Convenient formal synthesis of (±)-paroxetine

Article abstract of DOI:10.1080/00397910701545130

A formal total synthesis of antidepressant (±)-paroxetine employing a solvent-free Heck reaction is disclosed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701545130

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Convenient Formal Synthesis of
(±)‐Paroxetine
Subhash P. Chavan a , Dushant A. Khobragade a , Ashok B. Pathak a & Uttam
R. Kalkote a
a Division of Organic Chemistry: Technology, National Chemical Laboratory,
Pune, India
Version of record first published: 10 Sep 2007.
To cite this article: Subhash P. Chavan , Dushant A. Khobragade , Ashok B. Pathak & Uttam R. Kalkote (2007):
Convenient Formal Synthesis of (±)‐Paroxetine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:18, 3143-3149
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Synthetic Communicationsw, 37: 3143–3149, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701545130
Convenient Formal Synthesis
of (+)-Paroxetine
Subhash P. Chavan, Dushant A. Khobragade, Ashok B. Pathak,
and Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical
Laboratory, Pune, India
Abstract: A formal total synthesis of antidepressant (+)-paroxetine employing a
solvent-free Heck reaction is disclosed.
Keywords: antidepressants, carbamate, electrophile, Heck reaction, piperidines
INTRODUCTION
In connection with an ongoing program on the synthesis of biologically active
compounds, we have recently developed a technically and economically viable
protocol[1] for synthesis of the antidepressant drug venlafaxine 1. Our interest in
development of practical routes for such molecules prompted us to undertake
synthesis of another highly active antidepressant drug, paroxetine 2.
The piperidine nucleus is ubiquitous in a wide variety of naturally
occuring and synthetic compounds. Of these, 3,4-disubstitued piperidine
derivatives[2] exhibit a profile of biological and pharmacological properties,
for example, paroxetine 2, femoxetine 3 and Roche-1 4 (Fig. 1). (-)-Paroxetine
in the form of its hydrochloride salt is used in the treatment of depression,
obsessive–compulsive disorder, and panic and is popularly known as an
SSRI (selective serotonin reuptake inhibitor) marketed under various trade
names such as Paxil and Seroxat.
Received in India January 29, 2007
Address correspondence to Subhash P. Chavan, Division of Organic Chemistry:
Technology, National Chemical Laboratory, Pune 411 008, India. E-mail: sp.chavan@
ncl.res.in
3143

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S. P. Chavan et al.
Figure 1. Antidepressant venlafaxine 1.
RESULTS AND DISCUSSION
A literature survey revealed that several methods[3–12] have been devised to
prepare a 4-arylpiperidine motif (Figure 2). Although organic synthesis has
enormously benefited from Heck chemistry,[13–17] to our surprise, until
recently not a single approach was reported[3a] where the Heck protocol is
employed to a construct 4-arylpiperidine system, forging a bond between C-4
of piperidine nucleus and an aryl moiety. This may be attributable to the resist-
ance of such complex acrylates to undergo arylation, resulting in low conver-
sions or yields of the desired Heck adducts, serious drawbacks.
Accompanying decomposition, polymerization, or side reactions under the
harsh reaction conditions generally employed for such substrates could be
other possible factors. A recent report on the synthesis of paroxetine[3a]
prompted us to disclose our findings in this area. We investigated our
synthetic plan employing traditional, commercially available halide (viz., p-
fluorobromobenzene) as the coupling partner as compared to more a conven-
tional iodo compound or the p-fluorobenzenediazonium tetrafluoroborate salt
recently reported in literature (Scheme 1).
Retrosynthetic analysis revealed that the target molecule 2 could be
obtained from aminoalcohol 5, which in turn could be derived from aminoester
6, which presumably could be built from the olefin 7 and p-fluorobromobenzene
8 employing the Heck reaction. Olefin 7 could be conveniently prepared from
the simplest and commercially available materials (viz, methyl acrylate 9 and
benzylamine 10) (Scheme 1).
Figure 2. Antidepressant paroxetine 2, femoxetine 3, and renin inhibitor Roche-1 4.

Convenient Formal Synthesis of (+)-Paroxetine
3145
Scheme 1. Retrosynthetic analysis.
Accordingly, methyl acrylate 9 and benzylamine 10 were refluxed in the
presence of triethylamine to furnish the double Michael adduct 11, which was
further subjected to Dieckmann condensation using sodium hydride in
refluxing benzene to give ketoester 12. Ketoester 12 was reduced with
sodium borohydride in methanol at 08C. The resulting alcohol was
mesylated in dichloromethane, which underwent concomitant elimination to
afford the desired olefin 7 (Scheme 2).
The feasibility of the Heck protocol was tested under various conditions.
Arylation of the olefin 7 with Pd(OAc)2 was not successful in different
Scheme 2. Reagents and conditions: (a) Et3N, reflux (neat), overnight, 90%; (b) NaH,
PhH, reflux, 3 h, 82%; (c) NaBH4, MeOH, 08C-rt, 2 h; (d) MsCl, Et3N, DCM, 08C–rt,
overnight, 75% (for two steps); (e) Pd(Ph3P)4, K2CO3, Bu4NBr, 1208C, 2 d.

