Z. Shiokawa et al. / Bioorg. Med. Chem. 21 (2013) 7938–7954
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a membrane filter, and the filtrate was concentrated under reduced
pressure. The residue was diluted with satd NaHCO3 and extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by NH silica gel column chromatography (3–30%
EtOAc in n-hexane). To the residue were added 20% Pd(OH)2/C
(3.92 g) and 10% HCl in MeOH (90 mL), and the mixture was stirred
at room temperature for 2 h under hydrogen pressure (3atom). The
mixture was filtered through a membrane filter, and the filtrate
was concentrated under reduced pressure. The residue and di-
tert-butyl dicarbonate (6.09 g, 27.9 mmol) were mixed in satd
NaHCO3/THF (1:1, 180 mL), and the reaction mixture was stirred
at room temperature for 1 h. Additional di-tert-butyl dicarbonate
(0.61 g, 2.79 mmol) was added to the mixture, and the reaction
mixture was stirred at room temperature for 30 min. The mixture
was partitioned between EtOAc and water, and the organic layer
was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (10–40% EtOAc in n-hexane) to give 24B (4.37 g,
72%) as colorless oil; 1H NMR (300 MHz, DMSO-d6): d 1.22–1.43
(9H, m), 2.76 (1H, dd, J = 16.4, 5.1 Hz), 3.08–3.30 (2H, m), 3.49–
3.77 (6H, m), 3.99–4.07 (1H, m), 4.41 (1H, t, J = 5.9 Hz), 6.55–6.75
(2H, m), 6.91–7.13 (2H, m); MS (ESI): m/z 333.3 (M+H)+.
3.84 (6H, m), 4.07–4.22 (1H, m), 4.47 (1H, t, J = 6.0 Hz), 6.75 (1H,
d, J = 8.1 Hz), 7.32–7.43 (1H, m), 7.47 (1H, dd, J = 8.1, 1.5 Hz); MS
(ESI): m/z 358.2 (M+H)+.
4.13. 2-tert-Butyl 3-methyl (3S,10aS)-6-chloro-3,4,10,10a-
tetrahydropyrazino[1,2-a]indole-2,3(1H)-dicarboxylate (27,28)
N-Chlorosuccinimide (771 mg, 5.78 mmol) was added to a solu-
tion of 24B (1.92 g, 5.78 mmol) in DMF (40 mL) at 0 °C, and the
reaction mixture was stirred at 50 °C for 16 h. The mixture was di-
luted with satd NaHCO3 and extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (1–15% EtOAc in n-hexane) to give 27
(800 mg, 33%) as pale yellow oil and 28 (500 mg, 28%) as pale yel-
low oil.
Compound 27; 1H NMR (300 MHz, DMSO-d6): d 1.22–1.44 (9H,
m), 2.77 (1H, dd, J = 16.9, 4.6 Hz), 3.08–3.29 (2H, m), 3.47–3.76 (6H,
m), 3.96–4.15 (1H, m), 4.34–4.50 (1H, m), 6.56–6.76 (1H, m), 6.97–
7.14 (2H, m); MS (ESI): m/z 367.2 (M+H)+.
Compound 28; 1H NMR (300 MHz, DMSO-d6): d 1.21–1.57 (9H,
m), 2.77–2.97 (1H, m), 3.07–3.26 (1H, m), 3.38–3.54 (1H, m), 3.62–
3.80 (4H, m), 3.82–4.07 (2H, m), 4.17 (1H, br s), 4.36 (1H, t,
J = 5.7 Hz), 6.59–6.84 (1H, m), 6.95–7.23 (2H, m); MS (ESI): m/z
367.1 (M+H)+.
4.11. 2-tert-Butyl 3-methyl (3S,10aS)-8-bromo-3,4,10,10a-
tetrahydropyrazino[1,2-a]indole-2,3(1H)-dicarboxylate (25)
4.14. 2-tert-Butyl 3-methyl (3S,10aS)-6,8-dichloro-3,4,10,10a-
tetrahydropyrazino[1,2-a]indole-2,3(1H)-dicarboxylate (29)
A solution of N-bromosuccinimide (562 mg, 3.16 mmol) in DMF
(5.0 ml) was added to a solution of 24B (1.05 g, 3.16 mmol) in DMF
(10 mL) at 0 °C, and the reaction mixture was stirred at room tem-
perature for 65 h. The mixture was diluted with satd NaHCO3 and
extracted with EtOAc. The organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (5–
50% EtOAc in n-hexane) to give 25 (1.22 g, 94%) as colorless oil;
1H NMR (300 MHz, DMSO-d6): d 1.21–1.44 (9H, m), 2.65–2.86
(1H, m), 3.09–3.30 (2H, m), 3.49–3.74 (5H, m), 3.98–4.12 (2H,
m), 4.42 (1H, t, J = 5.9 Hz), 6.62 (1H, d, J = 8.1 Hz), 7.10–7.25 (2H,
m); MS (ESI): m/z 411.1 (M+H)+.
