Enantioselective Synthesis of (S)-Dapoxetine
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1.82 (m, 2 H, 2-H) ppm. MS (ESI+): m/z (%) = 152 (100)
[M + H]+, 174 (5) [M + Na]+, 285 (45) [2 M – H2O + H]+.
Synthesis of (S)-3-(Dimethylamino)-3-phenylpropan-1-ol (12): A
30% aqueous solution of formaldehyde (1.5 mL, 16 mmol) was
added to a solution of (S)-11 (755 mg, 3 mmol) in formic acid
(0.6 ml), and the mixture was heated at reflux for 8 h. After this
time, the solution was basified with 3 m NaOH solution until pH
= 12. The mixture was extracted with EtOAc (3ϫ15 mL), and the
organic phases were combined, dried with Na2SO4 and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (65% MeOH/EtOAc) to afford a hygroscopic
solid (0.47 g, 84% isolated yield). Rf = 0.21 (60% MeOH/EtOAc).
[α]2D0 = +36.5 (c = 0.5, CHCl3) for 99% ee. 1H NMR (CDCl3,
300 MHz): δ = 7.38–7.15 (m, 5 H, Ar), 3.86–3.75 (m, 2 H, 1-H),
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3.75 (dd, JHH = 10.50, JHH = 3.75 Hz, 1 H, 3-H), 2.50–2.38 (m,
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Synthesis of (S)-Dapoxetine (13): 1-Naphthol (0.6 mL, 5 mmol) was
added to a solution of (S)-12 (0.9 g, 5 mmol) in dry THF (5.0 mL)
under nitrogen. The mixture was cooled to 0 °C, and PPh3 (1.43 g,
5.5 mmol) and DEAD (0.87 mL, 5.5 mmol) were successively
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10% MeOH/EtOAc) to yield colourless (S)-13 (1.07 g, 73% isolated
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(m, 1 H, Ar), 7.80–7.77 (m, 1 H, Ar), 7.59–7.50 (m, 2 H, Ar), 7.46–
7.30 (m, 7 H, Ar), 6.72–6.71 (m, 1 H, Ar), 4.17–4.02 (m, 1 H, 1-
H), 3.98–3.92 (m, 1 H, 1-H), 3.70–3.65 (m, 1 H, 3-H), 2.75–2.63
(m, 1 H, 2-H), 2.39–2.310 (m, 1 H, 2-H), 2.33 (s, 6 H, CH3) ppm.
MS (ESI+): m/z (%) = 306 (100) [M + H]+, 261 (35) [M –
NMe2]+.
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Supporting Information (see footnote on the first page of this arti-
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NMR data for key intermediates.
Acknowledgments
This work was supported by the Open Funding Project of the State
Key Laboratory of Bioreactor Engineering, the Fundamental Re-
search Funds for the Central Universities, and the Specialized Re-
search Fund for the Doctoral Program (New Teachers) of Higher
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Published Online: December 7, 2012
Eur. J. Org. Chem. 2013, 557–565
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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