A non-infringing route for enantioselective synthesis of antiepileptic agent lacosamide

Article abstract of DOI:10.1055/s-0033-1339901

A non-infringing route for enantioselective synthesis of lacosamide has been developed. The synthesis started from commercially available acrylic acid and was completed in eight steps using Sharpless asymmetric dihydroxylation as a key step with an overal

Full text of DOI:10.1055/s-0033-1339901

PAPER
▌3383
paper
A Non-infringing Route for Enantioselective Synthesis of Antiepileptic Agent
Lacosamide
Enantioselective Synthesis of Lacosamide
Sachin B. Wadavrao, Ashritha Narikimalli, A. Venkat Narsaiah*
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, 500007, India
Fax +91(40)27160387; E-mail: vnakkirala2001@yahoo.com
Received: 29.07.2013; Accepted: 11.09.2013
synthesis started from a chiral pool of unnatural amino
Abstract: A non-infringing route for enantioselective synthesis of
acid D-serine and its derivatives.4
lacosamide has been developed. The synthesis started from com-
mercially available acrylic acid and was completed in eight steps
using Sharpless asymmetric dihydroxylation as a key step with an
overall yield of 29%. All the reactions were very clean with good
yields.
As part of our regular research program for the synthesis
of biologically active molecules,5 herein we report a non-
infringing route for the enantioselective synthesis of
lacosamide from a non-amino acid starting material. As
shown in the retrosynthesis (Scheme 1), our synthetic
strategy started from commercially available acrylic acid
(2).
Key words: antiepileptic agent, dihydroxylation, tosylation, azide,
lacosamide
As shown in the Scheme 2, the peptide bond was formed
by reacting acrylic acid (2) with benzylamine (3) in pres-
ence of 1-hydroxybenzotriazole in N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide (EDCI) at 0 °C to room
temperature to obtain, N-benzylacrylamide (4) in 70%
yield.6 The amide compound was subjected to Sharpless
asymmetric dihydroxylation with AD-mix-β and meth-
anesulfonamide using a mixture of tert-butyl alcohol–
water (1:1) as solvent at 0 °C to afford (S)-N-benzyl-2,3-
dihydroxypropanamide (5) in very good yields with 93%
ee.7 The dihydroxy compound was treated with tosyl chlo-
ride and dibutyltin oxide in the presence of triethylamine
at 0 °C to obtain the primary hydroxy group tosylated
product, (S)-3-(benzylamino)-2-hydroxy-3-oxopropyl 4-
toluenesulfonate (6) in 95% yield exclusively.8 This tosyl
compound was treated with potassium carbonate in meth-
anol at 0 °C resulting in the in situ formation of an epoxide
that was opened by methanol to give (S)-N-benzyl-2-hy-
droxy-3-methoxypropanamide (7) in 90% yield. Com-
pound 7 was treated with tosyl chloride in the presence of
4-(dimethylamino)pyridine at 0 °C to obtain the second-
ary alcohol protected product, (S)-1-(benzylamino)-3-
methoxy-1-oxopropan-2-yl 4-toluenesulfonate (8) in ex-
cellent yield. The tosylated compound was treated with
sodium azide in N,N-dimethylformamide at 70 °C to yield
(R)-2-azido-N-benzyl-3-methoxypropanamide (9) in 87%
yield.9
Epilepsy is a common neurological disorder characterized
by the onset of spontaneous convulsant and nonconvul-
sant seizures that result from neuronal hyperexcitability
and hypersynchronous neuronal firing. Epilepsy affects
around 3% of the population worldwide and 2 million
people in the United States alone.1 This disorder encom-
passes a number of syndromes, many of which have a
strong genetic component, the predominant type of sei-
zure begins in both cerebral hemispheres. Treatment of
epilepsy often imposes an exposure to various antiepilep-
tic drugs (AEDs) and requires long-term commitment.
