Journal of Medicinal Chemistry
Article
silica gel column chromatography afforded N-{3-[2-(acetylamino)-
ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}propanamide (94.5 mg,
88%). A mixture of N-{3-[2-(acetylamino)ethyl]-4-hydroxy-2,3-
dihydro-1H-inden-5-yl}propanamide (88.5 mg, 0.305 mmol) and
pyridinium p-toluenesulfonate (15.3 mg, 0.061 mmol) in xylene (3.1
mL) was stirred at reflux for 2.5 h. The solvent was concentrated in
vacuo, and the residue was purified by silica gel column
chromatography to afford the title compound 3c (69.8 mg, 84%) as
solid. Total of 74% from 17. Mp 76−78 °C (recrystallized from ethyl
acetate/hexane). MS (ESI): m/z 273 (M + H)+. 1H NMR (CDCl3) δ
1.46 (3H, t, J = 7.7 Hz), 1.71−1.96 (2H, m), 1.98 (3H, s), 2.20−2.34
(1H, m), 2.36−2.51 (1H, m), 2.96 (2H, q, J = 7.7 Hz), 2.98−3.15
(2H, m), 3.28−3.41 (1H, m), 3.42−3.57 (2H, m), 5.54 (1 H, brs),
7.15 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz). Anal. Calcd for
C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.25; H, 7.35;
N, 10.33.
hydrogen atmosphere. The catalyst was removed by filtration, and the
filtrate was concentrated in vacuo. Purification by silica gel column
chromatography and recrystallization (ethyl acetate/hexane) afforded
3i (19.0 mg, 53%) as solid. Mp 132−134 °C (recrystallized from ethyl
acetate/hexane). MS (ESI): m/z 275 (M + H)+. 1H NMR (CDCl3) δ
1.80−1.97 (2H, m), 1.99 (3H, s), 2.08−2.25 (1H, m), 2.36−2.51
(1H, m), 2.91−3.16 (2H, m), 3.33−3.61 (4H, m), 4.90 (2H, d, J =
5.5 Hz), 5.57 (1H, brs), 7.19 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0
Hz). Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.54; H, 6.63; N, 10.11.
N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-
yl)ethyl]propionamide (3j). A mixture of 11b (21.0 mg, 0.0999
mmol) and Raney cobalt (200 mg, washed with water and ethanol
before use) in 0.6 M ammonia ethanol solution (1 mL) was stirred at
room temperature for 3 h under hydrogen atmosphere. The catalyst
was removed by filtration, and the filtrate was concentrated in vacuo.
The residue was dissolved in tetrahydrofuran (1 mL), and
triethylamine (18.1 μL, 0.13 mmol) and propionic anhydride (15.4
μL, 0.12 mmol) were added at 0 °C. After 15 min, saturated aqueous
sodium hydrogencarbonate was added, and the mixture was extracted
with ethyl acetate, washed with brine, and concentrated in vacuo. The
residue was purified by silica gel column chromatography. A mixture
of the obtained compound and 10% palladium on carbon (4.0 mg,
containing 50% water) in methanol (1 mL) was stirred at room
temperature for 20 h under hydrogen atmosphere. The catalyst was
removed by filtration, and the filtrate was concentrated in vacuo.
Purification by silica gel column chromatography afforded 3j (17.5
mg, 64%) as solid. Mp 111−113 °C (recrystallized from ethyl acetate/
N-[2-(2-Cyclopropyl-7,8-dihydro-6H-indeno[5,4-d][1,3]-
oxazol-8-yl)ethyl]acetamide (3d). By a similar procedure to that
used for 3c, 3d (70%) was prepared from 17 and cyclopropylcarbonyl
chloride as solid. Mp 92−95 °C (recrystallized from ethyl acetate/
1
hexane). MS (ESI): m/z 285 (M + H)+. H NMR (CDCl3) δ 1.10−
1.20 (2H, m), 1.21−1.29 (2H, m), 1.69−1.93 (2H, m), 1.98 (3H, s),
2.11−2.30 (2H, m), 2.31−2.49 (1H, m), 2.84−3.16 (2H, m), 3.25−
3.57 (3H, m), 5.73 (1H, brs), 7.11 (1H, d, J = 8.0 Hz), 7.38 (1H, d, J
= 8.0 Hz). Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85.
