A method for the synthesis of indole aldehydes and derivatives thereof

Abstract

The present application relates to a kind of synthesis method of indole aldehyde and its derivative, after the reaction of o-nitro halogenated benzene compound and 4-isoxazole boronic acid pinacol ester, ring closure is obtained target product while reducing nitro group.The present application provides a kind of synthesis method of indole aldehyde and its derivative, which generates aldehyde group while synthesizing indole ring, compared with existing reference, the range of raw material selection is wide, route is short, synthesis operation is simple, reaction condition is mild, and environment is friendly.

Description

Technical Field

[0001] This invention relates to the field of biomedical synthesis technology, and in particular to a method for synthesizing indolealdehyde and its derivatives. Background Technology

[0002] Among nitrogen-containing aromatic heterocyclic compounds, those containing the indole skeleton possess unique chemical structures and pharmacological activities, especially the derived indole pharmaceutical compounds, which clearly inherit these unique activities. Currently, many physiologically active natural products and important pharmacologically active pharmaceutical intermediates are derived from indole derivatives. Indole, indole aldehyde, and their derivatives are widely found in nature and have been extensively studied due to their unique chemical and biological activities. As important pharmaceutical intermediates with extremely high medicinal value, the synthesis of indole aldehyde and its derivatives has become a key focus of research for chemists.

[0003] Most of the existing synthetic methods involve introducing an aldehyde group through phosphorus oxychloride and N,N-dimethylformamide or other oxidation methods, after obtaining the indole ring. These reactions are environmentally unfriendly, risky to scale up, and cumbersome to operate.

[0004] In view of the above-mentioned shortcomings, the designer has actively researched and innovated in order to create a method for synthesizing indolealdehyde and its derivatives, making them more industrially valuable. Summary of the Invention

[0005] To address the aforementioned technical problems, the present invention aims to provide a method for synthesizing indolealdehyde and its derivatives.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing indolealdehyde and its derivatives, comprising the following steps:

[0008] Step S1: The solution of o-nitrohalobenzene compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)isoxazole, palladium catalyst and potassium fluoride in N,N-dimethylformamide / water is stirred, the mixture is diluted with water and extracted with EtOAc, the combined organic layers are dried with anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by thin-layer chromatography to obtain the product o-(isoxazole-4-yl)nitrobenzene compound;

[0009] Step S2: Dissolve the o-(isoxazole-4-yl)nitrobenzene compound obtained in step S1 and ammonium chloride in a solvent. After the reaction solution is heated to 50-100℃, add a reducing agent. Stir the reaction solution at 50-100℃ for 3 hours. Filter and concentrate the mixture. The crude product is purified by thin-layer chromatography to obtain the target product 3-formyl-1H-indole compound.

[0010] As a further improvement of the present invention, the o-nitrohalobenzene compound is an o-nitroiodobenzene compound, an o-nitrobromobenzene compound, or an o-nitrochlorobenzene compound.

[0011] As a further improvement of the present invention, the o-nitrohalobenzene compound is a 1-bromo-2-nitrobenzene compound.

[0012] As a further improvement of the present invention, the stirring conditions in step S1 are stirring at 50°C for 3 hours; in step S2, after the reaction solution is heated to 70-90°C, the reducing agent is added, and the reaction solution is stirred at 70-90°C for 3 hours.

[0013] As a further improvement of the present invention, the palladium catalyst is Pd(dppf)Cl2 or Pd(dppf)Cl2.CH2Cl2 or Pd(PPh3)4 or Pd(dtbpf)Cl2 or Pd(OAc)2.

[0014] As a further improvement of the present invention, the solvent is a single or mixed solvent selected from ethanol, methanol, water, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetic acid, and toluene.

[0015] As a further improvement of the present invention, the solvent is a mixture of ethanol and water.

[0016] As a further improvement of the present invention, the reducing agent is iron powder, zinc powder, palladium on carbon, palladium hydroxide, palladium hydroxide on carbon, or platinum dioxide.

