2,3-Oxidosqualene Cyclase Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3367
mophenyl)-6-methoxy[d]benzisothiazole (22) (7.52 g, 73%): IR
(KBr) 2840, 1600, 1499, 1236, 1124, 1017, 829 cm-1; 1H NMR
(DMSO-d6) δ 3.94 (s, 3H), 7.07 (dd, J ) 8.8 Hz, 1H), 7.36 (d,
1H), 7.62-7.78 (m, 4H), 7.97 (d, J ) 9 Hz, 1H); MS m/z 318
(M+, 1Br).
Allyl[6-[3-(4-br om op h en yl)ben zo[b]th iop h en -6-yloxy]-
h exyl]m eth yla m in e‚F u m a r a te (1:1) (29‚F u m a r a te). Po-
tassium tert-butylate (2.55 g, 22.7 mmol) was placed in THF
(15 mL), and the solution was treated with 4e (2.50 g, 7.4
mmol) in THF (12 mL). The mixture was heated under reflux
and then treated with water and NH4Cl solution. The water
phases were extracted with ethyl acetate. The organic phases
were washed with a NaHCO3 solution and brine and dried
(Na2SO4). The crude product obtained after concentration (2.08
g) was dissolved in toluene (14 mL) and treated with trifluo-
roacetic acid (6 mL) at 0 °C (2 h). The mixture was neutralized
with a NaHCO3 solution. The aqueous phase was extracted
with ethyl acetate. The organic phases were washed with a
NaHCO3 solution and brine and dried (Na2SO4). The crude
product obtained was purified by column chromatography
(silica gel, ethyl acetate/n-hexane 1:6) and crystallized from
ethyl acetate/n-hexane. 3-(4-Bromophenyl)-6-methoxybenzo-
[b]thiophene (27) (476 mg, 20%) was obtained as white
crystals: mp 102.5-104.5 °C; IR (KBr) 2830, 1601, 1460, 1267,
1049, 825 cm-1; 1H NMR (CDCl3) δ 3.89 (s, 3H), 7.02 (dd, J )
8.9, 2.4 Hz, 1H), 7.21 (s, 1H), 7.37 (d, J ) 2.4 Hz, 1H), 7.43
(m, 2H), 7.60 (m, 2H), 7.72 (d, J ) 8.9 Hz, 1H); MS m/z 318
(M+, Br).
22 (6.32 g, 19.7 mmol) was dissolved in methylene chloride
(395 mL), and the mixture was cooled to -78 °C and treated
with a boron tribromide solution (1 M in methylene chloride,
49.3 mL, 49.3 mmol). The solution was thawed overnight and
then stirred at room temperature. The solution was added to
a NaHCO3 solution, the phases were separated, and the
aqueous phase was extracted with methylene chloride (150
mL). The organic phases were washed with brine, dried
(Na2SO4), and evaporated. (4-Bromophenyl)benzo[d]isothiazol-
6-ol (1.5 g, 25%) was crystallized from the crude product using
methylene chloride as solvent. The mother liquor was concen-
trated, dissolved in methylene chloride (320 mL), and treated
at -78 °C with boron tribromide solution (1 M in methylene
chloride, 40 mL, 40 mmol). After workup and crystallization,
further 3-(4-bromophenyl)benzo[d]isothiazol-6-ol (2.24 g, 37%)
was obtained: 1H NMR (DMSO-d6) δ 7.04 (dd, J ) 11 Hz, 1H),
7.51 (d, 1H), 7.79 (m, 4H), 8.0 (d, J ) 8.9 Hz, 1H), 10.38 (s,
1H).
This compound (3.0 g, 9.8 mmol) was treated as discribed
for 6e in general procedure B to give 6-(6-bromohexyloxy)-3-
(4-bromophenyl)benzo[d]isothiazole (23) (4.18 g, 91%) as a
pale-brown substance: 1H NMR (CDCl3) δ 1.56 (m, 4H), 2.9
(m, 4H), 3.44 (t, 3H), 4.08 (t, 3H), 7.07 (dd, 1H), 7.47 (d, 1H),
7.69 (m, 4H), 7.96 (d, J ) 9 Hz, 1H), 10.38 (s, 1H).