Found: C, 71.69; H, 7.11; N, 9.79.
N-[2-(2-Phenyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-
yl)ethyl]acetamide (3e). By a similar procedure to that used for 3c,
3e (73%) was prepared from 17 and benzoyl chloride as solid. Mp
124−126 °C (recrystallized from ethyl acetate/diisopropyl ether). MS
(ESI): m/z 321 (M + H)+. 1H NMR (CDCl3) δ 1.76−1.97 (2H, m),
1.99 (3H, s), 2.31−2.57 (2H, m), 2.92−3.18 (2H, m), 3.37−3.66
(3H, m), 5.59 (1H, brs), 7.21 (1H, d, J = 8.0 Hz), 7.50−7.60 (4H,
m), 8.20−8.27 (2H, m). Anal. Calcd for C20H20N2O2: C, 74.98; H,
6.29; N, 8.74. Found: C, 74.86; H, 6.26; N, 8.83.
N-[2-(2-Benzyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-
yl)ethyl]acetamide (3f). By a similar procedure to that used for 3c,
3f (7%) was prepared from 17 and phenylacetyl chloride as solid. MS
(ESI): m/z 335 (M + H)+. 1H NMR (CDCl3) δ 1.73−1.91 (2H, m),
1.93 (3H, s), 2.07−2.21 (1H, m), 2.35−2.49 (1H, m), 2.87−3.14
(2H, m), 3.14−3.30 (1H, m), 3.37−3.52 (2H, m), 4.27 (2H, s), 5.45
(1H, brs), 7.15 (1H, d, J = 8.0 Hz), 7.26−7.40 (5H, m), 7.47 (1H, d, J
= 8.0 Hz).
1
hexane). MS (ESI): m/z 273 (M + H)+. H NMR (CDCl3) δ 1.16
(3H, t, J = 7.6 Hz), 1.70−1.98 (2H, m), 2.15−2.51 (4H, m), 2.63
(3H, s), 2.88−3.15 (2H, m), 3.28−3.56 (3H, m), 5.54 (1H, brs), 7.14
(1H, d, J = 7.7 Hz), 7.44 (1H, d, J = 7.7 Hz). Anal. Calcd for
C16H20N2O2: C, 70.56; H, 7.39; N, 10.28. Found: C, 70.14; H, 7.28;
N, 10.23.
N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-
yl)ethyl]acetamide (4a). To a stirred solution of 23 (1.66 g, 7.14
mmol) in tetrahydrofuran (70 mL) were added triethylamine (2.00
mL, 14.3 mmol) and acetic anhydride (810 μL, 8.57 mmol) at 0 °C.
After 1 h, the reaction mixture was concentrated in vacuo, and the
residue was purified by silica gel column chromatography to afford 4a
(1.83 g, 93%) as solid. Mp 115−116 °C (recrystallized from ethyl
acetate). MS (ESI): m/z 275 (M + H)+. 1H NMR (CDCl3) δ 1.60−
1.80 (1H, m), 1.84−2.06 (4H, m), 2.14−2.30 (1H, m), 2.34−2.51
(1H, m), 2.82 (3H, s), 2.88−3.18 (2H, m), 3.24−3.51 (3H, m), 5.62
(1H, brs), 7.30 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz). Anal.
Calcd for C15H18N2OS: C, 65.66; H, 6.61; N, 10.21. Found: C, 65.59;
H, 6.62; N, 10.17.
N-[2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-
yl)ethyl]propionamide (4b). To a stirred solution of 23 (100 mg,
0.430 mmol) in tetrahydrofuran (4 mL) were added triethylamine
(120 μL, 0.861 mmol) and propionic anhydride (66.2 μL, 0.516
mmol) at 0 °C. After 1 h, the reaction mixture was concentrated in
vacuo, and the residue was purified by silica gel column
chromatography to afford 4b (110 mg, 89%) as solid. Mp 122−123
°C (recrystallized from ethyl acetate). MS (ESI): m/z 289 (M + H)+.
