Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An Antidepressant Drug

Article abstract of DOI:10.1080/00397911.2015.1050524

A simple and efficient process for the large-scale preparation of agomelatine (1), an antidepressant drug is, described. Agomelatine was prepared in a linear manner starting from readily available, inexpensive 2-naphthol. Key steps in the synthesis are Friedel-Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of keto intermediate, and nucleophilic displacement of chloro intermediate with sodium diformylamide. A systemic approach was described to streamline the process into a robust scalable process by controlling the impurities.

Full text of DOI:10.1080/00397911.2015.1050524

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Simple and Efficient Process for the Large-Scale
Preparation of Agomelatine: An Antidepressant Drug
Satish Kumar Vujjinia, Sunitha Vyalaa, Krishna Rao Badarlaa, Sreenatha Charyulu Kandalaa,
Rakeshwar Bandichhora, Mukkanti Kaggab & Praveen Cherukupallia
a Innovation Plaza, IPDO, Dr. Reddy's Laboratories Ltd, Telangana, India
b Department of Chemistry, Institute of Science and Technology, J.N.T. University,
Kukatpally, Hyderabad, India
Accepted author version posted online: 15 May 2015.
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To cite this article: Satish Kumar Vujjini, Sunitha Vyala, Krishna Rao Badarla, Sreenatha Charyulu Kandala, Rakeshwar
Bandichhor, Mukkanti Kagga & Praveen Cherukupalli (2015): Simple and Efficient Process for the Large-Scale Preparation
of Agomelatine: An Antidepressant Drug, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1050524
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1050524
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Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An
Antidepressant Drug
Satish Kumar Vujjini1, Sunitha Vyala1, Krishna Rao Badarla1, Sreenatha Charyulu
Kandala1, Rakeshwar Bandichhor1, Mukkanti Kagga2, Praveen Cherukupalli1
1Innovation Plaza, IPDO, Dr. Reddy’s Laboratories Ltd, Telangana, India 2Department of
Chemistry, Institute of Science and Technology, J.N.T. University, Kukatpally,
Hyderabad, India
Address correspondence to, Praveen Cherukupally, Innovation Plaza, IPDO, Dr. Reddy’s
Laboratories Ltd, Bachupalli, Qutubullapur, R. R. District, Telangana, India E-mail:
praveen_cherukupally@yahoo.in
Abstract
A simple and efficient process for the large scale preparation of agomelatine (1), an
antidepressant drug is described. agomelatine, was prepared in a linear manner starting
from readily available inexpensive 2-naphthol. Key steps in the synthesis are Friedel-
Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of keto
intermediate and nucleophilic displacement of chloro intermediate with
sodiumdiformylamide. Systemic approach was described to streamline the process into a
robust scalable process by controlling the impurities.
KEYWORDS: Agomelatine, Friedel-Crafts acylation, chloro acetylchloride and sodium
diformylamide
1

INTRODUCTION
Agomelatine has been reported as an effective melatonergic antidepressant.[1]
agomelatine has a new pharmacological mechanism of action which combines its
melatonin MT1 and MT2 agonist properties with a serotonin 5-HT2C antagonist effect.
Agomelatine was first synthesized by Yous et al.[2] in a multi-step synthetic route starting
from (7-methoxy-1-naphthyl) acetic acid. Zlotos[3] et al. reported a four step approach
which involves usage of pyrophoric reagents, ion exchange resins. Although, many
syntheses aiming at industrial scale have been published in the literature,[4-6] still it
remains challenging to develop a simple process which makes use of readily available
inexpensive raw materials, avoids the use of highly hazardous reagents, minimizes the
steps, simplifies work up procedures and precludes detrimental impurity issues. However,
developing new synthetic approaches to agomelatine from a cheap starting material other
than 7-methoxy-1-tetralone is still remains challenging. During the new synthesis of
agomelatine,[7] it was synthesized from 8-aminonaphthalen-2-ol by diazotization,
formylation, C–C bond formation and hydrogenation of β-nitrovinylnaphthalene. In this
synthesis toxic reagents like CuCN, pyrophoric reagents like DIBAL and n-BuLi were
used and also used temperatures ranging from -78 °C to 100 °C. In continuation of our
2

