Simple and efficient synthesis of (S)-dapoxetine

Article abstract of DOI:10.1080/00397911.2011.575522

A refinement in the synthetic strategy for (S)-dapoxetine 1 is described. The key features of synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and regioselective reductive ring opening of a 2,3-epoxy alcohol to elaborate the hydroxy-bearing stereogenic center at benzylic position; (b) regioselective functionalization of 1-naphthol and amine functionality through Mitsunobu procedures; and (c) Eschweiler-Clarke reductive methylation condition to access the target molecule.

Full text of DOI:10.1080/00397911.2011.575522

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Simple and Efficient Synthesis of (S)-
Dapoxetine
M. Sasikumar a & Milind D. Nikalje a
a Department of Chemistry, University of Pune, Ganeshkhind, Pune,
Maharashtra, India
Accepted author version posted online: 10 Jan 2012.Published
online: 21 Jun 2012.
To cite this article: M. Sasikumar & Milind D. Nikalje (2012): Simple and Efficient Synthesis of
(S)-Dapoxetine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:20, 3061-3067
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Synthetic Communications1, 42: 3061–3067, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.575522
SIMPLE AND EFFICIENT SYNTHESIS OF
(S)-DAPOXETINE
M. Sasikumar and Milind D. Nikalje
Department of Chemistry, University of Pune, Ganeshkhind, Pune,
Maharashtra, India
GRAPHICAL ABSTRACT
Abstract A refinement in the synthetic strategy for (S)-dapoxetine 1 is described. The key
features of synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and
regioselective reductive ring opening of a 2,3-epoxy alcohol to elaborate the hydroxy-
bearing stereogenic center at benzylic position; (b) regioselective functionalization of
1-naphthol and amine functionality through Mitsunobu procedures; and (c) Eschweiler–
Clarke reductive methylation condition to access the target molecule.
Keywords Intermolecular etherification; reductive methylation; Sharpless asymmetric
epoxidation
INTRODUCTION
Premature ejaculation (PE) is one of the most common male sexual
dysfunctions (MSDs). The prevalence of PE has been estimated to range from
21% to 32.5% in men aged 18–59.[1–3] Historically, the causes of PE were considered
to be purely psychological, and therefore early approaches to treatment consisted
primarily of behavioral therapy.[4] Conventional pharmacotherapy for PE involves
off-label use of selective serotonergic reuptake inhibitors (SSRIs), such as fluoxetine,
paroxetine, sertraline, and other antidepressants, which are known to cause delayed
ejaculation as a common side effect.[5–7] Dapoxetine is a serotonin transport inhibi-
tor that has been developed specifically for PE as an on-demand oral treatment.[8]
The clinical studies have shown that (S)-enantiomer of 1 is 3.5 times more
potent[9] than the (R)-1 (Fig. 1). As a result, numerous reports describing the prep-
aration of (S)-dapoxetine 1 have been reported.
Received January 29, 2011.
Address correspondence to Milind D. Nikalje, Department of Chemistry, University of Pune,
Ganeshkhind, Pune 411 007, Maharashtra, India. E-mail: mdnikalje@ymail.com
3061

