Method for preparing indole-dipyrrolylmethane derivative

Abstract

The invention belongs to the field of organic synthesis, and discloses a method for preparing an indole-dipyrromethene derivative, which comprises the following steps: firstly, carrying out Ugi reaction on glyoxal dimethyl acetal, isonitrile, trifluoroacetic acid and amine to obtain an alpha-acylamino amide compound; and then under the action of an acid catalyst, carrying out [3 + 2] cyclization aromatization on the indole-dipyrromethene derivative, 4-methoxy ethyl acetoacetate and an indole derivative to obtain the indole-dipyrromethene derivative. According to the method, the indole-dipyrromethene derivative is prepared from the Ugi adduct prepared through the Ugi reaction in which glyoxal dimethyl acetal participates through [3 + 2] cyclization aromatization with ethyl 4-methoxyacetoacetate and the indole derivative, precious metal is not used in the overall reaction, the final target product can be obtained through a one-pot two-step method, and the step operation is simple. In addition, no additional ligand or additive needs to be added, and the method has the advantages of being good in reaction selectivity, high in yield, easy in product separation and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and more particularly relates to a method for preparing indolodipyrromethane derivatives. BACKGROUND

[0002] Indolodipyrromethane derivatives are important fine organic intermediates and bioactive molecules, which are widely used in the fields of medicine, pesticide, material science, etc. Indolodipyrromethane derivatives also exist widely in many bioactive molecules and drugs. For example, such molecules can be used as adsorbent materials (Sustainable Chem. Pharm., 2020, 18, 100314.) or precursors of medicines, inhibitors of aromatic enzyme, etc. (J Enzym. Inhib. Med. Ch., 2007, 22(5), 667-676).

[0003] At present, the synthesis of indolodipyrromethane derivatives is mainly through the use of N,N-dimethylaminomethyl derivatives generated by the Mannich reaction between pyrrole or indole and Eschenmoser salt (Synlett, 2015, 26, 484-488.) to construct asymmetric indolodipyrromethane derivatives. The precursor construction of this method requires a reaction in acetonitrile for 26 hours, and then a microwave-assisted reaction at a high temperature of 150°C to obtain the target product. This method has high energy consumption and low atom utilization rate. In addition, other methods are mainly used to generate symmetric diindole or dipyrromethane derivatives (ACS Sustainable Chem. Eng., 2019, 7, 8429-8439; Chem. Sci., 2022, 13, 170-177.). At present, the synthesis of diindole or dipyrrole compounds mainly focuses on symmetric structures, and there is still a significant technical gap in the synthesis method of asymmetric indolodipyrromethane derivatives. Existing technologies usually rely on harsh reaction conditions, resulting in low yield, limited substrate applicability, and difficulty in efficiently constructing structurally diverse asymmetric target molecules. There are few methods for constructing asymmetric indolodipyrromethane derivatives using simple and mild methods.

[0004] Therefore, there is an urgent need for an environmentally friendly and mild method for constructing indolodipyrromethane derivatives. SUMMARY

[0005] In view of the above defects or improvement needs of the prior art, the present application aims to provide a method for preparing indole-dipyrromethane derivatives, wherein the Ugi adduct prepared by Ugi reaction involving glyoxal dimethyl acetal is reacted with 4-methoxyacetoacetic acid ethyl ester and indole derivatives by [3+2] cyclization aromatization to prepare indole-dipyrromethane derivatives, no noble metal is used in the overall reaction, the final target product can be obtained by one-pot two-step method, and the step operation is simple. In addition, no additional ligand or additive needs to be added, and the method has the advantages of good reaction selectivity, high yield, and easy separation of products.

[0006] To achieve the above-mentioned purpose, according to the present application, a method for preparing indole-dipyrromethane derivatives is provided, characterized in that the method is to first obtain an α-amido amide compound by Ugi reaction of glyoxal dimethyl acetal, isonitrile, trifluoroacetic acid, and amine, and then obtain an indole-dipyrromethane derivative by [3+2] cyclization aromatization of the α-amido amide compound, 4-methoxyacetoacetic acid ethyl ester, and indole derivatives under the action of an acidic catalyst.

