Synthetic method of ramelteon

Abstract

The invention discloses a synthesis method of ramelteon. The method comprises the following steps: based on commercially available compounds 4-amino-2,3-dihydrobenzofuran, under the reacting functionof sulfuric acid, sodium nitrite and potassium iodide, an aryl ammonia compound is converted into an aryl iodine compound; allowing the obtained aryl iodine compound to react with a bromo allyl alcohol compound under the action of a palladium catalyst, an inorganic base, a phosphine ligand, a norbornene derivative and an additive to obtain an aldehyde group-containing ramelteon intermediate; finally, the intermediate and propionamide are subjected to a reductive amination reaction under the action of trifluoroacetic acid and triethylsilane, a target compound ramelteon is obtained, the reactioncomprises three steps in total, and the total yield is 26%. Compared with the prior art, the synthesis method disclosed by the invention has the advantages that the target molecule ramelteon can be obtained from the commercially available compound 4-amino-2, 3-dihydrobenzofuran which is easy to prepare only by three steps, the synthesis steps are greatly shortened compared with other process routes, the steps are few, and the safety is high.

Description

technical field [0001] The invention relates to the field of organic chemistry or medicinal chemistry, in particular to a method for synthesizing ramelteon. Background technique [0002] Insomnia is a sleep disorder. Patients with insomnia often have difficulty falling asleep at night or staying awake for a long time, and often feel tired, irritable, and depressed during the day. Insomnia can lead to traffic accidents, difficulty concentrating, and reduced learning ability. Its duration can range from days or weeks to months or even years. Insomnia may be idiopathic or a symptom of another health problem or taking certain medications. Good sleep habits and a regular life routine are often the first choice for treating insomnia. The total number of Americans suffering from insomnia accounts for between 10% and 30% of the national total, and about 6% of insomnia patients are primary insomnia and last for more than one month. [0003] For patients who are difficult to treat ...

AI Technical Summary

Problems solved by technology

[0007] In 2012, the research group of Lv Wei, Department of Chemistry, East China Normal University, was in heterocyclic chemistry (X.Zhang, W.Yuan, Y.Luo, Q.-Q.Huang, W.Lu, Heterocycles.2012,85,73-84) It was reported above that ramelteon was successfully constructed through the Heck reaction and organocatalyzed asymmetric Michael addition reaction. only 3.5% higher (see image 3 shown)

[0008] In 2013, Chen's group reported on the tetrahedron journal (X.Fu, X.Guo, X.Li, L.He, Y.Yang, Y.Chen, Tetrahedron: Asymmetry.2013, 24, 827-832) through the Catellani reaction and The asymmetric Michael addition reaction controlled by chiral prosthetic groups has successfully constructed ramelteon, and its synthetic route is shown in the figure below, but the synthetic steps of this reaction are relatively long, with a total of 15 steps and a total yield of 4.1% (see Figure 4 shown)

[0009] In 2015, Zhou's group reported the synthesis of Ramelteon, but this route has 7 steps in total, and the total yield is 11%, and the starting material needs to be made through 7 steps (see Figure 5 shown)

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