Stereoselective and efficient synthesis of (S)-pregabalin from d-mannitol

Article abstract of DOI:10.1016/j.tetasy.2008.03.005

A straightforward synthesis of (S)-pregabalin in 28% overall yield starting from d-mannitol acetonide, as a primary source of chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as well as low-cost commercially available reagents.

Full text of DOI:10.1016/j.tetasy.2008.03.005

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Tetrahedron: Asymmetry 19 (2008) 651–653
Stereoselective and efficient synthesis of (S)-pregabalin
from D-mannitol
a
a
b
b
´
´
Sandra Izquierdo, Jordi Aguilera, Helmut H. Buschmann, Monica Garcıa,
Antoni Torrensb,* and Rosa M. Ortunoa,*
˜
a
`
Departament de Quı´mica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
bDepartament de Quı´mica ESTEVE, Mare de De´u de Montserrat, 221, 08041 Barcelona, Spain
Received 12 February 2008; accepted 5 March 2008
Abstract—A straightforward synthesis of (S)-pregabalin in 28% overall yield starting from D-mannitol acetonide, as a primary source of
chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as
well as low-cost commercially available reagents.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The first methods, which were developed to prepare enan-
tiomerically pure (S)-pregabalin 1, involved the previous
synthesis of a racemic mixture and subsequent resolution
into the (R)- and (S)-enantiomers.2 Different approaches
using diastereomeric resolution have been described. One
method starts with a Knoevenagel condensation of diethyl
malonate with 3-methylbutanal, followed by the treatment
with cyanide, decarboxylative hydrolysis, and hydrogena-
tion to yield racemic pregabalin, which undergoes resolu-
tion with (S)-(+)-mandelic acid.2,3 This route has the
advantage of an inexpensive manufacturing process, but
in this case undesired (R)-pregabalin cannot be efficiently
recycled and is discarded as waste. Another procedure for
the preparation of racemic pregabalin was patented by
Warner–Lambert and comprises of the synthesis of 3-
isobutylglutaric acid anhydride as a starting material. This
compound is converted into racemic 3-carbamoylmethyl-5-
methyl-hexanoic acid, which after resolution with (R)-(+)-
1-phenylethylamine, yields the (S)-enantiomer. Finally, this
compound undergoes a Hoffmann rearrangement to afford
(S)-pregabalin, 1.4
(S)-Pregabalin (LyricaÒ) 1 has been developed as a follow-
up compound to gabapentin (NeurontinÒ) for the treat-
ment of epilepsy, neuropathic pain, anxiety, and social
phobia. (S)-Pregabalin displays a new mechanism of action
and acts as a voltage-dependent calcium channel a2–d
subunit ligand. Both (S)-pregabalin and gabapentin are
analogues of 4-aminobutyric acid (GABA), a neurotrans-
mitter that is thought to play a major inhibitory role in
the central nervous system. (S)-Pregabalin has been found
to be useful in anticonvulsant therapy due to its activation
of GAD (L-glutamic acid decarboxylase) promoting the
production of GABA, which is released at 30% of the brain
synapses.1
CO2H
CO2H
NH2
H
NH2
gabapentin
(S)-pregabalin, 1
The pharmacological activity of 1 is primarily attributable
to the (S)-enantiomer and thus, several methods have been
developed to prepare (S)-pregabalin substantially free of
the (R)-enantiomer.
The current industrial process for the synthesis of
(S)-pregabalin 1 was developed by Pfizer and involves an
enzymatic resolution of racemic 2-(1-cyano-3-meth-
ylbutyl)malonic acid carried out by a lipase to give a mix-
ture of the (R)-diester and the (S)-monoester potassium
salt. The cyano group of the desired (S)-enantiomer is
hydrogenated in water and the resulting compound is final-
ly hydrolyzed and decarboxylated in water to afford 1.5
*
Corresponding authors. E-mail addresses: atorrens@esteve.es; rosa.
ortuno@uab.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.005

