Synthesis method of aromatic heterocyclic nitrone

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to a synthetic method of heterocyclic aromatic nitrone, which comprises the following steps: S1, mixing heterocyclic aromatic compound and phenyl nitrone in a molar ratio of 1: (1-1.5) with a catalyst, adding an organic solvent, and dissolving to obtain a mixture solution; and S2, reacting the mixture solution in the step S1 at 20-30 DEG C for 1-6 hours, carrying out reduced pressure distillation to remove the organic solvent, and carrying out column chromatography purification to obtain the aromatic heterocyclic nitrone. The synthesis method of the heterocyclic aromatic nitrone, which adopts the steps, has the advantages of mild reaction conditions, high heterocyclic aromatic nitrone yield and short reaction time, and can be used for gram-level reaction.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis chemistry, in particular to a synthesis method of aromatic heterocyclic nitrones. BACKGROUND

[0002] Aromatic heterocyclic nitrones, as a class of important nitrogen-containing heterocyclic compounds, have wide application prospects in the fields of organic synthesis, medicinal chemistry, material science, etc. Their unique chemical structure enables them to participate in various chemical reactions, such as 1,3-dipolar cycloaddition, etc., and they are key intermediates for constructing complex heterocyclic structures.

[0003] However, the existing synthesis methods of aromatic heterocyclic nitrones have many limitations. For example, some synthesis routes require the use of expensive reagents or catalysts, resulting in high production costs. Some methods have harsh reaction conditions, such as high temperature, high pressure, or anhydrous and anaerobic environment, increasing the operation difficulty and equipment requirements. Some synthesis methods are complicated, have low reaction efficiency, and have low product yield, and have many by-products, making it difficult to separate and purify. In addition, the existing methods have narrow applicability to substrates, and it is difficult to synthesize aromatic heterocyclic nitrone derivatives with diverse structures, limiting their further application in related fields.

[0004] Therefore, it is of great practical significance to develop a synthesis method of aromatic heterocyclic nitrones that is efficient, economical, mild in conditions, and has wide applicability to substrates. SUMMARY

[0005] The purpose of the present application is to provide a synthesis method of aromatic heterocyclic nitrones, which has mild reaction conditions, high yield of aromatic heterocyclic nitrones, and short reaction time, and can perform kilogram-scale reactions.

[0006] To achieve the above-mentioned purpose, the present application provides a synthesis method of aromatic heterocyclic nitrones, comprising the following steps,

[0007] S1, mixing an aromatic heterocyclic compound and a phenyl nitrone with a molar ratio of 1:1-1.5 with a catalyst, dissolving to obtain a mixture solution;

[0008] S2, reacting the mixture solution in S1 at 20-30℃ for 1-6h, removing the organic solvent by reduced pressure distillation, and purifying by column chromatography to obtain an aromatic heterocyclic nitrone.

[0009] Preferably, in S1, the structure of the aromatic heterocyclic compound is as shown below,

[0010]

[0011] wherein R 1 including one of halogen, methyl, methoxy, nitro, cyano, benzene ring, and hydrogen;

[0012] X comprises one of H, NH, NR 4 , O and S, NR 4 R 4 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl;

[0013] Y comprises one of H, NH2, NR 5 , O and S, CHO, COOH, COCH3, NR 5 R 5 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl.

[0014] Preferably, in S1, the structure of the phenyl nitrone is as follows,

[0015]

[0016] wherein R 2 and R 3 are independently selected from one of halogen, methyl, methoxy, nitro, cyano, benzene ring, hydrogen.

[0017] Preferably, in S1, the catalyst comprises one or more of lanthanum triflate, copper triflate, iron triflate, palladium trifluoroacetate, ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid.

[0018] Preferably, the molar ratio of the catalyst to the aromatic heterocyclic compound is 0.05-0.25:1.

[0019] Preferably, in S1, the organic solvent comprises one or more of toluene, xylene, mesitylene, chlorobenzene, chloroform, acetonitrile, ethanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, ethyl acetate.

[0020] Preferably, in S2, the structure of the aromatic heterocyclic nitrone is as follows,

[0021]

[0022] wherein R 1 and R 3 are independently selected from one of halogen, methyl, methoxy, nitro, cyano, benzene ring, hydrogen.

[0023] X comprises one of H, NH, NR 4 , O and S, NR 4 R 4 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl.

[0024] Therefore, the present invention employs the above-described method for synthesizing an aromatic heterocyclic nitrone, the advantages of which are as follows:

[0025] 1. The synthesis method provided by this invention has mild reaction conditions, high yield of aromatic heterocyclic nitrones, short reaction time, and can be carried out in gram-scale reactions;

[0026] 2. It is applicable to aromatic heterocyclic compounds and phenyl nitrones with various structures. By changing the substituents of the substrate, it is possible to synthesize aromatic heterocyclic nitrone derivatives with diverse structures, thus broadening the synthetic range of aromatic heterocyclic nitrones and meeting the needs of different fields for aromatic heterocyclic nitrones with various structures.