work on agomelatine[8] to reduce the length of the synthesis, herein, we report a simple
and improved process for the synthesis of agomelatine on large scale.
RESULTS AND DISCUSSION
The synthesis involves acetylation of 2-naphthol in acetone to give 2-
acetoxynaphthalene, 3 which on Friedel-Crafts acylation in the presence of AlCl3 using
chloro acetylchloride affords acylated intermediate, 4. This Friedel-Crafts acylation is a
regioselective reaction having 80% selectivity to provide the desired acylated product
along with other regio isomers, 7 and 8. Recrystallization of crude 4 in methanol removed
all the isomers and unreacted 2-acetoxy naphthalene.
Reagents and conditions: a) K2CO3, Ac2O, acetone, 55 °C, 2h, 92% b) AlCl3, chloro
acetyl chloride, DCM, -10 °C, MeOH, 55% c) TES, TiCl4, 0 °C, DCM d) K2CO3, MeOH,
n-Hexane, 0 °C, 85%.
Reduction of 5 using triethylsilane in presence of TiCl4 followed by ester hydrolysis
affords the intermediate, 6.
3

Methyl protection of intermediate 7 followed by reaction with sodium diformylamide[9]
in presence of TBAI catalyst in DMSO[10] affords 10 (a mixture of mono- and di-
formylamides 10a and 10b).
Reagents and conditions: e) DMS, K2CO3, MeOH, 25 °C f) Sodium diformylamide,
TBAI, DMSO, 85 °C, 76 %.
Hydrolysis of amides 10a and 10b gave the amine hydrochloride 11 which is
not isolated and on further amidation with acetic anhydride under basic conditions
afforded 1 in 85% yield.
Reagents and conditions: g) HCl, MeOH, 60 °C, 4h h) K2CO3, H2O, Ac2O, 10 °C, 85 %.
During initial experimentation, it was observed that significant amount of impurities 13
and 14 were formed in conversion of intermediate 9 to 10, which was due to high
reaction temperatures and also traces of sodium methoxide as sodium diformylamide was
prepared in-situ.
To minimize the formation of impurities 13 and 14, sodium diformylamide prepared and
isolated in pure form was employed in the reaction.
4

The impurity 14 will transform to impurity 15 in hydrolysis step, which is difficult to
minimize in isolation due to similar solubility of 15 and 1. Recrystallization of the
intermediate 10 in toluene/hexane mixture reduced the impurity 14 from 3.0% to 0.2%.
After hydrolysis step the acidic reaction mixture was extracted with toluene to remove
the organic impurities which are not forming the salts with aq. HCl. This modification
improved the quality and the yield of the agomelatine.
To overcome the loss of amine 11 in aqueous layer after hydrolysis step, we proceeded to
acetylation step in the same vessel by adding ethyl acetate K2CO3 solution and acetic
anhydride. After the reaction, organic layer was separated then concentrated and isolated
in toluene to afford 1 in 85% yield.
Impurity 16 will form by the demethylation of 11 in hydrolysis step followed by
acetylation. To control the formation of 16, the hydrolysis reaction was terminated after
4h reaction maintenance at 60 °C by monitoring TLC.
EXPERIMENTAL SECTION
Solvents and reagents were obtained from commercial sources and used without further
purification. 1H NMR spectra were recorded in CDCl3 or DMSO-d6 at room temperature
on Varian mercury plus at 400 MHz using TMS as an internal standard. 13C NMR spectra
were obtained from a Varian mercury plus 400 MHz spectrometer in DMSO-d6 at room
temperature. IR spectra were recorded in the solid state as KBr dispersion using Perkin-
5

