A method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton

Abstract

The present invention discloses a method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton, comprising the following steps: using N-phenylmaleimide ene and di-tert-butyl azodicarboxylate as reaction raw materials at a temperature of 75 °C, adding 1,4-dioxane as a reaction solvent, and K2CO3 as a catalyst, and obtaining the target product through silica gel column chromatography separation. The present invention uses di-tert-butyl azodicarboxylate as an ammoniating reagent to catalytically ammoniate N-phenylmaleimide ene to synthesize a nitrogen-containing heterocyclic compound containing a maleimide skeleton. The reaction method of the present invention has a fast reaction rate and a high yield, and the highest yield is 94%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton. Background Art

[0002] Maleimide structural units are widely present in natural products and drugs with biological activity, and can be easily converted into compounds containing tetrahydropyrrole, 2-pyrrolidone and succinimide structural units, which have high application value. Figure 1 The compounds shown in the above, natural products Moiramide B and Andrimid are a new type of antibiotics; Hydroxamic acid, as an effective inhibitor of histone acetylase (HDAC), has strong anti-tumor function; Dichlorolissoclimid and its derivatives extracted from the sea squirt Lissoclinumvoeltzkowi are a class of compounds with high anti-tumor activity; Tandospirone is a mature drug for the treatment of anxiety and depression. Therefore, it is of great significance to simply and effectively construct compounds with maleimide structural units.

[0003] Azodicarboxylic acid esters contain both ester groups and nitrogen-nitrogen double bonds. The nitrogen-nitrogen double bonds with electron-withdrawing groups are electrophilic and are often used as excellent electrophilic reagents and zwitterionic reagents as well as nitrogen source raw materials in carbon-nitrogen bond formation reactions. Common azodicarboxylic acid esters include dimethyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and dibenzyl azodicarboxylate. Amination of olefins is one of the important uses of azodicarboxylic acid esters. In 1986, Jenner et al. used diethyl azodicarboxylate and cycloheptatriene for catalytic amination. In 1991, Leblanc et al. used di(trichloroethyl) azodicarboxylate as an amination reagent to ammoniate olefins and found that the double bond position in the ammoniated product was shifted. At present, there is no report on the synthesis of nitrogen-containing heterocyclic compounds containing maleimide skeletons using N-phenylmaleimide olefins and azodicarboxylic acid esters as reaction substrates. Summary of the invention

[0004] In order to solve the defects of the prior art, the present invention provides a method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0006] The invention provides a method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton, comprising the following steps: taking N-phenylmaleimide olefin and di-tert-butyl azodicarboxylate as reaction raw materials at a temperature of 75°C, adding 1,4-dioxane as a reaction solvent, and using K2CO3 as a catalyst, and separating by silica gel column chromatography to obtain a target product.

[0007] Preferably, the mass ratio of N-phenylmaleimide to di-tert-butyl azodicarboxylate is 1.5:1 to 1.8:1.

[0008] Preferably, the K2CO3 loading is 20 mol%.

[0009] Preferably, the eluent ratio of the silica gel column chromatography separation is petroleum ether / ethyl acetate = 20 / 1 to 6 / 1.

[0010] Compared with the prior art, the present invention has the following beneficial effects:

[0011] The invention uses di-tert-butyl azodicarboxylate as an aminating agent to catalyze and aminize N-phenylmaleimide olefin to synthesize nitrogen-containing heterocyclic compounds containing a maleimide skeleton. The reaction method of the invention has fast reaction rate and high yield, and the yield is as high as 94%. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is a natural product and medicine containing maleimide structural unit in the prior art. DETAILED DESCRIPTION

[0013] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0014] Example 1: Synthesis of nitrogen-containing heterocyclic compounds containing maleimide skeleton.

[0015] At 75°C, 26 mg of N-phenylmaleimide and 28 mg of di-tert-butyl azodicarboxylate were used as reaction raw materials, 1 mL of 1,4-dioxane and 20 mol% K2CO3 were added, and the target product was obtained by silica gel column chromatography (eluent ratio was petroleum ether / ethyl acetate = 20 / 1, 15 / 1, 10 / 1, 8 / 1, 6 / 1).