[0027] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of a method for synthesizing an aromatic heterocyclic nitrone according to the present invention. Detailed Implementation

[0029] The present invention will be further described below with reference to the accompanying drawings and embodiments. Unless otherwise defined, the technical or scientific terms used in this invention should be understood in their ordinary sense by those skilled in the art. The features mentioned above or in the specific examples mentioned in this invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the invention and are not intended to limit the scope of the invention.

[0030] like Figure 1 As shown (R) 1 Includes one of halogen, methyl, methoxy, nitro, cyano, benzene ring, and hydrogen; X includes H, NH, and NR. 4 One of O and S, NR 4 Chinese R 4 Includes one of hydrogen, methyl, p-toluenesulfonyl, and p-nitrobenzenesulfonyl; Y includes H, NH2, and NR. 5 One of O and S, CHO, COOH, COCH3, NR 5 Chinese R 5 Including one of hydrogen, methyl, p-toluenesulfonyl, and p-nitrobenzenesulfonyl; R 2 and R 3 The individual radical is selected independently from halogen, methyl, methoxy, nitro, cyano, benzene ring, and hydrogen. This invention provides a method for synthesizing aromatic heterocyclic nitrones, comprising the following steps:

[0031] S1. Mix aromatic heterocyclic compounds and phenyl nitrone in a molar ratio of 1:1-1.5 with the catalyst, and dissolve them in an organic solvent to obtain a mixture solution;

[0032] S2. The mixture solution in S1 is reacted at 20-30℃ for 1-6 hours. The organic solvent is removed by vacuum distillation, and the aromatic heterocyclic nitrone is obtained after purification by column chromatography.

[0033] In some embodiments of the present invention, in S1, the structure of the aromatic heterocyclic compound is shown below.

[0034]

[0035] Among them, R 1 Including one of the following: halogen, methyl, methoxy, nitro, cyano, benzene ring, and hydrogen;

[0036] X includes H, NH, and NR. 4 One of O and S, NR 4 Chinese R 4 Including one of hydrogen, methyl, p-toluenesulfonyl, and p-nitrobenzenesulfonyl;

[0037] Y includes H, NH2, and NR. 5 One of O and S, CHO, COOH, COCH3, NR 5 Chinese R 5 It includes one of hydrogen, methyl, p-toluenesulfonyl, and p-nitrobenzenesulfonyl.

[0038] In some embodiments of the present invention, in S1, the structure of phenyl nitrone is shown below.

[0039]

[0040] Among them, R 2 and R 3 It is independently selected from one of the following: halogen, methyl, methoxy, nitro, cyano, benzene ring, and hydrogen.

[0041] In some embodiments of the present invention, in S1, the catalyst comprises a Lewis acid or a protic acid.

[0042] In some embodiments of the present invention, in S1, the catalyst includes one or more of the following: lanthanum trifluoromethanesulfonate, copper trifluoromethanesulfonate, ferric trifluoromethanesulfonate, palladium trifluoroacetate, ferric chloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid.

[0043] In some embodiments of the present invention, the molar ratio of the catalyst to the aromatic heterocyclic compound is 0.05-0.25:1.

[0044] In some embodiments of the present invention, in S1, the organic solvent includes one or more of toluene, xylene, mesitylene, chlorobenzene, chloroform, acetonitrile, ethanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, and ethyl acetate.

[0045] In some embodiments of the present application, the structure of the aromatic heterocyclic nitrones in S2 is as follows,

[0046]

[0047] wherein R 1 and R 3 are independently selected from one of halogen, methyl, methoxy, nitro, cyano, benzene ring, hydrogen;

[0048] X includes one of H, NH, NR 4 , O and S, NR 4 R 4 includes one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl.

[0049] Example 1

[0050] S1, 1-p-toluenesulfonyl-indole-3-carboxylic acid (R 1 = H; X = NR 4 , R 4 is p-toluenesulfonyl TS; Y = COOH; 0.10 mmol), phenyl nitrone (R 2 and R 3 are H; 0.12 mmol) and lanthanum triflate (0.02 mmol) are placed in a dry reaction tube equipped with a magnetic stirrer, and 2 mL of chlorobenzene is added to obtain a mixture solution.

[0051] S2, the mixture solution in S1 is reacted at 25°C for 1-6 h, and the magnetic stirring is continued until thin layer chromatography (TLC) detection shows that the raw material completely disappears. The chlorobenzene is removed by distillation under reduced pressure, and the aromatic heterocyclic nitrone is obtained after column chromatography purification, with a structure as follows, and a yield of 83%.