3062
M. SASIKUMAR AND M. D. NIKALJE
Figure 1. Structure of (S)-dapoxetine (1).
Generally, the methods include resolution of racemic intermediates,[10] chemoen-
zymatic routes,[11] or stereospecific procedures.[12–15] However, most of these methods
have several drawbacks such as tedious and time-consuming experiments, radical deox-
ygenation of undesired hydroxyl group, expensive or not readily available chiral cata-
lyst, and poor yield coupled with poor optical purity. Synthetic efforts now need to be
directed at short, practical routes that are amenable to scale-up for drug preparation.
Herein, we report a simple and efficient synthetic strategy for (S)-dapoxetine 1.
RESULTS AND DISCUSSION
As depicted in Scheme 1, synthesis of the target molecule (S)-dapoxetine 1 was
initiated from commercially available trans-cinnamyl alcohol 2, which was subjected
to Sharpless asymmetric epoxidation[16] to give (2S,3S)-epoxy alcohol 3 in 89% yield
25
25
and >98% ee; ½aꢀD ¼ ꢁ49.3 (c 2.4, CHCl3) [lit.[16] ½aꢀD ¼ ꢁ49.6 (c 2.4, CHCl3)].
1
(Enantiomeric excess was determined by H NMR spectroscopic analysis of the
Mosher’s ester derived from (þ)-MTPA chloride.) Regioselective reductive ring
opening of (2S,3S)-epoxy alcohol 3 with Red-Al[17a] gave the expected 1,3-diol 4
in 93% yield. Then, the napthyloxy moiety was introduced regioselectively on the pri-
mary hydroxyl group of compound 4 through intermolecular etherification using
Mitsunobu condition,[18] affording hydroxy ether 5 in 71% yield.
i
ꢂ
˚
Scheme 1. Reagents and conditions: (i) (þ)-DIPT, Ti(O Pr)4, TBHP, 4-A MS, DCM, ꢁ20 C, 3 h, 89%; (ii)
Red-Al, DME, 0 to 25 ꢂC, 3 h, 93%; (iii) 1-naphthol, Ph3P, DIAD, THF, 20 h, rt, 71%; (iv) phthalimide,
Ph3P, DIAD, THF, 4 h, 82%; (v) N2H4 ꢃ H2O, EtOH, reflux, 3 h; (vi) HCHO, HCO2H, reflux, 6 h, 73%,
two steps.

ASYMMETRIC SYNTHESIS OF (S)-DAPOXETINE
3063
The (S)-secondary alcohol 5 was readily transformed into (R)-phthalimido
ether 6 by stereospecific substitution of hydroxy group with phthalimide, employing
a typical Mitsunobu procedure.[19] Finally, a facile hydrazinolysis[19] of phthalimido
ether 6 with hydrazine hydrate in ethanol afforded the crude amine, which was sub-
jected directly to a reductive methylation using the Eschweiler–Clarke condition[20]
25
to give (S)-dapoxetine 1 in 73% yield; ½aꢀD ¼ þ65.4 (c 0.31, CHCl3) [lit.[15]
28
½aꢀD ¼ þ63 (c 0.3, CHCl3)]. The structure of (S)-dapoxetine 1 was confirmed by
1H NMR, 13C NMR, and mass spectroscopic analysis.
In conclusion, we synthesized (S)-dapoxetine in six steps from commercially
available trans-cinnamyl alcohol with an overall yield of 35%. Sharpless asymmetric
