Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile

A methoxyl and naphthyl technology, applied in a new preparation field, can solve the problems of harsh reaction requirements, environmental pollution, incomplete reaction, etc., and achieve the effects of mild reaction conditions, high product purity, and short reaction route

Inactive Publication Date: 2012-02-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, the first step Reformatsky reaction of above-mentioned preparation 2-(7-methoxy-1-naphthyl) acetocyanide, when being transformed into industrial production, finds that it is difficult to implement, and the reaction is harsh and reproducible, and the compound obtained by the reaction IV. Vigorous aromatization conditions are required, the reaction is incomplete, and post-treatment is difficult; subsequent acyl chloride, ammonification, and dehydration elimination reactions require the use of thionyl chloride and trifluoroacetic anhydride. These reagents are likely to cause environmental pollution , does not meet the requirements of environmental protection

Method used

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  • Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile
  • Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile
  • Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile

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Experimental program
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Effect test

Embodiment 1

[0029]

[0030] Dissolve 35.2 g of compound III (7-methoxytetralone) and 60.2 g of compound IX in 340 ml of toluene, heat to 100° C. until the raw materials disappear, and cool to room temperature. Wash and dry. The solvent was distilled off to obtain 36.0 g of compound XI. Yield: 90%. ESI-MS: [M+H] + 200.

Embodiment 2

[0032]

[0033] Dissolve 35.2 g of compound III (7-methoxytetralone) and 30.0 g of compound X in 170 ml of toluene, carefully add 13.6 g of sodium ethoxide, heat to 100°C until the raw materials disappear, and cool to room temperature. Wash and dry. The solvent was distilled off to obtain 36.5 g of compound XI. Yield: 91%. ESI-MS: [M+H] + 200.

Embodiment 3

[0035]

[0036] 36.0 g of compound XI prepared in Example 1 and 7.2 g of 10% Pd / C were dissolved in 180 ml of toluene, heated to reflux until the raw materials disappeared, and cooled to room temperature. Suction filtration, washing and drying. The solvent was distilled off to obtain the target compound I (30.6 g). Yield: 85%. Melting point: 83-84°C. ESI-MS: [M+H] + 198. 1 H-NMR (CDCl 3 , ppm): 7.20-7.79 (m, 5H, ArH), 7.0 (d, 1H, J=2.1Hz, ArH), 4.1 (s, 2H, ArCH 2 ), 3.94 (3, 3H, OCH 3 ).

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Abstract

The invention provides a new preparation method of an important intermediate of the antidepressant agomelatine, i.e. 2-(7-methoxy-1-naphthyl) acetonitrile. In the method, a compound of formula III is subjected to a Wittig reaction so as to obtain a compound of formula XI, which then undergoes an aromatization reaction, so that 2-(7-methoxy-1-naphthyl) acetonitrile can be obtained. The preparation method of the invention has a short reaction route, the Wittig reaction and the aromatization reaction both have high yield. With mild reaction conditions and without anything to do with reagents and solvents etc. of high toxicity, the preparation method provided in the invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new preparation method of an important intermediate of agomelatine, 2-(7-methoxy-1-naphthyl)acetocyanide. Background technique [0002] On February 24, 2009, agomelatine, the world's first melatonin receptor agonist antidepressant, was approved for marketing in the European Union. Agomelatine was developed by the French company Servier. , whose trade name is Valdoxan / Thymanax, is currently approved by the European Union for the treatment of depression in adults. Its chemical name is N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide, trade name Valdoxan, and its structural formula is as shown in formula II below: [0003] [0004] The launch of agomelatine is a new breakthrough in the field of depression treatment. Its innovation lies in its unique mechanism of action: it is the world's first melatonin (MT 1 , MT 2 ) receptor agonist, but also five serotonin 2c (5H...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/37C07C253/30
Inventor 邓斐张金生
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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