[0052]

[0053] 1 H NMR (400 MHz, DMSO-d6) δ 9.4 (s, 1H), 9.0 (s, 1H), 8.2 (d, J = 7.8 Hz, 1H), 8.0 (t, J = 7.1 Hz, 3H), 7.9 (d, J = 7.7 Hz, 2H), 7.6 (dt, J = 10.8, 6.9 Hz, 3H), 7.5-7.4 (m, 1H), 7.4 (d, J = 8.0 Hz, 3H), 2.3 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 147.1, 146.0, 133.7, 133.4, 130.4, 129.8, 129.0, 128.3, 127.6, 126.8, 125.8, 125.2, 123.8, 121.2, 120.4, 113.7, 113.2, 21.0.

[0054] Example 2

[0055] S1, 1 -p-Tolylsulfonyl-indole-3-ethanone (R 1 = H; X = NR 4 , R 4 is p-tolylsulfonyl TS; Y = COCH3; 0.10 mmol), phenylnitrone (R 2 and R 3 is H; 0.12 mmol) and copper triflate (0.02 mmol) were placed in a dry reaction tube, equipped with a magnetic stir bar, and 2 mL of acetonitrile was added to dissolve the mixture.

[0056] S2, the mixture solution in S1 was reacted at 25 °C for 1-6 h, with constant magnetic stirring until thin layer chromatography (TLC) detection showed that the raw material completely disappeared. The acetonitrile was removed by distillation under reduced pressure, and the aromatic heterocyclic nitrone was obtained after column chromatography purification, with a yield of 91%.

[0057] 1 H NMR (400 MHz, DMSO-d6) δ 9.4 (s, 1H), 9.0 (s, 1H), 8.2 (d, J = 7.8 Hz, 1H), 8.0 (t, J = 7.1 Hz, 3H), 7.9 (d, J = 7.7 Hz, 2H), 7.6 (dt, J = 10.8, 6.9 Hz, 3H), 7.5 - 7.4 (m, 1H), 7.4 (d, J = 8.0 Hz, 3H), 2.3 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 147.1, 146.0, 133.7, 133.4, 130.4, 129.8, 129.0, 128.3, 127.6, 126.8, 125.8, 125.2, 123.8, 121.2, 120.4, 113.7, 113.2, 21.0.

[0058] Example 3

[0059] S1, 1 -p-Tolylsulfonyl-indole-3-ethanone (R 1 = H; X = NR 4 , R 4 is p-tolylsulfonyl TS; Y = NH2; 0.10 mmol), phenylnitrone (R2 and R 3 0.12 mmol H and 0.02 mmol ferric chloride were placed in a dry reaction tube equipped with a magnetic stir bar, and 2 mL of toluene was added to dissolve them to obtain a mixed solution.

[0060] S2. The mixture solution from S1 is reacted at 25°C for 1-6 hours with continuous magnetic stirring until thin-layer chromatography (TLC) shows complete disappearance of the starting material. Toluene is removed by vacuum distillation, and the product is purified by column chromatography to obtain an aromatic heterocyclic nitrone in 80% yield.

[0061] 1 H NMR (400MHz, DMSO-d6) δ9.4(s,1H),9.0(s,1H),8.2(d,J=7.8Hz,1H),8.0(t,J=7.1Hz,3H),7.9( d,J=7.7Hz,2H),7.6(dt,J=10.8,6.9Hz,3H),7.5–7.4(m,1H),7.4(d,J=8.0Hz,3H),2.3(s,3H). 13 C NMR(101MHz,DMSO-d6)δ147.1,146.0,133.7,133.4,130.4,129.8,129.0,1 28.3,127.6,126.8,125.8,125.2,123.8,121.2,120.4,113.7,113.2,21.0.

[0062] Example 4

[0063] S1, 1-p-toluenesulfonyl-indole-3-carboxaldehyde (R 1 =H; X=NR 4 R 4 p-Toluenesulfonyl TS; Y = CHO; 0.10 mmol), phenyl nitrone (R 2 and R 3 0.12 mmol H and 0.02 mmol aluminum trichloride were placed in a dry reaction tube equipped with a magnetic stir bar, and 2 mL of ethanol was added to dissolve them to obtain a mixed solution.

[0064] S2. The mixture solution from S1 was reacted at 25°C for 1-6 hours with continuous magnetic stirring until thin-layer chromatography (TLC) showed complete disappearance of the starting material. Ethanol was removed by vacuum distillation, and the product was purified by column chromatography to obtain an aromatic heterocyclic nitrone in 87% yield.