1H NMR (CDCl3) δ 1.13 (3H, d, J = 7.6 Hz), 1.67−1.81 (1H, m),
1.88−2.06 (1H, m), 2.09−2.29 (3H, m), 2.33−2.52 (1H, m), 2.82
(3H, s), 2.90−3.19 (2H, m), 3.26−3.51 (3H, m), 5.42 (1H, brs), 7.30
(1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.2 Hz). Anal. Calcd for
C16H20N2OS: C, 66.63; H, 6.99; N, 9.71. Found: C, 66.62; H, 7.02;
N, 9.66.
N-[2-(2-Methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-
a]pyridin-9-yl)ethyl]acetamide (5a). A mixture of 28 (140 mg,
0.487 mmol) and 12 M hydrochloric acid (5 mL) was stirred at 100
°C for 2 days, and the reaction mixture was concentrated in vacuo.
The residue was dissolved in tetrahydrofuran (5 mL), and
triethylamine (1.36 mL, 9.76 mmol) and acetic anhydride (115 μL,
1.22 mmol) were added at 0 °C. After 15 min, the reaction solution
was diluted with saturated aqueous sodium hydrogen carbonate and
extracted with ethyl acetate. The extract was dried over anhydrous
N-[2-(2-Methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-
8-yl)ethyl]acetamide (3g). A mixture of 17 (100 mg, 0.369 mmol)
and tetramethoxymethane (151 mg, 1.11 mmol) in tetrahydrofuran
(3.7 mL) was stirred at reflux for 2 h. The reaction mixture was
diluted with ethyl acetate and saturated aqueous sodium hydro-
gencarbonate. The mixture was washed with brine, dried over
anhydrous sodium sulfate, and concentrated in vacuo. Purification by
silica gel column chromatography afforded 3g (58.4 mg, 58%) as a
solid. Mp 126−128 °C (recrystallized from ethyl acetate). MS (ESI):
+
1
m/z 275 (M + H) . H NMR (CDCl3) δ: 1.72−1.94 (2H, m), 1.98
(3H, s), 2.13−2.29 (1H, m), 2.31−2.48 (1H, m), 2.85−3.12 (2H, m),
3.23−3.37 (1H, m), 3.37−3.55 (2H, m), 4.21 (3H, s), 5.57 (1H, brs),
7.09 (1H, d, J = 8.0 Hz), 7.29 (1H, d, J = 8.0 Hz). Anal. Calcd for
C15H18N2O3: C, 65.68; H, 6.61; N, 10.21. Found: C, 65.56; H, 6.48;
N, 10.22.
N-(2-{2-[(Benzyloxy)methyl]-7,8-dihydro-6H-indeno[5,4-d]-
[1,3]oxazol-8-yl}ethyl)acetamide (3h). By a similar procedure to
that used for 3c, 3h (18%) was prepared from 17 and (benzyloxy)-
1
acetyl chloride as solid. MS (ESI): m/z 365 (M + H)+. H NMR
(CDCl3) δ 1.75−1.94 (2H, m), 1.95 (3H, s), 2.20−2.34 (1H, m),
2.37−2.51 (1H, m), 2.93−3.15 (2H, m), 3.24−3.38 (1H, m), 3.41−
3.58 (2H, m), 4.70 (2H, s), 4.78 (2H, s), 5.62 (1H, brs), 7.21 (1H, d,
J = 8.0 Hz), 7.28−7.42 (5H, m), 7.54 (1H, d, J = 8.0 Hz).
N-{2-[2-(Hydroxymethyl)-7,8-dihydro-6H-indeno[5,4-d]-
[1,3]oxazol-8-yl]ethyl}acetamide (3i). A mixture of 3h (50.0 mg,
0.131 mmol) and 10% palladium on carbon (100 mg, containing 50%
water) in methanol (1 mL) was stirred at 50 °C for 24 h under
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J. Med. Chem. 2021, 64, 3059−3074