A facile synthesis of melatonergic antidepressant agomelatine

Article abstract of DOI:10.1016/j.tetlet.2012.10.077

Agomelatine was synthesized from 8-aminonaphthalen-2-ol by diazotization-iodination, formylation, C-C bond formation by nitroaldol and Pd/C hydrogenation of β-nitrovinylnaphthalene followed by N-acetylation. The route reported employs readily and commercially viable starting materials and reagents, and can potentially be utilized for process synthesis of agomelatine.

Full text of DOI:10.1016/j.tetlet.2012.10.077

Tetrahedron Letters 53 (2012) 7125–7127
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Tetrahedron Letters
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A facile synthesis of melatonergic antidepressant agomelatine q
Bhaskar Kandagatla a, Vetukuri Venkata Naga Kali Vara Prasada Raju b, Ganta Madhusudhan Reddy b,
Sirigiri Chandrakanth Rao a, Javed Iqbal a, Rakeshwar Bandichhor b, Srinivas Oruganti a,
⇑
a COSMIC Discoveries, Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
b API R&D, IPDO-Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupally, Qutubullapur, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Agomelatine was synthesized from 8-aminonaphthalen-2-ol by diazotization-iodination, formylation, C–
C bond formation by nitroaldol and Pd/C hydrogenation of b-nitrovinylnaphthalene followed by N-acet-
ylation. The route reported employs readily and commercially viable starting materials and reagents, and
can potentially be utilized for process synthesis of agomelatine.
Received 14 September 2012
Revised 17 October 2012
Accepted 20 October 2012
Available online 26 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sandmeyer reaction
Formylation
Henry reaction
b-Nitrovinylnaphthalene
Catalytic hydrogenation
Search for better drugs for the clinical management of depres-
sion has been driving the development of more selective antide-
pressant drugs with a novel biological mechanism of action. Most
of the known antidepressants act through monoaminergic mecha-
nisms, and recent research has focused on the development of non-
monoaminergic approaches for potentially improved treatment.
Agomelatine 1, a melatonin analogue (Fig. 1), represents a new
class of antidepressants and possesses both melatonergic agonist
and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist
properties, and has been reported to be an effective antidepressant
therapy.1 Recently, agomelatine 1 (Valdoxan/Thymanax, Servier)
was approved for the treatment of major depression and is the first
known antidepressant that works via a non-monoaminergic mech-
anism of action.2
A medicinal chemistry route to agomelatine 1 was first reported
by Yous et al. starting from (7-methoxynaphth-1-yl)acetic acid.3
Most of the known literature procedures involve the preparation
of 7-methoxy-1-naphthylacetonitrile as the key intermediate
which is derived from a relatively expensive 7-methoxy-1-tetra-
lone, as the starting material.4 Recently, synthesis of agomelatine
from naphthylglyoxylic acid as an alternate starting material has
been reported as a viable approach.5 Before attempting modifica-
tions to improve the yields and substrate scope in the process
development of agomelatine 1,6 key chemistry issues related to
selective reduction of acid derivatives and nitriles with excess
NHAc
NHAc
MeO
MeO
N
H
Melatonin
Agomelatine 1
Figure 1. Melatonergic antidepressants melatonin and agomelatine 1.
reducing reagent under high pressure conditions need to be ad-
dressed. Accordingly, the development of new and simple routes
utilizing alternate starting materials is necessary.
As a part of our ongoing program on the identification of scalable
and cost-effective processes for active pharmaceutical ingredients,
we were interested in identifying inexpensive and readily available
chemicals which would serve as the starting point for the synthesis.
In this regard, we report a facile route for agomelatine 1, starting
from 8-aminonaphthalen-2-ol 4 by sequential diazotization-iodin-
ation, formylation, Henry reaction, further reduction of the double
bond and finally N-acetylation. (Fig. 2), by using low cost bench-
top chemicals and reagents.
Our initial efforts focused upon the preparation of 8-bro-
monaphthalen-2-ol 3a from commercially available 2-napthol 2a.
Attempted bromination of 2a using bromine and acetic acid gave
a mixture of products (Scheme 1). Also, bromination on protected
napthols 2b, 2c gave an inseparable mixture of isomers. Isolation of
q
DRL-IPD Communication No.: IPDO-IPM-00345
⇑
Corresponding author. Tel.: +91 40 6657 1637.
E-mail address: soruganti@ilsresearch.org (S. Oruganti).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.077

