An efficient and stereoselective synthesis of (3S,4R)-(-)-trans-4- (4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

Article abstract of DOI:10.1016/j.tetasy.2010.12.020

An asymmetric conjugate addition reaction between a chiral α,β-unsaturated amido ester and ethyl-N-methylmalonamide has been used as a key step in the synthesis of (3S,4R)-(-)-trans-4-(4′- fluorophenyl)-3-hydroxymethyl-N-methylpiperidine, a key intermediate for (-)-paroxetine.

Full text of DOI:10.1016/j.tetasy.2010.12.020

Tetrahedron: Asymmetry 22 (2011) 1–3
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Tetrahedron: Asymmetry
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An efficient and stereoselective synthesis of
(3S,4R)-(ꢀ)-trans-4-(40-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine
Sripathi Somaiah a, Suthrapu Sashikanth a, Veeramalla Raju a, Karnati Venugopal Reddy b,
⇑
a Department of Research and Development, Srini Pharmaceuticals Ltd, Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee Hills, Hyderabad 500 033, Andhrapradesh, India
b Department of Chemistry, Osmania University, Tarnaka, Hyderabad 500 007, Andhrapradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric conjugate addition reaction between a chiral
a,b-unsaturated amido ester and ethyl-N-
methylmalonamide has been used as a key step in the synthesis of (3S,4R)-(ꢀ)-trans-4-(40-fluoro-
phenyl)-3-hydroxymethyl-N-methylpiperidine, a key intermediate for (ꢀ)-paroxetine.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 September 2010
Revised 26 November 2010
Accepted 23 December 2010
Available online 31 January 2011
1. Introduction
trans-3,4-disubstituted piperidine alcohol 7 could be obtained
from amido ester 4, which in turn was obtained from 4-fluorocin-
Paroxetine 1 (PaxilÒ) is an enantiomerically pure (ꢀ)-trans-3,4-
disubstituted piperidine, used for the treatment of depression,
obsessive compulsive disorder and panic disorders.1,2 Moreover,
it is a potent and selective inhibitor of 5-hydroxytriptamine up-
take, with a reduced propensity to cause the side-effects usually
associated with tricyclic antidepressants.3,4
namic acid 2.
Herein we report a strategy involving a chiral auxiliary based
Michael addition reaction as the key step for the synthesis of
(ꢀ)-trans-3,4-disubstituted piperidine alcohol 7, which is a key
intermediate for (ꢀ)-paroxetine. As outlined in Scheme 2, the cou-
pling of 4-fluorocinnamic acid 28 with (R)-4-phenyl oxazolidinone
3 was achieved through a mixed anhydride using pivaloyl chloride
and triethylamine in dichloromethane. The chemoselective attack
of the chiral auxiliary 3 led to desired product 4. Next, the key step
in our synthesis is the one-pot reaction, that is, asymmetric
conjugate addition of the ethyl-N-methylmalonamide 59 with
F
O
O
chiral
a,b-unsaturated amido ester 4 in the presence of sodium
O
hydride followed by in situ cyclisation to afford the diketo ester
6 with 80% yield.
N
For the first time we report the conjugate addition of an unsym-
metrical 1,3-dicarbonyl nucleophile to a chiral oxazolidinone
acceptor. In this particular step the attack of the ethyl-N-meth-
ylmalonamide 5 onto the asymmetric olefinic amido ester 4 oc-
curred from the less hindered face of the double bond and in situ
cyclisation led to the formation of 6 with excellent diastereoselec-
tivity by the removal of chiral auxiliary. Treatment of amide 5 with
excess base facilitated cyclisation step and generated two stereo-
genic centers in single pot reaction with good yield. It is worth not-
ing that the NMR spectrum of the conjugate addition product
showed high diastereoselectivity (95:5). The pure compound 6
. HCl
H
paroxetine 1
Numerous syntheses of this potent antidepressant drug have
been reported by various workers.5 Other methods to obtain the de-
sired chirality at C-3 and C-4 positions of the piperidine ring include
resolutions of diastereomeric salts6 and enzymatic hydrolyses of the
various ester precursors.7 The common deficiency for these resolu-
tions is that 50% of the material is lost as the unwanted isomer,
which will greatly diminish their synthetic utility for scale-up.
from heptane has the specific rotation of ½a D25
¼ ꢀ24:6 (c 1, etha-
ꢁ
2. Results and discussion
nol). The by-product 4-phenyl oxazolidinone 3 was recovered in
pure form undissolved during purification in diisopropyl ether.
The degree of asymmetric induction was assessed by 1H NMR
analysis of the diastereomeric mixtures and the absolute stereo-
chemistry at C-3 and C-4 of the diketo ester 6 was determined
by conversion to piperidine alcohol 7 with lithium aluminium
hydride in tetrahydrofuron. The (3S,4R)-absolute configuration
The retrosynthetic analysis for the planned synthesis of 7 is
shown in Scheme 1. The diketo ester 6 precursor to the (ꢀ)-
⇑
Corresponding author.
E-mail address: drkvr_ou@yahoo.com (K.V. Reddy).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.020

