3100 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Bo¨hme et al.
to give the desired product 6c (43.1 g, 73%). 1H NMR (DMSO-
d6): δ ) 2.65 (t, J ) 7.1 Hz, 2H), 3.25-3.30 (m, 2H), 3.69 (s,
3H), 6.72-6.74 (m, 3H), 7.16 (t, J ) 6.8 Hz, 1H), 7.94 (s, 1H),
8.01 (bs, 1H). MS: m/z 180.1 (M + 1)+. The compound 6b was
obtained following the preparation similar to that of 6c.
with CH2Cl2 (3 × 50 mL). The organic layer was dried (MgSO4)
and concentrated in vacuo. The dark oil was dissolved in
ethanol (2 mL)/ether (10 mL) and HCl gas was bubbled into
the solution for 1 min. This mixture was kept at 5 °C for
approximately 16 h. The suspension was filtered, and the solid
residue was basified with aqueous K2CO3 (10%), extracted with
CH2Cl2 (3 × 50 mL), dried (Na2SO4), and concentrated in vacuo
P r ep a r a tion of 6-Meth oxy-3,4-d ih yd r o-isoqu in olin e
(7d ) (Sch em e 3). Phosphorus oxychloride (80 mL, 0.85 mol)
was added dropwise to 6c (41.1 g, 0.24 mol), and the mixture
was refluxed for 1 h. The reaction mixture was then cooled to
room temperature, and hexane was added and decanted off
(3 × 100 mL). Water (200 mL) was added slowly to the dark
oily solution with stirring. The mixture was basified with
NaOH to pH > 13, extracted with ethyl acetate, dried (Na2-
SO4), and concentrated in vacuo to afford the desired product
7d (26.1 g, 67%). 1H NMR (DMSO-d6): δ ) 2.61 (t, J ) 7.7
Hz, 2H), 3.53 (t, J ) 7.7 Hz, 2H), 3.74 (s, 3H), 6.76 (s, 1H),
6.81 (d, J ) 8.3 Hz, 1H), 7.27 (d, J ) 8.3 Hz, 1H), 8.18 (s, 1H).
MS: m/z 162.1 (M + 1)+. The compound 7a was obtained
following the preparation similar to that of 7d .
P r ep a r a tion of 6-Ch lor o-3,4-d ih yd r o-isoqu in olin e (7b)
(Sch em e 3). Polyphosphoric acid (50 g) was added to 6b (3.7
g, 0.02 mol), and the mixture was heated for 20 min at 140
°C. The reaction mixture was then poured on ice chips (30 g).
Water (100 mL) was added to the dark oily solution with
stirring. The mixture was basified with NaOH to pH > 13,
extracted with ethyl acetate, dried (Na2SO4), and concentrated
in vacuo to afford the desired products 7b,c as a mixture (1.1
g, 33%). MS: m/z 165.1 (M + 1)+ and 167.1 (M + 1)+.The
mixture was used without further workup for the synthesis
of 17 and 18.
P r ep a r a tion of 3,4-Dih yd r o-isoqu in olin -6-ol HBr (7e)
(Sch em e 3). Compound 7d (2.5 g, 15.4 mmol) was refluxed
in 47% HBr (10 mL) for 3 h under nitrogen. The solution was
concentrated in vacuo. The residue was recrystallized from
ethanol/ethyl acetate (1:1) to yield purple crystals of 3,4-
dihydro-isoquinolin-6-ol-HBr (7e) (1 g, 44%). 1H NMR (DMSO-
d6): δ ) 3.02 (t, J ) 8.1 Hz, 2H), 3.76-3.80 (t, J ) 8.1 Hz,
2H), 6.81 (s, 1H), 6.84-6.87 (m, 1H), 7.74 (d, J ) 8.5 Hz, 1H),
8.93 (s, 1H). MS: m/z 147.9 (M + 1)+.