epoxidation and Mitsunobu reaction have been successfully employed to get the
required amine functionality in a stereoselective manner. The present synthetic strat-
egy is the refinement in the existing synthetic route for (S)-dapoxetine.
EXPERIMENTAL
All the reagents were purchased from Aldrich Chemical and were used without
further purification. Solvents were purified and dried by standard procedures prior to
use. Melting points were recorded in a Buchi capillary melting-point (R-535) apparatus
and are uncorrected. Infrared (IR) spectra were recorded on Shimadzu Fourier trans-
form (FT)–IR 8400 instrument. 1H NMR and 13C NMR spectra were recorded on Bru-
ker AC-200 and Varian Mercury spectrometers at 300MHz using CDCl3 as a solvent.
Chemical shifts are given in parts per million (ppm) with respect to internal tetramethyl-
silane (TMS), and J values are quoted in hertz. Monitoring of reactions was carried out
using thin-layer chromatographic (TLC) plates (Merck silica gel 60 F254) and visualiza-
tion with ultraviolet light (254 and 365 nm), I2, and anisaldehyde in ethanol as develop-
ment reagents. Optical rotations were measured with a Jasco P 1020 digital polarimeter.
Mass spectra were recorded on Shimadzu GCMS-QP5050A spectrometer. Elemental
analyses were carried out with a Carlo Erba CHNS–O EA 1108 elemental analyzer.
Enantiomeric excess was determined by 1H NMR analysis of Mosher’s ester.
(2S,3S)-(3-Phenyl-oxiranyl)-methanol 3
Ti(OiPr)4 (0.59 mL, 2 mmol), and 5–6 M solution of TBHP in undecane (8 mL,
40 mmol) were added sequentially to a stirred solution of L-(þ)-diisopropyl tartrate
ꢂ
˚
(0.53 mL, 2.5 mmol) in CH2Cl2 (180 mL) at ꢁ20 C, 1 g of activated powdered 4-A
molecular sieves. The mixture was allowed to stir at ꢁ20ꢂC for 1 h and then a solution
of freshly distilled (E)-3-phenyl-2-propenol 2 (2.57 mL, 20 mmol) in 5 mL CH2Cl2 was
added dropwise over 30 min. After 3 h at ꢁ20ꢂC, the reaction was quenched at ꢁ20ꢂC
with 10% aqueous solution of NaOH saturated with NaCl (2 mL). After diethyl ether
(30 mL) was added, the cold bath was allowed to warm to 10ꢂC, stirring was main-
tained at 10ꢂC, while MgSO4 (2 g) and celite (500 mg) were added. After another
15 min of stirring, the mixture was allowed to settle, and the clean solution was filtered
through a pad of celite and washed with diethyl ether. Azeotropic removal of
TBHP with toluene at a reduced pressure and high vacuum gave 3 as yellow oil.
Recrystallization from petroleum ether–diethyl ether gave 3 as a white crystals
25
(2.68 g, 89%); mp: 52–54ꢂC [lit.[16] mp: 51.5–53ꢂC]; ½aꢀD ¼ ꢁ49.3 (c 2.4, CHCl3)

