A simple and efficient procedure for synthesis of agomelatine

Article abstract of DOI:10.14233/ajchem.2016.19712

A simple and efficient process for the large scale preparation of agomelatine, an antidepressant drug is described. Agomelatine was synthesized from 7-methoxy-1-tetralone in five steps. The route reported employs readily, commercially viable starting materials, reagents and potentially be utilized for the process of synthesis of agomelatine.

Full text of DOI:10.14233/ajchem.2016.19712

Asian Journal of Chemistry; Vol. 28, No. 6 (2016), 1367-1370
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19712
A Simple and Efficient Procedure for Synthesis of Agomelatine
*
G. GURUNADHAM, R. MADHUSUDHAN RAJU and Y. VENKATESWARLU
Department of Chemistry, Osmania University, Hyderabad-500 007, India
Corresponding author: E-mail: garlapati.gb7@gmail.com
Received: 1 November 2015; Accepted: 30 January 2016;
*
Published online: 29 February 2016;
AJC-17809
A simple and efficient process for the large scale preparation of agomelatine, an antidepressant drug is described. Agomelatine was
synthesized from 7-methoxy-1-tetralone in five steps. The route reported employs readily, commercially viable starting materials, reagents
and potentially be utilized for the process of synthesis of agomelatine.
Keywords: Knoevenagel condensation, Decarboxylation, Esterification, Aromatization, Reductive acetylation, Agomelatine.
Agomelatine as the first known antidepressant that works via
a non-monoaminergic mechanism of action was approved for
the treatment of major depression in Europe in 2009.
INTRODUCTION
Depression is a common illness worldwide, with an
estimated 350 million people affected. It is different from usual
mood fluctuations and short-lived emotional responses to
challenges in everyday life. By 2020, according to the WHO
report, depression will be the second disease next to ischemic
heart disease and become one of the major contributors to the
global disease burden [1,2]. The current antidepressant drugs
in clinic can generally be classified into several categories,
which include tricyclic antidepressant, monoamine oxidase
inhibitors, selective serotonin, serotonin norepinephrine,
noradrenaline and dopamine-noradrenaline reuptake inhibitors
Agomelatine was first synthesized byYous et al. [14] in a
multistep synthetic route starting from (7-methoxy-1-naphthyl)
acetic acid. The majority of the known literature procedures
involve the preparation of 7-methoxy-1-naphthylacetonitrile
synthesis of agomelatine from naphthyl glyoxylic acid as an
alternate starting material have been reported as a feasible
approach [15]. Before attempting modifications to improve
the yields and substrate scope in the process development of
agomelatine [16],recently facile route for agomelatine starting
from 8-aminonaphthalene-2-ol by sequential diazotization,
iodination, formylation, Henry reaction, further reduction of
the double bond and finally N-acetylation key chemistry issues
related to selective reduction of acid derivatives and nitriles
with excess reducing reagent under high pressure conditions
need to be addressed. Accordingly, the development of new
and simple routes utilizing alternate starting materials is
necessary. Several modifications of the original procedure,
mostly aiming at industrial scale synthesis, have been published
later in the patent literature [17].
(
Fig. 1) [3-5]. Agomelatine is a melatonin analog represents a
new class of antidepressants. It is a potent melatonergic agonist
MT1 and MT2) and also has 5-hydrotryptamine 2C (5-HT2
(
C
)
antagonist properties. In particular, a great deal of pre-clinical
and clinical data indicated that agomelatine has a comparable
antidepressant efficacy to other well as established antidepre-
ssants [6-10]. Furthermore, there are no increases in specific
side effects such as sexual disfunction and body weight gains,
which are common with some classes of antidepressants [11-13].
O
H
N
O
H
N
N
H
O
O
O
NH
O
O
N
H
N
H
Agomelatine
Melatonin
Ramelteon
Pinoline
Fig. 1. Chemical structures of representative antidepressants