N-Chlorosuccinimide (178 mg, 1.33 mmol) was added to a solu-
tion of 28 (489 mg, 1.33 mmol) in DMF (20 mL), and the reaction
mixture was stirred at 50 °C for 2 h. The mixture was diluted with
satd NaHCO3 and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography (3–30% EtOAc in n-hexane) to give 29 (484 mg, 60%)
as pale yellow oil; 1H NMR (300 MHz, DMSO-d6): d 1.33 (9H, br
s), 2.78–2.95 (1H, m), 3.10–3.26 (1H, m), 3.39–3.54 (1H, m),
3.63–3.80 (4H, m), 3.85–3.98 (2H, m), 4.19 (1H, br s), 4.38 (1H, t,
J = 5.7 Hz), 7.16 (2H, dd, J = 13.7, 1.8 Hz); MS (ESI): m/z 401.1
(M+H)+.
4.12. 2-tert-Butyl 3-methyl (3S,10aS)-8-cyano-3,4,10,10a-
tetrahydropyrazino[1,2-a]indole-2,3(1H)-dicarboxylate (26)
4.15. tert-Butyl (3S,10aR)-3-[(4R)-3,4-dihydro-2H-chromene-4-
ylcarbamoyl]-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-
2(1H)-carboxylate (30)
A mixture of 25 (1.20 g, 2.92 mmol), cupper cyanide(I) (784 mg,
8.75 mmol) and cupper iodide (1.67 g, 8.75 mmol) in DMF (10 mL)
was stirred at 180 °C for 1 h under microwave irradiation. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. To the residue were added satd NaHCO3
(10 mL) and di-tert-butyl dicarbonate (955 mg, 4.38 mmol) in
THF (10 mL) successively, and the mixture was stirred at room
temperature for 4 h. Additional di-tert-butyl dicarbonate
(480 mg, 2.20 mmol) was added to the mixture, and the reaction
mixture was stirred at room temperature for 2 h. Additional
di-tert-butyl dicarbonate (480 mg, 2.20 mmol) was added to the
mixture, and the reaction mixture was stirred at room temperature
for 2 h. Further additional di-tert-butyl dicarbonate (480 mg,
2.20 mmol) was added to the mixture, and the reaction mixture
was stirred at room temperature for additional 17 h. The mixture
was diluted with EtOAc and water, filtered through CeliteÒ and
partitioned between EtOAc and water. The organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (5–50% EtOAc in n-hexane) to give 26 (305 mg,
29%) as pale yellow oil; 1H NMR (300 MHz, DMSO-d6): d 1.33
(9H, s), 2.80 (1H, dd, J = 17.0, 5.1 Hz), 3.12–3.30 (2H, m), 3.54–
A mixture of 24A (256 mg, 0.77 mmol) and lithium hydroxide
monohydrate (97 mg, 2.31 mmol) in THF/water (5:1, 6.0 mL) was
stirred at 50 °C for 20 h. The mixture was neutralized with 1 M
HCl, concentrated under reduced pressure, and the concentrate
was coevaporated with toluene in vacuo. To the mixture of the res-
idue,
(4R)-3,4-dihydro-2H-chromene-4-amine
hydrochloride
(172 mg, 0.92 mmol) and HOBt (156 mg, 1.16 mmol) in DMF
(3.0 mL) were successively added DIPEA (0.402 mL, 2.31 mmol)
and EDC (179 mg, 1.16 mmol) at 0 °C. The mixture was stirred at
room temperature for 17 h, and then partitioned between EtOAc
and water. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (5–30% EtOAc
in n-hexane) to give 30 (280 mg, 72%) as white solid; 1H NMR
(300 MHz, DMSO-d6): d 1.33–1.50 (9H, m), 1.73–2.08 (2H, m),
2.52–2.58 (1H, m), 2.90–3.31 (4H, m), 3.78–4.36 (4H, m), 4.40–
4.68 (1H, m), 4.86–5.11 (1H, m), 6.35–6.51 (1H, m), 6.60 (1H, t,
J = 7.4 Hz), 6.70–6.86 (2H, m), 6.89–7.24 (4H, m), 8.22–8.68 (1H,
m); MS (ESI): m/z 450.3 (M+H)+.