[0007] As a further preferred embodiment of the present application, the indole-dipyrromethane derivative has the following structural formula:

[0008]

[0009] wherein R 1 is hydrogen, benzyl, or alkyl with a carbon number of 1-2; R 2 is hydrogen or halogen; R 3 is hydrogen, methyl, aldehyde group, halogen, thiophene, or aryl; and R 1 , R 2 , and R 3 are not all hydrogen.

[0010] As a further preferred embodiment of the present application, the reaction formula of the [3+2] cyclization aromatization reaction of the α-amido amide compound, 4-methoxyacetoacetic acid ethyl ester, and indole derivatives under the action of an acidic catalyst is as follows:

[0011]

[0012] As a further preferred embodiment of the present application, the preparation method specifically comprises the following steps:

[0013] (S1) Ugi reaction of glyoxal dimethyl acetal, trifluoroacetic acid, tert-butyl isonitrile, and n-butylamine in a solvent at a temperature not higher than 40°C for 12-24 hours; after the reaction, an α-amido amide compound is separated;

[0014] (S2) the [3+2] cyclization aromatization reaction of the α-amido amide compound, the ethyl 4-methoxyacetoacetate, the indole derivative and the acidic catalyst in a solvent at 60-100℃ for 3-5h; after the reaction, the indole-dipyrromethane derivative is separated.

[0015] As a further preferred embodiment of the present application, the reaction route of the preparation method is as follows:

[0016]

[0017] As a further preferred embodiment of the present application, in step (S1), the molar ratio of the glyoxal dimethyl acetal, the trifluoroacetic acid, the tert-butyl isocyanide and the n-butylamine is 1:1:1:1-2:2:2:1.

[0018] As a further preferred embodiment of the present application, in step (S2), the molar ratio of the α-amido amide compound, the ethyl 4-methoxyacetoacetate and the indole derivative is 1:1:1-1:2:2.

[0019] As a further preferred embodiment of the present application, in step (S2), the acidic catalyst is any one of p-toluenesulfonic acid, triflic acid, aluminum trifluoromethanesulfonate, aluminum trichloride, trifluoroacetic acid or acetic acid.

[0020] As a further preferred embodiment of the present application, in step (S1) and step (S2), the solvent is independently any one of dichloromethane, dichloroethane, toluene, methanol, ethanol, acetonitrile, tetrahydrofuran or 1,4-dioxane;

[0021] And, in step (S1) and step (S2), the solvent is recovered by distillation after the reaction.

[0022] By the above technical scheme of the present application, compared with the prior art, the following advantages can be achieved

[0023] Advantages:

[0024] (1) The present application uses glyoxal dimethyl acetal, isocyanide, trifluoroacetic acid and amine to construct α-amido amide compound through Ugi reaction, and then uses the α-amido amide compound, ethyl 4-methoxyacetoacetate and indole derivative to prepare indole-dipyrromethane derivative through [3+2] cyclization aromatization reaction, without the need to adjust the pH value separately, the target indole-dipyrromethane derivative can be obtained smoothly; the raw materials used are all industrialized commodities, which are simple to obtain and widely available. In addition, the [3+2] cyclization aromatization reaction in the present application can be carried out in the presence of an acidic catalyst, and the preferred acidic catalyst (i.e. p-toluenesulfonic acid, triflic acid, aluminum trifluoromethanesulfonate, aluminum trichloride, trifluoroacetic acid and acetic acid) is also a common commercial reagent, which is very stable.

[0025] (2) The preparation method of the indolium-dipyrromethane derivative in the application has mild reaction conditions, and the reaction solvent can be recovered by simple distillation, which is a relatively green and environmentally friendly synthesis process.

[0026] The synthesis method of the indolium-dipyrromethane derivative in the application adopts a one-pot two-step reaction, which is simple to operate, and the raw materials are simple to prepare and have high utilization rate. Specifically, the glyoxal bis(methyl) acetal, isonitrile, acid and amine can be dissolved in a protic solvent to obtain an alpha-amido amide compound through a classic Ugi reaction, and then the alpha-amido amide compound, ethyl 4-methoxyacetoacetate and a solvent are mixed to obtain the indolium-dipyrromethane derivative through a [3+2] cyclization aromatization reaction under the action of a catalyst.