3064
M. SASIKUMAR AND M. D. NIKALJE
25
[lit.[16] ½aꢀD ¼ ꢁ49.6 (c 2.4, CHCl3)]; IR (CHCl3, cmꢁ1): 3446, 3032, 2922, 1606, 1462,
1
1400, 1199, 1074, 927, 854, 759; H NMR (300 MHz, CDCl3): dH 1.79–1.84 (dd,
J ¼ 7.95, 5.1 Hz, 1H, OH), 3.22–3.25 (m, 1H, CH), 3.76–3.85 (m, 1H, CH2O),
3.92–3.93 (d, J ¼ 2.1 Hz, 1H, benzylic CH), 4.02–4.09 (m, 1H, CH2O), 7.26–7.39 (m,
5H, Ar); 13C NMR (75 MHz, CDCl3): dC 55.5, 61.2, 62.5, 125.7, 128.3, 128.5, 136.5.
(R)-3-Phenyl-1,3-dihydroxypropane 4
To a solution of (2S,3S)-2,3-epoxycinnamyl alcohol 3 (1.5 g, 10 mmol)
in dimethoxyethane (50 mL) was added a 3.4 M solution of sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) in toluene (3.1 mL, 10.5 mmol) drop-
wise under nitrogen at 0ꢂC. After stirring at room temperature for 3 h, the solution
was diluted with ether and quenched with 15% HCl solution. After further stirring at
room temperature for 30 min, a white precipitate formed and was removed by fil-
tration, boiled with ethyl acetate, and filtered again. The combined organic extracts
were dried with magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by column chromatography [silica gel, petroleum ether–
ethyl acetate (70:30)] to afford 4 as a white crystal (1.42 g, 93%); mp: 62–64ꢂC (lit.[17b]
25
25
mp: 62–66ꢂC); ½aꢀD ¼ þ66 (c 1, CHCl3) [lit.[17b] ½aꢀD ¼ þ65 (c 1, CHCl3)]; IR (KBr,
cmꢁ1): 3392, 3313, 2955, 1595, 1489, 1444, 1209, 1082, 1037, 972, 879, 742; H
1
NMR (300 MHz, CDCl3): dH 1.91–2.07 (m, 2H, CH2), 2.34 (br s, 2H, OH),
3.86–3.89 (t, J ¼ 5.4 Hz, 2H, CH2O), 4.95–4.99 (dd, J ¼ 8.7, 3.6 Hz, 1H, benzylic
CH), 7.26–7.37 (m, 5H, Ar); 13C NMR (75 MHz, CDCl3): dC 40.3, 61.1, 73.8,
125.6, 127.4, 128.4, 144.2; MS (m=z): 152 (23) [Mþ], 134 (17), 117 (35), 107 (100).
(R)-3-(Naphthalen-1-yloxy)-1-pheny-propae-1-ol 5
A solution of DIAD (0.63 mL, 3.2 mmol) in anhydrous THF (5 mL) was added
to a mixture of (R)-3-phenyl-1,3-dihydroxypropane 4 (456 mg, 3 mmol), 1-naphthol
(576 mg, 4 mmol), and triphenylphosphine (840 mg, 3.2 mmol) in 15 mL of anhydrous
THF under N2 at room temperature. The resulting mixture was stirred until TLC indi-
cated that the diol was consumed (20 h, TLC). The solvent was evaporated and residue
was purified by flash column chromatography [silica gel 230–400 mesh, petroleum
25
ether–ethyl acetate (80:20)] to afford 5 as colorless oil (592 mg, 71%); ½aꢀD ¼ þ122 (c
1
1.3, CHCl3); IR (neat, cmꢁ1): 3375, 3053, 2935, 1590, 1388, 1253, 1078, 765; H
NMR (300 MHz, CDCl3): dH 1.66 (br s, 1H, OH), 2.15–2.26 (m, 1H, CH2),
2.35–2.47 (m, 1H, CH2), 3.83–3.91 (m, 1H, CH2O), 3.95–4.03 (m, 1H, CH2O),
5.57–5.62 (dd, J ¼ 8.8, 3.9 Hz, 1H, benzylic CH), 6.64–6.66 (d, J ¼ 7.2 Hz, 1H, Ar),
7.16–7.54 (m, 9H, Ar), 7.76–7.79 (m, 1H, Ar), 8.38–8.41 (m, 1H, Ar); 13C NMR
(75 MHz, CDCl3): dC 41.4, 59.7, 77.5, 106.9, 120.3, 121.8, 125.3, 125.6, 125.7, 126.3,
127.5, 127.6, 128.7, 134.5, 141.4, 153.2; MS (m=z): 278 (5) [Mþ], 260 (5), 144 (100).
Anal. calcd. for C18H19O2: C, 81.91; H, 6.52%. Found: C, 81.89; H, 6.54%.
(S)-2-[3-(Naphthalen-1-yloxy)-1-phenyl-propyl]-isoindole-1,3-dione 6
To a mixture of alcohol 5 (556 mg 2 mmol), phthalimide (367 mg, 2.5 mmol),
and triphenylphosphine (577 mg, 2.2 mmol) in 10 mL of anhydrous THF under N2

