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
O
O
OH
OMe
2
3
References and notes
NHBoc
NHBoc
iii
iv
1.
HO
OMe
HO
OMe
O
4
5
NHBoc
OMe
NHAc
v
BnHN
BnHN
OMe
O
O
3.
6
(
R)-Lacosamide (1)
4.
5.
6.
7.
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
(
8.
alcohol 210 with methyl iodide in THF in the presence of sodium
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%
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
9
.
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),
5
6
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.