CN111978236A - Preparation method of N-substituted-3-morpholinyl-4-phenylseleno maleimide compound - Google Patents

Abstract

The invention relates to a preparation method of an N-substituted-3-morpholinyl-4-phenylselenoyl maleimide compound. In an organic solvent, under oxygen conditions, phenylboronic acid, selenium powder, morpholine and N ‑Substituted maleimide is used as the raw material for the reaction, and under the joint catalysis of transition metal copper catalyst, silver salt, ligand and base, N‑substituted‑3‑morpholinyl‑4‑ is obtained through a four-component series reaction Phenylselenomaleimide compound. The method has simple reaction conditions, high product yield and high purity, opens up a synthetic route and method for the preparation of N-substituted-3-morpholinyl-4-phenylselenylmaleimide compounds, and has good application potential and research value.

Description

A kind of preparation of N-substituted-3-morpholinyl-4-phenylselenyl maleimide compound method

technical field

The invention belongs to the technical field of organic compound synthesis, in particular to a preparation method of an N-substituted-3-morpholinyl-4-phenylselenyl maleimide compound.

Background technique

3,4-Difunctionalized maleimide as the core skeleton widely exists in marine natural alkaloids and antitumor active molecules with important biological activities, drug candidate 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 be converted into various functional groups to synthesize derivatives such as succinimide, tetrahydropyrrole and 2-pyrrolidone. Therefore, exploring the efficient construction of 3,4-difunctionalized maleimides from cheap and readily available raw materials has become one of the hotspots in current organic chemistry, medicinal chemistry and materials science.

Reactive molecules of 3,4-difunctionalized maleimides

On the other hand, considering the potential application value of arylselenide compounds in drug research and development, the development of methods to introduce arylselenoyl groups into the molecular structure of maleimide has attracted the attention of synthetic chemists. Baidya's group reported that transition metal ruthenium catalyzed the oxidoselenylation of maleimide and diaryl diselenide. However, the pre-preparation of diaryl diselenide and the use of precious metal ruthenium catalyst made this reaction impossible. It can be effectively applied to late-stage modification of drug molecules, reducing the chance of discovery of innovative drug molecules. Therefore, the development of new selenylation reagents to directly catalyze amine arylselenylation of maleimide will be an effective strategy, which can realize the efficient construction of carbon-nitrogen bonds and double carbon-selenium bonds in one step. Introduction of drug-containing molecules. Recently, our research group reported the copper-catalyzed amine selenation of maleimides (Oxidative Aminoarylselenation of Maleimides via Copper-Catalyzed Four-Component Cross-Coupling, Organic Letters 2019, 21, 3, 745-748). Considering the importance of arylselenyl and maleimide core structures in the development of innovative drugs, it is necessary to prepare N-substituted-3-morpholinyl-4 from facile, easy-to-handle, inexpensive and readily available starting materials. -Phenylselenylmaleimide compounds are particularly important, especially the preparation of N-substituted-3-morpholinyl-4-phenylselenyl by using phenylboronic acid, which is cheap, easy to obtain, stable, and convenient for experimental operation as a phenylation reagent The reaction of the maleimide compound has not been reported so far, and there is still a need for continued research and exploration, which is also the basis and motivation for the completion of the present invention.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is the synthetic route problem of the preparation method of the N-substituted-3-morpholinyl-4-phenylselenyl maleimide compound.

For solving the above technical problems, the present invention provides the following technical solutions:

A kind of preparation method of N-substituted-3-morpholinyl-4-phenylselenoyl maleimide compound, in organic solvent, under oxygen condition, with phenylboronic acid, selenium powder, morpholine and N-substituted N-substituted-3-morpholinyl-4-phenylselenyl group was obtained through a four-component series reaction under the synergistic catalysis of transition metal copper catalyst, silver salt, ligand and base using leimide as the raw material. Maleimide compounds;

The above-mentioned reaction process can be represented by the following reaction formula:

The molar ratio of phenylboronic acid, selenium powder, morpholine and N-substituted maleimide is 3:3:3:1.

(1) transition metal copper catalyst

The transition metal copper catalyst in the present invention is copper acetate, cuprous bromide, copper triflate, cuprous chloride, cupric bromide or cuprous iodide, preferably cuprous iodide, in molar terms, The amount of the cuprous iodide is 20% of the amount of the N-substituted maleimide.