652
S. Izquierdo et al. / Tetrahedron: Asymmetry 19 (2008) 651–653
Alternatively, (S)-pregabalin
1
has been synthesized
Since (S)-pregabalin has been launched as a marketed
through different enantioselective routes that mostly com-
prise of the use of chiral auxiliaries or chiral catalysts.
One approach to the preparation of 1 involves a chiral
aluminum salen catalyst in the conjugate addition of
trimethylsilyl cyanide to the corresponding precursor a,b-
unsaturated imide.6 While this route affords high enantio-
meric purity, it shows practical limitations for large-scale
synthesis because it employs expensive and sophisticated
reagents. Another synthesis involves the asymmetric hydro-
genation of 3-cyano-5-methylhexanoate with a rhodium
Me–DuPHOS catalyst.7 Other processes use chiral auxilia-
ries, such as (S)-phenylethyl amine8 or Evans oxazolidinon-
es2 to obtain (S)-pregabalin in good enantiomeric excesses.
Very recently, (S)-pregabalin has also been prepared via
quinine-mediated desymmetrization of a cyclic anhydride,9
and from a chiral c-butyrolactone,10 respectively.
pharmaceutical product, there is a need for an alternative,
efficient, and cost effective process for its large-scale synthe-
sis, which overcomes at least some of the disadvantages
mentioned above.
Herein, we report a new enantioselective process for the
straightforward synthesis of (S)-pregabalin, 1, starting
from a polyfunctionalized oxazolidin-2-one prepared, in
turn, from inexpensive D-mannitol acetonide. This com-
pound is one of the components of the so-called chiral pool
of natural products and has been widely used in the indus-
trial synthesis of enantiomerically pure products.12
2. Results and discussion
Recently, Domingos et al. described the preparation of
pyrrolidin-2-ones from a (Z)-enoate derived from D-manni-
tol. The key step was the stereoselective 1,4-addition of
nitromethane to afford a nitroester that, upon reduction,
gave lactam 4.13 In our laboratory, we have adapted this
synthetic route in order to confer it with efficiency allowing
the use of common reagents and simple processes. Thus,
Nevertheless, despite the abundance of these processes to
prepare (S)-pregabalin 1, they are often unsuitable for
multi-gram synthesis due to the high price of reagents
and/or substrates, and the difficulty of some chemical
manipulations regarding their intrinsic risk and the
required equipment.11
O
O
O
HO
H
H
O
O
(EtO)2P-CHCO2Et
H
NaIO4
H
O
H
O
2 x
OH
O
CO2Et
t-BuOK / CH2Cl2
CHO
THF - H2O
93%
H
80%
1
2
O
D-mannitol bisacetonide
O
O
NH4HCO2, 20% Pd(OH)2/C
CH3NO2 / TBAF
O
H
O
H
O
CO2Et
NO2
MeOH
85%
THF
75%
H
NH
H
4
3
Scheme 1.
(Boc)2O
O
HO
H
O
H
HO
TEA, DMAP
90% AcOH
100%
NaIO4
OHC
O
O
O
4
H
H
H
100%
MeOH - H2O
100%
N
N
N
Boc
Boc
Boc
6
5
7
H2, HCl
20% Pd(OH)2/C
1M LiOH
THF
Ph3P
O
CO2H
CO2H
NH2
THF
60%
MeOH
100%
H
H
H
100%
N
NHBoc
Boc
9
8
(S)-pregabalin, 1
Scheme 2.

