M. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 245–249
249
overnight, the reaction mixture was poured into water and extracted with
EtOAc. The combined organic layer was washed with brine, dried over Na2SO4,
and filtered. The solvent was removed in vacuo, and the crude product was
purified by preparative TLC plate (100:3 CH2Cl2/MeOH) to give 4 (200.0 mg,
80%) as a red solid: mp 102–104 °C; 1H NMR (DMSO-d6) d 11.19 (s, 1H), 8.11 (s,
1H), 7.72 (d, J = 2.0 Hz, 1H), 7.50–7.47 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.14 (td,
J = 1.0, 8.0 Hz, 1H), 6.79 (td, J = 1.0, 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.89 (s,
3H); HRMS (EI, m/z): calcd for C19H12N2O2Cl2 ([M]+) 370.0270, found 370.0268.
triphenylphosphine (2 mol %) was added to a stirred solution of compound 9
(304.0 mg, 1.0 mmol) and 2,4-dichlorophenyl boronic acid (286.0 mg,
1.5 mmol) in dimethoxyethane (3 mL) under nitrogen atmosphere. The
pressure tube was fitted with a Teflon cap and heated at 100 °C overnight.
The mixture was cooled to ambient temperature and diluted with EtOAc. The
organic layer was washed with saturated NH4Cl, brine, dried over Na2SO4, and
filtered. The solvent was removed in vacuo, and the crude product was purified
by preparative TLC plate column chromatography (2:1 hexanes/acetone) to
give 10 (280.0 mg, 75%) as a red solid: MS (ESI, m/z): 371 ([M+H]+, 100%). (m)
3-(2,4-Dichlorophenyl)-4-(1H-indol-3-yl)furan-2,5-dione (11). To a solution of
compound 10 (120.0 mg, 0.32 mmol) in dioxane (8 mL) was added 2 N KOH
(10 mL). After the reaction mixture was heated at reflux overnight, it was
poured into ice-water and acidified to pH 2.0 with 5 N HCl. The mixture was
then extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na2SO4, and filtered. The solvent was removed in vacuo, and
the crude product was purified by preparative TLC plate (2:1 hexanes/acetone)
to give 11 (51.0 mg, 44%) as a red solid: mp 220–221 °C; 1H NMR (DMSO-d6) d
12.35 (s, 1H), 8.22 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 2.0, 8.5 Hz, 1H),
7.51 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.13 (td, J = 1.0, 8.0 Hz, 1H), 6.81
(td, J = 1.0, 8.0 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H); MS (ESI, m/z): 358 ([M+H]+,
100%); HRMS (EI, m/z): calcd for C18H9NO3Cl2 ([M]+) 356.9954, found 356.9967.
(n) Methyl 2-(1H-indol-3-yl)-2-oxoacetate (12). To a solution of indole (2.0 g,
17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL, 17.2 mmol)
dropwise at 0 °C. The yellow slurry was stirred at same temperature for 0.5 h
and then cooled to À78 °C. A solution of NaOMe in MeOH (25 wt %, 7.8 mL,
34.1 mmol) was added to this slurry at same temperature. After addition, the
reaction mixture was allowed to warm to ambient temperature, and quenched
by addition of H2O (10 mL). The precipitate was collected by filtration, washed
with H2O and dried to give 12 (2.5 g, 73%) as a yellow solid: mp 160 °C (dec.);
1H NMR (DMSO-d6) d 12.42 (s, 1H), 8.45 (d, J = 3.5 Hz, 1H), 8.16 (dd, J = 1.5,
6.0 Hz, 1H), 7.55 (dd, J = 1.5, 6.0 Hz, 1H), 7.32–7.27 (m, 2H), 3.89 (s, 3H). (o) 3-
(f) Methyl 2-(1-methyl-1H-indol-3-yl)-2-oxoacetate (5). To
a solution of
compound 1 (1.0 g, 7.6 mmol) in Et2O (10 mL) was added oxalyl chloride
(0.7 mL, 8.02 mmol) dropwise at 0 °C. The yellow slurry was stirred at same
temperature for 0.5 h and then cooled to À78 °C.
