Chiral pool approach for the synthesis of functionalized amino acids: Synthesis of antiepileptic drug (R)-lacosamide

Article abstract of DOI:10.1016/j.tetlet.2015.08.077

An efficient total synthesis of (R)-lacosamide 1 has been achieved from N-Boc-N,O-isopropylidene-l-serinol 2 which could easily be obtained from natural l-serine. Our synthesis of 1 starting from 2 using chiral pool strategy resulted in 54% overall yield.

Full text of DOI:10.1016/j.tetlet.2015.08.077

Tetrahedron Letters 56 (2015) 5802–5803
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral pool approach for the synthesis of functionalized amino acids:
synthesis of antiepileptic drug (R)-lacosamide
⇑
Eswar K. Aratikatla, Asish K. Bhattacharya
Division of Organic Chemistry, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008, India
Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient total synthesis of (R)-lacosamide 1 has been achieved from N-Boc-N,O-isopropylidene-L-
Received 31 July 2015
Revised 24 August 2015
Accepted 26 August 2015
Available online 28 August 2015
serinol 2 which could easily be obtained from natural
chiral pool strategy resulted in 54% overall yield.
L
-serine. Our synthesis of 1 starting from 2 using
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
L-Serine
Chiral pool
Total synthesis
Antiepileptic drug
Introduction
starting materials. The kinetic resolution of the key intermediate
using Hydrolytic Kinetic Resolution (HKR) leads to the loss of yield
3
Epilepsy is a neurological disorder due to which patients suffer-
ing from this disease witness recurrent spontaneous seizures. It is
believed that this disease affects approximately 50 million people
worldwide and India alone accounts for approximately 10 million
during the resolution step whereas Trost’s dynamic kinetic asym-
metric transformation (DYKAT) requires ligands, which are expen-
6
sive. In some of the synthesis racemic lacosamide has been
7
a
resolved to (R)-enantiomer either using crystallization with chi-
1
7b
cases. (R)-lacosamide 1 (Vimpat, Fig. 1) is currently being used
ral carboxylic acid or chiral chromatography. The synthesis of 1
clinically in the U.S. and Europe to treat people suffering from this
disease. Although, the exact mode of action of this drug in humans
is not yet deciphered however, it is widely believed that it
increases the slow inactivation of the voltage-gated sodium chan-
nels thus inhibiting repetitive neuronal firing.2
utilizing
D-serine as a starting material involves O-methylation
8
c,g–j,l
which undergoes racemization. In order to overcome this
drawback, Kohn et al. used neutral but rather expensive Kuhn’s
O-methylation protocol, which requires Ag O.
2
8
c
8
a
Till date several synthesis of 1 have been reported using race-
Results and discussions
3
4
5
mic epichlorohydrin or acrylic acid or ethyl
L
-lactate or racemic
6
7
8
butadiene monoepoxide or
D
,L
-serine or
D-serine, respectively as
We thought of an efficient and straightforward synthesis of 1,
which could be achieved on an industrial scale at a much cheaper
cost. We envisaged the synthesis of 1 could be achieved as delin-
eated in Scheme 1. The key starting material, N-Boc-N,O-isopropy-
NHAc
9
lidene-L-serinol 2 could easily be synthesized in gram scale from
BnHN
OMe
natural
L
-serine in four steps without the need of any purification
of the intermediates. N-Boc-protected alcohol 4 would lead us to
the desired product 1 after protection/deprotection and functional
group manipulations. Also, our synthesis would enable the gener-
ation of various O-substituted congeners of (R)-lacosamide 1 for
further development of new potent anti-epileptic agents.
O
(
R)-Lacosamide (1)
Figure 1. Structure of antiepileptic drug, Lacosamide 1.
We started the synthesis of (R)-lacosamide 1 from readily avail-
⇑
Corresponding author. Tel.: +91 20 25902309; fax: +91 20 25902629.
E-mail address: ak.bhattacharya@ncl.res.in (A.K. Bhattacharya).
9
able N-Boc-N,O-isopropylidene-
L
-serinol 2. Methylation of the
http://dx.doi.org/10.1016/j.tetlet.2015.08.077
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