23 (4.15 g, 8.84 mmol) was treated as described for 7b in
general procedure A to give colorless crystals of 24‚fumarate
(3.43 g, 67%): mp 122-123.5 °C; IR (KBr) 2591, 2504, 1671,
1589, 1391, 1237, 960 cm-1; 1H NMR (DMSO-d6) δ 1.31-1.58
(m, 4H), 1.66 (m, 2H), 1.81 (m, 2H), 2.69 (s, 3H), 3.05 (t, 2H),
3.70 (d, 2H), 4.12 (t, 2H), 5.50 (d, 1H), 5.54 (d, 1H), 5.90 (m,
1H), 6.62 (s, 2H), 7.15 (dd, J ) 8.9 Hz, 1H), 7.80 (m, 5H), 8.06
(d, J ) 9 Hz, 1H); MS m/z 459 (M + H+, 1Br). Anal. (C23H27N2-
OBr‚C4H4O4) C, H, N, Br, S.
Analogous to general procedure C, 29‚fumarate was ob-
tained from 27 in 35% yield: IR (KBr) 2496, 1704, 1270, 1233,
1068, 984, 824 cm-1; 1H NMR (DMSO-d6) δ 1.20-1.58 (m, 6H),
1.76 (m, 2 H), 2.25 (s, 3H), 2.38-2.56 (m, 2H), 3.12 (d, J ) 6.4
Hz, 2H), 4.05 (t, J ) 5 Hz, 2 H), 5.19 (d, J ) 10 Hz, 1H), 5.25
(d, J ) 17.5 Hz, 1H), 5.82 (m, 1H), 6.58 (s, 2H), 7.05 (dd, J )
8.9 Hz, 1H), 7.5-7.77 (m, 2H), 13.0 (s, br, 2H); MS m/z 457
(M + H+, Br). Anal. (C24H28NOBrS‚C4H4O4) C, H, N, S.
Allyl[6-[3-(4-br om op h en yl)ben zofu r a n -6-yloxy]h exyl]-
m eth yla m in e‚F u m a r a te (34‚F u m a r a te). 4-Bromophenacyl
bromide (11.5 g, 41.5 mmol) was dissolved in acetone (250 mL),
and after the addition of K2CO3 (5.75 g, 41.5 mmol) and
3-methoxyphenol (4.5 mL, 41.5 mmol), the reaction mixture
was stirred at room temperature for 18 h and the mixture was
subsequently filtered. The filtrate was concentrated and
chromatographed over silica gel with ethyl acetate/n-hexane
(5:95 to 10:90). 1-(4-Bromophenyl)-2-(3-methoxyphenoxy)etha-
none (32) (7.3 g, 55%) was isolated as an off-white solid: 1H
NMR (CDCl3) δ 3.78 (s, 3H), 5.19 (s, 2H), 6.50-6.57 (m, 3H),
7.19 (t, J ) 8.8 Hz, 1H), 7.65 (d, J ) 8.6 Hz, 2H), 7.90 (d, J )
8.6 Hz, 2H); MS m/z 320 (M+, 1Br).
Ally l[6-[4-(6-b r o m o b e n zo [d ]is o t h ia zo l-3-y l)p h e n -
oxy]h exyl]m eth yla m in e‚F u m a r a te (1:1) (31‚F u m a r a te).
31‚fumarate was synthesized from 4-bromo-2-fluorobenzoyl
chloride and anisole (Id ) via (4-bromo-2-fluorophenyl)(4-meth-
oxyphenyl)methanone (30) following general procedure A (63%
yield) and general procedure C (38% yield): mp 134-135 °C;
IR (KBr) 2643, 1696, 1608, 1581, 1516, 1462, 1252, 840 cm-1
;
32 (5.0 g, 15.6 mmol) was dissolved in polyphosphoric acid
(53 g), and the mixture was heated for 1.5 h at 80 °C. The
mixture was then adjusted to pH ∼8 with a Na2CO3 solution,
cooled, and subsequently extracted with ethyl acetate. The
organic extracts were dried (Na2SO4) and concentrated. 3-(4-
Bromophenyl)-6-methoxybenzofuran (33) (4.6 g, 98%) was
obtained: 1H NMR (CDCl3) δ 3.88 (s, 3H), 6.95 (dd, J 1 ) 8.6
Hz, J 2 ) 2.1 Hz, 1H), 7.07 (d, J ) 2.1 Hz, 1H), 7.49 (d, J ) 8.4
Hz, 2H), 7.58 (d, J ) 8.4 Hz, 2H), 7.63 (d, J ) 8.6 Hz, 1H),
7.70 (s, 1H); MS m/z 302 (M+, 1Br).