2
S. Somaiah et al. / Tetrahedron: Asymmetry 22 (2011) 1–3
Organic solvents were distilled before use or, if otherwise noted,
dried according to the typical procedures.
F
F
4.1. 3-[3-(4-Fluorophenyl)-acryloyl]-4-phenyloxazolidin-2-one 4
O
O
To a solution of the 4-fluorocinnamic acid 2 (10.0 g, 60.18
mmol) in dichloromethane (50.0 mL) was added triethylamine
(14.6 g, 144.5 mmol) at 25 °C followed by pivaloyl chloride (8.7 g,
72.15 mmol) at the same temperature and the reaction mixture
was stirred for 2 h. (R)-Phenyl oxazolidinone (9.82 g, 60.18 mmol)
and catalytic DMAP was added to the above solution and refluxed
for 6 to 8 h. The reaction mixture was cooled to room temperature,
diluted with water and extracted with dichloromethane (2 ꢂ 20
mL). The solvent was removed under reduced pressure and the
crude compound was recrystallized from heptane to afford com-
O
OH
O
N
N
CH3
CH3
7
6
O
F
F
pound 4 (15.7 g, 84%) as an off white solid. ½a D25
¼ ꢀ34:5 (c 1, eth-
ꢁ
O
OH
N
anol); IR (cmꢀ1): 1769, 1685, 1622, 1596, 1346, 1104; 1H NMR:
(400 MHz, CDCl3) d, ppm: 7.67–7.89 (m, 4H), 7.25–7.42 (m, 5H),
7.02–7.1 (m, 2H), 5.5–5.57 (dd, J = 9.3 Hz, 1H), 4.69–4.78 (dd,
J = 9.3 Hz,1H), 4.28–4.35 (dd, J = 9.3 Hz, 1H); 13C NMR (400 MHz,
CDCl3): d 163.5, 160.3, 155.0, 145.4, 130.7, 129.3, 126.1, 116.7,
116.1, 70.15, 58.0; MS: m/z: 312.3 [M+H+].
O
O
Ph
2
4
Scheme 1. Retrosynthetic analysis for 7.
4.2. (3S,4R)-3-Ethoxycarbonyl-4-(40-fluorophenyl)-N-methyl
piperidine-2,6-dione 6
was confirmed by the comparison of their measured specific rota-
tions with that of the known (ꢀ)-trans (3S,4R) alcohol 7.9 The phys-
ical and spectroscopic data of all the compounds are in good
agreement with the proposed structures and with the literature
data.
To a stired solution of ethyl-N-methylmalonamide 5 (4.84 g,
33.34 mmol) in dimethylsulfoxide (40.0 mL) was added sodium
hydride (60%, 1.8 g, 45.0 mmol) slowly under nitrogen. The reac-
tion mixture was cooled to room temperature, compound 4 added
(10.0 g, 32.12 mmol) in a single portion and the whole mixture was
stirred for 3–4 h at room temperature. The mixture was neutral-
ized with acetic acid (ꢃ4.0 mL) and extracted with ethyl acetate
(2 ꢂ 25 mL) and the combined organic portions were washed with
water (30.0 mL) and brine (30.0 mL). The solvent was removed un-
der reduced pressure and the residue was diluted with diisopropyl
ether (80.0 mL). The separated undissolved solid (phenyl oxazolid-
inone) was filtered and the mother liquor was evaporated and the
residue recrystalized from heptane to afford 6 (7.5 g, 80%) as an off
3. Conclusion
In conclusion, a highly stereoselective method for the prepara-
tion of a key synthetic precursor of paroxetine has been achieved
by an asymmetric conjugate addition reaction.
4. Experimental
General: The 1H and 13C spectra were recorded in CDCl3 at 400
MHz on a Varian Gemini 400 MHz FT NMR spectrometer. The
chemical shifts were reported in d ppm relative to TMS. The FT-
IR spectra were recorded in the solid state as KBr dispersion using
a Perkin–Elmer 1650 FT-IR spectrometer. The mass spectrum
(70 eV) was recorded on an Agilent-6310 LC–MS spectrometer.
white solid. ½a 2D5
ꢁ
¼ ꢀ24:6 (c 1, ethanol); IR (cmꢀ1): 2965, 1746,
1725, 1671, 1311, 1109; 1H NMR: (400 MHz, CDCl3) d, ppm:
7.16–7.20 (m, 2H), 7.01–7.05 (m, 2H), 4.07–4.12 (q, J = 8 Hz, 2H),
3.63–3.77 (m, 2H), 3.20 (s, 3H), 2.98–3.03 (dd, J = 9.3 Hz, 1H),
2.76–2.84 (dd, J = 9.3 Hz, 1H) , 1.08–1.11 (t, J = 8 Hz, 3H); 13C
F
O
O
F
O
O
O
a
HN
Ph
OH
F
+
N
+
O
N
H
O
O
O
Ph
2
3
5
4
F
c
b
O
O
OH
O
N
O
N
CH3
CH3
6
7
Scheme 2. Reagents and conditions: (a) pivaloyl chloride, CH2Cl2, Et3N, DMAP, rt to reflux, 6–8 h, 84%; (b) NaH, DMSO, rt, 3–4 h, 80%; (c) LAH, THF, 0–60 °C, 2 h, 80%.

S. Somaiah et al. / Tetrahedron: Asymmetry 22 (2011) 1–3
3
NMR (400 MHz, CDCl3): d 170.5, 168.7, 167.6, 163.6, 134.4, 128.6,
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Acknowledgements
We thank the management of Srini Pharmaceuticals Ltd, for
extending support to the work. Co-operation from the project col-
leagues and analytical department is highly appreciated.
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