A solution of sodium
methoxide in MeOH (25 wt %, 4.5 mL, 19.7 mmol) was added to this slurry at
same temperature. After addition, the reaction mixture was allowed to warm
to room temperature and quenched with water (5 mL). The precipitate was
collected by filtration, rinsed with water, Et2O and dried to give 5 (565 mg,
34%) as a tan solid: mp 80–81 °C; 1H NMR (DMSO-d6) d 8.50 (s, 1H), 8.18 (d,
J = 7.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.38–7.31 (m, 2H), 3.92 (s, 3H), 3.90 (s,
3H). (g). 2-(2,4-Dichlorophenyl)acetamide (6).
A
suspension of 2,4-
dichlorophenylacetic acid (2.0 g, 9.8 mmol) in thionyl chloride (7 mL) was
stirred at ambient temperature overnight. The excess thionyl chloride was
removed in vacuo, keeping the temperature below 30 °C. The residue was
taken up into toluene and the solvent was removed in vacuo. This operation is
repeated three times to remove the thionyl chloride. The residue was re-
dissolved in THF (50 mL), and ammonia gas is bubbled through the solution,
keeping the temperature below 10 °C. The resulting suspension was diluted
with cold water to get a clear solution, which was concentrated to small
volume. The precipitate was collected by filtration, rinsed with 1:8 THF/H2O
and dried to give 6 (1.73 g, 65%) as a white solid: mp 168–169 °C (lit.21 168–
169 °C); 1H NMR (DMSO-d6) d 7.56 (s, 1H), 7.49 (br s, 1H), 7.40–7.36 (m, 2H),
7.00 (br s, 1H), 3.55 (s, 2H). (h). Alternate synthetic procedure for compound 4.
To a stirred suspension of compound 5 (250.0 mg, 1.2 mmol) and compound 6
(117.3 mg, 0.58 mmol) in THF (10 mL) was added 1.0 M KOBut in THF (2.6 mL,
2.6 mmol) under nitrogen atmosphere. After stirring at ambient temperature
for 4 h, the reaction mixture was quenched with 1 N HCl (8 mL) and extracted
with EtOAc. The combined organic layer was washed with brine, dried over
Na2SO4, and filtered. The solvent was removed in vacuo, and the crude product
was purified by column chromatography with (2:1 hexanes/acetone) to give 4
(182.0 mg, 85%) as a red solid. The analytical data were obtained as same as
above. (i) 2-(1-Methyl-1H-indol-3-yl)-2-oxoacetamide (7). To a concentrated
(2,4-Dichlorophenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (13). To
a
suspension of compound 12 (1.17 g, 5.7 mmol) and compound 6 (586.5 mg,
2.9 mmol) in THF (50 mL) was added 1.0 M KOBut in THF (11.5 mL, 11.5 mmol)
under nitrogen atmosphere. After stirring at ambient temperature for 5 h, the
reaction mixture was quenched with 1 N HCl (50 mL) and extracted with
EtOAc. The combined organic layer was washed with brine, dried over Na2SO4,
and filtered. The solvent was removed in vacuo, and the crude product was
purified by column chromatography with (2:1 hexanes/acetone) to give 13
(726.0 mg, 71%) as an orange solid: mp 254–256 °C; 1H NMR (DMSO-d6) d
12.02 (s, 1H), 11.19 (s, 1H), 8.04 (d, J = 3.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.49
(dd, J = 2.0, 8.5 Hz, 1H), 7.43 (dd, J = 3.0, 8.5 Hz, 2H), 7.09–7.06 (m, 1H), 6.76–
