Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine

A technology of methoxynaphthalene and compounds, which is applied in the field of preparation of agomelatine intermediates, can solve the problems of poor reproducibility, easy spontaneous combustion, and incompleteness of the reaction, and achieve short reaction time, low cost, and high yield Effect

Active Publication Date: 2011-02-16
NANTONG BOTAO CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The disadvantage of this method is that a. there are many steps; b. the reproducibility of the first step reaction is poor; in addition, the aromatization of compound (B) in step (2) and subsequent steps are often incomplete, and in (3) The mixture obtained by step saponification is difficult to purify, and column chromatography purification is required c. (7) step hydrogenation pressure is high, and the pressure reported in the patent is 300 atm, which is difficult to realize in industrial production; d. The yield is low, and the average total yield is less than 30%
[0007] The document Synthesis of Naphthalenic Melatonin Receptor Ligands has recorded the compound of the above formula (G), i.e. the three-step synthetic method of (7-methoxy-1-naphthyl) acetonitrile, the first step is solvent with THF, and Li CH CN Function, the reaction is carried out at -78°C, and 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 o

Method used

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  • Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine
  • Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine
  • Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine

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Experimental program
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Effect test

Embodiment 1

[0032] Add 2.3g of 3-(7-methoxynaphthalene-1-yl)propionic acid, 20ml of toluene, and 1.5ml of triethylamine into a 50ml reaction flask, cool down to -10°C, and then dilute 3.03g of phosphoric azide Add diphenyl ester dropwise to the cooled reaction solution, keep it warm for 6 hours, then slowly raise the temperature to 80°C and heat it for 6 hours, then cool down to below 0°C, then dropwise add 0.88g of sodium hydroxide solution Aqueous solution, stirring reaction at room temperature, adding 10ml of water to the reaction solution after completion, separating the layers, extracting the aqueous layer with toluene (10ml) for 3 times, combining the organic layers, drying over anhydrous sodium sulfate, and evaporating the solvent to obtain the target product, light yellow The oil was 1.87g, the yield was 93%, and the HPLC (normalized method) purity was 95%.

Embodiment 2

[0034] Add 2.3g 3-(7-methoxynaphthalene-1-yl)propionic acid, 20ml toluene, 1.53g diisopropylethylamine to the 50ml reaction flask, cool down to 0°C, then dilute the diluted 3.03g Add diphenylphosphoryl azide dropwise to the cooled reaction solution, keep it warm for 1.5 hours, then slowly raise the temperature to 60°C and heat it for 6 hours, then cool down to below 0°C, then dropwise add 1.12g of hydrogen into the cooling solution An aqueous solution of potassium oxide was stirred at room temperature until the reaction was completed. Add 10ml of water to the reaction solution, separate the layers, extract the aqueous layer 3 times with toluene (10ml), combine the organic layers, dry over anhydrous sodium sulfate and evaporate the solvent to obtain the target product, 1.85g of light yellow oil, yield 92 %, HPLC (normalized method) purity 94%.

Embodiment 3

[0036] Add 2.3g 3-(7-methoxynaphthalene-1-yl)propionic acid, 20m dichloromethane, 1.53g triethylamine to the 50ml reaction bottle, cool down to 30°C, then dilute 3.03g azide Add diphenyl phosphate dropwise to the cooled reaction liquid, keep it warm for 0.5 hours, then slowly raise the temperature to 60°C and heat it for 2 hours, then cool down to below 0°C, then dropwise add 0.88g of sodium hydroxide into the cooling liquid aqueous solution, and the reaction was stirred at room temperature until completion. Add 10ml of water to the reaction solution, separate the layers, extract the aqueous layer 3 times with dichloromethane (10ml), combine the organic layers, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain the target product, 1.68g of light yellow oil, collected Yield 85%, HPLC (normalized method) purity 90%.

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Abstract

The invention provides a preparation method of a valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine, which has the advantages of simple and convenient operation, moderate conditions, short reaction time, high yield and high purity. In the method, 3-(7-methoxy-1-naphthyl)propionic acid reacts with diphenylphosphoryl azide to generate an acyl azide, and basic hydrolysis is carried out on the acyl azide to obtain the target product without separation and purification. The method is applicable to industrial production.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an intermediate of agomelatine. technical background: [0002] Agomelatine, whose chemical name is N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide and whose trade name is Valdoxan, is a melatonin agonist developed by Servier company in France. Antagonizing the 5HT2c receptor, it is the first melatonin antidepressant, which can effectively treat depression and improve sleep parameters. Agomelatine has the structure shown in formula (5) [0003] [0004] There are many synthesis methods of agomelatine reported. In EP0447285, 7-methoxy-1-tetralone is used as starting material, and agomelatine is synthesized through eight-step reaction. The reaction process is as follows [0005] [0006] The disadvantage of this method is that a. there are many steps; b. the reproducibility of the first step reaction is poor; in addition, the aromatization o...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C217/60
Inventor 齐云
Owner NANTONG BOTAO CHEM
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