Lacosamide (1, Figure 1) was recently approved as an an-
tiepileptic drug for adjunctive therapy of partial onset sei-
zures in the United States and European Union.2
OMe
O
H
N
N
H
O
lacosamide (1)
Figure 1
The pharmaceutical importance of lacosamide has attract-
ed many synthetic chemists and led to its synthesis by dif-
ferent routes.3 Many reports are patents and their
O
O
O
MeO
N
HO
N
1
H
H
OH
OTs
OH
2
5
8
Scheme 1 Retrosynthesis of (R)-lacosamide (1)
SYNTHESIS 2013, 45, 3383–3386
Advanced online publication: 02.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339901; Art ID: SS-2013-Z0527-OP
© Georg Thieme Verlag Stuttgart · New York

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S. B. Wadavrao et al.
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O
O
O
a
b
H2N
HO
N
N
+
H
OH
H
OH
2
3
4
5
O
O
O
d
c
TsO
N
N
MeO
N
H
H
O
H
OH
OH
6
7
O
O
e
g
f
MeO
N
MeO
N
H
H
N3
OTs
8
9
O
O
h
MeO
N
MeO
N
H
H
NH2
10
NH
O
Scheme 2 Reagents and conditions: (a) HOBt, EDCI, Et3N, CH2Cl2, 0 °C–r.t., 8 h, 70%. (b) AD-mix-β, MsNH2, t-BuOH–H2O (1:1), 0 °C, 4
80%. (c) Bu2SnO, TsCl (1 equiv), Et3N, CH2Cl2, 0 °C, 2 h, 95%. (d) K2CO3, MeOH, 0 °C, 8 h, 90%. (e) TsCl, Et3N, DMAP, CH2Cl2, 0 °C,
92%. (f) NaN3, DMF, 70 °C, 6 h, 87%. (g) Ph3P, THF–H2O (9:1), 50 °C, 12h, 85%. (h) Ac2O, DMAP, CH2Cl2, 0 °C, 1 h, 90%.
brine (25 mL), dried (Na2SO4), and evaporated under reduced pres-
sure. The obtained residue was purified by column chromatography
(60–120 mesh silica gel, EtOAc–hexane, 2:8) to afford pure 4 (1.56
g, 70%) as a solid; mp 58–59 °C.
Reduction of azide 9 with triphenylphosphine in tetrahy-
drofuran–water (9:1) mixture at 50 °C to afforded (R)-2-
amino-N-benzyl-3-methoxypropanamide (10) in very
good yield.10 The thus-obtained amine compound was
treated with acetic anhydride in dichloromethane at 0 °C
for one hour to afford the target molecule, (R)-2-acetami-
do-N-benzyl-3-methoxypropanamide (1), in 90% yield.
All the products were characterized by their 1H NMR, 13C
NMR, IR, HRMS, and optical rotation data compared
with literature reports.1a,3a
IR (KBr): 3285, 2930, 2851, 1654, 1623, 1536, 1453, 1240, 956,
695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.27–7.40 (m, 5 H), 6.33 (dd,
J = 15.6, 1.5 Hz, 1 H), 6.11 (dd, J = 16.9, 10.2 Hz, 1 H), 5.89 (br s,
1 H), 5.67 (dd, J = 10.4, 1.3 Hz, 1 H), 4.53 (d, J = 5.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 165.4, 137.9, 130.6, 128.6, 127.3,
127.5, 126.7, 43.6.
In conclusion, a non-infringing route for enantioselective
synthesis of (R)-lacosamide (1) has been carried out suc-
cessfully. The synthesis started from a commercially
available acrylic acid and was completed within eight
steps with an overall yield of 29%.
MS (ESI): m/z = 162 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C10H12NO: 162.09078; found:
162.09134.
(S)-N-Benzyl-2,3-dihydroxypropanamide (5)
To a 250-mL round-bottomed flask were added t-BuOH (40 mL),
H2O (40 mL), and AD-mix-β (10 g, 1.4 g/mmol), and MsNH2 (0.68
g, 0.09 g/mmol). The mixture was stirred at r.t. for ~15 min, and
then cooled to 0 °C. To this cooled solution was added 4 (1.4 g, 7.1
mmol) and the mixture was stirred for 48 h at 0 °C. The mixture was
quenched with solid Na2SO3 (10.7 g) at r.t. The mixture was diluted
with EtOAc (50 mL) and, after separation of the layers, the aqueous
layer was further extracted with EtOAc (2 × 25 mL). The combined
organic layers were washed with brine (50 mL) and dried (anhyd
Na2SO4). After evaporation of the solvent, the residue was purified
by column chromatography (silica gel, EtOAc–hexane, 6:4) to give
5 (1.35 g, 80%) as a white solid; mp 81–82 °C (Lit.3g 83–84 °C);
93% ee [chiral HPLC analysis: (Chiralcel OD-H, 0.46 nm i.d. × 25
cm, n-hexane–i-PrOH, 9:1; flow rate 0.5 mL/min; UV detector: 254
nm): tR = 6.08 (minor, R-isomer), 8.31 min (major, S-isomer)].
IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectro-
1
photometer. H NMR spectra were recorded on Bruker-300 MHz,
spectrometer in CDCl3 using TMS as internal standard. Mass spec-
tra were recorded on a Finnigan MAT 1020 mass spectrometer op-
erating at 70 eV.
N-Benzylacrylamide (4)
A solution of acrylic acid (2, 0.95 mL, 13.8 mmol), HOBt (2.06 g,
15.2 mmol), and EDCI (2.92 g, 15.2 mmol) in anhyd CH2Cl2 (20
mL) was stirred at 0 °C under a N2 atmosphere for 15 min. This
mixture was treated with benzylamine (3, 1.73 mL, 16.6 mmol) and
Et3N (3.8 mL, 27.7 mmol) and stirred for an additional 8 h. The
mixture was quenched with sat. NH4Cl soln (20 mL) and after 10
min, extracted with CH2Cl2 (2 × 25 mL). The combined organic lay-
ers were washed with H2O (20 mL), NaHCO3 soln (20 mL), and
[α]D25 –34.3 (c 0.1, MeOH) {Lit.3g [α]D25 –35.1 (c 0.1, MeOH)}.
Synthesis 2013, 45, 3383–3386
© Georg Thieme Verlag Stuttgart · New York

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Enantioselective Synthesis of Lacosamide
3385
IR (KBr): 3406, 3296, 2924, 1629, 1536, 1427, 1243, 1071, 695 cm–1.
purified by column chromatography (silica gel, EtOAc–hexane,
3:7) to afford pure 8 (1.5 g, 92%) as a white solid; mp 77–78 °C.
[α]D25 +0.80 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.25–7.37 (m, 5 H), 7.11 (br s, 1
H), 4.48 (d, J = 6.0 Hz, 2 H), 4.18–4.25 (m, 1 H), 3.82–3.98 (m, 2
H), 3.40–3.48 (m, 1 H), 2.63 (br s, 1 H).
IR (KBr): 3424, 2925, 2855, 1744, 1686, 1538, 1454, 1364, 1174,
670 cm–1.
13C NMR (75 MHz, CDCl3): δ = 171.9, 137.6, 128.7, 127.6, 72.2,
64.1, 43.2.
MS (ESI): m/z = 196 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C10H14NO3: 196.09616;
found: 196.09682.
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 8.5 Hz, 2 H), 7.17–
7.37 (m, 7 H), 6.69 (br s, 1 H), 5.00 (dd, J = 4.3, 2.6 Hz, 1 H), 4.40–
4.46 (m, 2 H), 3.80 (dd, J = 11.1, 4.3 Hz, 1 H), 3.64 (dd, J = 11.1,
2.6 Hz, 1 H), 3.25 (s, 3 H), 2.45 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 166.1, 145.5, 137.2, 132.8, 129.9,
128.6, 127.9, 127.5, 127.5, 79.2, 71.7, 59.2, 43.3, 21.7.
MS (ESI): m/z = 364 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO5S: 364.12004;
(S)-3-(Benzylamino)-2-hydroxy-3-oxopropyl 4-Toluenesulfo-
nate (6)
To a stirred solution of diol 5 (1.2 g, 6.1 mmol) in CH2Cl2 (10 mL)
were added Bu2SnO (0.30 g, 1.23 mmol), TsCl (1.17 g, 6.1 mmol),
and Et3N (1.0 mL, 7.38 mmol) at 0 °C. The mixture was stirred until
TLC indicated complete consumption of the starting material. The
reaction was quenched with H2O and the aqueous layer was extract-
ed with CH2Cl2 (2 × 10 mL). The combined organic layers were
washed sequentially with H2O and brine, dried (Na2SO4), and con-
centrated in vacuo. The crude product was purified by column chro-
matography (silica gel, EtOAc–hexane, 2:8) to afford pure 6 (2.04
g, 95%) as a viscous liquid.
found: 364.12132.
