Preparation method of N-substituted-3-methylmercapto-4-morpholinyl maleimide compound

Abstract

The invention relates to a preparation method of an N-substituted-3-methylmercapto-4-morpholinyl maleimide compound, which comprises the following steps: in an organic solvent and under the oxygen condition, taking methylmercapto-Bunte salt, morpholine and N-substituted maleimide as reaction raw materials and obtaining the N-substituted-3-methylmercapto-4-morpholinyl maleimide compoundthrough a cascade reaction catalyzed by transition metal copper. The method is simple in reaction condition and high in product yield and purity, opens up a synthetic route and method for preparation of the N-substituted-3-methylmercapto-4-morpholinyl maleimide compound, and has good application potential and research value.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a preparation method of an N-substituted-3-methylmercapto-4-morpholino maleimide compound. Background technique [0002] 3,4-Difunctionalized maleimide as the core skeleton widely exists in marine natural alkaloids and anti-tumor active molecules with important biological activities, candidate drug molecules and AIE fluorescent materials, such as: G2 cell cycle checkpoint kinase Isogranulatimide, LPS-induced macrophage inhibitor Himanimide A, anti-breast cancer drug Camphorataimide B, specific porcupine inhibitor, marine alkaloid aqabamycin G, and liver X receptor agonist GSK3987. In addition, maleimide can also undergo a variety of functional group transformations to synthesize derivatives such as succinimide, tetrahydropyrrole and 2-pyrrolone. Therefore, exploring the efficient construction of 3,4-difunctionalized maleimides from cheap and readil...

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Problems solved by technology

[0005] Because compounds containing maleimide structures are so important, medicinal chemists have conducted a lot of research on the modification and synthesis of their parent structures, however, only a few cases of 3-mercapto-4-aminomaleimide derivatives have been reported so far The synthetic method of: In 2002, Dubinina, G.G. et al reported (Reactions of 3,4-dichloromaleimides with N-andS-nucleophiles, Ukrainskii Khimicheskii Zhurnal, 68,47-51; 2002), using 3,4-dichloromaleimides The 3-amino-4-arylmercaptomaleimide compound is obtained by reflux of arylamine, arylamine and thiophenol under the condition of triethylamine, but the reaction requires expensive 3,4-dichloromaleimide Amines as raw materials, even using foul-smelling thiophenols are likely to cause environmental pollution

In 2018, Professor Zhao Shengyin of Donghua University and others reported (Three-Component Coupling Reactions of Maleimides, Thiols, and Amines: One-Step Construction of 3,4-Heteroatom-functionalized Maleimides by Copper-Catalyzed C(sp2)-H Thioamination, AdvancedSynthesis & Catalysis, 2018, 360, 173-179;), Using transition metal copper / oxygen to catalyze the three-component cascade reaction of maleimide, arylamine and thiophenol to realize 3-amino-4-arylmercaptomaleimide The preparation of amine target compounds, the use of foul-smelling thiophenols is likely to cause environmental pollution

In 2020, our research group also reported the synthesis of N-substituted-3-methylmercapto-4-morpholinylmaleyl by copper-catalyzed multi-component tandem reaction of maleimide, morpholine and methylmercapto Buente salt imine compounds (Copper-Catalyzed Oxidative Thioamination of Maleimides with Amines and BunteSalts, Organic Letters 2020, 22, 5, 1863-1867). Suitable for morpholine compounds with special structures, but lacks a simple, efficient, and universally applicable catalytic system for a series of morpholine compounds

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