An efficient synthesis for eslicarbazepine acetate, oxcarbazepine, and carbamazepine

Article abstract of DOI:10.1016/j.tetlet.2013.03.089

Efficient methods have been developed for the synthesis of three active pharmaceutical ingredients (APIs) carbamazepine (Tegretol) 1, oxcarbazepine (Trileptal) 2, and eslicarbazepine acetate (Exalief) 3 by employing enantioselective reduction and carboxamidation reaction.

Full text of DOI:10.1016/j.tetlet.2013.03.089

Tetrahedron Letters 54 (2013) 2841–2844
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis for eslicarbazepine acetate, oxcarbazepine,
and carbamazepine
B. Ravinder a, S. Rajeshwar Reddy a, M. Sridhar a, M. Murali Mohan a, Katkam Srinivas a, A. Panasa Reddy b,
Rakeshwar Bandichhor a,
⇑
a Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Innovation Plaza, Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India
b Department of Chemistry, Osmania University, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient methods have been developed for the synthesis of three active pharmaceutical ingredients (APIs)
carbamazepine (TegretolÒ) 1, oxcarbazepine (TrileptalÒ) 2, and eslicarbazepine acetate (ExaliefÒ) 3 by
employing enantioselective reduction and carboxamidation reaction.
Received 6 January 2013
Revised 17 March 2013
Accepted 20 March 2013
Available online 27 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Anti-epileptic
Enantioselective reduction
Carboxamidation
Antiepileptic drugs (AEDs) are meant for the treatment of epi-
lepsy which is one of the most common serious chronic neurolog-
ical disorders resulting in recurrent gratuitous seizures. In the past
twenty years, fifteen new antiepileptic drugs (AEDs) were ap-
proved. Among all, eslicarbazepine acetate 31 (Fig. 1) was launched
in Europe (2009) for the treatment of adjunctive therapy for partial
onset of seizures, with or without secondary generalizations in
adults with epilepsy.2 The mechanism of its action is the inhibition
of voltage gated sodium channels in the brain, as a result, making
them less prone to excitability.3
Eslicarbazepine acetate 3 is considered to be a second genera-
tion drug to oxacarbazepine4 2 and a third generation drug to car-
bamazepine 1. Except the variation at the 10 and 11 positions,
eslicarbazepine acetate 3 is structurally similar to 1 and 2. It is ad-
judged as a prodrug to (S)-licarbazepine 12 which is also an active
metabolite of 2. Eslicarbazepine acetate 3 is evolved from 1 and 2
in order to have improved efficacy and safety preventing the for-
mation of toxic epoxide metabolite. Eslicarbazepine acetate 3 is
metabolized to (S)-licarbazepine in the liver thereby improving
its efficacy.5
anism of action of both oxcarbezepine 2 and eslicarbazepine
acetate 3 is found to be indistinguishable.9 Oxcarbezepine 2, is a
second generation drug of the dibenz[b,f]azepine family and used
in the treatment of epilepsy,10 psychosomatic diseases,11 trigemi-
nal neuralgia,11 Parkinsonian syndromes,12 and AIDS-related neu-
ral disorders.13 Most of the syntheses toward
2 involve
transformations with the iminostilbene or iminodibenzyl rings ob-
tained through a sequence of oxidation and reduction reactions
from o-nitro toluene.14 The worldwide consumption of oxcarbeze-
pine 2 is 359,322 kg and 521.9 M $USD per annum.6 Schindler et al.
developed the first synthesis of carbamazepine 1, a dibenz[b,f]aze-
pine based drug, and was approved as an anticonvulsant agent15 in
1965 in the United Kingdom. Prior to this, the carbamazepine 1
was also marketed as a drug for the treatment of trigeminal neural-
gia in 1962.16 Being a first generation antiepileptic drug,17 the
worldwide
consumption
of
carbamazepine
1
reached
1,003,807.8 kg per annum with the sales of 651.3 M $USD.6 The
current industrially practiced route for the synthesis of compound
1, generally involves the amidation of iminostilbene with sodium
isocyanate/chloro acetic acid.18 Since, there is a huge market po-
tential for carbamazepine (TegretolÒ) 1, oxcarbazepine (TrileptalÒ)
2, and eslicarbazepine acetate (ExaliefÒ) 3, as antiepileptic drug
products, we explored the possibilities for the synthesis of these
compounds starting from commercially available 10-methoxy-
5H-dibenzo[b,f]azepine 4.
This drug was discovered and developed by Bial and the world-
wide consumption of eslicarbazepine acetate 3 is 4283.7 kg and
26.4 M $USD per annum.6 The current industrially practiced route
for the synthesis of compound 3 generally involves the asymmetric
catalytic reduction of oxcarbazepine7 or resolution of racemic lica-
rbazepine8 followed by acetylation to get compound 3. The mech-
In our endeavor, we developed a straightforward and high-
yielding synthesis of three active pharmaceutical ingredients
(API’s) carbamazepine (TegretolÒ) 1, oxcarbazepine (TrileptalÒ) 2,
and eslicarbazepine acetate (ExaliefÒ) 3 starting from common
⇑
Corresponding author.
E-mail address: rakeshwarb@drreddys.com (R. Bandichhor).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.089