[0027] The synthesis method of the indolium-dipyrromethane derivative in the application can obtain the indolium-dipyrromethane derivative by performing a [3+2] cyclization aromatization reaction on the Ugi reaction adduct, ethyl 4-methoxyacetoacetate and an indole derivative in the presence of a catalyst in a solvent, especially at 60-100 DEG C.

[0028] The application first constructs an alpha-amido amide compound through a Ugi reaction, that is, using a glyoxal bis(methyl) acetal compound with multiple reaction sites and trifluoroacetic acid with high leaving property as substrates, a mature and efficient Ugi reaction is used to construct an alpha-amido amide compound, which has rich reaction sites and high activity, which is conducive to the subsequent reaction, and other general aldehydes and low leaving acids are difficult to construct alpha-amido amide compounds with high activity and multiple reaction sites.

[0029] The application uses suitable substrates to enable the subsequent alpha-amido amide compound to easily react with ethyl 4-methoxyacetoacetate and an indole derivative to obtain the target product, and the method has low energy consumption and mild conditions. The raw materials used are industrialized commodities, which are simple to obtain and widely available. In the prior art, N,N-dimethylaminomethyl derivatives are used to construct target products through microwave-assisted reactions at high temperatures, which is not environmentally friendly due to high energy consumption.

[0030] The application constructs an alpha-amido amide compound by using simple glyoxal dimethylhydrazone, an amine, trifluoroacetic acid and isonitrile as raw materials, and the asymmetric indole-dipyrromethane derivative is prepared by reacting the alpha-amido amide compound with 4-methoxyacetoacetic acid ethyl ester and an indole derivative in cooperation with a common acidic catalyst and a solvent, and the reaction operation is simple and the reaction condition is mild. The application realizes efficient and controllable synthesis of the asymmetric indole-dipyrromethane derivative, has the advantages of simple operation, mild condition and adjustable product structure, fills the technical blank of the synthesis method of the asymmetric indole-dipyrromethane derivative, and provides key technical support for large-scale preparation and functional development of the compound. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical scheme and advantages of the application clearer and more apparent, the application will be further described in detail below with reference to examples. It should be understood that the specific examples described herein are only used to explain the application and not to limit the application. In addition, the technical features involved in each embodiment of the application described below can be combined with each other as long as they do not conflict with each other.

[0032] Example 1

[0033] The Ugi adduct alpha-amido amide compound prepared based on glyoxal dimethylhydrazone, acid, isonitrile and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((1-methyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, which includes the following steps:

[0034] Step (1): Put n-butylamine (11.01 g, 150 mmol), tert-butyl isonitrile (12.48 g, 150 mmol) and trifluoroacetic acid (17.10 g, 150 mmol) into a 1000 mL round-bottom flask, and add methanol (150 mL). Mix at room temperature, and add glyoxal dimethylhydrazone aqueous solution (60 wt.%, 100 mmol of solute, 17.35 g of the whole solution) to the mixed solution under stirring. Stir the reaction solution at 40°C for 24 h. After the reaction is completed, wash with saturated aqueous sodium chloride solution for 3 times, 300 ml each time, separate the organic layer solution after concentration, and then separate by silica column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to obtain the product Ugi reaction adduct, with a yield of 87%.

[0035] Step (2): Into a 50 ml round bottom flask, the Ugi adduct (1.07 g, 3 mmol) obtained in step (1), 4-methoxyacetoacetate (0.48 g, 3 mmol), N-methylindole (0.39 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml dichloroethane were added respectively, the mixture was stirred at 80 °C for 4 hours, after the reaction was completed, the mixture was concentrated, the residue was separated by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((1-methyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.09 g, 86%).