(2) Silver salt

The silver salt in the present invention is silver oxide, silver carbonate, silver acetate or silver nitrate, preferably silver carbonate, on a molar basis, the consumption ratio of the silver salt to the N-substituted maleimide consumption is 2 : 1.

(3) Ligand

The ligand in the present invention is triphenylphosphine, tricyclohexylphosphine, 1,10-o-phenanthroline or 2,2'-bipyridine, preferably 1,10-o-phenanthroline. On a molar basis, the amount of the ligand is 20% of the amount of the N-substituted maleimide.

(4) Alkali

The alkali in the present invention is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate or sodium phosphate, preferably cesium carbonate, in molar terms, the consumption of the cesium carbonate and the N-substituted maleyl The imine dosage ratio was 3:1.

(5) Organic solvent

The reaction solvent in the present invention is an organic solvent, and the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4 -At least one of dioxane, 1,2-dichloroethane, acetonitrile, toluene, and tetrahydrofuran, preferably N,N-dimethylformamide.

(6) Reaction temperature

In the preparation method of the present invention, the reaction temperature is 120-140°C, such as 120°C, 130°C and 140°C without limitation, and the reaction temperature is preferably 140°C.

(7) Response time

In the preparation method of the present invention, the reaction time is not particularly limited. For example, a suitable reaction time can be determined by detecting the residual percentage of the target product or raw material by liquid chromatography, which is usually 30-36 hours. 30 hours, 32 hours, 34 hours or 36 hours, the reaction time is preferably 36 hours.

(8) Separation and purification

In a preferred embodiment, the post-processing step after the reaction is completed can be the following method: after the reaction is completed, the reaction solution is cooled and then added with water and ethyl acetate for extraction, the organic phase is dried with anhydrous sodium sulfate, and filtered to chicken heart bottle, then spin off the solvent, separate the concentrate by column chromatography, use the mixture of petroleum ether and ethyl acetate as the eluent, collect the eluent, and concentrate to obtain the target product.

The preparation method of the N-substituted-3-morpholinyl-4-phenylselenoyl maleimide compound provided by the present invention has the following beneficial effects:

a) high reaction efficiency, high yield and easy post-processing;

b) using cheap and readily available selenium powder as a selenoylation reagent;

c) Utilize cheap and easy copper as a catalyst;

In the invention, phenylboronic acid, selenium powder, morpholine and N-substituted maleimide are used as reaction raw materials, and under the joint catalysis of transition metal copper catalyst, silver salt, ligand and base, a series reaction of four components is carried out. The N-substituted-3-morpholinyl-4-phenylselenomaleimide compound was obtained. The reaction raw materials of the invention are cheap and easy to obtain, the yield and purity of the products are high, the synthesis route and method are opened up for the preparation of N-substituted-3-morpholinyl-4-phenylselenoyl maleimide compounds, and the double-substituted The molecular design and synthesis of maleimide derivatives provide new ideas and have important social and economic significance.

Detailed ways

The present invention will be described in detail below through specific examples, but the purposes and purposes of these exemplary embodiments are only used to illustrate the present invention, and do not constitute any limitation to the actual protection scope of the present invention, nor do they limit the present invention. The scope of protection is limited to this.

The data and purity of the novel compounds given in the following examples were identified by nuclear magnetic resonance.

Implementation 1:

Synthesis of N-cyclohexyl-3-morpholinyl-4-phenylselenomaleimide compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-cyclohexylmaleimide (0.2 mmol, 1.0 equiv) were combined ), cuprous iodide (0.04mmol, 0.2equiv), 1,10-o-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether:ethyl acetate 9:1), the product is a yellow liquid, the yield is 80%, and the weight of the product is 67 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.30-7.28 (m, 2H), 7.26-7.23 (m, 2H), 7.19 (t, J=7.0 Hz, 1H), 4.11 (t, J=4.70 Hz) , 4H), 3.96 (tt, J=8.3, 3.4Hz, 1H), 3.66 (t, J=4.70Hz, 4H), 2.10-2.03 (m, 2H), 1.82 (d, J=3.1Hz, 2H) , 1.68-1.66 (m, 2H), 1.34-1.18 (m, 4H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 170.2, 166.4, 149.5, 132.4, 129.4, 129.3, 126.6, 87.6, 66.9, 51.4, 48.4, 29.9, 26.0, 25.2;

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₀ H ₂₄ N ₂ O ₃ Se[M+Na] ⁺ 443.0850, found 443.0864.

