CN111548299A - Preparation method of N-methyl-3-benzylmercapto-4-amino maleimide compound - Google Patents
Preparation method of N-methyl-3-benzylmercapto-4-amino maleimide compound Download PDFInfo
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Abstract
The invention relates to a preparation method of N-methyl-3-benzylmercapto-4-amido maleimide compound, which comprises the steps of taking benzylmercapto bunnith salt, secondary amine and N-methyl maleimide as reaction raw materials in an organic solvent under the condition of oxygen, and obtaining the N-methyl-3-benzylmercapto-4-amido maleimide compound through a series reaction catalyzed by transition metal copper. The method has simple reaction conditions and high yield and purity of the product, develops a synthetic route and a method for preparing the N-methyl-3-benzylmercapto-4-amido maleimide compound, and has good application potential and research value.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of an N-methyl-3-benzylmercapto-4-amino maleimide compound.
Background
Maleimide as an important amide compound is widely present in natural products, bioactive molecules and clinical drug molecules, and the parent structure can also be used for preparing derivatives such as succinimide, pyrrolidine and lactam through various conversion reactions, so that how to efficiently and greenly synthesize the derivatives with maleimide skeletons is a target pursued by organic chemists based on the application of maleimide compounds in different fields.
In 2002, Dubinia, G.G. et al reported (Reactions of 3, 4-dichloromaleimides with N-and S-nucleophiles, Ukrains kii Khimichischii Zhurnal, 68, 47-51; 2002) that 3-amino-4-arylmercaptomaleimide compounds were obtained by refluxing 3, 4-dichloromaleimide, arylamine and thiophenol under triethylamine conditions, however, this reaction required expensive 3, 4-dichloromaleimide as a raw material and was liable to cause environmental pollution even with malodorous thiophenol, and the reaction formula was as follows:
in 2018, professor Zhao Sheng Ting of the university of east Hua reported (Three-Component coupling reactions of Maleimides, Thiols, and Amines: One-Step Construction of 3, 4-heteoatom-functionalized Maleimides by coater-catalyst C (sp2) -HThioamino, Advanced Synthesis & Catalysis, 2018, 360, 173-; 179), the preparation of 3-amino-4-arylmercaptomaleimide target compounds was achieved by the Three-Component cascade reaction of transition metal Copper/oxygen Catalyzed maleimide, arylamine, and thiophenol, which is prone to environmental contamination with malodorous thiophenol, as follows:
although the prior art can solve the amine sulfhydrylation reaction of maleimide, the use of malodorous and unstable thiol as the sulfhydrylation reagent in the reaction process limits the further industrial application of the reaction and the research on the pharmacological activity or biological activity of molecular compounds, and the utilization of odorless and stable bunnit salt as the sulfhydrylation reagent has not been reported so far. Therefore, it is very important to prepare the N-methyl-3-benzylmercapto-4-amino maleimide compound from the raw materials which are simple, easy to process and cheap and easily available in substrate, especially to synthesize the N-methyl-3-benzylmercapto-4-amino maleimide compound by the three-component tandem reaction in which the bunyate salt is used as the sulfhydrylation reagent, and the need of continuing research and exploration still exists, which is the basis and the motivation for completing the invention.
Disclosure of Invention
The technical problem to be solved by the invention is the synthetic route problem of the preparation method of the N-methyl-3-benzylmercapto-4-amido maleimide compound.
In order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of N-methyl-3-benzylmercapto-4-amino maleimide compound comprises the steps of taking benzylmercapto bunnitum salt, secondary amine and N-methyl maleimide as reaction raw materials in an organic solvent under the condition of oxygen, and carrying out tandem reaction under the catalysis of transition metal copper to obtain the N-methyl-3-benzylmercapto-4-amino maleimide compound.
The above reaction process can be represented by the following reaction formula:
the molar ratio of the benzylmercaptobunyate salt, the secondary amine and the N-methylmaleimide is 3: 2: 1.
(1) Transition metal copper catalyst
The transition metal copper catalyst in the invention is copper acetate, copper chloride, copper bromide or cuprous iodide, preferably cuprous iodide, and the dosage of the cuprous iodide is 10% of the dosage of the N-methylmaleimide by molar amount.
(2) Organic solvent
The reaction solvent in the invention is an organic solvent, and the organic solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, pyridine, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, toluene and tetrahydrofuran, and preferably 1, 2-dichloroethane.
