), 7.98 (s, 1H, CH Im); 13C
NMR (CD3OD) δ: 61.4, 71.9, 115.9, 118.5, 118.8, 121.0, 121.1,
127.2, 127.4, 127.5, 127.7, 128.7, 129.4, 137.7, 140.1, 145.4, 148.8,
148.9, 151.8, 155.0; MS (EI) 411/413 (M)+. Anal. (C17H15-
ClFN3O4S‚H2O) C, H, N.
2-{4-[4-Chloro-1-(4-(methylsulfonyl)phenyl)-1H-imidazol-5-
yl]-2-fluorophenoxy}ethyl Nitrate (11). The title product was
synthesized starting from 11a following a procedure similar to that
used for the preparation of 8 from 8a. The product was partly
purified by flash chromatography (eluent PE/EtOAc 1/1 v/v) and
then by preparative HPLC (Lichrospher 250-25 C18, mobile phase
MeCN/H2O 1/1 v/v, flow-rate 39 mL/min, λ ) 254 nm) to give
the title compound as a white powder. Yield 35%. Mp 60-65 °C;
1H NMR (CDCl3) δ: 3.10 (s, 3H, CH3), 4.33-4.36 (m, 2H), 4.83-
4.86 (m, 2H) (CH2CH2), 6.86-7.01 (m, 3H, C6H3), 7.33 (d, 2H,
C6H4), 7.65 (s, 1H, CH Im), 7.99 (d, 2H, C6H4); 13C NMR (CDCl3)
δ: 44.4, 65.7, 70.7, 115.6, 117.8, 118.0, 120.9, 121.0, 125.5, 125.7,
126.1, 129.3, 130.2, 135.7, 140.3, 140.5, 146.3, 146.4, 150.7, 154.0;
MS (EI) 455/457 (M)+. Anal. (C18H15ClFN3O6S) C, H, N.
4-{4-Chloro-5-[3-fluoro-4-(2-hydroxypropoxy)phenyl]-1H-
imidazol-1-yl}benzenesulfonamide (9a). The product was obtained
by the same procedure as for 8a, using (3-bromopropoxy)-tert-
butyldimethylsilane. Yield 82%. Mp 194-195 °C (MeOH); 1H
NMR (CD3OD) δ: 2.00 (m, 2H, CH2CH2OH), 3.74 (t, 2H, 3JHH
)
6.2 Hz), 4.15 (t, 2H, 3JHH ) 6.1 Hz) (CH2CH2CH2OH), 6.94-7.11
(m, 3H, C6H3), 7.43 (d, 2H, C6H4), 7.94-7.97 (m, 3H, C6H4, CH
Im); 13C NMR (CD3OD) δ: 32.8, 58.9, 66.7, 115.4, 118.1, 118.4,
120.4, 120.5, 126.9, 127.2, 127.3, 127.4, 127.5, 128.4, 129.0, 129.4,
137.4, 139.8, 145.1, 148.6, 151.4, 154.7; MS (EI) 425/427 (M)+.
Anal. (C18H17ClFN3O4S) C, H, N.
