J Kranthi Kumar; Siva Ganesh Narala; A Venkat Narsaiah

doi:10.19080/OMCIJ.2018.07.555715

Efficient Synthesis of Anti-depressant Agent Agomelatine

J Kranthi Kumar, Siva Ganesh Narala and A Venkat Narsaiah*

Department of Fluoro-Agro Chemicals, Organic Synthesis Laboratory, India

Submission: July 23, 2018; Published: July 30, 2018

*Corresponding author: A Venkat Narsaiah, Department of Fluoro-Agro Chemicals, Organic Synthesis Laboratory, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India, Fax: +91-40-27160387; Email: vnakkirala2001@yahoo.com

How to cite this article: J Kranthi K, Siva G N, A Venkat N. Efficient Synthesis of Anti-depressant Agent Agomelatine. Organic & Medicinal Chem IJ. 2018; 7(3): 555715. DOI: 10.19080/OMCIJ.2018.07.555715

Abstract

A simple and efficient synthesis of anti-depressant agent Agomelatine has been achieved in 5 steps with an overall yield 63%. The synthesis was started from commercially available starting material, ethyl-2(7-methoxynaphthalen-1-yl)-acetate (2). All the reactions are very clean and yield excellent.

Keywords:Agomelatine; Antidepressant; Reduction; Azide; Acetylation

Introduction

Depression is a devastating disorder and it covers around 20% of the population. The depression affects all ages, races and economic groups and for some unknown reason, women suffer almost twice as much as men do [1,2]. Depression is more complicated and not just the result of a chemical imbalance in the brain but it is caused by a combination of biological, psychological and social factors. This disease can be successfully treated in more than 80% of cases, which includes pharmacotherapy as well as psychotherapy. Mild depression can be treated with psychotherapy and moderate depression requires pharmacotherapy. Depressive disorders come in different types, but each type has its own unique symptoms and treatments (Figure 1) [3-5].

Agomelatine, {N-[2-(7-methoxynaphthlen-1-yl)ethyl]-acetamide} is a melatonin receptor agonist, a new anti-depressant, antianxiety, anti-psychotic drug and also have positive effects on sleep [6,7]. The chemical structure of Agomelatine is very similar to that of melatonin. Agomelatine has a new pharmacological mechanism of action, which combines melatonin MT1 and MT2 agonist properties with serotoninergic 5-HT2C antagonist effect. The biological importance of Agomelatine has attracted many researchers towards its synthesis [8-14], but most of the literature for the synthesis of this molecule is in the form of patents [15-24].

Results and Discussions

As part of our regular research program in design and synthesis of biologically active compounds [25-29], herein we report, a simple and scalable route for the synthesis of Agomelatine. The synthesis was started from commercially available, ethyl-2(7-methoxy naphthalen-1-yl) acetate (2). The ester 2 was reduced with LiAlH4 in dry THF to afford, 2-(7-methoxynaphtha len-1-yl)-ethanol (3) in excellent yields. Compound 3 was reacted with methane sulphonyl chloride, triethylamine in CH₂Cl₂ to achieve, 2-(7-methoxynaphtha-len- 1-yl)-ethyl methane sulfonate (4) in 93% yield. Thus, obtained mesyl compound 4 on reaction with sodium azide in DMF at 80 °C to derive the nucleophilic substituted product, 1-(2-azidoethyl)- 7-methoxy naphthalene (5) in 91% yield. c) NaN₃, DMF, 80 °C, 1h, 90%. (d) Zn/NH₄Cl, EtOH, H2O, 40 °C, 1h, 89%. (e) Ac2O, DMAP, CH₂Cl₂, 0 °C, 1h, 94%.

The azide compound 5 was subjected to reduction with Zn-NH₄Cl in ethanol-water to obtain the respective product, 2-(7-methoxynaphthalen-1-yl)-ethanamine (6) in very good yields. Thus afforded primary amine compound 6 was acetylated with acetic anhydride in CH₂Cl₂ to give the target molecule, N-[2(7-methoxynaphthalen-1-yl)ethyl]acetamide (1) in 93% yield as shown in the Scheme 1. All the products were characterized and confirmed by their 1H-NMR, 13C-NMR, IR and mass spectroscopy analysis.

Conclusion

.In conclusion, Agomelatine synthesis has been achieved in five synthetic steps with an overall yield 63% from a commercially available starting material, ethyl-2(7-methoxy naphthalen-1-yl)-acetate (2). The performed reactions involve the use of inexpensive and commercially available reagents, as well as high yield chemical transformations, which are suitable for scaling up the process with an excellent overall yield.