[0016] Proton spectrum data of the target product: 1 H NMR (400MHz, CDCl3) δ7.78(d,J=1.89Hz,1H),7.61(s,1H),(q,J=9.53Hz,4H),7.34(t,J=8.16Hz,5H),5.92(s,1H),1.47(s,9H),1.18(s,9H).

[0017] Example 2: Investigation of the biological activity of the target product.

[0018]

[0019] Common fungal pathogens that mainly exist in the human digestive and urinary systems: Candida albicans; food-borne bacterial pathogens that often parasitize on human skin, oral cavity, nasal cavity, etc.: Staphylococcus aureus.

[0020] Take a 96-well culture plate, dilute the sample to be tested, add bacterial (fungal) liquid to each well, and the final concentration is 5×105CFU / mL; culture at 28℃ (37℃) for 24 hours, and detect the absorbance at 625nm with an enzyme marker. The experiment also sets up a culture medium blank control group, a bacterial control, and a penicillin G sodium (amphotericin B) positive drug control.

[0021] The antifungal and antibacterial activity of the target product was tested using Staphylococcus aureus and Candida albicans. The experiment set up a blank culture medium and a positive control group. The inhibitory effect of penicillin G sodium was used as a positive control for bacteria, and the inhibitory effect of amphotericin B was used as a positive control for fungi. The results are shown in the table.

[0022] Table 1: Antibacterial effect of the target products on different bacterial species.

[0023]

[0024] As shown in Table 1, there are obvious differences in the antibacterial effects of the target product on fungi and bacteria. Penicillin G sodium and amphotericin B were selected as positive controls for the target product against Staphylococcus aureus and Candida albicans, respectively: the inhibition rate of penicillin G sodium against Staphylococcus aureus was about 99.958%, and the inhibition rate of the target product against Staphylococcus aureus was about -33.199%; the inhibition rate of amphotericin B against Candida albicans was almost 100%, and the inhibition rate of the target product against Candida albicans was about 42.121%.

[0025] In the study of the antibacterial activity of the target product against two bacteria, it was found that when the sample concentration was 100 μM, the sample had no inhibitory effect on Staphylococcus aureus, but had a certain inhibitory effect on Candida albicans.

[0026] Comparative Example 1: Effect of catalyst on reaction.

[0027]

[0028] Table 2: Reaction results of different catalysts

[0029]

[0030] According to the reaction route, N-phenylmaleimide olefin 1 and di-tert-butyl azodicarboxylate 2 were selected as template substrates, CH2Cl2 was used as the reaction solvent, and the catalyst dosage was 20% mol. The effect of the catalyst type on the reaction was investigated. A clean and dry reaction tube was taken, 26 mg N-phenylmaleimide olefin 1 and 28 mg di-tert-butyl azodicarboxylate 2 were used as the reaction raw materials at a temperature of 25°C, 1 mL of dichloromethane was used as the reaction solvent, and the catalyst dosage was 20 mol%. The target product was separated by silica gel column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 20 / 1, 15 / 1, 10 / 1, 8 / 1, 6 / 1), and the effect of different catalysts on the reaction was investigated. The results showed that the yield of 55%-84% was obtained when the organic bases DBACO, DMAP, Et3N and the like catalyzed the reaction; the inorganic base K2CO 3、 The yields of 27% to 90% were obtained when Na2CO3 and NaHCO3 were used as catalysts, while the catalytic effects of KOH and NaOH were very poor. The best result (90%) was obtained when K2CO3 was used as catalyst.

[0031] Comparative Example 2: Effect of solvent on the reaction.

[0032]

[0033] Table 3: Reaction results of different solvents.

[0034]

[0035]

[0036] The reaction solvent was investigated using K2CO3 as a catalyst. According to the reaction route, a clean and dry reaction tube was taken, 26 mg of N-phenylmaleimide olefin 1 and 28 mg of di-tert-butyl azodicarboxylate 2 were used as the reaction raw materials at 25°C, 1 mL of reaction solvent and 20 mol% K2CO3 were added, and the target product was obtained by silica gel column chromatography (the eluent ratio was petroleum ether / ethyl acetate = 20 / 1, 15 / 1, 10 / 1, 8 / 1, 6 / 1). Through investigation, it was found that the yield was higher in halogenated hydrocarbons; the yield was 22% in DMF; the yield was 67-86% in acetonitrile, toluene, and tetrahydrofuran; no reaction occurred in DMSO, ethanol, and petroleum ether; the yield was 80% in ether; the yield was medium in methyl tert-butyl ether; and the highest yield was obtained in 1,4-dioxane.