7126
B. Kandagatla et al. / Tetrahedron Letters 53 (2012) 7125–7127
NHAc
NH2
I
I
a
HO
HO
b
MeO
CHO
MeO
HO
MeO
HO
4
5
6
NO2
Agomelatine
CHO
NH2
X
MeO
e
MeO
c or d
NH2
7
8
X = Br, I
Figure 2. Retrosynthetic analysis of agomelatine 1.
NHAc
g
f
MeO
MeO
Br
RO
a
RO
Agomelatine 1
9
Scheme 2. Reagents and conditions: (a) (i) NaNO2, HCl, H2O, 0–5 °C, 1 h, (ii) aq KI,
0–5 °C, 2 h, 73%; (b) dimethyl sulfate, K2CO3, Acetone, rt, 2 h, 95%; (c) (i) CuCN, NMP,
150 °C, 2 h, 76%, (ii) DIBAL, THF, À78 °C, 2 h, 72%; (d) n-BuLi, THF, À78 °C, 20 min,
then DMF, rt, 2 h, 70%; (e) CH3NO2, NH4OAc, AcOH, 100 °C, 2 h, 76%; (f) 10% Pd-C,
H2, EtOAc rt, 12 h, 80%; (g) AcCl, Et3N, CH2Cl2, 0 °C, 2 h, 95%.
2a-c
2a, 3a: R = H; 2b ,3b: R = OMe; 2c, 3c: R = OAc
Scheme 1. Reagents and conditions: (i) Br2, AcOH or NBS, CH3CN.
3a-c
the iodo group in 6 by halogen/metal exchange with n-butyl lithium
at À78 °C in THF, followed by the addition of DMF, to obtain 7 in 70%
yield.
the desired 1-bromo substituted product required column chro-
matographic purification, and this method was not amenable for
an efficient preparation of the starting material required for a
large-scale synthesis of 1.
The key step of chain homologation was effected by the C–C
bond formation via nitroaldol reaction7 of 7 with nitromethane
in the presence of ammonium acetate in acetic acid at 100 °C to ob-
tain selectively trans b-nitrovinylnaphthalene 8. The 1H NMR spec-
Due to the lack of success with direct halogenations of beta-nap-
thol or their protected derivatives, we have identified 8-amin-
onaphthalen-2-ol 4 as a cheap and readily available precursor for
accessing the 1-bromo or iodonapthalene derivative via Sandmeyer
reaction. Sandmeyer approach addresses the issue of regioselectiv-
ity of halogenation encountered during our attempts to directly
brominate beta-napthol. Diazotization–halogenations with sodium
nitrite and different halogen sources were examined in various
solvents (Table 1). We observed that the preparation of 8-bromo-
b-napthol via Sandmeyer reaction on 4 was not efficient. Diazotiza-
tion of 4 followed by treatment with potassium iodide furnished
8-iodo-b-napthol 5 in 73% yield (Scheme 2). The second step
involved the protection of the hydroxy group with dimethyl sulfate
in potassium carbonate and acetone to furnish 1-iodo-7-methoxy-
naphthalene 6 in 95% yield.
In the next step, formylation of 6 was carried out using two
different methods. In the first method, direct cyanation (Rosen-
mund-von Braun) of 6 with an excess of copper(I) cyanide in a
polar high-boiling solvent such as NMP at reflux temperature gave
the corresponding 7-methoxy-1-naphthonitrile in 76% yield, which
was further reacted with DIBAL to obtain 7-methoxy-1-naphthalde-
hyde 7 in 72% yield. The second method involved the replacement of
trum of compound 88 exhibited the hydrogen
a to the nitro group
as a doublet at d 7.66 ppm with J = 13.2 Hz and the hydrogen b to
the nitro group appeared as a doublet at d 8.77 ppm with a J value
of 13.2 Hz, confirming unambiguously to the existence of exclusive
trans b-nitrovinylnaphthalene. Preparation of arylethylamines
from b-nitrostyrenes using LiAH4 and borane is reported in the lit-
erature,9 but we decided to opt for hydrogenation in the presence
of palladium-carbon instead. We observed that the catalytic hydro-
genation of 8 using 5% Pd/C charcoal in EtOH,10 proceeded
smoothly under ambient pressure to furnish the corresponding
aryl ethylamine, namely, 2-(7-methoxynaphthalen-1-yl)ethan-
amine 9 with 80% yield. Finally, N-acetylation of 9 with acetyl chlo-
ride in the presence of triethylamine in dichloromethane afforded
the N-acetylated product agomelatine 1 in 95% yield. Encouraged
by the efficiency of the reduction of the b-nitrovinylnaphthalene,
we decided to carry out the reduction and acetylation steps in
one pot. Hydrogenation of 8 in the presence of 10% Pd-C, in the
presence of acetic anhydride and acetic acid as the solvent fur-
nished directly agomelatine 18 in 65% yield.
In conclusion, we have delineated a facile synthesis of melaton-
ergic antidepressant agomelatine 1 from the commercially available
8-aminonaphthalen-2-ol 5 by using sequential diazotization–iodin-
ation, formylation, C–C bond formation by nitroaldol and the reduc-
tion of b-nitrovinylnaphthalene followed by N-acetylation. This
approach also presents an efficient way to access 1-(2-amino-
ethyl)-2-methoxynapthalene 9, as compared to the literature
methods involving the reduction of either 2-(7-methoxynaphtha-
len-1-yl)acetonitrile or 2-(7-methoxynaphthalen-1-yl)acetamide.
Table 1
Sequential diazotization–halogenations of 8-aminonaphthalen-2-ol 4
Entry
Conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
CuBr, NaNO2, EtOH, H2O, 3N HCl
CuBr, NaNO2, H2O, 3N HCl
CuBr, NaNO2, Acetone, H2O, 3N HCl
CuBr, NaNO2, Methanol, H2O, 3N HCl
NaI, NaNO2, H2O, 3N HCl
NaI, NaNO2, EtOH, H2O, 3N HCl
NaI, NaNO2, MeOH, H2O, 3N HCl
NaI, NaNO2, Acetone, H2O, 3N HCl
KI, NaNO2, MeOH, H2O, 3N HCl
KI, NaNO2, H2O, 3N HCl
3
3
4
4.5
2
2
2.5
3
3
3
20
18
15
20
12
20
23
60
30
73
Acknowledgment
We thank the Institute of Life Sciences and Dr. Reddy’s Labora-
tories Ltd. for supporting this work.

