Preparation method of agomelatine intermediate

An intermediate, the technology of methoxynaphthalene, which is applied in the field of synthesis of chemical drug intermediates, can solve the problems of high cost, unfavorable to industrialization, medium yield, etc., and achieve the effect of less staff, stable product quality and easy operation

Active Publication Date: 2017-11-17
XUCHANG HENGSHENG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented technology allows for efficient preparation of 2-(substituents on naphtalenesulfonic acid), which has potential applications such as producing pharmaceuticals or chemical agents that have specific properties like solubility or stability over time. By reducing energy usage by only three stages during this step, it becomes cost-effective compared to traditional methods requiring multiple extraction processes. Additionally, there're no risk of contamination from any substances added at different points along the way due to its direct use within an organic synthesis procedure without being transferred between them. Overall, these technical results make the current methods expensive and difficult to achieve consistently.

Problems solved by technology

This patented technical problem addressed in this patents relates to efficiently preparing (S)-(-)-Agimeltanol), specifically (2R)-(E-2-(N-4'-dimethylaminosteary1)-5 '-norbitaliridazole).

Method used

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  • 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 a bromoacetonitrile mixed solution, and the resulting 1-bromo-7-methoxy Nagrignard reagent reaction solution was cooled to 5°C in a reaction flask, Slowly drop the bromoacetonitrile mixture into the reaction flask under stirring. After t...

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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

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Claims

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Application Information

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Owner XUCHANG HENGSHENG PHARMA
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