(R)-2-Azido-N-benzyl-3-methoxypropanamide (9)
To a stirred solution of 8 (1.4 g, 3.8 mmol) in anhyd DMF (15 mL)
at 70 °C under a N2 atmosphere was added NaN3 (1.25 g, 19.3
mmol). The mixture was then allowed to stir at 70 °C for 6 h, and
then quenched with cool H2O (15 mL) and extracted with EtOAc (2
× 30 mL). The combined organic extracts were washed with cool
H2O (20 mL) and brine (20 mL), dried (anhyd Na2SO4), and concen-
trated to give the crude product, which was purified by flash column
chromatography (silica gel, EtOAc–hexane, 2:8) to give azide 9
(0.78 g, 87%) as a pale yellow liquid.
[α]D25 –3.86 (c 0.5, CHCl3).
IR (neat): 3392, 2928, 1660, 1538, 1359, 1175, 972, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 8.5 Hz, 2 H), 7.22–
7.39 (m, 7 H), 7.08 (br s, 1 H), 4.36–4.48 (m, 4 H), 4.22–4.30 (m, 1
H), 3.44 (d, J = 4.5 Hz, 1 H), 2.46 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.9, 145.4, 137.4, 132.0, 130.2,
130.0, 128.7, 128.0, 127.9, 127.6, 127.6, 127.5.
MS (ESI): m/z = 350 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO5S: 350.10431;
[α]D25 +0.60 (c 0.5, CHCl3).
IR (neat): 3325, 2927, 2106, 1659, 1532, 1454, 1262, 1120, 678 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.27–7.40 (m, 5 H), 6.78 (br s, 1
H), 4.46 (d, J = 5.9 Hz, 2 H), 4.25 (dd, J = 6.8, 3.4 Hz, 1 H), 3.95
(dd, J = 10.2, 3.4 Hz, 1 H), 3.78 (dd, J = 10.0, 6.9 Hz, 1 H), 3.43 (s,
3 H).
13C NMR (75 MHz, CDCl3): δ = 166.8, 137.4, 128.7, 127.6, 72.9,
found: 350.10567.
63.2, 59.1, 43.5.
MS (ESI): m/z = 235 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H15N4O2: 235.11815;
found: 235.11895.
(S)-N-Benzyl-2-hydroxy-3-methoxypropanamide (7)
To a stirred solution of 6 (1.8 g, 5.1 mmol) in MeOH (20 mL) was
slowly added powdered K2CO3 (1.7 g, 12.9 mmol) at 10 °C and the
mixture was stirred at 0 °C for 8 h until TLC indicated complete
consumption of the starting material. The solvent was evaporated
under reduced pressure and the residue was dissolved in EtOAc (25
mL), washed with H2O (25 mL) and brine (25 mL), dried (Na2SO4),
and evaporated under reduced pressure. The crude product was pu-
rified by column chromatography (EtOAc–hexane, 3:7) to afford
pure 7 (0.97 g, 90%) as a viscous liquid.
(R)-2-Amino-N-benzyl-3-methoxypropanamide (10)
A solution of 9 (0.6 g, 2.5 mmol) and Ph3P (0.73 g, 2.8 mmol) in
THF–H2O (9:1, 20 mL) was stirred for 12 h at 50 °C under a N2 at-
mosphere. The mixture was then diluted with EtOAc (30 mL) and
acidified with 5% HCl (20 mL). The aqueous phase was extracted
with EtOAc (2 × 25 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The crude residue was purified
by column chromatography (silica gel, CHCl3–MeOH, 0.2:9.8) to
give pure 10 (0.45 g, 85%) as a viscous oil.
[α]D25 +1.66 (c 0.5, CHCl3).
IR (neat): 3399, 2925, 1655, 1535, 2454, 1247, 1103, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.27–7.37 (m, 5 H), 7.079 (br s, 1
H), 4.49 (d, J = 5.9, Hz, 2 H), 4.26 (dd, J = 9.9, 5.2 Hz, 1 H), 3.68
(dd, J = 5.6, 2.6 Hz, 1 H), 3.41 (s, 3 H), 3.25 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 171.4, 137.8, 128.7, 127.6, 127.5,
73.4, 70.4, 59.1, 43.2.