3-(Nitrooxy)propyl 4-Methylbenzenesulfonate (13). 3-Hydrox-
ypropyl nitrate (12, 1.10 g, 9.10 mmol) was dissolved in dry
pyridine (10 mL) at 0 °C, and p-methylbenzenesulfonyl chloride
(2.50 g, 13.1 mmol) was added in one portion. The reaction mixture
was kept at 0 °C for 5 h, and then it was poured into 1 N HCl
solution and extracted with EtOAc. The organic layer was washed
with 1 N HCl solution and brine, dried, and evaporated under
reduced pressure. The resulting oil was purified by flash chroma-
tography (eluent PE/EtOAc 95/5 v/v) to give the title compound
3-{4-[1-(4-(Aminosulfonyl)phenyl)-4-chloro-1H-imidazol-5-
yl]-2-fluorophenoxy}ethyl Nitrate (8). To a stirred suspension of
8a (0.80 g, 1.95 mmol) in acetonitrile (25 mL) were added AgNO3
(0.66 g, 3.89 mmol) and Ph3P (0.75 g, 2.86 mmol). The reaction
mixture was cooled at 0 °C, and NBS (0.50 g, 2.80 mmol) was
added in one portion. The stirring was continued at 0 °C for 1 h
and then at 60 °C for 3 h. The reaction mixture was filtered, and
the filtrate was evaporated under reduced pressure. The yellow oil
thus obtained was purified by flash chromatography (eluent CH2-
Cl2/MeOH 98/2 v/v). Recrystallization from MeOH gave the title
compound as white solid. Yield 20%. Mp 191-193 °C dec
1
as a colorless oil which solidified upon standing. Yield 55%. H
NMR (CDCl3) δ: 2.08 (m, 2H, CH2CH2CH2), 2.45 (s, 3H, CH3),
3
3
4.12 (t, 2H, JHH ) 5.9 Hz), 4.46 (t, 2H, JHH ) 6.1 Hz) (CH2-
CH2CH2ONO2), 7.36 (d, 2H, C6H4), 7.78 (d, 2H, C6H4); 13C NMR
(CDCl3) δ: 21.7, 26.6, 65.8, 68.6, 127.9, 130.0, 132.5, 145.3; MS
(EI) 275 (M)+; the compound was not characterized through
elemental analysis due to its instability, but it was immediately
reacted in the following step.
1
(MeOH); H NMR (CD3OD) δ: 4.34-4.37 (m, 2H), 4.85-4.89
(m, 2H) (CH2CH2OH), 6.96-7.14 (m, 3H, C6H3), 7.43 (d, 2H,
C6H4), 7.94-7.98 (m, 3H, C6H4, CH Im); 13C NMR (CD3OD)
δ: 66.9, 72.4, 116.3, 118.7, 119.0, 121.8, 121.9, 127.2, 127.4, 127.7,
127.8, 128.7, 129.5, 129.9, 135.6, 137.9, 145.4, 148.0, 148.1, 151.7,
155.0; MS (CI) 457/459 (M + 1)+. Anal. (C17H14ClFN4O6S) C,
H, N.
3-{4-[4-Chloro-1-(4-(methylsulfonyl)phenyl)-1H-imidazol-5-
yl]-2-fluorophenoxy}propyl Nitrate (14). To a stirred solution of
10 (0.25 g, 0.68 mmol) in dry THF (15 mL), kept under nitrogen,
was added a solution of t-BuO-K+ (0.09 g, 0.75 mmol) in dry THF
(10 mL). The obtained mixture was stirred for 15 min at room
temperature, and then 13 (0.20 g, 0.72 mmol) was added in one
portion. The reaction was left under stirring for 0.5 h and then was
heated at 75 °C for 8 h. After this time, the mixture was poured
into 2 N NaOH (20 mL) and extracted with CH2Cl2. The organic
layers were washed with water and brine, dried, and evaporated
under reduced pressure. The residue was purified by flash chro-
3-{4-[1-(4-(Aminosulfonyl)phenyl)-4-chloro-1H-imidazol-5-
yl]-2-fluorophenoxy}propyl Nitrate (9). The product was obtained
by the same procedure as for 8, using 9a as the starting compound.
The title product was recrystallized from EtOH. Yield 15%. Mp
169.5-170.5 °C dec (EtOH); 1H NMR (CD3OD) δ: 2.23 (m, 2H,
3
3
CH2CH2ONO2), 4.16 (t, 2H, JHH ) 5.9 Hz), 4.69 (t, 2H, JHH
)
6.3 Hz) (CH2CH2CH2ONO2), 6.95-7.12 (m, 3H, C6H3), 7.43 (d,
2H, C6H4), 7.94-7.98 (m, 3H, C6H4, CH Im); 13C NMR (CD3OD)
δ: 27.6, 70.9, 73.7, 115.6, 118.0, 118.2, 118.5, 118.7, 121.0, 121.1,