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

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 sodium diformylamide. A systemic approach was described to streamline the process into a robust scalable process by controlling the impurities. GRAPHICAL ABSTRACT


INTRODUCTION
Agomelatine has been reported as an effective melatonergic antidepressant. [1] Agomelatine has a new pharmacological mechanism of action that combines its melatonin MT 1 and MT 2 agonist properties with a serotonin 5-HT 2C antagonist effect.
Agomelatine was first synthesized by Yous et al. [2] in a multistep synthetic route starting from (7-methoxy-1-naphthyl) acetic acid. Zlotos et al. [3] reported a four-step approach that involves use of pyrophoric reagents and ion exchange resins. Although many syntheses aiming at industrial scale have been published in the literature, [4][5][6] still it remains challenging to develop a simple process that makes use of readily available inexpensive raw materials, avoids the use of highly hazardous reagents, minimizes the steps, simplifies workup 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 such as CuCN and pyrophoric reagents such as DIBAL and n-BuLi were used, as well as temperatures ranging from À78°C to 100°C. In continuation of our 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 a 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 AlCl 3 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 regioisomers, 7 and 8. Recrystallization of crude 4 in methanol removed all the isomers and unreacted 2-acetoxy naphthalene.
Reduction of 5 using triethylsilane in presence of TiCl 4 followed by ester hydrolysis afforded the intermediate, 6.
Methyl protection of intermediate 7 followed by reaction with sodium diformylamide [9] in the presence of TBAI catalyst in DMSO [10] afforded 10 (a mixture of mono-and di-formylamides 10a and 10b).
Hydrolysis of amides 10a and 10b gave the amine hydrochloride 11, which was not isolated, and further amidation with acetic anhydride under basic conditions afforded 1 in 85% yield.
During initial experimentation, it was observed that significant amounts of impurities 13 and 14 were formed in the 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.
The impurity 14 will transform to impurity 15 in the hydrolysis step, which is difficult to minimize in isolation because of 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, the acidic reaction mixture was extracted with toluene to remove the organic impurities that are not forming the salts with aqueous HCl. This modification improved the quality and the yield of the agomelatine.
To overcome the loss of amine 11 in the aqueous layer after the hydrolysis step, we proceeded to the acetylation step in the same vessel by adding an ethyl acetate K 2 CO 3 solution and acetic anhydride. After the reaction, the organic layer was separated, concentrated, and isolated in toluene to afford 1 in 85% yield.
Impurity 16 forms by the demethylation of 11 in the hydrolysis step when followed by acetylation. To control the formation of 16, the hydrolysis reaction was terminated after 4 h of reaction at 60°C by monitoring with thin-layer chromatography (TLC).

EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used without further purification. 1 H NMR spectra were recorded in CDCl 3 or dimethylsulfoxide (DMSO-d 6 ) at room temperature on a Varian Mercury Plus instrument at 400 MHz using tetramethylsulfoxide (TMS) as an internal standard. 13 C NMR spectra were obtained from a Varian Mercury Plus 400-MHz spectrometer in DMSO-d 6 at room temperature. IR spectra were recorded in the solid state as KBr dispersion using a Perkin-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 plates.

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 the hydrolysis step, and in situ acetylation leading to isolation of agomelatine in good yields.