P r epar ation of 1-(3-Meth yl[1,2,4]oxadiazol-5yl)pr opan -
2-on e (9a ) (Sch em e 4). To a solution of 2,2,6-trimethyl[1,3]-
dioxin-4-one (15 g, 105 mmol) in dioxane (150 mL), 8 (8 g, 72.4
mmol) and triethylamine (8.8 g, 87 mmol) were added and
refluxed for 15 h.28 The mixture was cooled to room temper-
ature, brine (100 mL) was added, and the emulsion was
extracted with ethyl acetate (2 × 100 mL). NaOH (2 N, 50
mL) was added to the water layer and extracted with ethyl
acetate (2 × 50 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give yellow crystals (9a )
(4.8 g, 47%). 1H NMR (DMSO-d6): δ ) 2.20 (s, 3H), 2.28 (s,
3H), 4.29 (s, 2H). MS: m/z 140.9 (M + 1)+.
P r ep a r a tion of 5-Hyd r oxy-2-p r op yl-1H-in d ole-3-ca r -
boxylic Acid Eth yl Ester (11g) (Sch em e 5). Ammonia was
bubbled into a solution of 9g in methanol (200 mL) at 5 °C for
15 min and then stirred at room temperature for 24 h to form
10g. The reaction mixture was concentrated, and acetic acid
(150 mL) and 1,4-benzoquinone (15.7 g, 0.145 mol) were added
and stirred for 3 h at room temperature. The suspension was
filtered, washed with CH2Cl2 (2 × 50 mL), and dried in a
vacuum oven at 50 °C for 24 h to give a beige solid (11g) (2.2
g, 6%). 1H NMR (DMSO-d6): δ ) 0.89 (t, J ) 7.3 Hz, 3H), 1.31
(t, J ) 7.1 Hz, 3H), 1.65 (m, 2H), 2.96 (t, J ) 7.7 Hz, 2H), 4.21
(q, J ) 7.1 Hz, 2H), 6.57 (dd, J ) 8.4 Hz, 4J ) 2.3 Hz, 1H),
7.10 (d, J ) 8.4 Hz, 1H), 7.30 (d, 4J ) 2.3 Hz, 1H), 8.80 (s,
1H), 11.46 (s, 1H). MS: m/z 248.1 (M + 1)+. The compounds
11a -f and 11h -p were obtained following the preparation
similar to that of 11g.
P r ep a r a tion of 4-(Dim eth yla m in o-m eth yl)-5-h yd r oxy-
2-p r op yl-1H-in d ole-3-ca r boxylic Acid Eth yl Ester (12g)
(Sch em e 5). To a solution of 11g (2.2 g, 8.9 mmol) in ethanol
(20 mL) were added formaldehyde (37%, 0.85 mL, 10.7 mmol)
and dimethylamine (40%, 2.2 mL, 19.6 mmol). The reaction
mixture was stirred for approximately 16 h at 50 °C. The
solution was then diluted with water (200 mL) and extracted
1
to give a brown solid (12g) (1.2 g, 44%). H NMR (DMSO-d6):
δ ) 0.87 (t, J ) 7.3 Hz, 3H), 1.27 (t, J ) 7.3 Hz, 3H), 1.61 (m,
2H), 2.17 (s, 6H), 2.79-2.83 (m, 2H), 3.98 (s, 2H), 4.18 (q, J )
7.3 Hz, 2H), 6.55 (d, J ) 8.5 Hz, 1H), 7.05 (d, J ) 8.5 Hz, 1H),
11.40 (s, 1H). MS: m/z 305.1 (M + 1)+. The compounds 12a -f
and 12h -s were obtained following the preparation similar
to that of 12g.
P r ep a r a tion of 2-Meth yl-5-tr iisop r op ylsila n yloxy-1H-
in d ole-3-ca r boxylic Acid Ben zyl Ester (13) (Sch em e 6).
To a solution of 11d (17.7 g, 62.9 mmol) and imidazole (10.7
g, 157 mmol) in dimethylformamide (DMF, 40 mL) was added
chloro-triisopropyl-silane (14.55 g, 75.5 mmol). The reaction
mixture was stirred for approximately 16 h, CH2Cl2 (150 mL)
was added, and the solution was washed with brine (3 × 100
mL), dried (MgSO4), concentrated in vacuo, and chromato-
graphed (80% hexane, 20% ethyl acetate) to give a brown solid
(13) (11.2 g, 41%). 1H NMR (DMSO-d6): δ ) 0.93-0.97 (m,
18H), 1.00-1.08 (m, 3H), 2.58 (s, 3H), 5.24 (s, 2H), 6.62-6.65
(m, 1H), 7.16 (d, J ) 8.5 Hz, 1H), 7.30-7.43 (m, 6H), 11.71 (s,
1H). MS: m/z 438.3 (M + 1)+.