[0017] As a further improvement of the present invention, the reducing agent is iron powder.

[0018] As a further improvement of the present invention, thin-layer chromatography one uses petroleum ether / ethyl acetate = 5 / 1; thin-layer chromatography two uses petroleum ether / ethyl acetate = 2 / 1.

[0019] By means of the above-described solution, the present invention has at least the following advantages:

[0020] This invention provides a method for synthesizing indole aldehyde and its derivatives. This method generates an aldehyde group while synthesizing the indole ring. Compared with existing references, this method has a wider range of raw material selection, a shorter route, simpler synthesis operation, milder reaction conditions, and is more environmentally friendly.

[0021] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, the preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings. Attached Figure Description

[0022] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 This is the structural formula of the target product of the present invention, wherein R1-R4 represent electron-withdrawing or electron-donating groups such as hydrogen, methyl, methoxy, and ester groups;

[0024] Figure 2 This is the reaction equation for the synthesis process of the target product of this invention;

[0025] Figure 3 This is the reaction equation for step S1 in the first embodiment of the present invention;

[0026] Figure 4 This is the reaction equation for step S2 in the first embodiment of the present invention;

[0027] Figure 5 This is the reaction equation for the synthesis process in the second embodiment of the present invention;

[0028] Figure 6 This is the reaction equation for the synthesis process in the third embodiment of the present invention;

[0029] Figure 7 This is the reaction equation for the synthesis process in the fourth embodiment of the present invention. Detailed Implementation

[0030] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0031] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The components of the embodiments of the present invention described and shown in the accompanying drawings can generally be arranged and designed in various different configurations. Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0032] Example

[0033] like Figures 1 to 7 As shown,

[0034] A method for synthesizing indolealdehyde and its derivatives, comprising the following steps:

[0035] Step S1: The solution of o-nitrohalobenzene compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)isoxazole, palladium catalyst and potassium fluoride in N,N-dimethylformamide / water is stirred, the mixture is diluted with water and extracted with EtOAc, the combined organic layers are dried with anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by thin-layer chromatography to obtain the product o-(isoxazole-4-yl)nitrobenzene compound;

[0036] Step S2: Dissolve the o-(isoxazole-4-yl)nitrobenzene compound obtained in step S1 and ammonium chloride in a solvent. After the reaction solution is heated to 50-100℃, add a reducing agent. Stir the reaction solution at 50-100℃ for 3 hours. Filter and concentrate the mixture. The crude product is purified by thin-layer chromatography to obtain the target product 3-formyl-1H-indole compound.

[0037] Preferably, the o-nitrohalobenzene compound is an o-nitroiodobenzene compound, an o-nitrobromobenzene compound, or an o-nitrochlorobenzene compound.

[0038] Preferably, the o-nitrohalobenzene compounds are 1-bromo-2-nitrobenzene compounds.

[0039] Preferably, in step S1, the stirring conditions are stirring at 50°C for 3 hours; in step S2, after the reaction solution is heated to 70-90°C, the reducing agent is added, and the reaction solution is stirred at 70-90°C for 3 hours.

[0040] Preferably, the palladium catalyst is Pd(dppf)Cl2 or Pd(dppf)Cl2.CH2Cl2 or Pd(PPh3)4 or Pd(dtbpf)Cl2 or Pd(OAc)2.

[0041] Preferably, the solvent is a single or mixed solvent selected from ethanol, methanol, water, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetic acid, and toluene.

[0042] Preferably, the solvent is a mixture of ethanol and water.

[0043] Preferably, the reducing agent is iron powder, zinc powder, palladium on carbon, palladium hydroxide, palladium hydroxide on carbon, or platinum dioxide.

[0044] Preferably, the reducing agent is iron powder.

[0045] Preferably, thin-layer chromatography method one uses a petroleum ether / ethyl acetate ratio of 5 / 1; thin-layer chromatography method two uses a petroleum ether / ethyl acetate ratio of 2 / 1.

