BULLETIN OF THE
Article
Octahydroindene-2-spirooxazolidinone as a PAR1 Antagonist
KOREAN CHEMICAL SOCIETY
stirring at 0 ꢁC. The mixture was stirred for 4 h at refluxing
condition, diluted with H2O and 2 N NaOH (10 mL), and
additionally stirred for 30 min. After separation of layers,
the aqueous layer was extracted with ethyl acetate
(3 × 10 mL). Organic extracts were dried over MgSO4, and
filtered. After removal of all volatiles under reduced pres-
sure, the residue was purified using silica gel column chro-
matography (hexane:ethyl acetate = 1:1) to give
imidazolidinone 13 (colorless liquid, 80 mg, 81% yield).
1H NMR (300 MHz, CDCl3) δ 1.23–1.51 (m, 5H),
1.55–1.84 (m, 3H), 2.11–2.34 (m, 3H), 3.32 (d, J = 8.4 Hz,
1H), 3.36 (d, J = 8.4 Hz, 1H), 3.62 (m, 2H), 4.45 (m, 2H),
5.22 (s, 1H), 5.38 (s, 1H), 7.26–7.37 (m, 5H);
MS 350 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-difluoro-1-{(E)-2-[5-(3-fluorophe-
nyl)pyridine-2-yl]vinyl}octahydrospiro(indene-2,50-
oxazolidin)-20-one (19). Yield over two steps 34%. off
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white solid. H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H),
1.57–1.80 (m, 4H), 1.89 (m, 1H), 2.03 (dd, J = 14.0,
10.0 Hz, 1H), 2.11–2.23 (m, 2H), 2.33 (m, 2H), 3.58 (s,
2H), 4.99 (br s, 1H), 6.65 (m, 2H), 7.09 (t, J = 8.7 Hz,
1H), 7.25–7.49 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz, 1H),
8.75 (d, J = 2.4 Hz, 1H); MS 428 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-{(E)-2-[5-(3-fluorophe-
nyl)pyridine-2-yl]vinyl}decahydro-5’H-spiro(indene-2,50-
furan)-20-one (20). Yield over two steps 52%. Pale yellow
solid. 1H NMR (300 MHz, CDCl3) δ 1.29 (m, 1H),
1.54–1.79 (m, 4H), 1.81–1.95 (m, 3H), 2.13–2.36 (m, 6H),
2.45–2.53 (m, 2H), 6.63 (m, 2H), 7.09 (tdd, J = 8.1, 2.4,
0.9 Hz, 1H), 7.24–7.48 (m, 4H), 7.81 (dd, J = 8.1, 2.4 Hz,
1H), 8.74 (dd, J = 2.4, 0.6 Hz, 1H); MS 427 (M+).
General
Procedure
for
the
Preparation
of
(ꢀ)-1-(Hydroxymethyl)-5,5-difluorooctahydroindene
(14–18). 1-Methyl alcohols 14–18 were prepared starting
from 1-(benzyloxy)methyl compounds 7–13 independently,
according to the published methods.20
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-{(E)-2-[5-(3-fluorophe-
nyl)pyridine-2-yl]vinyl}octahydrospiro
(indene-2,50-
(ꢀ)-(1R,3aR,7aR)-1-(Hydroxymethyl)-5,5-difluorooctahy
imidazolidin)-20,40-dione (21). Yield over two steps 47%.
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drospiro(indene-2,50-oxazolidin)-20-one (14). Yield 72%.
Off white solid. H NMR (300 MHz, CDCl3) δ 1.20–1.63
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Off white oil. H NMR (300 MHz, CDCl3) δ 1.19–1.71
(m, 4H), 1.75–2.04 (m, 3H), 2.12–2.40 (m, 2H), 2.55 (dd,
J = 13.8, 6.9 Hz, 1H), 2.83 (dd, J = 10.8, 9.9 Hz, 1H), 6.25
(s, 1H), 6.50–6.72 (m, 2H), 7.09 (t, J = 8.4 Hz, 1H),
7.26–7.47 (m, 4H), 7.80 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H),
8.81 (s, 1H); MS 441 (M+).
(m, 4H), 1.72–2.07 (m, 4H), 2.17–2.38 (m, 3H), 3.37 (d,
J = 9.3 Hz, 1H), 3.73 (t, J = 5.5 Hz, 1H), 3.80–3.93 (m,
2H), 3.97 (d, J = 9.3 Hz, 1H), 5.48 (s, 1H); MS 261 (M+).
(ꢀ)-(1R,3aR,7aR)-1-(hydroxymethyl)-5,5-difluorodecah
ydro-5H-spiro(indene-2,50-furan)-20-one (15). Yield 88%.