(3) Reaction temperature
In the preparation method of the present invention, the reaction temperature is 100 ℃ to 120 ℃, and can be, for example, but not limited to, 100 ℃, 110 ℃ and 120 ℃, and the reaction temperature is preferably 100 ℃.
(4) Reaction time
In the production method of the present invention, the reaction time is not particularly limited, and a suitable reaction time can be determined by, for example, detecting the residual percentage of the objective product or raw material by liquid chromatography, and is usually 18 to 24 hours, such as 18 hours, 20 hours, 22 hours, 23 hours, or 24 hours, but is not limited thereto, and the reaction time is preferably 24 hours.
(5) Separating and purifying
In a preferred embodiment, the post-treatment step after the reaction is completed may be as follows: after the reaction is finished, cooling the reaction liquid, adding ethyl acetate for dilution, filtering the diluted solution to a heart-shaped bottle, then spinning off the solvent, separating the concentrate through column chromatography, taking the mixed liquid of petroleum ether and ethyl acetate as an eluent, collecting the eluent, and concentrating to obtain the target product.
The preparation method of the N-methyl-3-benzylmercapto-4-amino maleimide compound provided by the invention has the following beneficial effects:
a) the reaction has high efficiency, high yield and simple and convenient post-treatment;
b) utilizing tasteless and stable benzyl sulfydryl bunnit salt as a benzyl sulfydryl reagent;
c) cheap and easy copper/oxygen is used as a catalytic system;
the invention takes benzylmercaptobunnitol salt, secondary amine and N-methylmaleimide as reaction raw materials, and obtains the N-methyl-3-benzylmercapto-4-amido maleimide compound through tandem reaction under the catalysis of transition metal copper. The method has simple reaction conditions and high yield and purity of the product, develops a synthetic route and a method for preparing the N-methyl-3-benzylmercapto-4-amido maleimide compound, provides a new thought for molecular design and synthesis of the disubstituted maleimide derivative, and has important social and economic meanings.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
The data and purity of the novel compounds given in the following examples were determined by nuclear magnetic resonance.
Implementation 1:
synthesis of N-methyl-3-benzylmercapto-4-morpholinyl maleimide compound
Benzylthiocarbutes (0.6mmol, 3equiv), morpholine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether ═ 9: 1) as a yellow liquid in 83% yield, 53mg of product weight.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.31-7.24(m，3H)，7.13-7.11(m，2H)，3.85(s，2H)，3.78(t，J＝4.70Hz，4H)，3.46 (t，J＝4.70Hz，4H)，3.03(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.2，166.6，149.3，138.2，128.8，128.5，127.2，91.8，66.7，48.4，40.1，24.1；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H18N2O3S[M+H]+319.1117，found 319.1120。
implementation 2:
synthesis of N-methyl-3-benzylmercapto-4-piperidyl maleimide compound
Benzylthiocarbutes salt (0.6mmol, 3equiv), piperidine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 97-98 ℃, yield 56% and product weight 35 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.28-7.25(m，2H)，7.20(t，J＝7.30Hz，1H)，7.15(d，J＝7.20Hz，2H)，3.85(s，2H)， 3.72(t，J＝5.55Hz，4H)，3.01(s，3H)，1.56-1.51(m，2H)，1.44-1.40(m，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.6，166.7，150.0，138.3，128.9，128.4，127.0，49.7，40.2，26.2，24.1，23.9；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C17H20N2O2S[M+H]+317.1324，found 317.1325。
implementation 3:
synthesis of methyl 1- (4-benzylmercapto-1-methyl-maleimido) -4-piperidinecarboxylate compound