B. Kandagatla et al. / Tetrahedron Letters 53 (2012) 7125–7127
7127
6. (a) Zhou, S.; Jian, F. Faming Zhuanli Shenqing CN101759591, 2010.; (b) Hu, W.;
Xu, Q.; Yang, L. Faming Zhuanli Shenqing CN 101792400, 2010.; (d) Hardouin,
C.; Lecouve, J.-P.; Bragnier, N. PCT Int. Appl. WO2010015745, 2010.; (e)
Bontempelli, P.; Jalenques, X.; Starck, J.-B.; Sery, J.-P. PCT Int. Appl. WO
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Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.10.077.
7. Liu, J.-T.; Yao, C.-F. Tetrahedron Lett. 2001, 42, 6147.
8. Compound 8: IR (Neat) cmÀ1 3028, 2853, 1680, 1255; mp: 128–132 °C; 1H
NMR (400 MHz, CDCl3): d 8.77 (d, J = 13.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.81
(d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 13.2 Hz, 1H), 7.37 (t,
J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.23 (dd, J = 2.4 Hz, 1H), 3.99 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 158.35, 132.44, 130.73, 129.97, 129.37, 128.07, 127.49,
123.25, 118.28, 101.44, 75.22, 55.40, 31.04; ESI [M++H]: 229.9; HRMS (ESI) m/z
calcd. For C13H11NNaO3 [M+Na]+: 252.0637, found 252.0634; compound 1: IR
(Neat) cmÀ1 3252, 2937, 1621, 1509, 1031, 755; mp: 107–108 °C; 1H NMR
(400 MHz, DMSO-d6): d 7.72 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 6.5, 2.8 Hz, 2H),
7.44 (d, J = 2.4 Hz, 1H), 7.20–7.27 (m, 2 H), 7.13 (dd, J = 2.4, 8.8 Hz, 2H), 5.70 (br
s, 1H), 3.95 (s, 3H), 3.58 (q, J = 6.8 Hz, 2H), 3.21 (t, 2H), 1.89 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 171.30, 158.02, 133.24, 133.12, 130.28, 129.29, 127.15,
123.13, 118.30, 102.35, 55.56, 40.48, 32.96, 22.73. ESI [M++H]: 244.1
9. Kabalka, G. W.; Laila, G. M. H.; Varma, R. S. Tetrahedron 1990, 46, 7443.
10. Kohno, M.; Sasao, S.; Murahashi, S.-I. Bull. Chem. Soc. Jpn. 1990, 63, 1252.
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