6.73 (m, 1H), 6.40(d, J = 8.0 Hz, 1H); HRMS (EI, m/z): calcd for C18H10N2O2Cl2
([M]+) 356.0114, found 356.0126. (p) Alternate synthetic procedure for
compound 11. To a suspension of compound 13 (200.0 mg, 0.56 mmol) in
EtOH (3 mL) was added 5 N KOH (8 mL). After the reaction mixture was heated
at reflux overnight, EtOH was removed in vacuo. The residue was acidified to
pH 2.0 with 5 N HCl. The mixture was then extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4, and
filtered. The solvent was removed in vacuo, and the crude product was purified
by preparative TLC plate (2:1 hexanes/acetone) to give 11 (103.0 mg, 51%) as a
red solid: MS (ESI, m/z): 358 ([M+H]+, 100%). (q) 3-(2,4-Dichlorophenyl)-4-(1-
ammonium hydroxide solution (40 mL) was added compound
2 (1.5 g,
6.8 mmol) in small portions at 0 °C. The reaction mixture was stirred at same
temperature for 1 h. The precipitate was collected by filtration, rinsed with
water, Et2O and dried to give 7 (1.28 g, 93%) as a pale yellow solid: mp 186–
188 °C (lit.11 186–188 °C); 1H NMR (DMSO-d6) d 8.74 (s, 1H), 8.26–8.24 (m, 1H),
8.08 (br s, 1H), 7.73 (br s, 1H), 7.60–7.58 (m, 1H), 7.35–7.30 (m, 2H), 3.92 (s,
3H). (j) Methyl 2-(2,4-dichlorophenyl)acetate (8). To
a solution of 2,4-
dichlorophenylacetic acid (3.5 g, 17.1 mmol) in MeOH (100 mL) was added
concentrated H2SO4 (20 drops). After the reaction mixture was heated at reflux
overnight, the solvent was removed in vacuo. The residue was diluted with
cold water and extracted with EtOAc. The combined organic layer was washed
with saturated NaHCO3, brine, dried over Na2SO4, and filtered. The solvent was
removed in vacuo, and the crude product was purified by column
chromatography with (4:1 hexanes/EtOAc) to give 8 (3.56 g, 95%) as a clear
oil: 1H NMR (DMSO-d6) d 7.40 (s, 1H), 7.22 (d, J = 1.5 Hz, 2H), 3.74 (s, 2H), 3.71
(s, 3H). (k) 3-Bromo-4-(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione (9). To
a stirred solution of indole (2.47 g, 21.1 mmol) in THF (30 mL) was added a
solution of LiHMDS (1.0 M in THF, 50 mL, 50.0 mmol) dropwise under nitrogen
atmosphere at À20 °C. After stirring for 45 min at same temperature, a solution
of 2,3-dibromo-N-methylmaleimide (5.0 g, 18.6 mmol) in THF (30 mL) was
added dropwise at À20 °C, followed by stirring for 30 min at 0 °C. The reaction
mixture was poured into cooled 0.2 N HCl and extracted with EtOAc. The
combined organic layer was washed with saturated NaHCO3, brine, dried over
Na2SO4, and filtered. The solvent was removed in vacuo, and the residue was
recrystallized from MeOH to give 9 (5.4 g, 95%) as a red solid: mp 144 °C (dec.)
(lit.22,23 145 °C (dec.)); 1H NMR (DMSO-d6) d 12.12 (s, 1H), 8.06 (d, J = 3.0 Hz,
1H), 7.91 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.23 (td, J = 1.0, 8.0 Hz, 1H),
7.15 (td, J = 1.0, 8.0 Hz, 1H), 3.01 (s, 3H). (l) 3-(2,4-Dichlorophenyl)-4-(1H-
[
[
11C]methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione ([11C]SB-216763,
[
11C]4).
