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A kind of preparation method of agomelatine intermediate

An intermediate, methoxynaphthalene technology, applied in the field of chemical drug intermediate synthesis, can solve the problems of high cost, unfavorable industrialization, low yield, etc., and achieves the effects of less staff, stable product quality, and easy operation.

Active Publication Date: 2019-04-30
XUCHANG HENGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, allyl methacrylate and palladium carbon are expensive, and the yield is medium, which is not conducive to industrialization

Method used

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  • A kind of preparation method of agomelatine intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Put (24.0g, 1.0mol) magnesium chips and 0.1g iodine in a 2L three-necked flask, and add 55ml of tetrahydrofuran and stir evenly, and add 1-bromo-7-methoxynaphthalene (237.1g, 1.0mol ) into 340ml of tetrahydrofuran to make a mixed solution, and slowly add a few drops of the mixed solution to the reaction flask under stirring. After 5 minutes, the solution in the reaction flask boiled slightly, cooled to 5°C in an ice-water bath, and added 340ml of tetrahydrofuran to the reaction flask. Under stirring, start to drop the above-prepared mixed solution, control the reaction temperature to 40° C., and the reaction time to 0.5 h to obtain the reaction solution of 1-bromo-7-methoxy Nagrignard reagent.

[0020] Add (120.0g, 1.0mol) bromoacetonitrile to 340ml tetrahydrofuran to prepare a bromoacetonitrile mixed solution, cool the resulting 1-bromo-7-methoxy Nagrignard reagent reaction solution to 5°C in a reaction flask, and dissolve under stirring The prepared bromoacetonitrile ...

Embodiment 2

[0022] Put (26.4g, 1.1mol) magnesium chips and 0.1g iodine in a 2L three-necked flask, add 60ml tetrahydrofuran and stir evenly, add 1-bromo-7-methoxynaphthalene (237.1g, 1.0mol ) into 360ml of tetrahydrofuran to make a mixed solution, and slowly add a few drops of the mixed solution to the reaction flask under stirring. After 5 minutes, the solution in the reaction flask boiled slightly, cooled to 5°C in an ice-water bath, and added 360ml of tetrahydrofuran to the reaction flask. The mixed solution prepared above was started to be added dropwise under stirring, the reaction temperature was controlled at 38° C., and the reaction time was 2 h to obtain a reaction solution of 1-bromo-7-methoxy Nagrignard reagent.

[0023] Add (132.0g, 1.1mol) bromoacetonitrile to 360ml tetrahydrofuran to prepare a bromoacetonitrile mixed solution, cool the reaction solution of the obtained 1-bromo-7-methoxy Nagrignard reagent to 0°C in a reaction flask, and dissolve under stirring The prepared b...

Embodiment 3

[0025] Put (28.8g, 1.2mol) magnesium chips and 0.1g iodine in a 2L three-necked flask, and add 60ml of dioxane and stir evenly. In the dropping funnel, 1-bromo-7-methoxynaphthalene (237.1g , 1.0mol) into 360ml of dioxane to make a mixed solution, and slowly add a few drops of the mixed solution to the reaction bottle under stirring. After 5 minutes, the solution in the reaction bottle boiled slightly. 360ml of dioxane was added in the middle, and the mixed solution prepared above was added dropwise under stirring, the reaction temperature was controlled at 35°C, and the reaction time was 5h to obtain a reaction solution of 1-bromo-7-methoxy Nagrignard reagent.

[0026] (144.0g, 1.2mol) bromoacetonitrile was added to 360ml of dioxane to prepare bromoacetonitrile mixed solution, and the reaction solution of the obtained 1-bromo-7-methoxy Nagrignard reagent was cooled to 5°C in the reaction flask, Slowly add the bromoacetonitrile mixture into the reaction flask under stirring. Af...

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Abstract

The invention discloses a preparation method of an agomelatine intermediate. The preparation method comprises steps as follows: firstly, 1-bromo-7-methoxynaphthalene is dissolved in an organic solvent, and a mixed solution is formed; elementary alkali metal and an initiator are added to a reaction bottle, the organic solvent is added to the reaction bottle and stirred uniformly, the prepared mixed solution is dropwise added slowly, when a reaction liquid is boiled slightly, the organic solvent is supplemented into the reaction bottle and stirring is started, the prepared mixed solution is dropwise added continuously, and a reaction liquid of a 1-bromo-7-methoxynaphthalene Grignard reagent is obtained after the heat preservation reaction; bromoacetonitrile is added to the organic solvent, a bromoacetonitrile mixed liquid is prepared, the prepared bromoacetonitrile mixed liquid is dropwise added slowly to the reaction liquid of the Grignard reagent, and (7-methoxy-1-naphthyl) acetonitrile is obtained after the heat preservation reaction and aftertreatment. With the adoption of the method, industrial production can be realized, 1-bromo-7-methoxynaphthalene is taken as a starting material, the cost can be saved, the product quality is stable, the yield is high, and the preparation method is applicable to large-scale industrial stable production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drug intermediates, and in particular relates to a preparation method of agomelatine intermediates. Background technique [0002] Agomelatine, chemical name N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, agomelatine is the world's first melatonin receptor Antidepressants of body agonists, with their unique targets, enable patients to improve sleep quality while treating depression. 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. He is the first antidepressant of the melatonin class, effective in the treatment of d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C255/37C07C253/30C07F3/02C07B49/00
CPCC07B49/00C07C253/30C07F3/02C07C255/37
Inventor 蚩晓娜郭培谷志勇
Owner XUCHANG HENGSHENG PHARMA
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