S. Izquierdo et al. / Tetrahedron: Asymmetry 19 (2008) 651–653
653
the 1:9 (Z/E) mixture of enoates 2 was employed to prepare
nitroester 3 that, once purified, was a single diastereoiso-
mer obtained in 75% yield. Only trace amounts of a second
diastereoisomer were detected in the 1H NMR spectrum of
the reaction crude. This excellent p-facial diastereoselectiv-
ity can be rationalized on the basis of the previously pro-
posed models for the addition reactions of enoate 2 and
related substrates with nucleophiles and diazoalkanes.14
In turn, 2 was prepared by a Wadsworth–Emmons olefini-
zation of D-glyceraldehyde acetonide, 1, resulting from the
oxidative cleavage of commercial D-mannitol acetonide
(Scheme 1).15 The nitro group was reduced by hydrogen
transfer from ammonium formate using 20% Pd(OH)2/C
as a catalyst in refluxing methanol overnight.14c The
formed amino ester cyclized in situ to provide lactam 4 in
85% yield.
commercially available reagents, as well as high-yield
chemical transformations which are suitable for scaling-
up the process.
References
1. (a) Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19,
149; (b) Belliotti, T.; Capiris, T.; Ekhato, V.; Kinsora, J. J.;
Field, M. J.; Heffner, T. G.; Meltzer, L. T.; Schwarz, J. B.;
Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; Wise, L. D.;
Zhi-Su, T.; Weber, M.; Wustrow, D. J. J. Med. Chem. 2005,
48, 2294, and references therein.
2. Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern,
T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.;
Franklin, L. C.; Granger, E. J.; Karrick, G. L. Org. Process
Res. Dev. 1997, 1, 26.
3. Grote, T. M.; Huckabee, B. K.; Mulhern, T.; Sobieray, D.
M.; Titus, R. D. WO 9640617, 1996.
4. Huckabee, B. K.; Sobieray, D. M. WO 9638405, 1996.
5. Hu, S.; Martinez, C. A.; Tao, J.; Tully, W. E.; Kelleher, P.;
Dumond, Y. U.S. Patent 2,005,283,023, 2005.
In our synthesis of (S)-pregabalin, 1, the intermediate lac-
tam N-H was efficiently protected as a N-Boc derivative
by the treatment of compound 4 with (Boc)2O in the pres-
ence of TEA and DMAP to quantitatively afford the N-
Boc carbamate 5, which is a novel compound (Scheme 2).
6. Sammis, G.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442.
7. Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.;
Hoge, G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I.
C.; Mulhern, T. A.; Ramsden, J. A.; Wade, R. A. J. Org.
Chem. 2003, 68, 5731.
Subsequently, ketal protection was chemoselectively re-
moved by the treatment of 5 with 90% AcOH providing
diol 6 in 100% yield. The N-Boc protection was not altered
under these mild conditions. Diol 6 was then oxidatively
cleaved by NaIO4 in MeOH–H2O to give aldehyde 7.
The incorporation of the isopropyl group into the carbon
backbone of the (S)-pregabalin precursors was achieved
through a Wittig condensation of 6 with isopropylidenetri-
phenyl phosphorane leading to isobutenyl oxazolidin-2-one
8. The lactam-ring was then opened by the reaction be-
tween 8 and 1 M LiOH in THF at room temperature, fol-
lowing the procedure described by Seebach et al. for a
similar substrate16 to quantitatively afford acid 9, which
is the direct precursor of (S)-pregabalin, 1. The reduction
of the C–C double bond and the hydrolysis of the N-Boc
carbamate were carried out in one step by the hydrogena-
tion of 9 over 20% Pd(OH)2/C in ethanol, in the presence
of aqueous HCl, under 6 atmospheres pressure at room
temperature. In this way, enantiomerically pure (S)-pre-
gabalin, 1, [a]D = +10.0 (c 0.5, H2O) {Lit.2 [a]D = +10.1
(c 1.1 H2O)} was obtained in six steps and 60% overall
yield from oxazolidin-2-one 5.
´
8. Rodrıguez, V.; Quintero, L.; Sartillo-Piscil, F. Tetrahedron
Lett. 2007, 48, 4305.
9. Hamersak, Z.; Stipetic, I.; Avdagic, A. Tetrahedron: Asym-
metry 2007, 18, 1481.
10. Ok, T.; Jeon, A.; Lee, J.; Lim, J. K.; Hong, C. S.; Lee, H. S. J.
Org. Chem. 2007, 72, 7390.
11. For a recent review of the different synthesis of (S)-pregab-
´
´
alin, see Garcıa-Lopez, M.; Yenes, S.; Buschmann, H.;
Torrens, A. In Antidepressants, Antipsychotics, Anxiolytics.
From Chemistry and Pharmacology to Clinical Application;
´
´
Buschmann, H., Dıaz, J. L., Holenz, J., Parraga, A., Torrens,
A., Vela, J. M., Eds.; Wiley-VCH, 2007; Vol. 2, pp 1032–
1038.
12. Chirality in Industry; Collins, A. N., Sheldrake, G. N.,
Crosby, J., Eds.; John Wiley & Sons: Chichester, 1992.
13. Domingos, J. L. O.; Lima, E. C.; Dias, A. G.; Costa, P. R. R.
Tetrahedron: Asymmetry 2004, 15, 2313.
´
´
14. (a) Muray, E.; Alvarez-Larena, A.; Piniella, J. F.; Brancha-
dell, V.; Ortuno, R. M. J. Org. Chem. 2000, 65, 388; (b)
˜
´
Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena,
A.; Moltrasio, G. Y.; Branchadell, V.; Ortuno, R. M. J. Org.
´
˜
Chem. 2002, 67, 2402; (c) Moglioni, A. G.; Brousse, B. N.;
´
´
Alvarez-Larena, A.; Moltrasio, G. Y.; Ortuno, R. M.
˜
3. Conclusion
Tetrahedron: Asymmetry 2002, 13, 451.
15. Mann, J.; Partlett, N. K.; Thomas, A. J. Chem. Res. (S)
1987, 369, and references therein.
16. Brenner, M.; Seebach, D. Helv. Chim. Acta 1999, 82,
2365.
(S)-Pregabalin has been efficiently prepared in 10 synthetic
steps from the chiral precursor D-mannitol acetonide. The
performed reactions involve the use of inexpensive and