[0036] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 7.52 (d, J = 7.9 Hz, 1H), 7.21-7.11 (m, 2H), 7.09-6.99 (m, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 5.74 (s, 1H), 4.41 (s, 2H), 4.15 (t, J = 7.7 Hz, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 1.42 (q, J = 7.9 Hz, 2H), 1.34 (s, 9H), 1.12 (q, J = 7.6 Hz, 3H), 0.72 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.2, 161.4, 141.7, 137.0, 127.3, 126.7, 126.6, 121.6, 118.9, 118.6, 112.6, 111.2, 111.2, 109.2, 51.4, 51.1, 44.93, 33.7, 32.6, 28.9, 21.0, 19.9, 13.8.

[0037] The overall reaction formula of this example is as follows:

[0038]

[0039] The compound can be used to construct indolinone derivatives as precursors of phosphoinositide-dependent kinase-1 (PDK1) inhibitors, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0040] Example 2

[0041] The Ugi adduct prepared based on glyoxal bis-methylol, acid, isonitrile, amine, α-amidoamide compound deconstructed 1-butyl-5-(tert-butylcarbamoyl)-2-((1-methyl-2-formyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, comprising the following steps:

[0042] Step (1): The step (1) of this example is the same as Example 1.

[0043] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), N-methyl-2-formylindole (0.47 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((1-methyl-2-formyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (0.94 g, 70%).

[0044] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDCl3, TMS, 25°C) δ = 10.04 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.38-7.33 (m, 2H), 7.09 (td, J = 7.1, 1.3 Hz, 1H), 6.91 (s, 1H), 5.79 (s, 1H), 4.98 (s, 2H), 4.10 (t, J = 7.8 Hz, 2H), 4.05 (s, 3H), 3.83 (d, J = 1.2 Hz, 3H), 1.40 (s, 10H), 1.32-1.19 (m, 3H), 0.98 (q, J = 7.6 Hz, 2H), 0.67 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ = 182.52, 165.21, 161.03, 140.28, 139.55, 131.29, 127.27, 127.12, 126.01, 125.09, 121.29, 120.90, 112.62, 111.64, 110.36, 51.47, 51.22, 45.30, 33.33, 31.78, 28.88, 20.51, 19.80, 13.70.

[0045] The overall reaction formula of this example is as follows:

[0046]

[0047] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of a phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which further can alleviate a disease state (e.g., cancer) in a mammal by inhibiting PDK-1 activity.

[0048] Example 3

[0049] The Ugi adduct α-amidoamide compound prepared based on glyoxal bis-methylol, acid, isonitrile, amine was deconstructed to form 2-((1-benzyl-1H-indol-3-yl)methyl)-1-butyl-5-(tert-butylcarbamoyl)-1H-pyrrole-3-carboxylic acid methyl ester, which comprises the following steps:

[0050] Step (1): The step (1) of this example is the same as that of Example 1.

[0051] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), N-benzylindole (0.62 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol), and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 2-((1-benzyl-1H-indol-3-yl)methyl)-1-butyl-5-(tert-butylcarbamoyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.04 g, 70%).

[0052] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDCl3, TMS, 25°C) δ = 7.60 (d, J = 7.7 Hz, 1H), 7.25-7.19 (m, 3H), 7.18-7.07 (m, 2H), 7.06-7.00 (m, 2H), 6.91 (s, 1H), 6.64 (s, 1H), 5.80 (s, 1H), 5.22 (s, 2H), 4.52 (s, 2H), 4.23 (t, J = 7.7 Hz, 2H), 3.78 (s, 3H), 1.49 (td, J = 7.4, 3.9 Hz, 2H), 1.41 (s, 9H), 1.18 (q, J = 7.5 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDC13) δ = 165.25, 161.38, 141.47, 137.63, 136.65, 128.69, 127.67, 127.49, 126.73, 126.52, 126.21, 121.92, 119.26, 118.82, 112.66, 112.04, 111.33, 109.81, 51.40, 51.05, 49.98, 44.92, 33.61, 28.94, 21.18, 19.93, 13.79.

[0053] The overall reaction scheme of this example is as follows:

[0054]

[0055] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0056] Example 4

[0057] The Ugi adduct α-amidoamide compound prepared based on glyoxal bis-methylol, acid, isonitrile, and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((1-ethyl-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0058] Step (1): Step (1) of this example is the same as that of Example 1.