[0065] 1H NMR (400 MHz, DMSO-d6) δ 9.4 (s, 1H), 9.0 (s, 1H), 8.2 (d, J = 7.8 Hz, 1H), 8.0 (t, J = 7.1 Hz, 3H), 7.9 (d, J = 7.7 Hz, 2H), 7.6 (dt, J = 10.8, 6.9 Hz, 3H), 7.5 - 7.4 (m, 1H), 7.4 (d, J = 8.0 Hz, 3H), 2.3 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 147.1, 146.0, 133.7, 133.4, 130.4, 129.8, 129.0, 128.3, 127.6, 126.8, 125.8, 125.2, 123.8, 121.2, 120.4, 113.7, 113.2, 21.0.

[0066] Example 5

[0067] A method for the synthesis of an aromatic heterocyclic nitrone in a gram scale reaction comprising the steps of,

[0068] Dissolve 1 -p-tolylsulfonyl-indole-3-ethanone (1.56 g, 5.0 mmol) in 30 mL of tetrahydrofuran and add palladium trifluoroacetate (0.33 g, 1.0 mmol) and continue stirring. Then slowly add a solution of phenyl nitrone (1.18 g, 6.0 mmol) in 20 mL of tetrahydrofuran and continue stirring at 25 °C until thin layer chromatography (TLC) shows complete disappearance of starting material. Evaporate the tetrahydrofuran under reduced pressure and recrystallize the residue obtained using ethyl acetate / petroleum ether to obtain the aromatic heterocyclic nitrone weighing 1.63 g with a yield of 76%.

[0069] 1 H NMR (400 MHz, DMSO-d6) δ 9.4 (s, 1H), 9.0 (s, 1H), 8.2 (d, J = 7.8 Hz, 1H), 8.0 (t, J = 7.1 Hz, 3H), 7.9 (d, J = 7.7 Hz, 2H), 7.6 (dt, J = 10.8, 6.9 Hz, 3H), 7.5 - 7.4 (m, 1H), 7.4 (d, J = 8.0 Hz, 3H), 2.3 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 147.1, 146.0, 133.7, 133.4, 130.4, 129.8, 129.0, 128.3, 127.6, 126.8, 125.8, 125.2, 123.8, 121.2, 120.4, 113.7, 113.2, 21.0.

[0070] Therefore, the application adopts the above-mentioned synthesis method of the aromatic heterocyclic nitroketone, has mild reaction conditions, high yield of the aromatic heterocyclic nitroketone, and short reaction time, and can perform a kilogram reaction.

[0071] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application, but not to limit them. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can still be modified or replaced by equivalents, and these modifications or replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.

Claims

1. A method of synthesizing an aromatic heterocyclic nitroxide, characterized by: The method comprises the following steps, S1, mixing aromatic heterocyclic compounds and phenyl nitrone with a molar ratio of 1:1-1.5 and a catalyst, adding an organic solvent to dissolve to obtain a mixture solution; S2, the mixture solution in S1 is reacted at 20-30℃ for 1-6h, the organic solvent is removed by distillation under reduced pressure, and column chromatography purification is carried out to obtain aromatic heterocyclic nitrone.

2. The method of claim 1, wherein the aromatic heterocyclic nitrone is synthesized by the reaction of a compound of formula (II) with a compound of formula (III) in the presence of a base. In S1, the structure of the aromatic heterocyclic compound is as follows, wherein R 1 one of halogen, methyl, methoxy, nitro, cyano, phenyl ring, hydrogen; X comprises one of H, NH, NR 4 , O and S, NR 4 R 4 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl; Y comprises one of H, NH2, NR 5 , O and S, CHO, COOH, COCH3, NR 5 R 5 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl.

3. The method of synthesis of aromatic heterocyclic nitrones according to claim 1, wherein: In S1, the structure of the phenyl nitrone is as follows, wherein R 2 and R 3 is independently selected from halogen, methyl, methoxy, nitro, cyano, phenyl ring, hydrogen.

4. The method for synthesizing an aromatic heterocyclic nitrone according to claim 1, characterized in that: In S1, the catalyst comprises one or more of lanthanum triflate, copper triflate, iron triflate, palladium trifluoroacetate, ferric trichloride, aluminum trichloride, boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and phosphoric acid.

5. The method of synthesis of aromatic heterocyclic nitrones according to claim 1, wherein: The molar ratio of the catalyst to the aromatic heterocyclic compound is 0.05-0.25:

1.

6. The method of synthesis of aromatic heterocyclic nitrones according to claim 1, wherein: In S1, the organic solvent comprises one or more of toluene, xylene, mesitylene, chlorobenzene, chloroform, acetonitrile, ethanol, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, ethyl acetate.

7. The method of synthesis of aromatic heterocyclic nitrones according to claim 1, wherein: In S2, the structure of the aromatic heterocyclic nitrone is as follows, wherein R 1 and R 3 are independently selected from one of halogen, methyl, methoxy, nitro, cyano, phenyl ring, hydrogen; X comprises one of H, NH, NR 4 , O and S, NR 4 R 4 comprises one of hydrogen, methyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl.

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