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

A maleimide, morpholine-based technology, applied in the field of organic compound synthesis, can solve the problems of thiophenol environmental pollution, lack of simplicity and high efficiency, high price, etc., and achieves high yield and purity, high reaction efficiency, and post-processing. easy effect

Pending Publication Date: 2020-12-04
WENZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 Constructio

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0030] Synthesis of N-(3,4-dichlorobenzyl)-3-methylmercapto-4-morpholinylmaleimide

[0031]

[0032] At room temperature, methylmercapto Buente salt (0.6mmol, 3equiv), morpholine (0.6mmol, 3equiv), N-(3,4-dichlorobenzyl)maleimide (0.2mmol, 1equiv ), cuprous chloride (0.04mmol, 0.2equiv) and 2mL of toluene were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 120°C for 24h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered to a heart bottle, then the solvent was spun off, and the product was separated by column chromatography (eluent: petroleum ether: ether = 9: 1), and the product was a yellow solid. The melting point is 100-101° C., the yield is 90%, and the product weight is 69 mg.

[0033] The data of the proton nuclear magnetic resonance spectrum of gained product are as follows:

[0034] 1 H NMR (500MHz, CDCl 3 ): δ7.44(d, J=2.00Hz, 1H), 7.37(d, J=8.20Hz, 1H), 7.20(dd, J...

Embodiment 2

[0040] Synthesis of N-(4-bromobenzyl)-3-methylmercapto-4-morpholino maleimide compound

[0041]

[0042] At room temperature, methylmercapto Buente salt (0.6mmol, 3equiv), morpholine (0.6mmol, 3equiv), N-(4-bromobenzyl)maleimide (0.2mmol, 1equiv), chlorine Cuprous chloride (0.04mmol, 0.2equiv) and 2mL of toluene were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 120°C for 24h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered to a heart bottle, then the solvent was spun off, and the product was separated by column chromatography (eluent: petroleum ether: ether = 9: 1), and the product was a yellow solid. The melting point is 103-104° C., the yield is 92%, and the product weight is 73 mg.

[0043] The data of the proton nuclear magnetic resonance spectrum of gained product are as follows:

[0044] 1 H NMR (500MHz, CDCl 3 ): δ7.43(d, J=8.25Hz, 2H), 7.23(d, J=8.25Hz, 2H), 4.58(...

Embodiment 3

[0050] Synthesis of N-Benzyl-3-Methylmercapto-4-Morpholinylmaleimide

[0051]

[0052] At room temperature, methylmercapto Buente salt (0.6mmol, 3equiv), morpholine (0.6mmol, 3equiv), N-benzylmaleimide (0.2mmol, 1equiv), cuprous chloride (0.04mmol , 0.2equiv) and 2mL of toluene were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 120°C for 24h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered to a heart bottle, then the solvent was spun off, and the product was separated by column chromatography (eluent: petroleum ether: ether = 9: 1), and the product was a yellow solid. The melting point is 117-118° C., the yield is 93%, and the product weight is 59 mg.

[0053] The data of the proton nuclear magnetic resonance spectrum of gained product are as follows:

[0054] 1 H NMR (500MHz, CDCl 3 ): δ7.36-7.35(m, 2H), 7.32-7.29(m, 2H), 7.27-7.24(m, 1H), 4.64(s, 2H), 4.14(t, J=4.65Hz,...

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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...

Claims

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Application Information

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IPC IPC(8): C07D207/456
CPCC07D207/456Y02P20/584
Inventor 吴戈马云飞盛思佳
Owner WENZHOU MEDICAL UNIV
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