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Synthetic method for agomelatine

A synthetic method and compound technology, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as low yield, achieve high reaction yield, good controllability, and mild reaction conditions

Inactive Publication Date: 2010-08-04
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

When preparing (7-methoxy-1-naphthyl) acetonitrile (4) in this method, used poisonous allyl methacrylate as dehydrogenation agent and the high temperature above 200 ℃, not only can produce a large amount of environmental Pollution and energy consumption, and in the actual operation process, it is found that the yield of this step reaction is extremely low

Method used

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  • Synthetic method for agomelatine
  • Synthetic method for agomelatine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A, the preparation of 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthyl acetonitrile (3)

[0031] Add acetonitrile (15.6ml, 300mmol) into anhydrous tetrahydrofuran (500ml), cool to -78°C, slowly add n-decyllithium (120ml, 2.5M, 300mmol) dropwise, stir for 1h after dropping, keep at -78°C, Add 7-methoxy-1-tetralone (2) (35.2g, 199.7mmol) in tetrahydrofuran (250ml) dropwise, stir for 2h after dropping, add saturated ammonium chloride solution (100ml) dropwise to quench the reaction, Return to room temperature, add 200ml ethyl acetate to the reaction solution, separate the layers, dry the organic layer with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain the target compound (3), with a yield of 95%.

[0032] 1 H NMR (300MHz, CDCl 3 )δ1.78-2.25(m, 4H), 2.40(s, 1H), 2.70(m, 2H), 2.75, 2.87(2d, 2H, J=16.8Hz), 3.77(s, 3H), 6.77(dd , 1H, J=2.7, 8.4Hz,), 7.0(d, 1H, J=8.4Hz), 7.07(d, 1H, J=2.7Hz,).

[0033] B, the pre...

Embodiment 2

[0043] A, the preparation of 1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthyl acetonitrile (3)

[0044] Add acetonitrile (12.5ml, 239.6mmol) into anhydrous tetrahydrofuran (500ml), cool to -78°C, slowly add n-decyllithium (95.9ml, 2.5M, 239.6mmol) dropwise, stir for 1h after dropping, keep- 78°C, add 7-methoxy-1-tetralone (2) (35.2g, 199.7mmol) in tetrahydrofuran solution (250ml) dropwise, stir for 2h after dropping, add saturated ammonium chloride solution (100ml) dropwise to quench Extinguish the reaction, return to room temperature, add 200ml ethyl acetate to the reaction solution, separate the layers, dry the organic layer with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain the target compound (3), with a yield of 90%.

[0045] B, the preparation of (7-methoxy-1-naphthyl) acetonitrile (4)

[0046] 1-Hydroxy-7-methoxy-1,2,3,4-tetrahydro-1-naphthylacetonitrile (3) (20.0g, 98.4mmol) was added to toluene (150ml), di...

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Abstract

The invention relates to a synthetic method for agomelatine. The method comprises the following steps: reacting 7-methoxy-1-tetralone (2) serving as a raw material with acetonitrile under the action of n-butyl lithium to obtain 1-hydroxy-7-methoxy-1,2,3,4-tetralin-1-naphthyl acetonitrile (3); then uniformly mixing the compound (3) and acetic acid solvent or toluene, adding dichloro dicyano benzoquinone into the mixture for reacting at the temperature of between 50 and 150 DEG C for 4 to 20 hours to obtain a compound (4); adding the compound (4) into uniformly mixed solution of lithium aluminum hydride and tetrahydrofuran for reacting at the temperature of between 0 and 60 DEG C for 5 to 24 hours to obtain (7-methoxy-1-naphthyl) ethylamine (5); and finally uniformly mixing the compound (5)and triethylamine or naphthyridine, and adding acetylchloride into the mixture for reacting at the temperature of between 0 and 25 DEG C for 1 to 5 hours to obtain the agomelatine (1). The synthetic method for the agomelatine of the invention has the advantages of high yield, low cost, high controllability, simple processing after the reaction and environment protection and is suitable for industrial production of the melatonin antidepressant.

Description

technical field [0001] The invention relates to a synthesis method of agomelatine, which belongs to the technical field of chemical and medical synthesis. Background technique [0002] Agomelatine, chemical name N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, trade name Valdoxan, is a melatonin agonist developed by the French Servier company , both antagonizing 5HT 2c Receptor action, it is the first melatonin antidepressant, can effectively treat depression. Its structural formula is as shown in (1): [0003] [0004] The synthetic method reported in patent EP0447285: 7-methoxyl-1-tetralone (2) and ethyl bromoacetate undergo Reformatsky reaction, and sulfur dehydrogenation aromatizes to obtain 7-methoxyl-1-naphthylacetic acid Ethyl ester, and then through hydrolysis, acyl chloride, ammoniation, dehydration elimination, reduction, acetylation to prepare agomelatine (1), the reaction is as long as 8 steps. The steps are numerous, the total yield is low, and the multi-step ...

Claims

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Application Information

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IPC IPC(8): C07C233/18C07C231/02
Inventor 胡文浩徐勤耀杨琍苹
Owner EAST CHINA NORMAL UNIVERSITY
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