Syntheses of a Flobufen Metabolite and Dapoxetine
combined organic layers were washed with brine, dried with anhy-
drous MgSO4, filtered, and concentrated under reduced pressure.
Column chromatography of the residue on silica gel (hexane/
CDCl3): δ = 176.76, 162.42 (dd, J = 248.1, 11.8 Hz), 159.74 (dd, J
= 249.2, 11.7 Hz), 138.88, 135.18, 131.35 (dd, J = 9.3, 4.7 Hz),
129.29, 129.28, 125.47, 124.60 (dd, J = 13.5, 3.8 Hz), 111.67 (dd, J
EtOAc, 5:1) furnished compound 8 (0.82 g, 85%) as a colorless oil; = 21.0, 3.8 Hz), 104.45 (app t, J = 25.8 Hz), 80.88, 30.93,
[α]2D0 = –41.4 (c = 0.87, CHCl3). H NMR (600 MHz, CDCl3): δ =
7.45–7.39 (m, 3 H), 7.37–7.35 (m, 2 H), 6.96–6.93 (m, 1 H), 6.92–
6.88 (m, 1 H), 4.79 (dd, J = 6.6, 5.4 Hz, 1 H), 3.66–3.60 (m, 2 H),
1.85–1.55 (m, 5 H), 0.91 (s, 9 H), 0.06 (s, 3 H), –0.09 (s, 3 H) ppm.
28.90 ppm. 19F NMR (300 MHz, CDCl3): δ = –110.87 to –110.97
1
(m, 1 F), –113.50 to –113.59 (m, 1 F) ppm. IR (KBr): νmax = 3034,
˜
2998, 2980, 2953, 2890, 1769, 1622, 1589, 1503, 1407, 1138, 848,
806 cm–1. HRMS: calcd. for C16H12F2O2Na [M + Na] 297.07031;
13C NMR (150 MHz, CDCl3): δ = 162.13 (dd, J = 247.1, 11.9 Hz), found 297.06977. Rf = 0.23 (hexane/EtOAc, 3:1; silica gel plate).
159.73 (dd, J = 248.9, 11.7 Hz), 144.71, 133.48, 133.37 (dd, J = 9.3,
(3R,5S)-5-[2Ј,4Ј-Difluoro(1,1Ј-biphenyl)-4-yl]-3-methyldihydrofuran-
5.0 Hz), 128.56, 128.54, 125.97, 125.13 (dd, J = 13.4, 3.8 Hz),
2(3H)-one (1): Lactone 10 (64 mg, 0.23 mmol) was dissolved in
111.47 (dd, J = 20.9, 3.5 Hz), 104.31 (app t, J = 26.0 Hz), 74.43,
THF (6 mL), and the resulting solution was cooled to –78 °C. A
62.98, 37.11, 28.48, 25.85, 18.23, –4.62, –4.98 ppm. 19F NMR
solution of lithium diisopropylamide (0.14 mL, 0.28 mmol) was
added dropwise, and the mixture was stirred for 1.5 h. After this
(300 MHz, CDCl3): δ = –111.79 to –111.89 (m, 1 F), –113.43 to
–113.53 (m, 1 F) ppm. IR (KBr): ν
= 3330, 3025, 2953, 2929,
˜
max
period of time, methyl iodide (20 μL, 0.32 mmol) was added, and
the reaction was stirred for 13 h as it warmed to ambient tempera-
ture. A saturated solution of ammonium chloride (8 mL) was
poured into the reaction mixture, and the resulting mixture was
then extracted with EtOAc (3ϫ 5 mL). The combined organic frac-
tions were dried with anhydrous MgSO4, filtered, and evaporated
under reduced pressure. Column chromatography of the residue on
silica gel (hexane/EtOAc, 3:1) furnished compound 1 (40 mg, 60%)
as a colorless solid. [α]D = –5.0 (c = 1.4, CHCl3); [α]2D0 = +7.3 (c =
1.1, CH3OH). 1H NMR (600 MHz, CDCl3): δ = 7.53–7.51 (m, 2
H), 7.41–7.37 (m, 3 H), 6.98–6.94 (m, 1 H), 6.93–6.90 (m, 1 H),
5.62 (dd, J = 7.8, 4.2 Hz, 1 H), 2.80–2.73 (m, 1 H), 2.51–2.47 (m,
1 H), 2.42–2.37 (m, 1 H), 1.35 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 176.76, 162.41 (dd, J = 248.0, 11.9 Hz),
159.73 (dd, J = 249.0, 11.9 Hz), 139.30, 134.92, 131.33 (dd, J = 9.3,
4.8 Hz), 129.26, 129.24, 125.17, 124.58, (dd, J = 13.2, 3.6 Hz),
111.67 (dd, J = 20.9, 3.5 Hz), 104.44 (app t, J = 25.8 Hz), 78.03,
38.34, 33.56, 15.40 ppm. 19F NMR (300 MHz, CDCl3): δ = –110.98
to –111.00 (m, 1 F), –113.52 to –113.614 (m, 1 F) ppm. IR (KBr):
2887, 2857, 1616, 1589, 1497, 1407, 1260, 1138, 1099, 1057, 967,
836, 773 cm–1. HRMS: calcd. for C22H30F2O2SiNa [M + Na]
415.18808; found 415.18739. Rf = 0.27 (hexane/EtOAc, 5:1; silica
gel plate).