Elmer 1650 FT IR spectrometer. The mass spectrum (70 eV) was recorded on an HP
5989 A LC-MS spectrometer. TLC analyses were performed on Merck silica gel 60 F254
plate.
1-(N,N-diformylaminoethyl)-7-methoxynaphthalene and N-[2-(7-methoxy-1-
naphthyl)ethyl]formamide (10): To a solution of methanol (175 mL) and 1-(2-
chloroethyl)-7-hydroxynaphthalene 6 (35 g, 0.17 mol), K2CO3 (61 g, 0.44 mol) was
added and cooled the reaction mixture to 15 °C. Dimethyl sulphate (40 mL, 0.42 mol)
was added to the reaction mixture and stirred the reaction mixture for 2h at 25 °C. The
reaction was monitored by TLC and diluted with water (420 mL), extracted with ethyl
acetate (175 mL). Organic layer was washed with 10% NaCl solution (175 mL) and
concentrated under reduced pressure to get oily residue (9). The oily residue was
dissolved in DMSO (105 mL), sodium diformylamide (64.4 g, 0.68 mol) and TBAI (0.7
g) were added. The resulting mixture was heated to 85 °C and stirred for 2-3 h. The
reaction was monitored by TLC and it was cooled to 20 °C, diluted with water (350 mL)
then extracted with ethyl acetate (175 mL). Organic layer was separated then washed
with 10% NaCl solution (175 mL). The organic layer was distilled under reduced
pressure to get crude. The crude was dissolved in toluene (105 mL) at 60 °C and n-
hexane (263 mL) was added slowly at 30 °C. The reaction mixture was further cooled to
0 °C and stirred for 2 h. The solid was filtered and dried at 45 °C under vacuum to afford
the mixture of 10a and 10b (32 g, 77.7 %).
6

10a ESI-MS: m/z = 228 (M-H); calcd. for C14H15NO2: 229.27; 1H NMR (400 MHz,
DMSO-d6) δ = 3.13 (t, J= 8.24 Hz, 2H, CH2CH2N), 3.46 (m, 2H, CH2CH2N), 3.95 (s,
3H, OCH3), 7.18 (dd, J = 2.5, 8.92 Hz, 1H, Ar-H), 7.24-7.32 (m, 2H, Ar-H), 7.56 (s, 1H,
Ar-H), 7.72 (d, J= 7.8 Hz, 1H, Ar-H), 7.83 (d, J = 8.9 Hz, 1H, Ar-H), 8.99 (s, 2H,
NCOHCOH); 13C NMR (400 MHz, DMSO-d6) δ = 31.3, 38.3, 39.0, 39.2, 39.4, 39.8,
40.0, 40.2, 55.6, 102.7, 118.6, 123.7, 127.5, 127.9, 129.3, 130.7, 133.1, 133.2, 158.1,
166.9; IR υmax cm-1 3264, 2941, 1652, 1627, 1509, 1258, 1215, 1030. Anal. Calcd for
C14H15NO2: C, 73.34; H, 6.59; N, 6.11; O, 13.96. Found: C, 73.36; H, 6.57; N, 6.13; O,
13.94.
10b ESI-MS: m/z = 258 (M+H); calcd. for C15H15NO3: 257.28; 1H NMR (400 MHz,
DMSO-d6) δ = 3.20 (t, J= 6.16 Hz 2H, CH2CH2NH), 3.43-3.48 (m, 2H, CH2CH2NH),
3.73 (s, 3H, OCH3), 7.19 (dd, J = 2.5, 8.9 Hz, 1H, Ar-H), 7.27-7.31 (m, 1 H, Ar-H), 7.37
(dd, J= 1.04, 6.88 Hz 1H, Ar-H), 7.55 (d, J= 2.44 Hz 1H, Ar-H), 7.74 (d, J= 8.04 Hz, 1H,
Ar-H), 7.84 (dd, J = 2.36, 8.96 Hz, 1H, Ar-H), 8.09 (s, 1H, NHCHO), 8.26 (br s, 1H,
NHCO); 13C NMR (400 MHz, DMSO-d6) δ = 33.1, 34.7, 38.6, 39.0, 39.4, 39.6, 39.8,
40.0, 40.2, 42.1, 55.7, 102.9, 118.4, 123.7, 127.1, 127.5, 129.3, 130.6, 133.2, 134.2,
157.9,162.2, 165.1; IR υmax cm-1 3389, 1753, 167, 1625, 1212, 1134, 1025. Anal. Calcd
for C14H15NO3: C, 70.02; H, 5.88; N, 5.44; O, 18.66. Found: C, 70.06; H, 5.84; N, 5.42;
O, 18.68.
N-[2-(7-methoxy-1-naphthylen-1-yl) ethyl] acetamide (1): To a solution of methanol
(250 mL) and intermediate 9, (mixture of N-[2-(7-methoxy-1-naphthyl)ethyl]formamide)
7

