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Preparation method of agomelatine intermediate

A technology for an intermediate and a synthesis method, which is applied in the field of preparation of agomelatine intermediates, can solve the problems of high difficulty in industrialization, harsh reaction conditions, long reaction routes, etc., and achieves simple and safe reaction operation, mild reaction conditions, and reaction short step effect

Inactive Publication Date: 2022-04-26
SHANDONG WEIFANG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route also uses azide compounds, and there are certain safety hazards in industrialization
[0014] The preparation method of the above-mentioned agomelatine intermediate has the disadvantages of long reaction route, cumbersome reaction operation, high safety risk, harsh reaction conditions, and high difficulty in industrialization. Therefore, the agomelatine intermediate 2-(7-methoxy- The preparation of 1-naphthyl)ethylamine urgently needs a short synthetic route, few reaction steps, simple operation, mild reaction conditions, no special equipment, easy separation and purification of intermediates, and a method suitable for industrial production

Method used

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  • Preparation method of agomelatine intermediate
  • Preparation method of agomelatine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: A kind of preparation method of agomelatine intermediate

[0050] 1. Acid chloride of 7-methoxy-1-naphthylpropionic acid

[0051]In a 1L glass reaction flask, add 863.40 g of methylene chloride and 57.56 g (0.25 mol) of 7-methoxy-1-naphthylpropionic acid in sequence, and raise the temperature to 35°C until 7-methoxy-1-naphthyl All propionic acid was dissolved. Control the temperature at 35°C, and slowly add 59.48g (0.5mol) of thionyl chloride dropwise to the reaction system under the state of slight reflux. The dropwise addition time is 2 hours. The reaction was continued for 3.5 hours. After the reaction was completed, dichloromethane and excess thionyl chloride were distilled off under reduced pressure to obtain 7-methoxy-1-naphthylpropionyl chloride.

[0052] 2. Amidation

[0053] All the 7-methoxyl-1-naphthyl propionyl chloride obtained in step 1 was dissolved in 460 grams of ethyl acetate, and the reaction system was kept at 0°C under an ice-water...

Embodiment 2

[0059] Embodiment 2: A kind of preparation method of agomelatine intermediate

[0060] 1. Acid chloride of 7-methoxy-1-naphthylpropionic acid

[0061] In a 1L glass reaction flask, add 575.6 grams of methylene chloride and 57.56 g (0.25 mol) of 7-methoxy-1-naphthyl propionic acid in sequence, and heat up to 30°C until 7-methoxy-1-naphthalene All propionic acid was dissolved. Control the temperature at 30°C and slowly add 29.74 g (0.25 mol) of thionyl chloride to the reaction system dropwise under the state of slight reflux. The dropwise addition time is 1 hour. The reaction was continued for 2 hours. After the reaction was completed, the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain 7-methoxy-1-naphthylpropionyl chloride.

[0062] 2. Amidation

[0063] Dissolve all the 7-methoxy-1-naphthylpropionyl chloride obtained in step 1 in 345.36 grams of ethyl acetate, and keep the temperature of the reaction system at -5°C in an ice-water b...

Embodiment 3

[0069] Embodiment 3: A kind of preparation method of agomelatine intermediate

[0070] 1. Acid chloride of 7-methoxy-1-naphthylpropionic acid

[0071] 1151.20 g of dichloromethane and 57.56 g (0.25 mol) of 7-methoxy-1-naphthylpropionic acid were successively added to a 2 L glass reaction flask, and the temperature was raised to 40°C until complete dissolution. Control the temperature at 40°C and add 118.97 g (1 mol) of thionyl chloride slowly to the reaction system in a micro-reflux state. The dropwise addition time is 4 hours. During the dropping process, keep the system in a micro-reflux state. React for 6 hours. After the reaction was completed, the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain 7-methoxy-1-naphthylpropionyl chloride.

[0072] 2. Amidation

[0073] Dissolve all the 7-methoxy-1-naphthylpropionyl chloride obtained in step 1 in 575.6 grams of ethyl acetate, keep the temperature of the reaction system at 5°C in an ice...

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Abstract

The invention relates to a preparation method of an agomelatine intermediate, which belongs to the field of drug intermediates, and comprises the following four steps: acylating chlorination and amidation of 7-methoxy-1-naphthyl propionic acid, Hofmann degradation of 7-methoxynaphthalene-1-yl propanamide, and post-treatment. 7-methoxy-1-naphthyl propionyl chloride obtained by carrying out acylating chlorination on the 7-methoxy-1-naphthyl propionic acid is subjected to amidation to obtain 7-methoxy-1-naphthyl propionamide, and then the 7-methoxy-1-naphthyl propionamide is subjected to Hofmann degradation to obtain the agomelatine intermediate 7-methoxy-1-naphthyl ethylamine. The preparation method disclosed by the invention is short in reaction step and mild in reaction condition, the reaction temperature is-5 to 100 DEG C, and the reaction pressure is normal pressure; an azide is not used, Raney nickel catalysis or palladium carbon catalytic hydrogenation operation is not involved, and the reaction operation is simple and safe; the total yield of the 7-methoxy-1-naphthyl ethylamine can reach 67.1%-78.4%, and the liquid phase purity can reach 98.1%-98.9%.

Description

technical field [0001] The invention specifically relates to a preparation method of an intermediate of agomelatine, belonging to the field of pharmaceutical intermediates. Background technique [0002] Agomelatine, systematic name: N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, CAS number: 138112-76-2, developed by Servier company, in 2009 Available in Europe. Agomelatine is both the first melatonin receptor agonist and 5-hydroxytryptamine 2c (5HT2c) receptor antagonist. Possesses active activity in the treatment of major depressive disorder, seasonal affective disorder, sleep disturbance, cardiovascular disease, digestive system disease, jet lag-induced insomnia and fatigue, appetite disturbance and obesity. The structural formula of agomelatine is shown as compound I in the figure below. The key intermediate for the preparation of agomelatine is 2-(7-methoxy-1-naphthyl)ethylamine, and its structural formula is as follows (compound II) Show: [0003] [0004] There a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C217/60C07C213/10C07C231/02C07C235/34C07C51/60C07C59/64
CPCC07C213/02C07C231/02C07C51/60C07C213/10C07C217/60C07C235/34C07C59/64
Inventor 谭新步雁冰李金姑周青青赵娜孙园园
Owner SHANDONG WEIFANG PHARMA FACTORY
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