2842
B. Ravinder et al. / Tetrahedron Letters 54 (2013) 2841–2844
O
AcO
AcO
O
HO
CH3
O
N
H2N
N
N
H
N
N
O
O
N
NH2
O
O
NH2
NH2
3
9
O
NH2
1
2
3
12
Carbamazepine
Oxcarbazepine
(Trileptal®
Eslicarbazepine acetate
(Exalief ®
(S)-Licarbazepine
O
O
(Tegretol ®
)
)
)
Figure 1. Structure of three active pharmaceutical ingredients (APIs) carbamaze-
pine (TegretolÒ) 1, oxcarbazepine (TrileptalÒ
(ExaliefÒ) 3 and licarbazepine 12.
)
2, and eslicarbazepine acetate
N
N
H
H
4
6
Scheme 1. Retrosynthetic approach to 3.
and
easily
accessible
intermediate,
10-methoxy-5H-
dibenzo[b,f]azepine 4.
There are several methods reported in the literature for the syn-
thesis of eslicarbazepine acetate 3 and most of the syntheses re-
ported in the literature utilize resolution of 1219–24 whereas, we
developed an enantioselective approach toward the synthesis of
eslicarbazepine acetate 3. In the reduction step, we employed R-
2-Me-CBS to obtain a chiral alcohol in high enantiomeric purity.
This reduction laid a foundation for asymmetric synthesis of 3.
There are many other approaches which employ very expensive
reducing agents such as (S,S)-TsDAEN and [Rh(COD)(RcSp-Duan-
Phos)]BF4 and other chiral catalysts.25 Unless the turn over number
of these contemporary catalysts is extremely high we cannot uti-
lize them in the development of cost effective synthesis of 3. Keep-
ing cost component as the high priority, we envisioned to develop
the cost efficient synthesis of 3 by employing R-Me-CBS in the
reduction step. Considering the current rate of catalysts, compara-
tive cost analysis of both the reagents is included in Table 1.
Retrosynthetic analysis revealed that one can synthesize 3
starting from 6 as shown in Scheme 1. However, compound 6
can be obtained from its methyl enolate 4. In particular, the syn-
thesis of eslicarbazepine acetate 3 starts from 4 that involves a
de-protection strategy in the presence of 50% HCl in isopropyl alco-
hol affording product 6 in >85% yield. Asymmetric reduction of ke-
tone functionality in 6 by employing R-2-Me-CBS led to an access
of corresponding alcohol 7a. Compound 7a was subjected to acyl-
ation affording intermediate 9 in 80% yields. The compound 9 in
turn was treated with chlorosulfonyl isocyanate (ClSO2NCO) to ob-
tain eslicarbazepine acetate 3 in 77% yield as shown in Scheme 2.
The key step turned out to be enantioselective reduction which
was optimized to obtain optimal quantities of catalyst and reduc-
ing agent as 0.02 mol % and 1.3 equiv of BH3ÁDMS, respectively.
As a result, optimized conditions afforded the product (S)-(À)-
10,11-dihydro-5H-dibenzo[b,f]azepin-10-ol, 7a in 91% isolated
yield with >99% of enantiomeric purity as shown in Table 2 (entry
3).
O
O
HO
a
b
N
H
N
H
N
H
4
6
7(a)
O
O
O
O
d
c
N
N
H
O
H2N
3
9
(a) 50% aq.HCl, isopropyl alcohol, 60-65°C, 2-3 h, 85.5% (b) BH3 : DMS
(1.3 eq.), R-2-Me-CBS (0.02 mol%), CH2Cl2, 0-10 °C, 3-4 h, 91% (c)
Ac2O/DCM, 80% (d) ClSO2CN, CH2Cl2 /0-5 °C - 25°C, 77%
Scheme 2. Synthesis of 3.
yield. There are several reagent combinations for carboxamidation
of the compound 9 to obtain 3. We attempted a few of them for
example, urea/aq HCl26 (degradation of starting material along
with traces of 3), sodium isocyanate (incomplete conversion),
and sodium isocyanate/pyridinium p-toluene sulfonate27 (product
formation was in good yields but the work up procedure was quite
tedious) gave the required compound 3 in good yields. As the last
resort in our endeavor, we attempted this transformation by
employing sulfurisocyanatidic chloride,28 and eslicarbazepine ace-
tate 3 was obtained in very good yield, purity, and enantiomeric
excess (77%, >99%, and >98.5%, respectively). The structure of the
product was confirmed by 1H NMR, Mass, IR spectra as well as
other spectral and analytical methods. Use of sulfurisocyanatidic
chloride reagent in carboxamidation yielded a very clean product
and the work-up procedure was very simple and suitable for large
scale manufacturing. As regards our strategy to develop a process
for 3, the carboxamidation of compound 9 using sulfurisocyanati-
dic chloride is not precedented in this context. The proposed mech-
anism for this transformation is featured in Scheme 3.
The poor reactivity of aniline nitrogen in compound 7a, led us to
develop a process for the selective o-acetylation to obtain the ad-
vanced intermediate 9. During acetylation with the use of acetic
anhydride in dichloromethane, we observed a slight racemization
leading to only 98% enantiomeric purity. However, the conversion
was quite efficient as we were able to isolate the product in 80%
En route to the synthesis of 3 we were also able to synthesize
carbamazepine (TegretolÒ) 1 as shown in Scheme 4. Schindler
Table 1
Current cost analysis of reagents
Catalyst
% Yield
% ee
Catalyst loading (mol %)
Cost per kg in lakhs
R-2-Me-CBS
91
>99
17
94
0.02
5
0.002
0.02
1.5
8.5
7.2
5.5
(S)-
a,a
-Diphenylprolinol
Incomplete conversion
Not available
95
[Rh(COD)(RcSp-DuanPhos)]BF4
(S,S)-TsDAEN/RuCl2(p-cymene)2
97.8