1H NMR (DMSO-d6) δ 1.28-1.58 (m, 6H), 1.76 (m, 2H), 2.24
(s, 3H), 2.38-2.58 (m, 2H), 3.10 (d, J ) 5 Hz, 2H), 4.06 (t, J )
8 Hz, 2H), 5.18 (d, J ) 9 Hz, 1H), 5.25 (d, J ) 15.4 Hz, 1H),
5.82 (m, 1H), 6.57 (s, 2H), 7.13 (d, J ) 8.7 Hz, 2H), 7.70 (dd,
J ) 8.7 Hz, 1H), 7.81 (d, J ) 8.7 Hz, 2H), 8.12 (d, J ) 8.7 Hz,
1H), 8.61 (dd, 1H), 13.0 (s, br, 2H); MS m/z 458 (M+, 1Br).
Anal. (C23H27N2OBrS‚2C4H4O4) C, H, N, Br, S.
Allyl[6-[4-(6-br om o-1,1-d ioxoben zo[d ]isoth ia zol-3-yl)-
p h en oxy]h exyl]m eth yla m in e‚F u m a r a te (1:1) (26‚F u m a -
r a te). 23 (2.34 g, 4.99 mmol) was taken up in methylene
chloride (40 mL) and treated with potassium permanganate
(8.5 g, 5.38 mmol) adsorbed on silica gel.46 The suspension was
stirred at room temperature and then treated with Na2SO4
and filtered through silica gel. After concentration, the crude
product was crystallized from ethyl acetate and n-hexane to
give 6-(6-bromohexyloxy)-3-(4-bromophenyl)benzo[d]isothiaz-
ole 1,1-dioxide (25) (650 mg, 28%) and starting material 23
(1.23 g, 52%). 25: 1H NMR (CDCl3) δ 1.54 (m, 4H), 1.9 (m,
4H), 3.44 (t, 2H), 4.13 (t, 2H), 7.14 (dd, 1H), 7.47 (d, 1H), 7.67-
7.77 (m, 3H), 7.84 (d, 2H); MS m/z 499 (M+, 1Br).
Analogous to general procedure A for compound 7b, 26‚
fumarate was isolated as an oil in a yield of 55%: IR (KBr)
2640, 1714, 1604, 1169, 1011, 963, 844 cm-1; 1H NMR (DMSO-
d6) δ 1.33-1.59 (m, 4H), 1.68 (m, 2H), 1.85 (m, 2H), 2.50 (s,
3H), 2.74 (m, 2H), 3.40 (d, J ) 8 Hz, 2H), 4.10 (t, J ) 6 Hz,
2H), 5.32 (d, J ) 6 Hz, 1H), 5.36 (d, J ) 10 Hz, 1H), 5.93 (m,
1H), 6.79 (s, 2H), 7.16 (dd, 1H), 7.46 (d, 1H), 7.69-7.77 (m,
3H), 7.79-7.86 (m, 2H)); MS m/z 491 (M + H+, 1Br). Anal.
(C23H27N2O3BrS‚C4H4O4) C, H, N, Br, S.
33 (3.0 g, 9.9 mmol) in methylene chloride (100 mL) was
treated at 0 °C with a boron tribromide solution (1 M in
methylene chloride, 100 mL, 100 mmol). The ice bath was
removed, and the reaction mixture was stirred for 4 h,
subsequently poured into a Na2CO3 solution, and extracted
with methylene chloride. The organic phases were washed with
brine, dried (Na2SO4), and evaporated to give 3-(4-bromophen-
yl)benzofuran-6-ol (2.83 g, 99%): 1H NMR (CDCl3) δ 6.86 (dd,
J 1 ) 8.6 Hz, J 2 ) 2.1 Hz, 1H), 7.04 (d, J ) 2.1 Hz, 1H), 7.48
(d, J ) 8.5 Hz, 2H), 7.58 (d, J ) 8.5 Hz, 2H), 7.60 (d, J ) 8.6
Hz, 1H), 7.69 (s, 1H); MS m/z 288 (M+, 1Br).
Analogous to general procedure B, 34 was obtained in a total
yield of 37% and the compound was converted into 34‚
fumarate, following the general procedure for the formation
of fumarates: 1H NMR (DMSO-d6) δ 1.37 (m, 2H), 1.50 (m,
4H), 1.75 (m, 2H), 2.28 (s, 3H), 2.50 (m, 2H), 3.17 (d, J ) 6.6
Hz, 2H), 4.03 (t, J ) 6.5 Hz, 2H), 5.20-5.30 (m, 2H), 5.77-
5.92 (m, 1H), 6.57 (s, 2H), 6.97 (dd, J 1 ) 8.6 Hz, J 2 ) 2.1 Hz,
1H), 7.27 (d, J ) 2.1 Hz, 1H), 7.68 (s, 4H), 7.77 (d, J ) 8.6 Hz,