E. K. Aratikatla, A. K. Bhattacharya / Tetrahedron Letters 56 (2015) 5802–5803
5803
NHAc
NHBoc
OMe
yielding reaction steps without the need of any kinetic resolution
or the use of chiral ligands thereby making it more commercially
viable considering that the molecule is presently being used as a
drug. Further using our synthesis, diverse O-substituted analogues
of (R)-lacosamide 1 could be synthesized for further development
of new potent anti-epileptic agents.
BnHN
OMe
HO
O
4
(
R)-Lacosamide (1)
Acknowledgments
NBoc
NH2
O
OH
HO
OH
This work was supported by the Council of Scientific and Indus-
trial Research (CSIR), New Delhi sponsored network project
2
O
(
NaPAHA, CSC0130). E.K.A. is grateful to University Grants
L-Serine
Commission (UGC), New Delhi for the award of a Senior Research
Fellowship (SRF).
Scheme 1. Retrosynthetic analysis of Lacosamide 1.
Supplementary data
NBoc
i
NBoc
ii
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.
O
O
OH
OMe
0
77.
2
3
References and notes
NHBoc
NHBoc
iii
iv
1.
(a)
‘Epilepsy’
World
Health
Organization:
http://www.who.
HO
OMe
HO
OMe
int/mediacentre/factsheets/fs999/en/index. html; (b) Sridharan, R.; Murthy, B.
N. Epilepsia 1999, 40, 631; (c) Stafstrom, C. E. J. Cereb. Blood Flow Metab. 2006,
26, 983; (d) Duncan, J. S.; Sander, J. W.; Sisodia, S. M.; Walker, M. C. Lancet 2006,
O
4
5
3
67, 1087; (e) Costigan, M.; Scholz, J.; Woolf, C. J. Annu. Rev. Neurosci. 2009, 32,
; (f) Miziak, B.; Błaszczyk, B.; Chros c´ i n´ ska, M. K.; Danilkiewicz, G.; Jagiełło, E.
W.; Czuczwar, S. J. Expert Opin. Drug Saf. 2014, 13, 935.
1
NHBoc
OMe
NHAc
v
2. (a) Simoens, S. Curr. Med. Res. Opin. 2011, 27, 1329; (b) Mcintyre, J. A.; Castaner,
J.; Martin, L. Drugs Future 2004, 29, 992; (c) Perucca, E.; Yasothan, U.; Clincke,
G.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2008, 7, 973; (d) Bialer, M.; White, H. S.
Nat. Rev. Drug Disc. 2010, 9, 68.
BnHN
BnHN
OMe
O
O
3.
Muthukrishnan, M.; Mujahid, M.; Sasikumar, M.; Mujumdar, P. Tetrahedron:
Asymmetry 2011, 22, 1353.
6
(
R)-Lacosamide (1)
4.
5.
6.
7.
Wadavrao, S. B.; Narikimalli, A.; Narsaiah, A. V. Synthesis 2013, 3383.
Stecko, S. J. Org. Chem. 2014, 79, 6342.
Garg, Y.; Pandey, S. K. J. Org. Chem. 2015, 80, 4201.
Scheme 2. Synthesis of Lacosamide 1. Reagents and conditions: (i) NaH, MeI, THF,
rt, 30 min, 88%; (ii) PTSA, MeOH, rt, 5 h, 86%; (iii) TEMPO, NaOCl, NaClO , CH CN, rt,
h, 99%; (iv) C CH NH , N-methyl morpholine, isobutyl chloroformate, THF,
À78 °C to rt, 1 h, 90%; (v) (1) TFA, DCM, rt, overnight; (2) Ac O, DMAP, DCM, rt, 4 h,
80% over 2 steps).
2
3
(a) Bologna, A.; Castoldi, P.; Vergani, D.; Bertolini, G. Patent US 20130030216,
3
H
6 5
2
2
2013; (b) Bouvy, D.; Merschaert, A.; Pinilla, V.; Hamann, J.; Kanzler, R.; Thomas,
2
A. Patent WO 2010052011 A1, 2010.
(
8.
(a) Kuhn, R. Angew. Chem., Int. Ed. Engl. 1962, 1, 19; (b) Morieux, P.; Stables, J. P.;
Kohn, H. Bioorg. Med. Chem. 2008, 16, 8968; (c) Choi, D.; Stables, J. P.; Kohn, H. J.
Med. Chem. 1996, 39, 1907; (d) Salome, C.; Grosjean, E. S.; Park, K. D.; Morieux,
P.; Swendiman, R.; DeMarco, E.; Stables, J. P.; Kohn, H. J. Med. Chem. 2010, 53,
alcohol 210 with methyl iodide in THF in the presence of sodium
1288; (e) Morieux, P.; Salome, C.; Park, K. D.; Stables, J. P.; Kohn, H. J. Med.
hydride furnished the ether 3 in 88% yield (Scheme 2). Deprotec-
tion of acetonide group10 of 3 with p-toluene sulphonic acid in
methanol resulted in the formation of compound 4, which on oxi-
dation of the primary alcoholic group with TEMPO resulted in the
