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Preparation method of Agomelatine

A compound, sodium borohydride technology, applied in the preparation field of agomelatine, can solve the problems of high equipment requirements, low yield, easy spontaneous combustion, etc., and achieve the effects of simple operation, stable process and high yield

Inactive Publication Date: 2010-06-16
万全万特制药江苏有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] EP0447285 describes the preparation and therapeutic use of agomelatine, which is prepared by using 7-methoxy-1-tetralone as the starting material, reacting with ethyl bromoacetate through Reformatsky reaction, and sulfur dehydrogenation aromatization (7-Methoxyl-1-naphthyl)ethyl acetate, and then synthesize agomelatine through a total of eight reaction steps of hydrolysis, acyl chloride, ammoniation, dehydration elimination, reduction, and acetylation, with a yield of less than 30 %
The first step uses highly irritating ethyl bromoacetate, which is not conducive to environmental protection
The second step of aromatization is incomplete, and it is difficult to obtain a relatively pure product after saponification
In addition, the seventh step adopts high-pressure operation, which needs to be carried out under 300 atmospheres, which requires high equipment and is difficult to apply to industrialization
[0008] The document Synthesis of Naphthalenic Melatonin Receptor Ligands describes the above formula (II) compound, i.e. the three-step synthetic method of (7-methoxyl-1-naphthyl) acetonitrile, the first step uses THF as a solvent, and LiCH 2 CN effect, reaction at -78°C, ultra-low temperature operation is difficult to achieve in industrialization
In the third step, benzene reflux is used in the dehydration step, which does not meet the requirements of industrial production in terms of cost and environment
[0011] Disclosed in CN101161638A is the preparation method of agomelatine intermediate, that is, the compound of formula (II) (7-methoxy-1-naphthyl) acetonitrile is prepared by melting dehydrogenation reaction at high temperature with palladium charcoal, and the price of palladium charcoal Expensive, prone to spontaneous combustion, special attention should be paid during use, high temperature reaction needs to be carried out at 200°C, which is not conducive to industrial transformation

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0030] Preparation of (7-methoxyl-1-naphthyl)acetonitrile:

[0031] 200 g of DDQ and 2 L of chloroform were added to the reaction flask, and a solution of 270 g of (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile in 0.5 L of chloroform was added dropwise with stirring. After the dropwise addition was completed, the reaction was refluxed. After the reaction was completed, suction filtered, and the filtrate was washed with saturated sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off from the filtrate under reduced pressure to obtain a brown solid. The solid was stirred in ethanol, filtered with suction, and the filter cake was dried to obtain 251 g of a light yellow solid with a yield of 95%.

[0032] Melting point: 82-84°C

Embodiment 2

[0034] Preparation of 2-(7-methoxy-1-naphthyl)ethylamine:

[0035] Add 193 g of (7-methoxy-1-naphthyl) acetonitrile, 40 g of nickel chloride, and 1 L of ethanol to the reaction flask, and add dropwise a solution of 45 g of sodium borohydride in 0.5 L of ethanol while stirring. After the dropwise addition, react at room temperature. After the reaction was complete, hydrochloric acid was added, and the residue was evaporated to dryness under reduced pressure, dissolved in water, filtered with suction, and the filtrate was washed with ethyl acetate. The aqueous phase was adjusted to pH 9-10 with sodium hydroxide solution, extracted with ethyl acetate, and washed with water until neutral. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness under reduced pressure to obtain 159 g of oil, with a yield of 80%.

Embodiment 3

[0037] Preparation of agomelatine (N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide):

[0038] Add 1L of dichloromethane, 126g of 2-(7-methoxy-1-naphthyl)ethylamine to the reaction flask, add 95g of triethylamine under stirring, then dropwise add a mixed solution of 100g of acetyl chloride in 200ml of dichloromethane , room temperature reaction. After the reaction was completed, the solvent was evaporated from the reaction liquid under reduced pressure, water was added, and the crystallization was carried out with stirring. After suction filtration, the filter cake was dried to obtain 148 g of solid, with a yield of 98%.

[0039] Melting point: 105-107°C

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Abstract

The invention relates to a preparation method of Agomelatine, which aims at economically preparing the Agomelatine on a large scale. The preparation method is characterized by comprising the following steps of: carrying out the dehydrogenation on a compound in a formula (I) under the action of DDQ to obtain a compound in a formula (II), reducing the compound in the formula (II) by sodium borohydride to obtain a compound in a formula (III), and reacting the compound in the formula (III) with acetylchloride to obtain a compound in a formula (IV), that is to say, the compound in the formula (IV) is the Agomelatine.

Description

technical field [0001] The invention relates to a preparation method of agomelatine. Background technique [0002] Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, is the first melatonin receptor agonist with good antidepressant effect. Its onset is fast, and it has a good curative effect on depression and its accompanying symptoms such as anxiety and insomnia. It has few adverse reactions and high safety. It provides a new method for the clinical treatment of MDD, and has high-value pharmacological properties. Its structural formula is as follows: [0003] [0004] agomelatine [0005] Agomelatine was developed by Servier and was approved for marketing in Europe in May 2009. [0006] [0007] EP0447285 describes the preparation and therapeutic use of agomelatine, which is prepared by using 7-methoxy-1-tetralone as the starting material, reacting with ethyl bromoacetate through Reformatsky reaction, and sulfur dehydrogenation aromatization (7-Methoxyl-1-...

Claims

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Application Information

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IPC IPC(8): C07C233/18C07C231/02
Inventor 张志强李萍徐剑谌伦华卢文
Owner 万全万特制药江苏有限公司
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