Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide

A methoxynaphthalene and methoxyl technology, which is applied in the field of preparation of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, can solve the problem of large harm to the human body, pollution, aromatic Incomplete structure and other problems, to achieve the effect of reducing industrial costs, good refining effect, and simple operation

Inactive Publication Date: 2010-06-30
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problem of this process is that the aromatization is not complete, resulting in the inability to obtain pure compounds after saponification
[0005] CN1680284 has reported the synthetic technique of (7-methoxy-1-naphthyl) acetonitrile, and this method is mainly to generate 2-(1,2- Dihydro-6-methoxynaphthalene-4-yl)acetonitrile, and then in the presence of hydrogenation catalyst Pd-C, dehydrogenation is carried out with methacrylate as dehydrogenating agent, thereby obtaining (7-methoxy- 1-naphthyl) acetonitrile, the main problem of this process is that poisonous methyl methacrylate is used as dehydrogenation agent in the dehydrogenation process, which not only produces a large amount of pollution, but also causes great harm to human body
[0006] "Synthesis communication" (synthesis communication), 2001, 31 (4) 621-629 reported the synthetic technique of (7-methoxy-1-naphthyl) acetonitrile, this method uses highly toxic benzene in the dehydration step As a solvent, it is more harmful to the human body and does not meet the requirements of industrial production

Method used

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  • Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide
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  • Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide

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Embodiment 1

[0032] The preparation method of 2-(1,2,3,4-tetrahydro-1-hydroxyl-7-methoxynaphthalen-1-yl)acetonitrile:

[0033] Add acetonitrile (7ml, 132mmol) and THF (150ml) to the reaction flask, cool to -78°C, add 2.2N n-butyllithium (60ml, 132mol) dropwise under nitrogen protection, dropwise, stir at -78°C for 0.5h, Add dropwise 7-methoxy-1-tetralone (15.5g, 88mmol) / THF (50rml) solution; dropwise, stir at -78°C for 1h, quench with saturated ammonium chloride aqueous solution (300ml), ethyl acetate (200ml*2) extracted the aqueous layer, combined the organic layers, dried over anhydrous MgSO4, filtered, and evaporated the excess solvent under reduced pressure to obtain 18.2 g of brown-yellow oily liquid, with a yield of 95.2%.

Embodiment 2

[0035] The preparation method of 2-(1,2-dihydro-1-hydroxyl-7-methoxynaphthalene-1-yl)acetonitrile:

[0036] Add (1-hydroxyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthyl)acetonitrile (12g, 55mmol), dichloromethane (250ml), DDQ (15.5g , 66mmol), stirred at room temperature for 1.5h, filtered, washed with 10% NaOH aqueous solution (200ml*2), washed with water (300ml*2), dried with anhydrous MgSO4, filtered, concentrated under reduced pressure to remove excess solvent, and obtained 10.7g of brown-red oily liquid , yield 90%.

Embodiment 3

[0038] The preparation method of (7-methoxy-1-naphthyl) acetonitrile:

[0039] ((1-Hydroxy-7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (11g, 51mmol), cyclohexane (110ml), TsOH.H2O (0.2g, 1.06mmol), heated to reflux for 1.5h, hot filtered, cooled and crystallized at 0°C under stirring to obtain 8g of brown-yellow to off-white solid powder, with a yield of 80%.

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Abstract

The present invention relates to a preparing method of agomelatine (N-[2-(7- anisyl-1- naphthyl) ethide] acetamide) of melatonin antidepressant drugs of commercial production. Firstly, 7- anisyl-1-tetralone is used as raw material, and is prepared into 2-(1,2,3,4- tetrahydrochysene-1- oxhydryl-7- methoxynaphthalene-1-base) acetonitrile in a cyanophoric way; then, 2-(1,2- dihydro-1-oxhydryl-7- methoxynaphthalene-1-base) acetonitrile is generated in an aromatization dehydrogenation way, and (7-- anisyl-1- naphthyl) acetonitrile is generated in a backflow reaction dehydrogenation way; finally, the agomelatine (N-[2-(7- anisyl-1- naphthyl) ethide] acetamide) is generated by reducing and acetylizing in a one-kettle way. The present invention has the advantages of high product purity, friendly environment, convenient operation and low cost, and is suitable for the commercial production.

Description

technical field [0001] The present invention relates to a new preparation method and crystallization method of agomelatine N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide. Background technique [0002] The common name of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is agomelatine (Agomelatine), which is developed by Servier, a new type of antidepressant. It is a melatonin receptor agonist and a 5-hydroxytryptamine (5-HT) 2C receptor antagonist, and is mainly used for the treatment of melatonin-related diseases. On February 24, 2009, agomelatine was approved for marketing in the EU. its trade name The drug is currently approved in the European Union for the treatment of depression in adults. Its structural formula is as follows: [0003] [0004] EP 0447285 reports agomelatine, its preparation, its therapeutic use and its synthesis method. The method disclosed in this patent synthesizes agomelatine through eight-step reactions, and the average yield is less than 30%. The me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18C07C231/06A61K31/165A61P25/24
Inventor 周世伟蹇锋
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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