[0046] The principle of the synthesis method of indolealdehyde and its derivatives of the present invention:

[0047] This invention involves reacting an ortho-nitrohalobenzene compound with pinacol 4-isooxazoloborate, thereby reducing the nitro group and simultaneously cyclizing to obtain the target product.

[0048] like Figure 3 and Figure 4 The first embodiment of the present invention:

[0049] Step S1: A solution of 1-bromo-2-nitrobenzene (100 mg, 495.03 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)isoxazole (106.2 mg, 544.54 μmol), Pd(dppf)Cl2 (36 mg, 49.5 μmol), and potassium fluoride (86.3 mg, 1.49 mmol) in N,N-dimethylformamide / water (2 / 0.5 mL) was stirred at 50 °C for 3 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the product 4-(2-nitrophenyl)isoxazole (60 mg, yield 57.4%) as a yellow solid.

[0050] LCMS: m / z 191.05 [M+H]

[0051] 1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),8.41(d,J=1.6Hz,1H),8.00–7.93(m, 1H),7.66(tt,J=7.6,1.6Hz,1H),7.59–7.52(m,1H),7.47(dt,J=7.6,1.6Hz,1H).

[0052] Step S2: Dissolve 4-(2-nitrophenyl)isoxazole (60 mg, 315.53 μmol) and ammonium chloride (168.8 mg, 3.16 mmol) in ethanol / water (4 / 0.5 mL). After the reaction solution is heated to 80 °C, add iron powder (88.1 mg, 1.58 mmol). Stir the reaction solution at 80 °C for 3 hours. Filter and concentrate the mixture. Purify the crude product by thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain a yellow oily 1H-indole-3-carboxaldehyde (27 mg, yield 59%).

[0053] LCMS: m / z 146.15 [M+H]

[0054] 1 H NMR (400MHz, Chloroform-d) δ10.08(s,1H),8.79(s,1H),8.36–8.28(m,1H),7.85(d,J=3.1Hz,1H),7.48–7.41(m,1H),7.35–7.31(m,2H).

[0055] like Figure 5 The second embodiment of the present invention:

[0056] Step S1 yields 4-(4-methyl-2-nitrophenyl)isoxazole.

[0057] LCMS:m / z 205.00[M+H]

[0058] 1 H NMR (400MHz, Chloroform-d) δ8.58(s,1H),8.38(s,1H),7.77(s,1H),7.48–7.43(m,1H),7.33(d,J=7.8Hz,1H),2.48(s,3H).

[0059] Step S2 yields the target product 6-methyl-1H-indole-3-carboxaldehyde.

[0060] LCMS: m / z 160.30 [M+H]

[0061] 1H NMR (400MHz, Chloroform-d) δ10.03(s,1H),8.64(s,1H),8.18(d,J=8.2Hz,1H),7.78(d,J=3.2Hz,1H),7.23(s,1H),7.16(d,J=8.2Hz,1H),2.48(s,3H).

[0062] like Figure 6 The third embodiment of the present invention:

[0063] Step S1 yields methyl 4-(isoxazole-4-yl)-3-nitrobenzoate.

[0064] LCMS: m / z 249.10 [M+H]

[0065] 1 H NMR (400MHz, Chloroform-d) δ8.69(s,1H),8.44(s,1H),8.28(dd,J=8.2,1.8Hz,1H),7.86(d,J=8.0Hz,1H),7.57(d,J=8.0Hz,1H),4.00(s,3H).

[0066] Step S2 yields the target product, methyl 3-formyl-1H-indole-6-carboxylate.

[0067] LCMS:m / z 204.10[M+H]

[0068] 1 H NMR (400MHz, Chloroform-d) δ10.10(s,1H),9.10(s,1H),8.35(d,J=8.4Hz,1H),8.20(brs,1H),8.04–7.97(m,2H),3.96(s,3H).