Implementation 2:

Synthesis of N-benzyl-3-morpholinyl-4-phenylselenomaleimide compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-benzylmaleimide (0.2 mmol, 1.0 equiv) were combined ), cuprous iodide (0.04mmol, 0.2equiv), 1,10-o-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol, 3.0equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether:ethyl acetate 9:1), the product is a yellow liquid, the yield is 79%, and the weight of the product is 67 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.41-7.39 (m, 2H), 7.36-7.22 (m, 8H), 4.72 (s, 2H), 4.16 (t, J=4.70 Hz, 4H), 3.66 (t, J=4.70Hz, 4H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 170.0, 166.3, 149.7, 136.5, 132.3, 129.5, 129.4, 128.6, 128.6, 127.7, 126.7, 87.2, 66.9, 48.5, 42.1;

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₁ H ₂₀ N ₂ O ₃ Se[M+H] ⁺ 429.0718, found 429.0726.

Implementation 3:

Synthesis of N-(4-methylbenzyl)-3-morpholinyl-4-phenylselenomaleimide compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-(4-methylbenzyl)maleimide (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1,10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6 mmol, 3.0 equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether:ethyl acetate: 9:1), the product is a yellow solid, the melting point is 116-117°C, the yield is 77%, and the weight of the product is 68 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.29-7.19 (m, 7H), 7.12-7.11 (m, 2H), 4.65 (s, 2H), 4.12 (t, J=4.70 Hz, 4H), 3.61 (t, J=4.70Hz, 4H), 2.32(s, 3H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 170.0, 166.2, 149.7, 137.5, 133.6, 132.3, 129.4, 129.3, 128.7, 126.7, 87.2, 66.9, 48.4, 41.8, 21.1;

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₂ H ₂₂ N ₂ O ₃ Se[M+H] ⁺ 443.0875, found 443.0883.

Implementation 4:

Synthesis of N-(4-Methoxybenzyl)-3-morpholinyl-4-phenylselenomaleimide Compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-(4-methoxybenzyl)maleimide Amine (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1,10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate ( 0.6 mmol, 3.0 equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether: ethyl acetate 9: 1), the product is a yellow liquid, the yield is 88%, and the weight of the product is 80 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.36-7.20 (m, 7H), 6.86-6.85 (m, 2H), 4.65 (s, 2H), 4.14 (t, J=4.70 Hz, 4H), 3.80 (s, 3H), 3.64 (t, J=4.70Hz, 4H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 170.1, 166.3, 159.2, 149.7, 132.3, 130.2, 129.4, 129.4, 128.8, 126.7, 114.0, 87.1, 66.9, 55.3, 48.4, 41.5;

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₂ H ₂₂ N ₂ O ₄ Se[M+H] ⁺ 459.0824, found 459.0832.

Implementation 5:

Synthesis of N-(4-Fluorobenzyl)-3-morpholinyl-4-phenylselenomaleimide Compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-(4-fluorobenzyl)maleimide ( 0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1,10-o-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6mmol) , 3.0 equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether:ethyl acetate 9:1), the product is a yellow liquid, the yield is 65%, and the weight of the product is 60 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.39-7.37 (m, 2H), 7.32-7.30 (m, 2H), 7.28-7.21 (m, 4H), 7.02 (t, J=8.6 Hz, 2H) , 4.68(s, 2H), 4.16(t, J=4.70Hz, 4H), 3.66(t, J=4.70Hz, 4H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 169.9, 166.2, 162.4 (d, J _F = 246.5 Hz), 149.7, 136.0, 132.3 (d, J _F = 3.2 Hz), 132.2, 130.5 (d, J _F = 3.2 Hz) = 8.1 Hz), 129.4 (d, J _F =9.3 Hz), 126.7, 115.4 (d, J _F =21.6 Hz), 87.2, 66.9, 48.5, 41.3;

The data of the fluorine nuclear magnetic resonance spectrum of the obtained product are as follows:

¹⁹ F NMR (470 MHz, CDCl ₃ ): δ-62.7 (s, 1F);

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₁ H ₁₉ FN ₂ O ₃ Se[M+H] ⁺ 447.0624, found 447.0639.