1
368 Gurunadham et al.
EXPERIMENTAL
Solvents and reagents were obtained from commercial
Asian J. Chem.
obtained crude was purified by column chromatography on
00-200 silica gel by eluting 50 % ethyl acetate in n-hexane,
1
to get off-white solid (3.45 g, 71.6 % yield).
–1
sources and used without further purification. The reactions
were monitored by TLC plates Merck silica gel 60, F254 and
visualization with UV light (254 and 365 nm). H NMR spectra
IR (KBr, νmax, cm ): 3017, 2927, 2842, 2731, 2642, 2533,
2362, 2338, 2082, 1876, 1712, 1492, 1461, 1698, 1566, 1407,
1444, 1298, 1373, 1335, 1251, 1220, 1197, 1170, 1080, 1042,
1
1
were recorded on Bruker-400 spectrometer in CDCl
3
using
392, 889, 812, 754, 731, 656; H NMR (400 MHz, CDCl
7.04 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.8 (dd, J
3
): δ
1
TMS as internal reference. IR spectra were recorded on a Perkin-
Elmer FT-IR spectrophotometer using KBr discs. The Mass
spectrum (70 eV) was recorded on an HP 5989 A LC-MS
spectrometer. Melting points were recorded on Buchi R-535
apparatus and are uncorrected.
=
2.8 Hz, J = 8.0 Hz, 1H), 6.02 (t, J = 4.4 Hz, 1H), 4.14 (q, J =
2
7.1 Hz, 2H), 3.78 (s, 3H), 3.41 (s, 1H), 3.40 (s, 1H), 2.72 (t,
J = 8.0 Hz, 2H), 2.23-2.32 (m, 2H), 1.24 (t, J = 7.4 Hz, 3H);
EI-MS m/z (272.21 %, M + 1).
Step-1: Synthesis of [(E)-2-cyano-2-(2,3-dihydro-6-
methoxy naphthalen-4(1H)-ylidene) acetic acid] (2a): This
Knoevenagel reaction was initiated. It was noticed that less
product formation and incompleteness of reaction even after
heating reaction at 100-110 °C for 24 h. Better conversion
and product formation observed in using ammonium acetate
and acetic acid as dehydrating agent. Reactions were screened
using different bases and solvents, KO Bu, NaH, TEA,
piperidine and NaOMe without encouraging results as shown
in the below table (entry 1-10, Table-1).
A mixture of the 7-methoxy-1-tetralone (10.0 g, 56.7 mmol),
ethyl cyanoacetate (7.7 g, 68.1 mmol), then added ammonium
acetate (1.09 g, 14.1 mmol) followed by added glacial acetic
acid (5 mL, 2.0 vol) in toluene (100 mL, 10 vol) the mixture
warmed to reflux with a Dien stark water trap for 24 h. The
reaction mixture was cooled and diluted with toluene (100
mL, 10 vol) washed with water (2 × 100 mL) and the washed
aqeous layer were extracted with toluene (2 × 100 mL), the
Step-2b: 2-(2,3-Dihydro-6-methoxynaphthalen-4(1H)-
ylidene)malononitrile: To a solution of 7-methoxy-3,4-dihydro-
naphthalen-1(2H)-one (10 g, 56.7 mmol,) and malononitrile
(4.07 mL, 64.7 mmol) in toluene (40.0 mL, 4 vol) was added
ammonium acetate (0.938 g, 13.1 mmol) and acetic acid (3.90
mL, 68.1 mmol). The mixture was refluxed vigorously for
17 h and water was removed by using a Dien stark trap under
the reflux condenser. The resulting mixture was concentrated
and purified by silica gel column chromatography to give (9.32
g, 73.2 % yield).
t
–1
IR (KBr, νmax, cm ): 2939, 2838, 2216, 1724, 1608, 1493,
1