Benzylthiocarbutes (0.6mmol, 3equiv), methyl 4-piperidinecarboxylate (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: 9: 1) as a yellow solid with a melting point of 93-94 ℃, yield 82% and weight of 61 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.29-7.26(m，2H)，7.22-7.19(m，1H)，7.14-7.13(m，2H)，4.48(dt，J＝13.6Hz， 3.7Hz，2H)，3.86(s，2H)，3.68(s，3H)，3.02-2.96(m，5H)，2.43(tt，J＝4.2Hz，1.9Hz，2H)，1.78-1.75(m，2H)， 1.56-1.48(m，2H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：174.2，170.4，166.6，149.8，138.2，129.3，128.8，128.6，128.5，127.1，91.7，51.8， 47.7，40.1，40.0，28.1，24.1；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C19H22N2O4S[M+H]+375.1379，found 375.1385。
implementation 4:
synthesis of (R) -1- (4-benzylmercapto-1-methyl-maleimido) -3-tert-butoxycarbonylaminopiperidine compound
Benzylthiocarbapentate (0.6mmol, 3equiv), (R) -3-tert-butoxycarbonylaminopiperidine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered to a heart flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 109-.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.30-7.27(m，2H)，7.21(t，J＝7.31Hz，1H)，7.17(d，J＝7.45Hz，2H)，4.54(brs，1H)，3.99(brs，1H)，3.91-3.84(m，2H)，3.75(brs，1H)，3.54-3.44(m，2H)，3.01(s，3H)，1.80-1.79(m，1H)， 1.57-1.32(m，13H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.3，166.5，154.8，150.3，138.3，128.9，128.4，127.2，92.9，79.6，53.1，48.8，46.9， 40.1，29.6，28.4，24.1，22.6；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C22H29N3O4S[M+H]+432.1958，found 432.1968。
implementation 5:
synthesis of 4- (4-benzylmercapto-1-methyl-maleimido) -1-tert-butyloxycarbonyl piperazine compound
Benzylthiobulnett salt (0.6mmol, 3equiv), N-tert-butoxycarbonylpiperazine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered to a heart vial, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 137 and 138 ℃, yield 79% and product weight 66 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.29-7.27(m，2H)，7.24-7.21(m，1H)，7.14-7.12(m，2H)，3.86(s，2H)，3.70(t， J＝5.05Hz，4H)，3.21(t，J＝5.05Hz，4H)，3.03(s，3H)，1.46(s，9H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.2，166.5，154.4，149.6，138.2，128.8，128.5，127.2，92.5，80.3，47.9，40.0，28.3， 24.2；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C21H27N3O4S[M+H]+418.1801，found 418.1804。
implementation 6:
synthesis of 3-benzylmercapto-1-methyl-4- (4-phenylpiperazino) maleimide compound
Benzylthiocarbutes (0.6mmol, 3equiv), N-phenylpiperazine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow liquid in 52% yield with a weight of 41 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.28-7.25(m，4H)，7.19-7.14(m，3H)，6.89(t，J＝7.30Hz，1H)，6.83(d，J＝8.10Hz， 2H)，3.94(t，J＝5.05Hz，4H)，3.87(s，2H)，3.03(S，3H)，2.97(t，J＝5.05Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.3，166.6，150.6，149.4，138.3，129.2，128.9，128.5，127.2，120.4，116.3，91.7， 49.2，47.9，40.1，24.1；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C22H23N3O2S[M+H]+394.1590，found 394.1598。
implementation 7:
synthesis of N-methyl-3-benzylmercapto-4-pyrrolidinylmaleimide compound
Benzylthiocarbutes salt (0.6mmol, 3equiv), pyrrolidine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow liquid in 61% yield with a weight of 37 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.28-7.24(m，2H)，7.20-7.17(m，1H)，7.09(d，J＝7.15Hz，2H)，3.74(s，2H)，3.50 (br，4H)，3.04(s，3H)，1.67(d，J＝6.80Hz，4H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：171.3，166.0，148.6，138.5，129.4，128.9，128.5，128.3，126.9，87.1，51.1，41.0， 24.9，24.1；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H18N2O2S[M+H]+303.1168，found 303.1170。
implementation 8:
synthesis of 3- (4-benzylmercapto-1-methylmaleimide) -3-methylaminopropionitrile compound
Benzylthiocarbutene salt (0.6mmol, 3equiv), 3-methylaminopropionitrile (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 73-74 ℃ in 86% yield and a weight of 49 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.32-7.29(m，2H)，7.26-7.25(m，1H)，7.14-7.13(m，2H)，3.89(s，2H)，3.79(t， J＝6.85Hz，2H)，3.16(s，3H)，3.04(s，3H)，2.34(t，J＝6.85Hz，2H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.1，166.2，148.7，138.1，128.9，128.7，127.3，117.2，92.9，49.4，41.3，40.2，24.2， 16.7；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C16H17N3O2S[M+H]+316.1120，found 316.1122。
