Preparation method for agomelatine

A naphthyl and methoxyl technology, applied in the field of agomelatine preparation, can solve the problems of shortened production cycle, complicated reaction steps, harsh reaction conditions, etc., and achieve the effects of reducing reaction materials, shortening synthesis steps, and low cost

Inactive Publication Date: 2011-10-05
QINGDAO HUANGHAI PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Aiming at the disadvantages of complex reaction steps, harsh reaction conditions and high cost in the preparation method of agomelatine in the prior art, the present invention provides an improved preparation method of agomelatine. The method of the present invention uses (7-Methoxy-1-naphthyl)acetonitrile (the following structural formula (II)) is used as the starting material, and the production process of "one-pot cooking" is adopted, which is easy to operate, less energy consumption, low cost, and the production cycle is greatly shortened , and can obtain the final product with high yield, good purity and quality requirements, the overall process is more suitable for industrial continuous production

Method used

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  • Preparation method for agomelatine
  • Preparation method for agomelatine
  • Preparation method for agomelatine

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Embodiment 1

[0026] A kind of reaction formula of preparing agomelatine described in the present invention is as follows:

[0027]

[0028] in:

[0029] Formula 1 is (7-methoxy-1-naphthyl) acetonitrile

[0030] Formula 2 is 2-(7-methoxy-1-naphthyl) ethylamine

[0031] Formula 3 is N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide

[0032] a is a reducing agent including: potassium borohydride, sodium borohydride, lithium aluminum tetrahydrogen, etc.;

[0033] b is nickel chloride hexahydrate; c is acetic anhydride

[0034] A flow chart of steps for preparing agomelatine according to the present invention is as follows figure 1 Shown (reducing agent is example with sodium borohydride).

[0035] In three 1L reactors, add 6.8g of (7-methoxy-1-naphthyl)acetonitrile, 5.1g of nickel chloride hexahydrate, 6.7g of acetic anhydride, and 150ml of methanol, and stir to dissolve at room temperature. Cool in an ice bath to -10°C, then add potassium borohydride, sodium borohydride, and lithium alumi...

Embodiment 2

[0037] In four 1L reactors, add (7-methoxy-1-naphthyl) acetonitrile 6.8g, nickel chloride hexahydrate 5.1g, acetic anhydride 6.7g, methanol 150ml, stir and dissolve at room temperature. Cool in an ice bath to -10°C, then add 2.6g, 3.9g, 5.2g, and 6.4g of sodium borohydride respectively, control the internal temperature of the reactor below 20°C, and stir at room temperature for 3 hours after the addition is complete. After completion of the reaction, concentrate the solvent to dryness under reduced pressure, add 100ml of ethyl acetate to dissolve the solid, then add 100ml of dilute hydrochloric acid with a concentration of 10%, extract the aqueous phase twice with 100ml of ethyl acetate after liquid separation, combine the organic phases, and wash with saturated salt Wash with water until nearly neutral, then add an appropriate amount of anhydrous sodium sulfate to dry; after drying, filter, add activated carbon to the filtrate and reflux for 30 minutes for decolorization. Act...

Embodiment 3

[0039]In three 1L reactors, add 6.8 g of (7-methoxy-1-naphthyl) acetonitrile, 5.1 g of nickel chloride hexahydrate, 6.7 g of acetic anhydride, and 150 ml of methanol, and stir to dissolve at room temperature. Cool in an ice bath to -10°C, add 5.2 g of sodium borohydride to the three reactors, strictly control the internal temperature of the reactors to not exceed 0°C, 10°C, and 20°C, respectively, and stir at room temperature for 3 hours after the addition is complete. After the reaction is complete, concentrate the solvent to dryness under reduced pressure, add 100ml of ethyl acetate to dissolve the solid, then add 100ml of dilute hydrochloric acid with a concentration of 10%, extract the aqueous phase twice with 100ml of ethyl acetate after liquid separation, combine the organic phases, and wash with saturated salt Wash with water until nearly neutral, then add an appropriate amount of anhydrous sodium sulfate to dry; after drying, filter, add activated carbon to the filtrate...

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Abstract

The invention provides an improved preparation method for agomelatine. The method comprises the following steps of: carrying out reduction reaction with (7-methoxy-1-naphthyl) acetonitrile used as a starting raw material and methanol used as a reaction medium in the presence of nickel chloride hexahydrate and a reducing agent, and then carrying out acetylation reaction with acetic anhydride to generate agomelatine; and separating and purifying a reaction liquid after reaction, drying, decoloring and recrystallizing to obtain agomelatine. The preparation method provided by the invention employs a one-pot synthesis process, shortens synthesis steps, and reduces the difficulty in product purification caused by multiple secondary reaction; the reaction conditions are mild, and the cost and potential safety problem are reduced; a catalyst for the reaction is low; and the product acquired by the process has high yield and high purity, thus promoting the industrial production of agomelatine.

Description

technical field [0001] The invention belongs to the technical field of chemical and medical synthesis, and in particular relates to a method for preparing agomelatine. Background technique [0002] Agomelatine, the chemical name is N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, the trade name is Valdoxan, and it is developed by Servier in the field of mental illness. Another "blockbuster" drug. Structural formula is as follows formula (I): [0003] [0004] (I): Structural formula of agomelatine [0005] Agomelatine, a melatonin analogue, is not only the first melatonin receptor agonist, but also a 5-hydroxytryptamine 2C (S-HTx) receptor antagonist. Clinical trials have shown that agomelatine has good antidepressant effects. Its onset of action is fast, and it has a good curative effect on depression and its accompanying symptoms such as anxiety and insomnia, and has few adverse reactions and high safety. It provides a new method for the clinical treatment of depressive ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18C07C231/02
Inventor 纪存朋高义才吴立明鲁大东李永刚祝少良赵国栋胡杰于华芝
Owner QINGDAO HUANGHAI PHARM CO LTD
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