[0037] Comparative Example 3: Effect of temperature on reaction.

[0038]

[0039] Table 4: Reaction results at different temperatures.

[0040]

[0041] The reaction temperature has an effect on the activity of the catalyst. Generally speaking, the higher the reaction temperature, the faster the reaction rate. However, the reaction temperature and catalyst activity are not necessarily linearly related. Only at the appropriate temperature can the catalyst activity reach the best. According to the reaction route, a clean and dry reaction tube was taken, and 26 mg of N-phenylmaleimide 1 and 28 mg of di-tert-butyl azodicarboxylate 2 were used as reaction raw materials at a certain temperature, 1 mL of 1,4-dioxane and 20 mol% K2CO3 were added, and the target product was obtained by silica gel column chromatography separation (the eluent ratio was petroleum ether / ethyl acetate = 20 / 1, 15 / 1, 10 / 1, 8 / 1, 6 / 1). As shown in Table 4, in 1,4-dioxane, the reaction time gradually decreased when the temperature increased from 0°C to 75°C. When the temperature was increased from 75°C to the reflux temperature, the reaction time was almost unchanged, and the reaction yield increased from 39% to 92%. The reaction was carried out in 1,4-dioxane, and the reaction rate was fastest (2h) and the yield was the highest (92%) at 75°C.

[0042] Comparative Example 4: Effect of material ratio and catalyst loading on the reaction.

[0043]

[0044] Table 5: Reaction results of different material ratios and catalyst loadings.

[0045]

[0046] According to the reaction route, a clean and dry reaction tube was taken, and the following x mg N-phenylmaleimide olefin 1 and y mg di-tert-butyl azodicarboxylate 2 were used as the reaction raw materials at a temperature of 75°C, 1 mL 1,4-dioxane, z mol% K2CO3 were added, and the target product was obtained by silica gel column chromatography separation (the eluent ratio was petroleum ether / ethyl acetate = 20 / 1, 15 / 1, 10 / 1, 8 / 1, 6 / 1). From the experimental data, as the reaction substrate N-phenylmaleimide olefin 1 or di-tert-butyl azodicarboxylate 2 was excessive, the reaction rate accelerated. When N-phenylmaleimide olefin was excessive, the reaction rate gradually increased (90-94%); when di-tert-butyl azodicarboxylate was excessive, the reaction yield remained unchanged and then decreased (92%-88%). Since the reaction produces a byproduct of the reaction of an equivalent amount of N-phenylmaleimide olefin with an equivalent amount of di-tert-butyl azodicarboxylate, the yield decreases as the amount of di-tert-butyl azodicarboxylate increases. When the material ratio is 1.5 / 1, the reaction achieves the highest yield (94%). Generally speaking, the greater the catalyst loading, the faster the reaction rate. When the material ratio is 1.5 / 1, as the catalyst loading increases, the yield increases (84-94%), so we believe that 20mol% is the optimal catalyst loading.

[0047] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton, characterized in that: The following steps are involved: At a temperature of 75°C, N-phenylmaleimide olefin and di-tert-butyl azodicarboxylate were used as reaction raw materials, 1,4-dioxane was added as a reaction solvent, K2CO3 was used as a catalyst, and the target product was obtained by silica gel column chromatography separation; the synthesis route of the nitrogen-containing heterocyclic compound containing a maleimide skeleton is as follows: ； Wherein, Formula 1 is N-phenylmaleimide olefin, Formula 2 is di-tert-butyl azodicarboxylate, and Formula 3 is a nitrogen-containing heterocyclic compound containing a maleimide skeleton.

2. The method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton according to claim 1, characterized in that: The mass ratio of the N-phenylmaleimide olefin to di-tert-butyl azodicarboxylate is 1.5:1 to 1.8:

1.

3. The method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton according to claim 1, characterized in that: The K2CO3 loading is 20 mol%.

4. The method for synthesizing a nitrogen-containing heterocyclic compound containing a maleimide skeleton according to claim 1, characterized in that: The eluent ratio of the silica gel column chromatography separation is petroleum ether / ethyl acetate=20 / 1 to 6 / 1.

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