MS (ESI): m/z = 210 [M + Na]+.
[α]D25 –2.0 (c 0.5, CHCl3).
IR (neat): 3450, 3448, 2924, 1671, 1450, 1115, 769, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.80 (br s, 1 H), 7.22–7.37 (m, 5
H), 4.39–4.52 (m, 2 H), 3.57–3.70 (m, 2 H), 3.39–3.42 (m, 1 H),
3.37 (s, 3 H), 2.38 (br s, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C11H16NO3: 210.11190;
found: 210.11247.
13C NMR (75 MHz, CDCl3): δ = 166.8, 137.4, 128.7, 127.6, 72.9,
59.1, 53.4, 43.5.
MS (ESI): m/z = 209 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H17N2O2: 209.12800;
(S)-1-(Benzylamino)-3-methoxy-1-oxopropan-2-yl 4-Toluene-
sulfonate (8)
To a stirred solution of 7 (0.9 g, 4.3 mmol) in CH2Cl2 (10 mL) were
added sequentially Et3N (0.7 mL, 5.1 mmol), TsCl (0.9 g, 4.7
mmol), and catalytic amount of DMAP at 0 °C. The mixture was
stirred for 2 h until TLC indicated complete consumption of the
starting material. The reaction was quenched with H2O (10 mL) and
the aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com-
bined organic layers were washed sequentially with H2O and brine,
dried (Na2SO4), and concentrated in vacuo. The crude product was
found: 209.12845.
(R)-2-Acetamido-N-benzyl-3-methoxypropanamide (Lacos-
amide, 1)
To a stirred solution of 10 (0.3 g, 1.4 mmol) in anhyd CH2Cl2 (5 mL)
was slowly added Ac2O (0.20 mL, 2.1 mmol) dissolved in anhyd
CH2Cl2 (1 mL) and catalytic amount of DMAP. The resulting solu-
tion was stirred at r.t. for 1 h. The solvent was removed under re-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3383–3386

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S. B. Wadavrao et al.
PAPER
(3) (a) Muthukrishnan, M.; Mujahid, M.; Sasikumar, M.;
duced pressure and the residue was purified by column
chromatography (silica gel, CHCl3–MeOH, 0.1:9.9) to afford pure
1 (0.32 g, 90%) as a white solid; mp 140–141 °C (Lit.1a 143–
144 °C); 95% ee [chiral HPLC analysis: (Chiralcel OD-H, 0.46 nm
i.d. × 25 cm, n-hexane–i-PrOH–TFA, 60:40:1; flow rate 0.5
mL/min; UV detector: 220 nm): tR = 10.40 (R-isomer), 11.6 min (S-
isomer).
Mujumdar, P. Tetrahedron: Asymmetry 2011, 22, 1353.
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[α]D25 +16.2 (c 1, MeOH) {Lit.1a [α]D25 +16.4 (c 1, MeOH)}.
IR (KBr): 3288, 3067, 2923, 2854, 1636, 1547, 1453, 1384, 1121,
696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.24–7.40 (m, 5 H), 6.78 (br s, 1
H), 6.48 (br s, 1 H), 4.51–4.60 (m, 1 H), 4.48 (d, J = 5.7 Hz, 2 H),
3.81 (dd, J = 9.5, 4.2 Hz, 1 H), 3.40–3.48 (m, 1 H), 3.38 (s, 3 H),
2.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 169.9, 137.8, 128.7, 127.5,
71.6, 59.1, 52.4, 43.6, 23.2.
MS (ESI): m/z = 251 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O3: 251.13818;
found: 251.13902.
(5) (a) Wadavrao, S. B.; Ghogare, R. S.; Narsaiah, A. V.
Tetrahedron Lett. 2012, 53, 3955. (b) Narsaiah, A. V.;
Narsimha, P. Med. Chem. Res. 2012, 21, 538. (c) Narsaiah,
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Acknowledgement
S.B.W. is thankful to CSIR-New Delhi and CSIR-IICT Hyderabad
for providing a fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
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nnfomartit
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