[0059] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), N-ethyl-2-phenylindole (0.66 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol), and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((1-ethyl-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.05 g, 68%).

[0060] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 7.41 (dd, J = 5.6, 1.8 Hz, 3H), 7.35 - 7.26 (m, 4H), 7.24 - 7.16 (m, 1H), 7.08 - 7.00 (m, 1H), 6.74 (s, 1H), 5.68 (s, 1H), 4.54 (s, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.91 (t, J = 7.6 Hz, 2H), 3.78 (s, 3H), 1.37 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.5 Hz, 2H), 0.86 (q, J = 7.6 Hz, 2H), 0.61 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.33, 161.20, 141.42, 137.39, 135.82, 131.78, 130.59, 128.24, 128.19, 127.60, 126.33, 121.66, 119.46, 119.18, 112.51, 111.69, 109.48, 109.02, 51.25, 50.94, 44.92, 38.56, 33.17, 28.92, 21.17, 19.74, 15.36, 13.77.

[0061] The overall reaction scheme of this example is as follows:

[0062]

[0063] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0064] Example 5

[0065] The Ugi adduct α-amido amide compound prepared based on glyoxal dimethyl hydride, acid, isonitrile, and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0066] Step (1): Step (1) of this example is the same as that of Example 1.

[0067] Step (2): Into a 50 ml round-bottom flask, the Ugi adduct (1.07 g, 3 mmol) obtained in step (1), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-phenylindole (0.58 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane were added, respectively, and the mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (0.99 g, 68%).

[0068] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 8.30 (s, 1H), 7.55-7.47 (m, 2H), 7.47-7.39 (m, 2H), 7.38-7.29 (m, 2H), 7.26-7.21 (m, 1H), 7.13 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.00-6.95 (m, 1H), 6.84 (s, 1H), 5.69 (s, 1H), 4.77 (s, 2H), 3.86 (s, 4H), 1.35 (s, 9H), 1.13-1.01 (m, 2H), 0.72 (q, J = 7.5 Hz, 2H), 0.53 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.62, 161.17, 141.05, 135.96, 134.93, 132.68, 128.79, 128.58, 128.55, 127.98, 126.58, 122.29, 119.90, 119.62, 112.49, 111.74, 110.72, 108.87, 51.28, 51.12, 44.96, 33.04, 28.88, 21.23, 19.62, 13.65.

[0069] The overall reaction formula of this example is as follows:

[0070]

[0071] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0072] Example 6

[0073] The Ugi adduct α-amidoamide compound prepared based on glyoxal dimethylhydrazone, acid, isonitrile, amine deconstructs 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, comprising the following steps:

[0074] Step (1): The step (1) of this example is the same as that of Example 1.

[0075] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct (1.07 g, 3 mmol) obtained in step (1), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-(4-methoxyphenyl)-1H-indole (0.67 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane, respectively, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.03 g, 71%).

[0076] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDCl3, TMS, 25°C) δ = 8.11 (s, 1H), 7.38-7.33 (m, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.04 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.92-6.86 (m, 3H), 6.77 (s, 1H), 5.62 (s, 1H), 4.66 (s, 2H), 3.78 (d, J = 4.4 Hz, 6H), 3.76-3.70 (m, 2H), 1.28 (s, 10H), 0.99 (td, J = 10.0, 6.5 Hz, 2H), 0.68 (h, J = 7.3 Hz, 2H), 0.48 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDC13) δ = 165.63, 161.20, 159.48, 141.18, 135.79, 134.89, 129.82, 126.55, 125.11, 121.99, 119.80, 119.40, 114.24, 112.50, 111.67, 110.60, 108.17, 55.40, 51.28, 44.95, 33.05, 28.88, 21.20, 19.67, 14.21, 13.68.

[0077] The overall reaction scheme of this example is as follows:

[0078]

[0079] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0080] Example 7

[0081] The Ugi adduct α-amido amide compound prepared based on glyoxal dimethyl hydride, acid, isonitrile, and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(p-tolyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0082] Step (1): Step (1) of this example is the same as that of Example 1.

[0083] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-(4-methylphenyl)-1H-indole (0.62 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol), and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(p-tolyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.03 g, 69%).

