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Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide

A technology of methoxyl and triethylamine, which is applied in the field of preparation of N-[2-ethyl]acetamide, can solve the problems of low yield and increased manufacturing cost, achieve high yield, reduce production cost, Effect of improving yield and purity

Inactive Publication Date: 2011-11-02
FUJIAN COSUNTER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When compound I is obtained by acylation, pyridine is used as a solvent, which is not suitable for the synthesis of pharmaceutical compounds
At the same time, there are reports in the literature (J.Med.Chem., 1992, 35, 1486-1489), the acylation reaction uses potassium carbonate to treat 7-methoxyl-1 naphthylethylamine hydrochloride, and neutralizes it as an acid-binding agent. and the hydrogen chloride produced, but the yield is low, only 55%, and therefore increases the manufacturing cost of this product

Method used

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  • Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide
  • Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide
  • Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide

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Embodiment 1

[0036] Embodiment 1. catalytic hydrogenation reaction

[0037] In a 500mL autoclave, add 20g of starting materials 7-methoxy-1-naphthaleneacetonitrile, 200mL of ethanol, stir evenly, add 40mL of ammonia water, 5g of newly prepared Raney nickel, and replace it with hydrogen for 3 times at 3-3.5MPa Stir the reaction at 30° C. for 12 h under pressure, and after TLC shows that the raw material is consumed, the Raney nickel is removed by filtration, and the reaction solution is filtered out. The ethanol was distilled off under reduced pressure to obtain a brown oil, ie, 7-methoxy-1-naphthylethylamine.

Embodiment 2

[0038] Embodiment 2. Salt-forming reaction

[0039] Add 150mL of ethyl acetate to dissolve the above oil, lower the temperature to below 10°C, add 36% concentrated hydrochloric acid dropwise with stirring to adjust the pH value to 3.0, stir and precipitate a white powdery solid, filter and dry to obtain 19g of 7-methoxy-1 -Naphthylethylamine hydrochloride.

Embodiment 3

[0040] Embodiment 3. Acylation reaction

[0041] Add 10 g of the obtained 7-methoxy-1-naphthylethylamine hydrochloride, 100 mL of ethyl acetate, and 10.6 g of triethylamine into a 250 mL three-necked flask, and stir for 30 min. The reaction solution was cooled to -5~0°C.

[0042] Weigh 4 g of acetyl chloride, dissolve it in 20 mL of ethyl acetate, and slowly add it dropwise to the above reaction solution, controlling the rate of addition and maintaining the reaction temperature. After the dropwise addition was completed, TLC showed that the raw materials had been consumed, and the mixture was raised to room temperature and kept stirring for 1 h.

[0043] Add 60mL of water, stir for 20min, remove the water layer, add 50mL of saturated sodium bicarbonate solution to the organic layer containing agomelatine, stir for 20min, remove the water layer, and concentrate the obtained organic phase to dryness at 40°C under vacuum. A pale yellow solid was obtained.

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Abstract

The invention relates to a method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide, comprising the following steps of: (1), performing catalytic hydrogenation: catalyzing and hydrogenating 7-methoxy-1-naphthyl acetonitrile in an organic solvent, removing the organic solvent, and obtaining 7-methoxy-1-naphthyl ethylamine; (2), performing a salification reaction: dissolving the reaction product in the step (1) in the organic solvent, salifying and separating through hydrochloric acid, and obtaining 7-methoxy-1-naphthyl ethylamine hydrochloride; (3), performing an acylation reaction: after treating the product obtained in the step (2) in the organic solvent through a bind acid agent, acylating by using acetylchloride, removing the solvent, and obtaining Agomelatine crude product; and (4), performing devitrification: dissolving the obtained crude product in the step (3), performing devitrification and filtering the solution, washing obtained crystals, and, after drying, obtaining Agomelatine solid.

Description

technical field [0001] The invention relates to a preparation method of N-[2-(7-methoxynaphthalene-1-yl)ethyl]acetamide. Background technique [0002] Agomelatine (agomelatine), chemical name N-[2-(7-methoxynaphthalene-1-naphthyl) ethyl] acetamide, its structural formula is as follows: [0003] [0004] Agomelatine has a dual action, not only an agonist of receptors of the melatoninergic system, but also an antagonist of 5HT2C receptors, and its properties make it active in the central nervous system, especially in major depression, seasonal Active in the treatment of affective disorders, sleep disorders, cardiovascular diseases, digestive disorders, jet lag-induced insomnia and fatigue, appetite disorders and obesity. It is the first melatonin-type antidepressant that is effective in the treatment of depression and improves sleep function. [0005] In the European patent specification EP0447285, a preparation method of agomelatine has been reported: 7-methoxy tetralone...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18C07C231/02
Inventor 邹巧根
Owner FUJIAN COSUNTER PHARMA
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