10a and N-formyl-N-[2-(7-methoxy-1-naphthyl)ethyl]formamide 10b) (50 g, 0.21 mol)
and HCl (42 g, 0.41 mol) was added. Then the reaction mixture was heated to 60 °C and
stirred for 4 h. The reaction mixture was concentrated under reduced pressure followed
by co-distillation with toluene (100 L) to obtain suspension which was dissolved in water
(600 mL) and washed with toluene (2 x 100 mL). The aqueous layer was treated with
carbon (5 g) and filtered through hyflow. To the filtrate, Ethyl acetate (375 mL) was
added and then K2CO3 solution (71 g, 0.51 mol of K2CO3 in 36 L water) was added
slowly. Then acetic anhydride (23 mL, 0.25 mol) was added slowly below 30 °C, and
continued stirring for 30 min. The reaction was monitored by TLC, organic layer was
separated and washed with 2 % NaCl solution (250 mL) then the organic layer was
concentrated under reduced pressure to obtain crude. Toluene (150 mL) was added and
co-distilled. Toluene (150 mL) was added again and heated to 65 °C. The reaction
mixture was cooled to 10 °C and stirred for 2h. The solid product was filtered and
washed with toluene (50 mL) then dried at 60 °C under vacuum to give 1 (42.5 g, 85 %)
having HPLC purity of 99.9%.
ESI-MS: m/z = 244.2 (M+H); calcd. for C15H17NO2: 243.0; 1H NMR (400 MHz, DMSO-
d6) δ = 1.84 (s, 3H, OCH3), 3.13 (t, J= 7.2 Hz, 2H, CH2CH2NHAc), 3.34 (m, 2H,
CH2CH2NHAc), 3.95 (s, 3H, OCH3), 7.17 (dd, J = 2.5, 8.9 Hz, 1H, Ar-H), 7.25-7.29 (m,
1 H, Ar-H), 7.32-7.34 (dd, J = 1.23, 6.96 Hz, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 7.71 (d, J=
7.8 Hz, 1H, Ar-H), 7.83 (d, J = 8.9 Hz, 1H, Ar-H), 8.13 (br s, 1H, NHCO); 13C NMR
(400 MHz, DMSO-d6) δ = 23.1, 33.5, 40.6, 55.7, 103.1, 118.5, 123.6, 127.0, 127.4,
129.3, 130.5, 133.4, 134.6, 157.9, 170.0; IR υmax cm-1 1639, 1626, 1509, 1251, 1031.
8

CONCLUSION
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 Friedel-Crafts acylation, minimization of impurities in hydrolysis step,
in-situ acetylation leading to isolation of agomelatine in good yields.
SUPPLEMENTAL MATERIAL
Detailed experimental procedures and spectral characterization data for this article can be
accessed on the publisher’s website.
ACKNOWLEDGMENT
We thank the management of Dr. Reddy’s Laboratories Ltd. for supporting this work.
Co-operation from the project colleagues of API-Analytical research department,
Integrated Product Development Organization, Dr. Reddy’s Laboratories Ltd. is highly
appreciated
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Dr. Reddy’s Communication no. IPDO IPM-00429
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Scheme 1.
11

Scheme-2.
12

Scheme 3.
13

Scheme 4. Synthesis of sodium diformylamide (12)
14

Figure 1. Structures of the impurities in the process
15

Figure 2. Impact of reaction time on formation of impurity 16
16