Experimental Section

IR Spectra were recorded on a Perkin-Elmer FT-IR 240- c spectrophotometer using KBr optics. 1H-NMR spectra were recorded on Bruker-300MHz, spectrometer in CDCl3 using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV..

2-(7-Methoxynaphthalen-1-yl)-ethanol (4)

To a stirred solution of lithium aluminum hydride (0.31g, 8.19 mmol) in dry THF (10mL) was slowly added a solution of the ester compound 3 (2g, 8.19 mmol), which was dissolved in dry THF (20mL) at 0 °C and continued stirring for 30 minutes and brought to room temperature. After completion (TLC), the reaction was cooled and quenched by adding alkali solution [15% NaOH]. The solvent THF was removed under reduced pressure and the residue was extracted with ethyl acetate (2x25mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh), while eluting with ethyl acetate-hexane (3:7) mixture. Pure compound, 2-(7-methoxynaphthalen-1-yl)-ethanol (4), obtained as a white solid, 1.5g (90.6%). Mp, 79-80 °C. IR (KBr): υ 3263, 3005, 2949, 2878, 2830, 1910, 1624, 1597, 1507, 1468, 1432, 1381, 1341, 1255, 1210, 1160, 1132, 1041, 910, 830, 785, 751, 694 cm.-1; 1H NMR (300MHz, CDCl3): δ 3.30 (t, 2H, J = 7.0Hz), 3.94 (s, 3H), 4.01 (t, 2H, J = 7.0Hz), 7.16 (dd, 1H, J1 = 9.0 Hz, J2 = 3.0Hz), 7.28 (dd, 1H, J1 = 9.0Hz, J2 = 3.0Hz), 7.30-7.35 (m, 2H), 7.68 (d, 1H, J = 8.0Hz), 7.76 (d, 1H, J = 9.0Hz).; l3C NMR (75MHz, CDCl3): δ 157.7, 133.1, 132.9, 130.3, 129.3, 127.5, 126.9, 123.2, 117.9, 102.4, 62.7, 55.2, 36.2.; EIMS m/z (%): 203 (M+ 60), 185 (30), 154 (10), 130 (10).

2-(7-Methoxynaphthalen-1-yl)-ethylmethane sulfonate (5)

To a stirred solution of 2-(7-methoxynaphthalen-1-yl)- ethanol (1.7g, 7.39mmol) in CH₂Cl₂ (20mL) at 0 °C was added Et3N (1.23mL, 8.87mmol) and followed by methane sulfonyl chloride (0.69mL, 8.9mmol). After being stirred for 30 minutes, the mixture was poured into 1N HC1 (50mL) and extracted with diethyl ether (2x20 mL). The combined organic extracts were washed with aq. NaHCO3, dried and concentrated in vacuo. Pure product obtained as a pale white solid, 2.23g (93%). Mp, 58-60 °C. IR (KBr): υ 3452, 3018, 2940, 2837, 1626, 1601, 1511, 1470, 1385, 1356, 1259, 1214, 1173, 1031,952, 914, 833, 780, 753, 716cm.-1; 1H NMR (300MHz, CDCl3): δ 2.84 (s, 3H), 3.52 (t, 2H, J = 7.5Hz), 3.96 (s, 3H), 4.54 (t, 2H, J = 7.5Hz), 7.18 (dd, 1H, J1 = 8.8 Hz, J2 = 2.0 Hz), 7.25-7.38 (m, 3H), 7.71 (d, 1H, J = 7.5Hz), 7.78 (d, 1H, J = 9.0Hz).; l3C NMR (75 MHz, CDCl3): δ 157.9, 132.8, 130.4, 130.3, 129.0, 127.7, 127.5, 123.0, 118.2, 101.7, 69.3, 55.2, 37.2, 33.0.; EIMS m/z (%): 298 (M+18, 100), 281(M+1 20), 185 (30).