Implementation 6:

Synthesis of N-(4-trifluoromethylbenzyl)-3-morpholinyl-4-phenylselenomaleimide compounds

At room temperature, phenylboronic acid (0.6 mmol, 3.0 equiv), selenium powder (0.6 mmol, 3.0 equiv), morpholine (0.6 mmol, 3.0 equiv), N-(4-trifluoromethylbenzyl)maleyl Imine (0.2mmol, 1.0equiv), cuprous iodide (0.04mmol, 0.2equiv), 1,10-phenanthroline (0.04mmol, 0.2equiv), silver carbonate (0.4mmol, 2.0equiv), cesium carbonate (0.6 mmol, 3.0 equiv), and 2 mL of N,N-dimethylformamide were added to the reaction tube, then filled with oxygen, and replaced three times, and stirred at a reaction temperature of 140° C. for 36 h. The reaction mixture was cooled, then diluted with ethyl acetate, extracted with brine, the organic phase was separated, dried with anhydrous sodium sulfate, filtered into a chicken heart flask, then the solvent was spun off, and the product was isolated by column chromatography (eluting). agent: petroleum ether: ethyl acetate is 9: 1), the product is a yellow liquid, the yield is 49%, and the weight of the product is 49 mg.

The data of the H NMR spectrum of the obtained product are as follows:

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.57 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.30-7.29 (m, 2H), 7.26-7.19 (m , 3H), 4.74 (s, 2H), 4.14 (t, J=4.70Hz, 4H), 3.64 (t, J=4.70Hz, 4H);

The data of the carbon nuclear magnetic resonance spectrum of the obtained product are as follows:

¹³ C NMR (125 MHz, CDCl ₃ ): δ 169.8, 166.2, 149.6, 140.3, 132.1, 130.0 (q, J _F = 32.4 Hz), 129.5, 129.4, 128.9, 126.8, 126.7, 126.2 (q, J _F = 32.4 Hz) 272.3 Hz), 125.6 (q, J _F =3.5 Hz), 87.2, 66.9, 48.5, 41.6;

The data of the fluorine nuclear magnetic resonance spectrum of the obtained product are as follows:

¹⁹ F NMR (470 MHz, CDCl ₃ ): δ-62.6 (s, 3F);

The high-resolution mass spectrometry data of the obtained product are as follows:

HRMS(ESI): calcd for C ₂₂ H ₁₉ F ₃ N ₂ O ₃ Se[M+H] ⁺ 497.0592, found 497.0584.

It can be seen from the above examples 1-6 that when the method of the present invention is adopted, the N-substituted-3-morpholinyl-4-phenylselenylmaleimide compound can be obtained with high yield and high purity .

Examples 7-11

Except for replacing the transition metal catalyst cuprous iodide with the following copper salts, respectively, Examples 7-11 were implemented in the same manner as Example 1, and the yields of the copper salt compounds and corresponding products used were as follows: 1 shown.

Table 1

Numbering transition metal copper catalyst Reaction yield (%) Example 7 copper acetate not responding Example 8 Cuprous Chloride not responding Example 9 Copper Bromide not responding Example 10 Cuprous Bromide not responding Example 11 copper difluoromethanesulfonate not responding

As can be seen from Table 1 above, when other copper salts are used, there is no target product, which proves that cuprous iodide is the key factor for the success of the reaction, and the reaction system is the most effective.

Examples 12-14

Except for replacing the 1,10-phenanthroline ligands with the following ligands, the same way as in Example 1 was carried out, and the yields of the ligands used and the corresponding products were respectively implemented in Examples 12-14. As shown in Table 2 below.

Table 2

Numbering Ligand Reaction yield (%) Example 12 Triphenylphosphine not responding Example 13 tricyclohexylphosphine not responding Example 14 2,2'-bipyridine 19

It can be seen from Table 2 above that when triphenylphosphine or tricyclohexylphosphine is used, the reaction cannot occur, and when 2,2'-bipyridine is used as a ligand, the yield is affected to a certain extent, which proves that 1,10-phenanthroline is the key factor for the success of this reaction, and it is the most effective for this reaction system.

Examples 15-17

Examples 15-17 were implemented in the same manner as in Example 1, except that the silver carbonate was replaced with the following silver salts, respectively. The yields of the silver salts used and the corresponding products are shown in Table 3 below.

table 3

Numbering silver salt Reaction yield (%) Example 15 silver oxide not responding Example 16 silver acetate not responding Example 17 silver nitrate not responding

As can be seen from the above table 3, when other silver salts are used, the reaction cannot occur, thus proving that the use of silver carbonate is the key factor for the success of the reaction, and the reaction system is the most effective.