[0084] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 8.21 (s, 1H), 7.35 - 7.31 (m, 3H), 7.29 - 7.22 (m, 2H), 7.18 (t, J = 3.6 Hz, 2H), 7.12 (t, J = 7.5 Hz, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.84 (s, 1H), 5.69 (s, 1H), 4.77 (s, 2H), 3.86 (s, 3H), 3.80 (t, J = 7.9 Hz, 3H), 2.39 (s, 3H), 1.35 (s, 10H), 1.07 (dtd, J = 15.7, 7.9, 5.5 Hz, 3H), 0.73 (p, J = 7.3 Hz, 3H), 0.53 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.66, 161.19, 141.15, 137.92, 135.89, 135.04, 129.76, 129.52, 128.59, 128.43, 126.56, 122.09, 119.80, 119.56, 112.52, 111.68, 110.66, 108.47, 59.43, 52.44, 51.28, 51.13, 45.57, 44.98, 33.07, 28.88, 21.27, 19.64, 13.66.

[0085] The overall reaction scheme of this example is as follows:

[0086]

[0087] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0088] Example 8

[0089] The Ugi adduct α-amidoamide compound prepared based on glyoxal dimethyl hydride, acid, isonitrile, and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4-chlorophenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0090] Step (1): Step (1) of this example is the same as that of Example 1.

[0091] Step (2): To a 50 ml round bottom flask was added the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-(4-chlorophenyl)-1H- indole (0.68 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane, respectively, and the mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4-chlorophenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.07 g, 69%).

[0092] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDC13) δ = 8.11 (s, 1H), 7.32 (d, J = 3.9 Hz, 4H), 7.26 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 7.09 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.93 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (s, 1H), 5.62 (s, 1H), 4.66 (s, 2H), 3.78 (s, 3H), 3.74 (dd, J = 9.1, 6.4 Hz, 3H), 1.30 (s, 10H), 1.03 (p, J = 7.9 Hz, 3H), 0.72 (dt, J = 15.3, 7.4 Hz, 3H), 0.51 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.49, 161.10, 140.73, 135.95, 134.01, 133.62, 131.10, 129.77, 128.89, 128.48, 126.60, 122.63, 120.13, 119.54, 112.43, 111.84, 110.77, 109.46, 51.33, 51.10, 44.96, 33.07, 28.88, 21.12, 19.72, 13.63.

[0093] The overall reaction formula of this example is as follows:

[0094]

[0095] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of a phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which further can alleviate a disease state (e.g., cancer) in a mammal by inhibiting PDK-1 activity.

[0096] Example 9

[0097] The Ugi adduct α-amidoamide compound prepared based on glyoxal bis-methylol, acid, isonitrile, amine was deconstructed to form 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4- bromophenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0098] Step (1): The step (1) of this example is the same as that of Example 1.

[0099] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-(4-bromophenyl)-1H- indole (0.81 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol), and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-(4-bromophenyl)-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.08 g, 64%).

[0100] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDC13, TMS, 25°C) δ = 7.34 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.19 - 7.11 (m, 3H), 7.06 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.92 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.74 (s, 1H), 5.63 (s, 1H), 4.61 (s, 2H), 3.76 (s, 3H), 3.72 - 3.61 (m, 2H), 1.29 (s, 10H), 1.05 - 0.90 (m, 2H), 0.66 (q, J = 7.5 Hz, 2H), 0.48 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDC13) δ = 165.55, 161.19, 140.94, 136.02, 133.77, 131.72, 131.54, 130.04, 128.46, 126.57, 122.54, 122.02, 120.02, 119.43, 112.49, 111.80, 110.92, 109.19, 51.37, 51.13, 44.89, 33.06, 28.89, 21.06, 19.70, 13.65.

[0101] The overall reaction scheme of this example is as follows:

[0102]

[0103] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0104] Example 10

[0105] The Ugi adduct α-amido amide compound prepared based on glyoxal dimethyl hydride, acid, isonitrile, and amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((5-chloro-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0106] Step (1): The step (1) of this example is the same as that of Example 1.