P r ep a r a tion of 2-Meth yl-5-tr iisop r op ylsila n yloxy-1H-
in d ole-3-ca r boxylic Acid (14) (Sch em e 6). Compound 13
(11.2 g, 25.6 mmol) was dissolved in ethanol (200 mL) and
debenzylated with 10% Pd/C (0,6 g) and H2 in the presence of
formic acid (88%, 10 mL). After 5 h, the solution was
concentrated in vacuo to give 14 (8.8 g, 99%). 1H NMR (DMSO-
d6): δ ) 1.01-1.09 (m, 21H), 2.55 (s, 3H), 6.61-6.64 (m, 1H),
7.13-7.15 (m, 1H), 7.40 (m, 1H), 11.53 (s, 1H), 11.70 (bs, 1H).
MS: m/z 348.2 (M + 1)+.
P r ep a r a t ion of 2-Met h yl-5-t r iisop r op ylsila n yloxy-
1H-in d ole-3-ca r boxylic Acid Eth yl-m eth yl-a m id e (11r )
(Sch em e 6). Compound 14 (8.8 g, 25.3 mmol) in DMF (50 mL)
was added sequentially to PyBOP (17.7 g, 34 mmol), HOBT
(4.6 g, 34 mmol), and tripropylamine (5 g, 35 mmol). The
mixture was allowed to stir for approximately 16 h at room
temperature. CH2Cl2 (200 mL) was added, and the organic
layer was washed with brine (2 × 100 mL) and concentrated
in vacuo. The residue was purified by chromatography (90%
hexane, 10% ethyl acetate) and concentrated in vacuo to give
an oil, which crystallized after standing at room temperature
for 1 day (6.8 g, 58%). To a solution of residue (2.33 g, 5 mmol)
in CH2Cl2 (20 mL), methyl-ethylamine (0.3 g, 5 mmol) was
added and the reaction mixture was allowed to stir at room
temperature for approximately 16 h. The organic layer was
washed with brine (2 × 50 mL) and 2% HCl (2 × 50 mL), dried
(MgSO4), and concentrated in vacuo to give the desired product
(11r ) (1.6 g, 82%). 1H NMR (DMSO-d6): δ ) 1.00-1.03 (m,
21H), 1.16-1.21 (m, 3H), 2.30 (s, 3H), 2.88 (s, 3H), 3.37-3.38
(m, 2H), 6.59 (d, J ) 8.5 Hz, 1H), 6.68 (s, 1H), 7.12 (d, J ) 8.5
Hz, 1H), 11.15 (s, 1H). MS: m/z 389.2 (M + 1)+.
P r ep a r a tion of 2-Meth yl-1H-in d ole-5-ol (15) (Sch em e
6). A suspension of 11q (7 g, 32 mmol) in aqueous HCl (20%,
500 mL) was refluxed for 2 h 30 min. The brown solution was
cooled to room temperature and adjusted to pH 5-6 by adding
aqueous 25% NaOH with cooling (5 °C). The resulting suspen-
sion was extracted with CH2Cl2 (3 × 150 mL), and the organic
layer was dried (MgSO4) and concentrated in vacuo to give a
1
bright brown solid (15) (4 g, 85%). H NMR (DMSO-d6): δ )
2.27 (s, 3H), 5.86 (s, 1H), 6.43 (dd, J ) 8.5 Hz, 4J ) 2.2 Hz,
1H), 6.66 (d, J ) 2.2 Hz, 1H), 6.98 (d, J ) 8.5 Hz, 1H), 8.43 (s,
1H), 10.49 (s, 1H). MS: m/z 147.9 (M + 1)+.
P r ep a r a tion of 3-Ben zyl-2-m eth yl-1H-in d ol-5-ol (11s)
(Sch em e 6). To a solution of 15 (3.75 g, 25.6 mmol) in
acetonitrile (100 mL) and K2CO3 (6.9 g, 50 mmol) was added
benzylbromide (4.38 g, 25.6 mmol). The reaction mixture was
refluxed for approximately 16 h, cooled to room temperature,
and concentrated in vacuo. The residue was purified by