Examples 18-21

Examples 18-21 were carried out in the same manner as in Example 1, except that the cesium carbonate was replaced with the following inorganic bases, respectively. The bases used and the yields of the corresponding products are shown in Table 4 below.

Table 4

Numbering base Reaction yield (%) Example 18 Sodium carbonate not responding Example 19 Potassium carbonate not responding Example 20 Potassium Phosphate not responding Example 21 Sodium Phosphate not responding

As can be seen from Table 4 above, when other inorganic bases are used, there is no product, which proves that the use of cesium carbonate is the key factor for the success of the reaction, and the reaction system is the most effective.

Examples 22-29

Except that the organic solvent N,N-dimethylformamide therein was replaced with the following organic solvents, respectively, implementations 22-29 were carried out in the same manner as in Example 1, and the organic solvents used and the corresponding products were recovered. The rates are shown in Table 5 below.

table 5

Numbering solvent Reaction yield (%) Example 22 N,N-Dimethylacetamide not responding Example 23 N-Methylpyrrolidone not responding Example 24 DMSO not responding Example 25 1,4-Dioxane not responding Example 26 1,2-Dichloroethane not responding Example 27 Acetonitrile not responding Example 28 Toluene not responding Example 29 tetrahydrofuran not responding

As can be seen from Table 5 above, other strong polar solvents such as dimethyl sulfoxide and N,N-dimethylacetamide, non-polar solvents toluene, and weakly coordinating solvents acetonitrile and tetrahydrofuran did not have any products, which proved that The appropriate choice of organic solvent has a significant or even decisive influence on whether the reaction can be carried out.

To sum up, it can be clearly seen from all the above examples that when the method of the present invention uses a transition metal catalyst (especially cuprous iodide), a ligand (especially 1,10-o-phenanthroline), silver In the catalytic reaction system composed of salt (especially silver carbonate), inorganic base (especially cesium carbonate) and suitable organic solvent (especially N,N-dimethylformamide), phenylboronic acid, selenium powder, morphine N-substituted-3-morpholinyl-4-phenylselenylmaleimide was synthesized in high yield and purity by copper-catalyzed four-component tandem reaction of morpholino and N-substituted maleimide compounds under oxygen conditions The imide compound provides a new synthetic route for the efficient and fast synthesis of this type of compound.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: It is still scientific research to modify the technical solutions recorded in the foregoing embodiments, or to make equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the technical solutions of the embodiments of the present invention. scope.

Claims (8)

1. A preparation method of N-substituted-3-morpholinyl-4-phenylseleno maleimide compound is characterized in that phenylboronic acid, selenium powder, morpholine and N-substituted maleimide are used as reaction raw materials in an organic solvent under the condition of oxygen, and under the co-concerted catalysis of a transition metal copper catalyst, a silver salt, a ligand and an alkali, the N-substituted-3-morpholinyl-4-phenylseleno maleimide compound is obtained through four-component series reaction;

the phenylboronic acid is: PhB (OH)₂

The selenium powder is as follows: se

The morpholine is as follows:

the N-substituted maleimide is:

the N-substituted-3-morpholinyl-4-phenylseleno maleimide compound is as follows:

the copper catalyst is cuprous iodide;

the silver salt is silver carbonate;

the ligand is 1, 10-phenanthroline;

the base is cesium carbonate;

the organic solvent is N, N-dimethylformamide.

2. The method of claim 1, wherein the molar ratio of the phenylboronic acid to the selenium powder to the morpholine to the N-substituted maleimide is 3: 1.

3. The production method according to claim 1, wherein the copper catalyst is used in an amount of 20% by mole based on the amount of the N-substituted maleimide.

4. The production method according to claim 1, wherein the ligand is used in an amount of 20% by mole based on the amount of the N-substituted maleimide.

5. The method according to claim 1, wherein the silver salt and the N-substituted maleimide are used in a molar ratio of 2: 1.

6. The process according to claim 1, wherein the base and the N-substituted maleimide are used in a molar ratio of 3: 1.

7. The method as claimed in claim 1, wherein the reaction temperature is 120-140 ℃.

8. The process according to claim 1, wherein the reaction time is 30 to 36 hours.