(S)-4-[2Ј,4Ј-Difluoro(1,1Ј-biphenyl)-4-yl]-4-(tert-butyldimethylsilyl-
oxy)butanoic Acid (9): Sodium periodate (60 mg, 0.28 mmol) was
added to a mixture of acetonitrile (1.5 mL), tetrachloromethane,
(0.5 mL) and water (1.3 mL). Ruthenium chloride (3 mg,
0.014 mmol) was added, and the mixture was stirred for 0.5 h.
Then, the mixture was added to the solution of alcohol 10 (56 mg,
0.14 mmol) in acetonitrile (3 mL). Another portion of the sodium
periodate (30 mg, 0.14 mmol) was added, and the reaction mixture
was stirred for 0.5 h. After this period of time, the reaction mixture
was filtered through a pad of Celite, and the volatiles were removed
under reduced pressure. Column chromatography of the residue on
silica gel (hexane/EtOAc, 3:2) gave compound 9 (46 mg, 81%) as a
colorless oil; [α]2D0 = –36.2 (c = 0.47, CHCl3). 1H NMR (600 MHz,
CDCl3): δ = 7.47–7.44 (m, 2 H), 7.41 (ddd, J = 8.4, 8.4, 6.6 Hz, 1
H), 7.38–7.36 (m, 2 H), 6.96–6.93 (m, 2 H), 6.92–6.88 (m, 1 H),
4.83 (dd, J = 6.6, 4.8 Hz, 1 H), 2.50–2.45 (m, 1 H), 2.40–2.35 (m,
1 H), 2.08–1.99 (m, 2 H), 0.91 (s, 9 H), 0.06 (s, 3 H), –0.10 (s, 3
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 179.82, 162.18 (dd, J
= 247.4, 11.7 Hz), 159.74 (dd, J = 248.0, 11.7 Hz), 144.02, 133.77,
133.37 (dd, J = 9.3, 5.0 Hz), 128.67, 128.66, 125.94, 125.07 (dd, J
= 13.5, 3.6 Hz), 111.49 (dd, J = 20.9, 3.5 Hz), 104.34 (app t, J =
26.0 Hz), 73.25, 35.17, 29.69, 25.01, 18.17, –4.68, –5.08 ppm. 19F
NMR (300 MHz, CDCl3): δ = –111.65 to –111.76 (m, 1 F), –113.41
ν
max = 3075, 3034, 2968, 2941, 2881, 2851, 1772, 1622, 1595, 1494,
˜
1410, 1278, 1210, 1177, 1147, 1096, 1006, 961, 848, 809 cm–1.
HRMS: calcd. for C17H15F2O2 [M H] 289.10346; found
+
289.10347. Rf = 0.45 (hexane/EtOAc, 3:1; silica gel plate). Spectral
characteristics were in agreement with previously published data.[2a]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of unreported com-
pounds, experimental procedures that were used for the synthesis
of dapoxetine, and other experimental details.
to –113.51 (m, 1 F) ppm. IR (KBr): νmax = 3072, 3031, 2959, 2926,
˜
2884, 2860, 2666, 1706, 1619, 1595, 1494, 1407, 1263, 1147, 1102,
967, 857, 836, 779 cm–1. HRMS: calcd. for C22H28F2O3SiNa [M +
Na] 429.16735; found 429.16703. Rf = 0.33 (hexane/EtOAc, 3:1;
silica gel plate).
Acknowledgments
This work was in part supported by grants from the Czech Ministry
of Education, Youth, and Sports (grant number MSM0021620857)
and the Czech Science Foundation (grant number P207/11/0587).
The authors would like to thank David Frejka and Carlos E. A.
Camões for their cooperation during the project.
(S)-5-[2Ј,4Ј-Difluoro(1,1Ј-biphenyl)-4-yl]dihydrofuran-2(3H)-one
(10): The starting compound 9 (288 mg, 0.71 mmol) was dissolved
in CH2Cl2 (25 mL). DMF (30 μL) was added, and the solution was
cooled to 0 °C. Oxalyl chloride (70 μL, 0.8 mmol) was added drop-
wise, and the mixture was stirred for 1 h. Then, aluminum chloride
(107 mg, 0.8 mmol) was added, and the reaction mixture was
stirred for 12 h as it warmed to room temperature. The mixture
was poured on crushed ice, and the resulting mixture was extracted
with CH2Cl2 (3ϫ 15 mL). The combined organic layers were dried
with anhydrous MgSO4, filtered, and the solvents were removed
under vacuum. Column chromatography of the residue on silica
gel (hexane/EtOAc, 3:2) provided compound 10 (128 mg, 66%) as
a colorless solid; [α]2D0 = –13.3 (c = 0.6, CHCl3). 1H NMR
(600 MHz, CDCl3): δ = 7.54–7.52 (m, 2 H), 7.42–7.38 (m, 3 H),
6.98–6.95 (m, 1 H), 6.94–6.90 (m, 1 H), 5.58–5.55 (m, 1 H), 2.74–
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Eur. J. Org. Chem. 2014, 2543–2548
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