1251, 1223, 1032; H NMR (300 MHz, CDCl ): δ 7.73 (d, J =
3
2.4 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.5
Hz, 1H), 3.84 (s, 3H), 3.00 (t, J = 6.5 Hz, 2H), 2.83 (t, J = 6.2
13
Hz, 2H), 1.99-1.96 (m, 2H), C NMR (75MHz, CDCl ): δ
3
172.6, 157.9, 134.5, 130.5, 130.4, 121.9, 114.2, 110.9, 79.6,
55.7, 33.1, 28.9, 22.5; EI-MS m/z: 225.25 (M + H).
Step-3: Ethyl 2-(1,2-dihydro-6-methoxynaphthalen-4-
yl)acetate (4): 2-(1,2-Dihydro-6-methoxynaphthalen-4-yl)
acetic acid (3 g, 13.7 mmol) was dissolved in ethanol (15 mL,
combined organic layer was over under Na
2
SO , the solvent
4
was evoparated and the resulting oil distilled under vacuum to
get a clear oil consisting of a mixture of 2 and its geometrical
5 vol) and H
2
SO (0.134 g, 1.3 mmol) was added drop wise to
4
isomers (12.67 g, 82.3 % yield). b.p.: 164-168 °C (0.3 mmHg).
the reaction mass, stir for 12 h at 100-102 °C. Ethanol was
evaporated under reduced pressure, obtained mass (crude) was
dissolved in ethyl acetate (30 mL, 10 vol) washed successively
with water (15 mL, 3 × 5 vol) and followed by brine (15 mL,
1
H NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 6.99 (dd, J
.33 (q, 7.2 Hz, 2H), 3.85 (s, 3H), 3.25 (t, J = 6.4 Hz, 2H), 2.7
t, J = 6.0 Hz, 2H), 1.83 (qt, J = 6.0 Hz, 2H), 1.38 (J = 7.2 Hz,
3
): δ 7.60 (d, J = 2.0 Hz, 2H), 7.12
(
1
= 2.4 Hz, J = 8.4 Hz, 1H),
2
4
(
3 × 5 vol), dried over with Na
2
SO . The solvent was evaporated
4
3
H); EI-MS m/z (%): 244 (M + 1, 26), 177 (98), 164 (20).
under reduced pressure to afford brown coloured compound,
crude was purified by column chromatography on 100-200
silica gel by eluting with 50 % ethyl acetate in n-hexane,
obtained colourless oily liquid (2.82 g, 83.4 % yield).
Step-2a: 2-(1,2-Dihydro-6-methoxynaphthalen-4-
yl)acetic acid (3): To a solution of step-1 (mixture of exo and
endo) (6 g, 22.1 mmol), in ethanol (60.0 mL, 10 vol) at 25-
–1
30 °C, was added 50 % NaOH (8.84 g, 221.1 mmol) solution
b.p.: 60-90 °C; IR (KBr, νmax, cm ): 2980, 28336, 2833,
1
drop wise in to reaction mass at 0-5 °C. After addition, the
mixture was stirred for overnight at 25-30 °C. Reaction mass
was concentrated completely under reduced pressure and
2360, 1996, 1736, 1605, 1572, 1492, 1278, 1155, 1043; H
NMR (400 MHz, CDCl
J = 2.4 Hz, 1H), 6.69 (dd, J
3
): δ 7.04 (d, J = 8.4 Hz, 1H), 6.78 (d,
1
= 2.4 Hz, J
2
= 8.0, 1H), 6.01 (t,
TABLE-1
DIFFERENT BASES AND SOLVENT SCREENING
S. No.
Base
TEA (2.0 eq)
NaH (1.5 eq)
Piperidine (1.2 eq)
Piperidine (1.2 eq)
NaOMe (1.5 eq)
KO Bu (1.5 eq)
KO Bu (1.5 eq)
Solvent
Toluene (10 vol)
THF (10 vol)
Acetic acid (1 vol)
Ethanol (10 vol)
THF (10 vol)
Temp. (°C)
100-110
60-65
110-115
80-85
60-65
60-65
100-110
100-110
100-110
100-110
Time (h)
24
Yield (%)
No conversion
12.0
1
2
3
4
5
6
7
8
9
24
24
24
24
24
24
24
24
24.5
No conversion
No conversion
5.0
No conversion
25.2
t
THF (10 vol)
t
Toluene (10 vol)
Toluene (10 vol)
Toluene (10 vol)
Toluene (10 vol)
Benzyl amine (0.3 eq)
NH OAc (2 eq)
NH OAc (0.25 eq)
56.8
82.3
4
10
24
4