[0069] like Figure 7 Fourth embodiment of the present invention:

[0070] Step S1 yields 4-(4-methoxy-2-nitrophenyl)isoxazole.

[0071] LCMS:m / z 221.10[M+H]

[0072] 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.77 (s, 1H), 7.64–7.56 (m, 2H), 7.37 (dd, J = 8.8, 2.8Hz, 1H), 3.88 (s, 3H).

[0073] Step S2 yields the target product 6-methoxy-1H-indole-3-carboxaldehyde.

[0074] LCMS: m / z 176.15 [M+H]

[0075] 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.86(s,1H),8.14(s,1H),7.93(d,J=8.6Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=8.8,2.4Hz,1H),3.79(s,3H).

[0076] In summary, this invention relates to a method for synthesizing indolealdehyde and its derivatives, which involves reacting an o-nitrohalobenzene compound with pinacol 4-isooxazoloborate, thereby reducing the nitro group and simultaneously cyclizing to obtain the target product.

[0077] This invention provides a method for synthesizing indole aldehyde and its derivatives. This method generates an aldehyde group while synthesizing the indole ring. Compared with existing references, this method has a wider range of raw material selection, a shorter route, simpler synthesis operation, milder reaction conditions, and is more environmentally friendly.

[0078] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various modifications and alterations without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

[0079] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing indolealdehyde and its derivatives, characterized in that, The steps are as follows: Step S1: The solution of o-nitrohalobenzene compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoxazole, palladium catalyst and potassium fluoride in N,N-dimethylformamide / water is stirred, the mixture is diluted with water and extracted with EtOAc, the combined organic layers are dried with anhydrous sodium sulfate, filtered and concentrated, and the residue is purified by thin-layer chromatography to obtain the product o-(isoxazole-4-yl)nitrobenzene compound; Step S2: Dissolve the o-(isoxazole-4-yl)nitrobenzene compound obtained in step S1 and ammonium chloride in a solvent. After the reaction solution is heated to 50-100℃, add a reducing agent. Stir the reaction solution at 50-100℃ for 3 hours. Filter and concentrate the mixture. The crude product is purified by thin-layer chromatography to obtain the target product 3-formyl-1H-indole compound. The reducing agent is iron powder; The molecular structural formula of the o-nitrohalobenzene compound is: Where X represents halogen, and R1-R4 represent hydrogen, methyl, and methoxy groups, respectively. The molecular structural formula of the o-(isoxazole-4-yl)nitrobenzene compound is: R1-R4 represent hydrogen, methyl, and methoxy groups, respectively. The molecular structural formula of the 3-formyl-1H-indole compound is as follows: R1-R4 represent hydrogen, methyl, and methoxy, respectively.

2. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, The o-nitrohalobenzene compounds are o-nitroiodobenzene, o-nitrobromobenzene, or o-nitrochlorobenzene.

3. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, The o-nitrohalobenzene compound is 1-bromo-2-nitrobenzene.

4. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, In step S1, the stirring conditions are 50°C for 3 hours; in step S2, after the reaction solution is heated to 70-90°C, the reducing agent is added, and the reaction solution is stirred at 70-90°C for 3 hours.

5. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, The palladium catalyst is Pd(dppf)Cl2 or Pd(dppf)Cl2.CH2Cl2 or Pd(PPh3)4 or Pd(dtbpf)Cl2 or Pd(OAc)2.

6. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, The solvent is a single or mixed solvent selected from ethanol, methanol, water, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, acetic acid, and toluene.

7. The method for synthesizing indolealdehyde and its derivatives as described in claim 6, characterized in that, The solvent is a mixture of ethanol and water.

8. The method for synthesizing indolealdehyde and its derivatives as described in claim 1, characterized in that, Thin-layer chromatography method one uses a petroleum ether / ethyl acetate ratio of 5 / 1; thin-layer chromatography method two uses a petroleum ether / ethyl acetate ratio of 2 / 1.

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