[0107] Step (2): A 50 ml round-bottom flask was added with the Ugi adduct (1.07 g, 3 mmol) obtained in step (1), 4-methoxyacetoacetate (0.48 g, 3 mmol), 5-chloro-2-phenyl-1H-indole (0.32 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol), and 10 ml of dichloroethane, respectively, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((5-chloro-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (0.87 g, 56%).

[0108] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 7.34 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.19 - 7.11 (m, 3H), 7.06 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.92 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.74 (s, 1H), 5.63 (s, 1H), 4.61 (s, 2H), 3.76 (s, 3H), 3.72 - 3.61 (m, 2H), 1.29 (s, 10H), 1.05 - 0.90 (m, 2H), 0.66 (q, J = 7.5 Hz, 2H), 0.48 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.55, 161.19, 140.94, 136.02, 133.77, 131.72, 131.54, 130.04, 128.46, 126.57, 122.54, 122.02, 120.02, 119.43, 112.49, 111.80, 110.92, 109.19, 51.37, 51.13, 44.89, 33.06, 28.89, 21.06, 19.70, 13.62.

[0109] The overall reaction scheme of this example is as follows:

[0110]

[0111] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0112] Example 11

[0113] The Ugi adduct α-amidoamide compound prepared based on glyoxal dimethyl acetal, acid, isonitrile, amine is used to construct 1-butyl-5-(tert-butylcarbamoyl)-2-((5-bromo-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, including the following steps:

[0114] Step (1): Step (1) of this example is the same as Example 1.

[0115] Step (2): Into a 50 ml round bottom flask, the Ugi adduct (1.07 g, 3 mmol) obtained in step (1), 4-methoxyacetoacetate (0.48 g, 3 mmol), 5-bromo-2-phenyl-1H-indole (0.81 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane were added respectively, and the mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((5-bromo-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (1.01 g, 60%).

[0116] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDC13, TMS, 25 °C) δ = 8.69-8.54 (m, 1H), 7.46-7.31 (m, 6H), 7.18 (s, 2H), 6.82 (s, 1H), 5.72 (s, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 3.77-3.62 (m, 2H), 1.36 (s, 9H), 1.04 (p, J = 7.6 Hz, 2H), 0.69 (q, J = 7.6 Hz, 2H), 0.53 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ = 165.66, 161.21, 140.61, 136.30, 132.11, 130.23, 128.82, 128.55, 128.28, 126.64, 125.01, 122.29, 112.96, 112.55, 112.24, 111.75, 108.43, 51.36, 51.21, 44.83, 33.11, 28.87, 20.84, 19.56, 13.67.

[0117] The overall reaction formula of this example is as follows:

[0118]

[0119] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which can further alleviate the disease state of mammals (such as cancer) by inhibiting the activity of PDK-1.

[0120] Example 12

[0121] The Ugi adduct prepared based on glyoxal bis-methylol, acid, isonitrile, amine, α-amidoamide compound deconstructed 1-butyl-5-(tert-butylcarbamoyl)-2-((5-bromo-2-phenyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester, comprising the following steps:

[0122] Step (1): The step (1) of this example is the same as Example 1.

[0123] Step (2): A 50 ml round-bottom flask was charged with the Ugi adduct obtained in step (1) (1.07 g, 3 mmol), 4-methoxyacetoacetate (0.48 g, 3 mmol), 2-thienyl-1H-indole (0.60 g, 3 mmol), aluminum trifluoromethanesulfonate (0.05 g, 0.03 mmol) and 10 ml of dichloroethane, and the mixture was stirred at 80°C for 4 hours. After the reaction was completed, the mixture was concentrated, and the residue was separated by silica chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 (v / v)) to obtain the corresponding 1-butyl-5-(tert-butylcarbamoyl)-2-((2-thienyl-1H-indol-3-yl)methyl)-1H-pyrrole-3-carboxylic acid methyl ester (0.65 g, 40%).