implementation 9:
synthesis of 3-benzylmercapto-1-methyl-4-methylpentylaminomaleimide compound
Benzylthiobulnett salt (0.6mmol, 3equiv), N-methyl-N-pentylamine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times with stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow liquid in 59% yield with a weight of 39 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.28-7.24(m，2H)，7.20(t，J＝7.45Hz，1H)，7.13(d，J＝7.20Hz，2H)，3.82(s，2H)， 3.54(t，J＝7.80Hz，2H)，3.06(s，3H)，3.01(s，3H)，1.42-1.36(m，2H)，1.31-1.25(m，2H)，1.19-1.13(m，2H)，0.89 (t，J＝7.25Hz，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.7，166.3，149.8，138.2，129.3，129.0，128.9，128.7，128.4，127.0，53.7，40.7， 40.5，28.5，27.6，24.1，22.4，13.9；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C18H24N2O2S[M+H]+333.1637，found 333.1641。
implementation 10:
synthesis of 3-benzylamino-4-benzylmercapto-1-methylmaleimide compound
Benzylpulfobentite (0.6mmol, 3equiv), N-methylbenzylamine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: ether ═ 9: 1) as a yellow solid with melting point 82-83 ℃, yield 81% and product weight 57 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.28-7.24(m，4H)，7.22-7.19(m，1H)，7.10(d，J＝7.05Hz，2H)，6.91(d，J＝8.40 Hz，2H)，4.79(s，2H)，3.84(s，2H)，3.04(s，3H)，2.98(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.6，166.4，150.0，138.0，136.4，128.9，128.7，128.4，127.6，127.2，127.1，90.8， 56.3，40.6，40.2，24.2；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C20H20N2O2S[M+H]+353.1324，found 353.1325。
example 11:
synthesis of 3-benzylmercapto-4- (4-methoxybenzyl methylamino) -1-methylmaleimide compound
Benzyl mercapto bunnett salt (0.6mmol, 3equiv), N- (4-methoxybenzyl) -N-methylamine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv) and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, stirring at 100 ℃ for 24 h. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 90-91 ℃, yield 83% and weight of 63 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.27-7.24(m，2H)，7.22-7.19(m，1H)，7.13-7.11(m，2H)，6.95(d，J＝8.60Hz，2H)，6.83(d，J＝8.60Hz，2H)，4.79(s，2H)，3.83(s，2H)，3.80(s，3H)，3.04(s，3H)，2.98(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.6，166.5，159.2，150.0，138.1，128.9，128.7，128.4，128.3，127.1，114.1，90.5， 55.7，55.3，40.6，39.8，24.2；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C21H22N2O3S[M+H]+383.1430，found 383.1435。
implementation 12:
synthesis of 3-benzylmercapto-4- (3-fluorobenzylamino) -1-methylmaleimide compound
Benzylpulfobentite (0.6mmol, 3equiv), N-methyl-3-fluorobenzylamine (0.4mmol, 2equiv), N-methylmaleimide (0.2mmol, 1equiv), cuprous iodide (0.02mmol, 0.1equiv), and 2mL of 1, 2-dichloroethane were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and stirred at 100 ℃ for 24 hours. The reaction mixture was cooled, then diluted with ethyl acetate, filtered into a heart-shaped flask, then the solvent was spun off and the product was isolated by column chromatography (eluent: petroleum ether: diethyl ether: 9: 1) as a yellow solid with melting point 70-71 ℃, yield 85% and weight of 63 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：7.29-7.25(m，3H)，7.22-7.19(m，1H)，7.10(d，J＝7.05Hz，2H)，6.96(td，J＝8.40 Hz，2.30Hz，1H)，6.77(d，J＝7.60Hz，1H)，6.70(d，J＝9.45Hz，1H)，4.83(s，2H)，3.84(s，2H)，3.04(s，3H)，2.99 (s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：170.4，166.3，164.1，162.1，149.8，139.1，139.0，138.0，130.3，130.2，128.9，128.5， 127.2，122.7，122.6，114.6，114.4，114.1，113.9，91.3，55.9，40.5，40.3，24.2；
the nmr spectra of the product obtained were as follows:
19F NMR(470MHz，CDCl3)：-112.4.7(s，1F)；
the high resolution mass spectral data of the resulting product are as follows:
HRMS(ESI)：calcd for C20H19FN2O2S[M+H]+371.1230，found 371.1235。
as can be seen from the above examples 1 to 12, when the method of the present invention is employed, N-methyl-3-benzylmercapto-4-aminomaleimide compounds can be obtained in high yield and high purity.