clean formation of the acid 5 in 99% yield that was used in the next
step as such. Next, the acid 5 was coupled with benzyl amine using
N-methyl morpholine and isobutyl chloroformate in THF to furnish
the amide 6 in 90% yield. The deprotection of the Boc group fol-
lowed by acetylation of the resulting amine was achieved in one
pot, which furnished the desired product (R)-lacosamide 1 in 80%
Chem. 2010, 53, 5716; (f) Park, K. D.; Stables, J. P.; Liu, R.; Kohn, H. Org. Biomol.
Chem. 2010, 8, 2803; (g) Andurkar, S. V.; Kohn, H. Patent US 6048899, 2000; (h)
Riedner, J. Patent EP 20040023556, 2006; (i) Riedner, J.; Dunne, G. Patent WO
2006037574, 2006; (j) Riedner, J.; Dunne, G. Patent US 20080027137, 2008; (k)
Riedner, J. European Patent EP 1642889A1, 2006; Chem. Abstr. 2006, 144,
331695; (l) Madhra, M. K.; Singh, P. K.; Khanduri, C. H. Patent US 20090143472
A1, 2009; Chem. Abstr. 2009, 151, 8933; (m) Vrbanec, G.; Harca, M.; Sucec, A.;
Sahnic, D.; Avdagic, A. PCT Int. Appl., WO 2010107993A2, 2010; Chem. Abstr.
2
010, 153, 431066; (n) Pandey, B.; Shah, K. PCT Int. Appl., WO 2011039781A1,
2011; Chem. Abstr. 2011, 154, 410331; (o) Bosch, I. L. J.; Duran, L. E. Patent WO
011158194, 2011; (p) Branneby, C. K.; Eek, M. Patent US 20130317109, 2013.
2
9
.
(a) Mckillop, A.; Taylor, R. J. K.; Waston, R. J.; Lewis, N. Synthesis 1994, 31; (b)
Dondoni, A.; Perrone, P. Synthesis 1997, 527; (c) Garner, P.; Park, J. M. J. Org.
Chem. 1987, 52, 2361; (d) Dondoni, A.; Perrone, P. Org. Synth. Coll. 2004, X, 320.
4
5
4
over two-steps {mp 140–141 °C [Lit. 140–141 °C, 142–143 °C,
6
25
1
+
43–144 °C ]; [
a]
D
+15.9 (c 1.01, MeOH) [Lit. +16.2 (c 1, MeOH),
10. Ojika, M.; Kigoshi, H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.;
5
6
Arakawa, M.; Ekimoto, H.; Yamada, K. Tetrahedron 2007, 63, 3138.
16.1 (c 1.2, MeOH), +16.1 (c 1, MeOH) ]}. The spectral data were
in complete agreement with reported literature data.
4
1
1. Spectral data of (R)-lacosamide (1): mp 140–141 °C [Lit. 140–141 °C, 142–
3–8,11
The chi-
5
6
25
4
1
43 °C, 143–144 °C ]; [a] +15.9 (c 1.01, MeOH) [Lit. +16.2 (c 1, MeOH),
D
5
6
ral HPLC analysis of compound 1 suggested that no racemization
has occurred during the synthesis (see Supporting information).
+16.1 (c 1.2, MeOH), +16.1 (c 1, MeOH) ]; IR (CHCl
3
)
t
max: 3671, 3421, 3304,
À1
1
3015, 2933, 2404, 1657, 1515, 1456, 1376, 1218, 1115, 927, 762, 668 cm ; H
3
NMR (400 MHz, CDCl ) d: 7.36–7.21 (m, 5H), 7.02 (br s, 1H), 6.66 (d, J = 6.1 Hz,
1
H), 4.60 (dt, J = 4.4, 7.0 Hz, 1H), 4.51–4.37 (m, 2H), 3.77 (ddd, J = 1.7, 4.2, 9.2
13
Hz, 1H), 3.46 (dd, J = 7.5, 8.7 Hz, 1H), 3.36 (s, 3H), 1.99 (s, 3H); C NMR
100 MHz, CDCl ) d: 170.5, 170.0, 137.9, 128.7, 127.4, 71.9, 59.1, 52.5, 43.5,
18 2 3
3.1; HRMS (ESI): m/z calcd for C13H N O Na [M+Na] 273.1210; found:
Conclusion
(
2
3
+
In summary,
R)-lacosamide 1 has been achieved in five steps with an overall
yield of 54%. The key starting material could be synthesized in
gram scale from -serine in four steps without requiring chro-
matography. The highlights of this synthesis are short and high
a
short and straightforward synthesis of
273.1195; ee >99.9% [The ee of (R)-lacosamide (1) was determined by chiral
n
(
HPLC analysis: Chiralcel OD-H (0.46 cm  25 cm), iso-propyl alcohol- hexane-
trifluoroacetic acid (30:70:0.1), flow rate 0.5 mL/min; UV detection at 220 nm;
t
R
= 10.5 min]; for complete experimental procedures and spectral data of all
L
the compounds, see Supporting information.