11C]CO2 was produced by the 14N(p, 11C nuclear reaction in small volume
a)
(9.5 cm3) aluminum gas target (CTI) from 11 MeV proton cyclotron on research
purity nitrogen (+1% O2) in a Siemens radionuclide delivery system (Eclipse
RDS-111). The proton-beam current was 55
30 min. The precursor 11 (0.1–0.3 mg) was dissolved in CH3CN (300
this solution was added NaH (1 mg). The mixture was transferred to a small
reaction vial. No-carrier-added (high specific activity)
11C]CH3I that was
produced by the gas-phase production method14 from 11C]CO2 through
11C]CH4 and [11C]CH3Br with NaI column was passed into the reaction vial
l
A, and the irradiation time was
lL). To
[
[
[
at 0 °C until radioactivity reached a maximum (ꢀ2 min), and then the reaction
vial was isolated and heated at 45 °C for 4 min to produce 3-(2,4-
dichlorophenyl)-4-(1-[11C]methyl-1H-indol-3-yl)furan-2,5-dione
([11C]3).
Then, a solution of HMDS (2 lL) and MeOH (2 lL) in DMF (300 lL) was
introduced to the reaction vial. The reaction mixture was sealed and heated at
80 °C for 8 min. The contents of the reaction vial were diluted with NaHCO3
(1 mL, 0.1 M), and injected onto the semi-preparative HPLC column with 2 mL
injection loop. The product fraction was collected, the solvent was removed by
indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione
(10)
using
n-butyl-di-1-
adamantylphosphine as ligand (I). In an Ace-pressure tube, 1 M K2CO3
(1.5 mL), Pd(OAc)2 (2 mol %) and n-butyl-di-1-adamantylphosphine (2 mol %)
was added to a stirred solution of compound 9 (152.0 mg, 0.5 mmol) and 2,4-
dichlorophenyl boronic acid (143.0 mg, 0.75 mmol) in dimethoxyethane
(1.5 mL) under nitrogen atmosphere. The pressure tube was fitted with a
Teflon cap and heated at 100 °C overnight. The mixture was cooled to ambient
temperature and diluted with EtOAc. The organic layer was washed with
saturated NH4Cl, brine, dried over Na2SO4, and filtered. The solvent was
removed in vacuo, and the crude product was purified by preparative TLC plate
column chromatography (2:1 hexanes/acetone) to give 10 (45.0 mg, 24%) as a
red solid: 200 °C (dec.); 1H NMR (CDCl3) d 8.80 (br s, 1H), 8.08 (d, J = 3.0 Hz,
1H), 7.44 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31–7.26 (m, 2H), 7.15 (t,
J = 7.5 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 3.18 (s, 3H); MS
(ESI, m/z): 371 ([M+H]+, 100%); HRMS (EI, m/z): calcd for C19H12N2O2Cl2 ([M]+)
370.0270, found 370.0263. Compound 10 using triphenylphosphine as ligand
(II). In an Ace-pressure tube, 1 M K2CO3 (3 mL), Pd(OAc)2 (2 mol %) and
rotatory evaporation under vacuum, and the final product,
formulated in saline, sterile-filtered through sterile vented Millex-GS
0.22 m cellulose acetate membrane, and collected into a sterile vial. Total
[
11C]4, was
a
l
radioactivity was assayed and total volume was noted for tracer dose
dispensing. The overall synthesis, purification and formulation time was 35–
40 min from EOB. Retention times in the analytical HPLC system were: tR
11 = 5.61 min, tR 3 = 7.48 min, tR 4 = 5.11 min, tR
11C]4 = 5.11 min. Retention times in the semi-preparative HPLC system were:
tR 11 = 7.23 min, tR 3 = 9.35 min, tR 4 = 6.78 min, tR
11C]3 = 9.35 min, and tR
[
11C]3 = 7.48 min, and tR
[
[
[
11C]4 = 6.78 min. The radiochemical yields were 20–30% decay corrected to
EOB, based on [11C]CO2.
21. Baskakov, Y. A.; MeI’nikov, N. N. Zh. Obshch. Khim. 1953, 23, 865.
22. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W. Tetrahedron 1988, 44, 2887.
23. Mahboobi, S.; Eichhorn, E.; Popp, A.; Sellmer, A.; Elz, S.; Möllmann, U. Eur. J.
Med. Chem. 2006, 41, 176.