Vol. 28, No. 6 (2016)
A Simple and Efficient Procedure for Synthesis of Agomelatine 1369
4
2
.4 Hz, 1H), 4.1 (q, J = 14 Hz, 2H), 3.78 (s, 3H), 3.40 (s, 2H),
.71 (t, J = 7.6 Hz, 2H), 2.32-2.21 (m, 2H), 1.21 (t, J = 7.2
stir for 2 h. The reaction mass stored for 48 h at 25-30 °C,
then mass was concentrated completely under reduced pressure
to obtained crude material which was triturated in toluene (20
mL, 10 vol) for 1 h and filtered the solid, then washed with
toluene (10 mL, 5 vol) suck dried the compound to get pale
yellow coloured solid (1. 5 g, 87.6 % yield).
Hz, 3H); EI-MS, m/z (%): 247 (M + 1, 100), 177 (17), 132
46), 118 (40).
Step-4: 1-(7-Methoxynaphthalen-1-yl)butan-2-one (5):
To a solution of ethyl-2-(2-methoxynaphthalen-8-yl) acetate
3 g, 12.1 mmol) in anhydrous dichloromethane (45 mL, 15
vol) and added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DDQ, 4.15 g, 18.2 mmol) at 15 °C.After addition, the mixture
was stirred at 25-30 °C for 12 h. The mixture was filtered and
the precipitate solid was washed with CH Cl (30 mL, 10 vol),
the combined organic phase was washed successively with
saturated NaHCO solution (15 mL, 3 × 5 vol), water (15 mL,
× 5 vol) and followed by brine (15 mL, 3 × 5 vol), organic
layer was dried over Na SO . The solvent was removed under
(
–1
(
IR (KBr, νmax, cm ): 3395, 3203, 2939, 2831, 1643, 1401,
1
1259, 1203, 1024, 827 ; H NMR (400 MHz, DMSO-d ): δ
6
(
7.84 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.61 (brs,
1H), 7.4 (t, J = 6.8 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.19 (dd,
2
2
J
1
= 2.0 Hz, J
2
= 9.2 Hz, 1H), 7.02 (brs, 1H), 3.87 (s, 3H), 3.81
1
3
(s, 2H); C NMR (100Hz, DMSO-d ): δ 172.14, 157.22,
6
3
133.14, 131.67, 129.87, 128.65, 128.20, 126.62, 123.01,
117.58, 103.37, 55.11; EI-MS m/z (%): 216 (M + 1, 84), 199
(27), 171 (100).
3
2
4
reduced pressure to afford brown coloured compound, crude
was purified by column chromatography on 100-200 silica
gel using 20 % ethyl acetate in n-hexane, to obtain colourless
oil (2.59 g, 87.3 % yield).
Step-6: N-[2-(2-Methoxynaphthalen-8-yl)ethyl]acetamide
(agomelaine): To a solution of 2-(2-methoxynaphthalen-8-
yl)acetamide (1.2 g, 5.57 mmol) in 1,4-dioxane (24 mL, 20 vol),
cooled to 5-10 °C, added acetic acid lot-I (2.0 g, 29.4 mmol)
–1
IR (KBr, νmax, cm ): 2981, 2937, 2834, 1733, 1627, 1601,
drop wise to reaction mass and added lot wise NaBH (1.14 g,
4
1
1
511, 1469, 1450, 1260, 1213, 1159, 133, 832; H NMR (400
29.4 mmol) at 5-10 °C with for the period of 30 min. The
reaction mass allowed to room temperature 25-30 °C and then,
warm to 95-98 °C, maintained for 5-6 h at same temperature.
The reaction mixtre was cooled to 30-32 °C and added acetic
acid lot-II drop wise (highly exothermic) at same temperature,
after added again warm to 95-98 °C and maintained for 16 h
at 95-98 °C. The starting material was disappeared in TLC.
1,4-Dioxane was removed from reaction mass under pressure,
obtained mass was dissloved in ethyl acetate (24 mL, 20 vol)
washed with water (12 mL, 10 vol) and followed by brine
MHz, CDCl
H) 7.38 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.16
dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 4.0
s, 2H), 3.93 (s, 3H), 1.2 (t, J = 7.2 Hz, 3H); C NMR (100Hz,
): δ 171.1, 157.46, 132.99, 130.01, 129.79, 128.74,
28.37, 127.25, 123.02, 117.88, 117.88, 102.76, 60.23, 54.94,
3
): δ 7.75 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz,
1
(
(
1
2
13
DMSO-d
6
1
1
4.0; EI-MS, m/z (%): 245 (M + 1, 100), 171 (17).
Step-5: 2-(2-Methoxynaphthalen-8-yl)acetamide (6):
Ethyl 2-(2-methoxy naphthalen-8-yl)acetate (2.0 g, 8.1 mmol)
was dissolved in ethanol (40 mL, 20 vol) and cooled to -78 to
(12 mL, 10 vol), organic layer was dried Na
2
SO , concentrated
4
-
74 °C, ammonia gas was purged to reaction mass for 30 min
solvent completly under reduced pressure, obtained crude was
purified by column chromatography on 100-200 silica gel by
at -78 to -74 °C, after purging slowly allowed to 25-30 °C and
O
NC
O
OEt
NC
O
OEt
O
O
Step-1
O
c = Hydrolysis
Decarboylation
O
OH
d = H SO4
OEt
2
a
O
2
O
EtOH
NC
CN
Step-2
Step-3
1
3
O
4
NC
CN
2
b
O
O
O
OEt
N
NH2
g = NaBH4/
AcOH
H
O
f = NH
3
gas
O
O
e =DDQ
Step-6
Step-4
Aromatization
Step-5
5
6
7
Scheme-I

1
370 Gurunadham et al.
Asian J. Chem.
using 20 % ethyl acetate in n-hexane to get desired compound
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1.03 g, 76.3 % yield).
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1
1
Conclusion
1
1
In conclusion, a simple and scalable process for the high
yielding synthesis of agomelatine has been discussed. The
important features of this procedure are control of the
impurities in Knoevenagel condensation, minimization of
impurities in the hydrolysis step and in situ acetylation leading
to isolation of agomelatine in good yields.
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financial support and laboratory facilities.