1S,3aR,7aR)-5,5-Difluoro-1-{(E)-2-[5-(3-fluorophenyl)
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Colorless oil. H NMR (300 MHz, CDCl3) δ 1.17–1.75 (m,
pyridine-2-yl]vinyl}octahydrospiro
(indene-2,50-
7H), 1.77–2.04 (m, 2H), 2.09–2.36 (m, 4H), 2.49–2.72 (m,
2H), 3.76 (dd, J = 11.3, 6.3 Hz, 1H), 3.83 (dd, J = 11.3,
3.6 Hz, 1H); MS 260 (M+).
imidazolidin)-20-one (22). Yield over two steps 34%. Off
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white solid. H NMR (300 MHz, CDCl3) δ 1.23–1.44 (m,
3H), 1.49–1.77 (m, 3H), 2.12–2.43 (m, 4H), 3.45 (d,
J = 8.7 Hz, 1H), 3.51 (d, J = 8.7 Hz, 1H), 4.43 (s, 1H),
4.91 (s, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.68 (dd, J = 15.6,
8.7 Hz, 1H), 7.09 (td, J = 8.4, 2.4 Hz, 1H), 7.26–7.47 (m,
4H), 7.80 (dd, J = 8.1, 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz,
1H); MS 427 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-(hydroxymethyl)octah
ydrospiro(indene-2,50-imidazolidin)-20,40-dione (16). Yield
83%. Off white solid. 1H NMR (300 MHz, CDCl3) δ
1.11–1.70 (m, 4H), 1.75–1.98 (m, 4H), 2.06–2.26 (m, 2H),
2.32 (dd, J = 13.4, 7.1 Hz, 1H), 3.63 (m, 2H);
MS 274 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-(hydroxymethyl)octa
hydrospiro(indene-2,50-imidazolidin)-20-one (17). Yield
82%. Off white solid. 1H NMR (300 MHz, CDCl3) δ
1.12–1.50 (m, 5H), 1.56–1.86 (m, 2H), 1.92 (m, 1H),
2.13–2.26 (m, 3H), 3.36 (s, 2H), 3.79 (m, 2H), 5.02 (s,
1H), 5.72 (s, 1H); MS 260 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-{(E)-2-[5-(3-fluorophe-
nyl)pyridine-2-yl]vinyl}octahydrospiro(indene-2,40-
oxazolidine)-20-one (23). Yield over two steps 47%. off
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white solid. H NMR (300 MHz, CDCl3) δ 1.21–1.46 (m,
3H), 1.52–1.87 (m, 4H), 1.96–2.13 (m, 2H), 2.20–2.36 (m,
2H), 2.90 (s, 3H), 4.19 (d, J = 8.7 Hz, 1H), 4.25 (d,
J = 8.7 Hz, 1H), 6.60 (d, J = 15.9 Hz, 1H), 6.70 (dd,
J = 15.9, 7.8 Hz, 1H), 7.09 (td, J = 8.1, 1.5 Hz, 1H),
7.26–7.48 (m, 4H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 8.76 (d,
J = 1.8 Hz, 1H); MS 428 (M+).
(ꢀ)-(1S,3aR,7aR)-1-(hydroxymethyl)-5,5-difluoroocta
hydrospiro(indene-2,40-oxazolidin)-20-one (18). Yield 86%.
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Colorless oil. H NMR (300 MHz, CDCl3) δ 1.03 (m, 1H),
1.16–1.63 (m, 4H), 1.64–1.96 (m, 3H), 2.10–2.34 (m, 3H),
3.73 (dd, J = 11.2, 7.5 Hz, 1H), 3.89 (dd, J = 11.2, 7.5 Hz,
1H), 4.03 (d, J = 9.3 Hz, 1H), 4.70 (d, J = 9.3 Hz, 1H),
6.85 (br s, 1H); MS 261 (M+).
(ꢀ)-(1S,3aR,7aR)-5,5-Difluoro-1-{(E)-2-[5-(3-fluorophe-
nyl)pyridine-2-yl]vinyl}-30-methyloctahydrospiro
(indene-2,50-oxazolidine)-20-one (24). To a solution of
oxazolidinone 19 (10.0 mg, 0.0233 mmol) in THF (1 mL)
was added NaH (1.87 mg, 0.0466 mmol) with stirring at
rt. After stirring for 30 min at rt., iodomethane (2.9 μL,
0.0466 mmol) was added to the mixture. The mixture was
stirred for 3 h at rt., and diluted with H2O (1 mL). The
layers were separated, and the water layer was extracted
with ethyl acetate (3 × 10 mL). Drying (MgSO4), filtering
General
Procedure
for
the
Preparation
of
(ꢀ)-5,5-Difluoro-[(E)-2-(octahydroindene-1-yl)vinyl]-fluo
rophenyl)pyridine (19–23). Compounds 19–23 were pre-
pared stating from alcohols 14–18 through aldehyde inter-
mediates independently, according to the published
methods.19,20
Bull. Korean Chem. Soc. 2019
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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