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S. P. Chavan et al.
Scheme 3. Reagents and conditions: (a) ClCO2Me, NaHCO3, DCM, rt, 24 h, 80%;
(b) 8, Pd(Ph3P)4, K2CO3, Bu4NBr, 1208C, 2 d, 45%; (c) ClCO2Me, K2CO3, DCM,
rt, overnight, 85%.
solvents such as DMF, MeOH, or CH3CN in the presence or absence of tetra-
butylammonium bromide (TBAB) using different bases such as Et3N, K2CO3,
Na2CO3, and NaHCO3. Even Pd(Ph3P)4 was not able to bring about arylation
under the aforementioned reaction conditions. Also, subjection of the olefin 7
as per the procedure reported by Correia et al.[3a] employing traditional com-
mercially available electrophile p-fluorobromobenzene did not furnish the
expected Heck adduct.
Benzyl protection of the acrylate was then exchanged with methyl
carbamate, and the carbamate was resubjected to Heck arylation. To our
delight, carbamate 14 underwent arylation smoothly under solvent-free con-
ditions 18 in a TBAB melt accompanied by concomitant unmasking of the
carbamate protection to furnish free amine 15, albiet in moderare yields
(Scheme 3). Conversion of amine 15 into paroxetine is known in the litera-
ture.[3b] Also, the carbamate derivative of 15, 16, was prepared whose con-
version to paroxetine is known.[3a,12e] Thus, formal total synthesis of
(+)-paroxetine is achieved.
EXPERIMENTAL
All solvents were freshly distilled before use. IR spectra were recorded on a
Perkin-Elmer infrared spectrophotometer model 68B or on a Perkin-Elmer

Convenient Formal Synthesis of (+)-Paroxetine
3147
1
1615 FT infrared spectrophotometer. H NMR spectra were recorded on a
Bruker AC-200 (200 MHz) instrument. 13C spectra were recorded on
Bruker AC-200 (50 MHz) or Bruker AC-400 (100 MHz) instruments. The
carbon spectra were assigned using a dimentionless enhancement by polariz-
ation transfer (DEPT) experiment. Coupling constants (J ) were recorded in
Hertz. Mass spectra were recorded at an ionization energy of 70 eV on a
Finnigan MAT-1020 and on API Q Starpulsar using electron-spray ionization
(ESI). Microanalytical data were obtained using a Carlo-Erba CHNS-O EA
1108 elemental analyzer. Progress of the reactions was monitered by thin-
layer chromatography (TLC) using Merck silica-gel 60 F254 precoated plate,
and compounds were visualized by fluorescence quenching, using iodine, or
charring after treatment with the mixture of p-anisaldehyde þ AcOH þ H2-
SO4 in ethanol. Column chromatography was performed using flash silica
gel (230–400 mesh size).
Methyl 4-(4-Fluorophenyl)-1,4,5,6-tetrahydropyridine-3-
carboxylate (15)
A mixture of olefin 14 (1 g, 5.024 mmol), p-fluorobromobezene 8 (1.76 g,
10.05 mmol), Pd(Ph3P)4 (0.58 g, 10 mol%), K2CO3 (1.386 g, 10.05 mmol),
and TBAB (2.33 g, 10.05 mmol) was heated at 1208C under an argon atmos-
phere for 2 days. The reaction mixture was allowed to cool; water was added
to it and extracted with ethyl acetate. It was washed with brine and dried
(anhydrous Na2SO4); solvent was evaporated in vacuo. Column chromato-
graphic purification using a ethyl acetate–pet. ether system (3:7–1:1)
furnished amine 15 as a colorless solid (0.531 g, 45% yield). Mp 156–
1588C. IR (CHCl3): 3467, 3019, 1682, 1626, 1506, 1438, 1353, 1314, 1284,
1216, 1108, 1070, 930, 757, 669 cm21; NMR (200 MHz, CDCl3) dH 7.73
(1H, d, J ¼ 6.31 Hz), 7.09–7.16 (2H, m), 6.90–6.99 (2H, m), 4.66 (1H, bs),
3.96 (1H, d, J ¼ 4.80 Hz), 3.59 (3H, s), 3.15 (1H, m), 2.93 (1H, dt, J ¼ 3.6,
12.8 Hz) 2.07–1.89 (1H, m) 1.79 (1H, m); dc 168.6 (C), 161.3 (C proximal
to F), 143.9 (CH), 142.0 (C), 129.0 (C-meta to F), 114.7 (C-ortho to F),
95.9 (C), 50.5 (CH3), 36.0 (CH2), 35.5 (CH), 28.9 (CH2); MS (ESI) m/z,
235 (Mþ), 221, 201, 199, 195, 187, 157, 130, 102. Analysis calculated for
C13H14FNO2: C,66.37; H,6.00; F,8.08; N,5.95. Found: C,66.25; H,5.82;
F,7.88; N,9.45.
ACKNOWLEDGMENTS
D. A. K. and A. B. P. thank Council for Scientific and Industrial Research
(CSIR), New Delhi, India, for providing fellowships. We are grateful to
Shinji Yamada and C. R. D. Correia for kindly providing spectral data of
the authentic samples.

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S. P. Chavan et al.
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