B. Ravinder et al. / Tetrahedron Letters 54 (2013) 2841–2844
2843
Table 2
Optimization of BH3ÁDMS and R-2-Me-CBS equivalence in the synthesis of 7a
Entry
BH3ÁDMS (equiv)
R-2-Me-CBS (mol %)
Chiral purity (ee)
% Yield
1
2
3
4
0.8
1.0
1.3
1.3
0.01
0.01
0.02
0.005
90
94
>99
92
Incomplete
81
91
84
AcO
O
O
AcO
O
a
+
N
N
N
N
N
H
H
O
O
O
10
9
HN
O
H2N
H2N
C
N
O
O
Cl
S
O
Cl
S
O
4
5
2
H2O
AcO
HCl
b
AcO
2
(a) ClSO2CN, CH2Cl2 /0-5 °C-25 °C (b) 50% aq.HCl, isopropyl
alcohol, 60-65°C, 2-3 h, 70% overall yield
N
N
O
O
H2SO4
HN
S
O
Scheme 5. Synthesis of 2.
H2N
OH
O
11
3
O
straightforward, and high-yielding synthesis of 2. In particular,
the treatment of methoxy dibenzo azepine 4 with sulfurisocyanati-
dic chloride afforded a mixture of methoxy carboxamide derivative
5 and oxcarbazepine 2 in almost 1:1 ratio.
H
H
Scheme 3. Proposed mechanism of carboxamidation.
The resulting crude mixture was further treated with IPA/HCl to
afford the desired oxcarbazepine 2 in good overall yield and purity
(70%, >99%).
O
O
HO
b
a
We have developed an efficient process for three antiepileptic
drug substances (carbamazepine 1, oxcarbazepine 2, and
eslicarbazepine acetate 3), starting from a readily available single
key starting material 4. The reduction of ketone in the presence
of R-2-Me-CBS catalyst gave an excellent enantiomeric excess dur-
ing the synthesis of eslicarbazepine acetate 3 and a novel carbox-
amidation strategy was employed to the azepine class of
compound 9, by using sulfurisocyanatidic chloride. The developed
process can be utilized for the commercial manufacturing of these
antiepileptic agents.
N
H
N
H
N
H
4
6
7(b)
c
d
N
N
H
O
H2N
1
8
(a) 50% aq.HCl, isopropyl alcohol, 60-65°C, 2-3 h, 85.5%
(b) NaBH4 (1.19 eq.), MeOH, 10-30 °C, 2-3 h, 89% (c) p-
toluenesulfonic acid (94.56 mmol), toluene, reflux, 6-8 h, 78% (d)
ClSO2CN, CH2Cl2 /0-5 °C-25°C, 78%
Supplementary data
Scheme 4. Synthesis of 1.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.03.089.
developed the first synthesis of carbamazepine 1. In addition to
this, several methods are also reported in the literature for the syn-
thesis of carbamazepine 12 by involving a series of reactions start-
ing with o-nitrotoleuene.29
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