1-(2-Azidoethyl)-7-methoxynaphthalene (5)

To a stirred solution of mesyl compound 5 (2.3g 8.02mmol) in dry DMF (10 mL) was added sodium azide (1.6g, 24.08mmol) at room temperature and continued stirring at 80 oC for 1 hour. After completion (TLC), the reaction was poured into water (20mL) and extracted with diethyl ether (2x25mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh), while eluting with ethyl acetate-hexane mixture (1:9). Pure product obtained as thick brown syrup, 1.64g (90%). IR (neat): υ 3447, 2936, 2834, 2097, 1626, 1600, 1511, 1468, 1386, 1345, 1260, 1213, 1178, 1138, 1033, 750, 704 cm.-1; 1H NMR (300MHz, CDCl3): δ 3.32 (t, 2H, J = 7.5Hz), 3.64 (t, 2H, J = 7.5Hz), 3.95 (s, 3H), 7.17 (dd, 1H, J1 = 9.0Hz, J2 = 2.5Hz), 7.22-7.37 (m, 3H), 7.70 (d, 1H, J = 8.0Hz), 7.78 (d, 1H, J = 9.0Hz).; l3C NMR (75MHz, CDCl3): δ 157.9, 132.7, 132.4, 130.5, 129.3, 123.2, 118.0, 102.0, 55.3, 51.4, 32.5.; EIMS m/z (%): 185 (100), 171 (35), 153 (23).

2-(7-Methoxynaphthalen-1-yl)-ethanamine (6)

To a stirred solution of azide compound 2 (0.5g 2.2mmol) and NH₄Cl (0.3g 5.5mmol) in EtOH-H2O mixture (5mL, 3:1) was added Zinc powder (0.23g 3.3mmol). The resulting reaction mixture was stirred vigorously at room temperature for 30 minutes. After completion of the reaction (TLC), ethyl acetate (15mL) aqueous ammonia (5mL) was added and extracted with ethyl acetate (2x25mL). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using neutral alumina, while eluting with methanol-chloroform mixture (2:8). Pure product was obtained as colorless liquid, 0.39g (89%). IR (neat): υ 3421, 2924, 1623, 1510, 1467, 1384, 1343, 1258, 1214, 1132, 1028, 908, 829, 750, 696cm.-1; 1H NMR (300MHz, CDCl3): δ 2.05 (brs, NH), 3.09-3.27 (m, 4H), 3.94 (s, 3H), 7.16 (dd, 1H, J1 = 9.0Hz, J2 = 2.3Hz), 7.23- 7.34 (m, 3H), 7.67 (d, 1H, J = 8.0Hz), 7.76 (d, 1H, J = 9.0Hz).; l3C NMR (75MHz, CDCl3): δ 156.7, 131.6, 128.9, 127.8, 126.1, 125.7, 121.9, 101.2, 54.3, 31.3, 21.2.; EIMSm/z (%): 202 (M+1 90), 185 (60).

N-[2(7-Methoxynaphthalen-1-yl)-ethyl]-acetamide (1)

To a stirred solution of amine 6 (0.43g, 2.15mmol) in CH₂Cl₂ (3mL) at 0 °C was added acetic anhydride (0.2mL, 2.15mmol) and after 10 minutes stirring was added a catalytic amount of DMAP and stirred for 30 minutes. After completion of the reaction as monitored by TLC, the reaction was poured into water and extracted with ethyl acetate (2x15mL). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography using neutral alumina, while eluting with ethyl acetate-hexane mixture (1:1). Pure product was obtained as a white solid, 0.48g (94%). Mp, 104- 105 °C. IR (neat): υ 3248, 3077, 2995, 2972, 2935, 2863, 1917, 1631, 1598, 1563, 1509, 1468, 1440, 1368, 1253, 1215, 1182, 1130, 1030, 904, 864, 833, 730cm.-1; 1H NMR (300MHz, CDCl3): δ 1.96 (s, 3H), 3.25 (t, 2H, J = 7.5Hz), 3.62 (q, 2H, J = 7.5Hz), 3.99 (s, 3H), 5.65 (brs, NH), 7.17 (dd, 2H, J1 = 9.0Hz, J2 = 2.2Hz) 7.25- 7.31 (m, 2H), 7.46 (d, 1H, J = 2.2Hz), 7.65-7.72 (m, 1H), 7.76 (d, 1H, J = 9.0Hz).; l3C NMR (75MHz, CDCl3): δ 170.5, 157.8, 133.5, 133.0, 130.1, 129.1, 126.9, 123.0, 118.2, 102.3, 55.4, 40.0, 33.0, 23.1.; EIMS m/z (%): 244 (M+1 100), 266 (M+23, 80).

Acknowledgement

JKK & SGN are thankful to the University Grants Commission, New Delhi, for the award of the fellowship.

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