[0124] The hydrogen spectrum data and carbon spectrum data of the product of step (2) are as follows: 1 H NMR (400 MHz, CDCl3, TMS, 25°C) δ = 8.29 (s, 1H), 7.41-7.36 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.25-7.22 (m, 1H), 7.16-7.07 (m, 3H), 6.98-6.86 (m, 2H), 5.74 (s, 1H), 4.83 (s, 2H), 3.91 (dd, J = 9.2, 6.5 Hz, 2H), 3.86 (s, 3H), 1.37 (s, 10H), 1.21-1.10 (m, 3H), 0.83 (p, J = 7.4 Hz, 2H), 0.58 (t, J = 7.3 Hz, 3H); 13 CNMR (101 MHz, CDCl3) δ = 165.59, 161.19, 140.68, 136.03, 134.05, 128.50, 128.46, 127.80, 126.72, 125.99, 125.88, 122.75, 120.13, 119.73, 112.56, 111.84, 110.64, 109.89, 51.33, 51.16, 45.10, 33.22, 28.90, 21.56, 19.72, 13.68.

[0125] The overall reaction formula of this example is as follows:

[0126]

[0127] Similar to the final product obtained in Example 1, the final product obtained in this example can be used to construct an indolinone derivative as a precursor of a phosphoinositide-dependent kinase-1 (PDK1) inhibitor, which further can alleviate the disease state (e.g., cancer) in mammals by inhibiting the activity of PDK-1.

[0128] Those skilled in the art will readily understand that the above description is only preferred embodiments of the present application and is not intended to limit the present application, and any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of indolodipyrromethane derivatives, characterized in that, The method is to obtain an alpha-amido amide compound by Ugi reaction of glyoxal dimethylhydrazone, isonitrile, trifluoroacetic acid and amine, and then to obtain an indole-dipyrromethane derivative by [3+2] cyclization aromatization of the alpha-amido amide compound, ethyl 4-methoxyacetoacetate and indole derivative under the action of an acidic catalyst.

2. The method of claim 1, wherein, The structure of the indole-dipyrromethane derivative is as follows: wherein R 1 is hydrogen, benzyl or an alkyl group having a carbon number of 1-2; R 2 is hydrogen or halogen; R 3 is hydrogen, methyl, aldehyde, halogen, thiophene or aryl; and, R 1 , R 2 , R 3 are not simultaneously hydrogen.

3. The method of claim 2, wherein, The reaction formula of the [3+2] cyclization aromatization reaction of the alpha-amido amide compound, ethyl 4-methoxyacetoacetate and indole derivative under the action of an acidic catalyst is as follows:

4. The method of claim 1, wherein, The preparation method specifically comprises the following steps: (S1) Ugi reaction of glyoxal dimethylhydrazone, trifluoroacetic acid, tert-butyl isonitrile and n-butylamine in a solvent at a temperature not higher than 40 DEG C for 12-24 hours; after the reaction, the alpha-amido amide compound is separated; (S2) [3+2] cyclization aromatization reaction of the alpha-amido amide compound, ethyl 4-methoxyacetoacetate and indole derivative in a solvent under the action of an acidic catalyst at 60-100 DEG C for 3-5 hours; after the reaction, the indole-dipyrromethane derivative is separated.

5. The method of claim 4, wherein, The reaction route of the preparation method is as follows:

6. The method of claim 4, wherein, In step (S1), the molar ratio of glyoxal dimethylhydrazone, trifluoroacetic acid, tert-butyl isonitrile and n-butylamine is 1:1:1:1-2:2:2:

1.

7. The method of claim 4, wherein, In step (S2), the molar ratio of the alpha-amido amide compound, ethyl 4-methoxyacetoacetate and indole derivative is 1:1:1-1:2:

2.

8. The method of claim 4, wherein, In step (S2), the acidic catalyst is any one of p-toluenesulfonic acid, triflic acid, aluminum trifluoromethanesulfonate, aluminum trichloride, trifluoroacetic acid and acetic acid.

9. The method of claim 4, wherein, In steps (S1) and (S2), the solvent is independently any one of dichloromethane, dichloroethane, toluene, methanol, ethanol, acetonitrile, tetrahydrofuran and 1,4-dioxane; In addition, in steps (S1) and (S2), the solvent is recovered by distillation after the reaction is completed.

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