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

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...

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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 of industrial production in terms of cost and environment

[0008] Disclosed in CN101161638A is the preparation method of agomelatine intermediate, that is, the formula (G) compound (7-methoxy-1-naphthyl) acetonitrile is prepared by melting and dehydrogenating palladium carbon at high temperature, palladium carbon 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

[0009] CN101735091A discloses a preparation method of agomelatine, in which the carcinogenic compound dichlorodicyanobenzoquinone is used in the first step of dehydrogenation reaction, which must be used with extra care, which is not conducive to large-scale production

[0010] Disclosed in CN101643434A is a kind of use 7-methoxyl-1-naphthol as raw material and vinyl substituent to carry out under palladium catalysis, then catalytic hydrogenation, acylation obtains agomelatine, used four ( Triphenylphosphine) palladium, high cost and harsh conditions

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