ASYMMETRIC SYNTHESIS OF (S)-DAPOXETINE
3065
at room temperature was added a solution of DIAD (0.46 mL, 2.2 mmol) in anhy-
drous THF (2 mL). The resulting mixture was stirred until TLC indicated that the
alcohol was consumed. The solvent was evaporated; the residue was subjected to
chromatography on silica gel (100–200 mesh) with (95:5) petroleum ether–ethyl acet-
ate to afford desired product 6 as a white crystal (0.67 g, 82%); mp: 156–158ꢂC;
25
½aꢀD ¼ þ195.6 (c 1, CHCl3); IR (CHCl3, cmꢁ1): 3036, 2937, 1768, 1707, 1591,
1
1383, 1244,1084, 949; H NMR (200 MHz, CDCl3): dH 2.20–2.40 (m, 1H, CH2),
2.50–2.69 (m, 1H, CH2), 3.86–3.97 (m, 1H, CH2O), 4.05–4.19 (m, 1H, CH2O),
5.46–5.52 (dd, J ¼ 8, 4 Hz, 1H, benzylic CH), 6.57–6.60 (d, J ¼ 6 Hz, 1H, Ar),
7.12–7.44 (m, 9 H, Ar), 7.61–7.75 (m, 5H, Ar), 8.34–8.39 (m, 1H, Ar); 13C NMR
(75 MHz, CDCl3): dC 35.3, 37.2, 78.0, 106.6, 120.1, 121.9, 122.9, 125.0, 125.6,
126.1, 127.3, 127.6, 128.6, 131.9, 133.6, 134.3, 140.8, 152.9, 168.2; MS (m=z): 407
(3) [Mþ], 266 (12), 264 (55), 160 (100), 144 (18). Anal. calcd. for C27H21NO3: C,
79.59; H, 5.19; N, 3.44%. Found: C, 79.61; H, 5.13; N, 3.41%.
(S)-Dapoxetine 1
Hydrazine hydrate (80%) solution (0.5 mL, 8 mmol) was added to a stirred sol-
ution of 6 (407 mg, 1 mmol) in ethanol (10 mL), and the resulting mixture was
refluxed for 3 h. The precipitated solid was filtered off, and the solvent was removed
under reduced pressure. The residue was dissolved in ether and extracted with 2 N
HCl, and the aqueous phase was treated with 2 N NaOH until pH > 12. The aqueous
phase was extracted with ether (3 ꢄ 20 mL), and the combined organic phases were
dried over Na2SO4 and evaporated under reduced pressure. The residue was used
in the next step.
To a solution of crude amine in 85% formic acid (227 mL, 5 mmol) was added
37% aqueous formaldehyde (220 mL, 3 mmol), and the mixture was heated at
95–100 ꢂC for 6 h. After the solution was cooled, it was acidified with 4 N HCl until
pH ¼ 1 and basified with 4 N NaOH. The aqueous phase was extracted with ether
(3 ꢄ 20 mL), and the combined organic phase was dried over Na2SO4 and evaporated
under reduced pressure. The residue was purified by flash column chromatography
25
(CH2Cl2=MeOH, 97:3) to afford (S)-1 as pale yellow oil (223 mg, 73%); ½aꢀD
¼
28
þ65.4 (c 0.31, CHCl3) [lit.[15] ½aꢀD ¼ þ63 (c 0.3, CHCl3)]; IR (Neat, cmꢁ1): 3057,
2953, 2775, 1583, 1456, 1394, 1269, 1238, 1099, 1068, 1022, 912, 850, 769; 1H
NMR (300 MHz, CDCl3): dH 2.25 [s, 6H, N (CH3)2], 2.26–2.29 (m, 1H, CH2),
2.58–2.69 (m, 1H, CH2), 3.58–3.63 (dd, J ¼ 9.3, 5.1 Hz, 1H, benzylic CH),
3.84–3.92 (m, 1H, CH2O), 4.02–4.09 (m, 1H, CH2O), 6.62–6.65 (dd, J ¼ 7.3,
1.8 Hz, 1H, Ar), 7.23–7.79 (m, 7H, Ar), 7.43–7.50 (m, 2H, Ar), 7.76–7.79 (m, 1H,
Ar), 8.21–8.25 (m, 1H, Ar); 13C NMR (75 MHz, CDCl3): dC 32.9, 42.7, 65.5, 67.5,
104.4, 119.9, 121.9, 124.9, 125.5, 125.7, 126.2, 127.2, 127.3, 128.1, 128.5, 134.3,
139.4, 154.5; MS (m=z): 305 (4) [Mþ], 134 (100), 115 (12). Anal. calcd. for
C21H23NO: C, 82.58; H, 7.59; N, 4.59%. Found: C, 82.54; H, 7.60; N, 4.50%.
ACKNOWLEDGMENT
The authors are thankful to the Department of Science and Technology for
financial support of this research.

3066
M. SASIKUMAR AND M. D. NIKALJE
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