Examples 13 to 15
Examples 13 to 15 were each carried out in the same manner as in example 1 except that cuprous iodide, which is a transition metal catalyst, was replaced with the following copper salt, respectively, and the yield of the copper salt compound used and the corresponding product were as shown in Table 1 below.
TABLE 1
| Numbering | Transition metal copper catalyst | Reaction yield (%) |
| Example 13 | Copper acetate | Is not reacted |
| Example 14 | Copper chloride | Is not reacted |
| Example 15 | Copper bromide | Is not reacted |
As can be seen from table 1 above, when other copper salts were used, none of the reactions could be made to proceed smoothly, thus proving that cuprous iodide is a key factor for the success of the reaction and is most effective for the reaction system.
Examples 16 to 24
Examples 16 to 24 were each carried out in the same manner as in example 1 except that the organic solvents 1, 2-dichloroethane were each replaced with the following organic solvents, and the organic solvents used and the yields of the corresponding products are shown in Table 2 below.
TABLE 2
| Numbering | Solvent(s) | Reaction yield (%) |
| Example 16 | N-methyl pyrrolidone | Is not reacted |
| Example 17 | N, N-dimethylformamide | Is not reacted |
| Example 18 | N, N-dimethyl acetamide | Is not reacted |
| Example 19 | Methylene dichloride | Is not reacted |
| Example 20 | Pyridine compound | Is not reacted |
| Example 21 | 1, 4-dioxahexaalkane | Is not reacted |
| Example 22 | Acetonitrile | Is not reacted |
| Example 23 | Toluene | Is not reacted |
| Example 24 | Tetrahydrofuran (THF) | Is not reacted |
From table 2 above, it can be seen that neither strongly polar solvents such as N-methylpyrrolidone, N-dimethylformamide and N, N-dimethylacetamide nor toluene, which is a non-polar solvent, nor acetonitrile and tetrahydrofuran, which are weakly coordinating solvents, have any product, demonstrating that the proper choice of organic solvent has a significant, even decisive influence on whether the reaction can proceed.
From the above, it is clear from all the examples that when the method of the present invention is adopted with a catalytic reaction system composed of a transition metal catalyst (especially cuprous iodide) and a suitable organic solvent (especially 1, 2-dichloroethane), the benzylmercaptobunnith salt, secondary amine and N-methylmaleimide can be synthesized into the N-methyl-3-benzylmercapto-4-amino maleimide compound in high yield and high purity by a three-component series reaction under the oxygen condition, and a completely new synthetic route is provided for the efficient and rapid synthesis of the compound.
Finally, it should be noted that: the above embodiments are only used to clarify the technical solution of the present invention, and not to limit it; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments are modified or some or all of the technical features are equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (5)
1. A preparation method of N-methyl-3-benzylmercapto-4-amino maleimide compound is characterized in that benzylmercapto-butyne salt, secondary amine and N-methyl maleimide are used as reaction raw materials in an organic solvent under the condition of oxygen, and the N-methyl-3-benzylmercapto-4-amino maleimide compound is obtained through a series reaction catalyzed by transition metal copper.
The benzylmercapto bunnit salt is:
BnS2O3Na
the secondary amine is:
the N-methylmaleimide is:
the N-methyl-3-benzylmercapto-4-amino maleimide compound is:
the copper catalyst is cuprous iodide;
the organic solvent is 1, 2-dichloroethane.
2. The method of claim 1, wherein the molar ratio of benzylmercaptobundant salt, secondary amine, and N-methylmaleimide is 3: 2: 1.
3. The production method according to claim 1, wherein the copper catalyst is used in an amount of 10% by mole based on the amount of the N-methylmaleimide.
4. The method as claimed in claim 1, wherein the reaction temperature is 100-120 ℃.
5. The process according to claim 1, wherein the reaction time is 18 to 24 hours.
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| WO2014085545A1 (en) * | 2012-11-30 | 2014-06-05 | The University Of Chicago | Methods and compositions involving rad51 inhibitors |
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| WO2014085545A1 (en) * | 2012-11-30 | 2014-06-05 | The University Of Chicago | Methods and compositions involving rad51 inhibitors |
| CN109651225A (en) * | 2018-11-28 | 2019-04-19 | 温州医科大学 | A kind of 1- methyl -3- amino -4- aromatic thiohydroxy maleimide compound and preparation method |
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