Large-steric-hindrance nitrile compound as well as preparation method and application thereof

Abstract

The invention discloses a large-steric-hindrance nitrile compound and a preparation method and application thereof.The preparation method comprises the steps that indole carbonate and benzyl isocyanide serve as reaction raw materials, and the nitrile compound with a large-steric-hindrance quaternary carbon center is prepared through a one-pot method in the presence of a metal salt catalyst and a solvent; the invention provides a large-steric-hindrance nitrile compound which has the advantages of higher step economy, atom economy, convenience in post-treatment, rapidness and high efficiency. The high-steric-hindrance nitrile compound is constructed in one step by using simple raw materials, has the advantages of cheap and easily available raw materials, simple and mild conditions, high atom economy, excellent yield and wide substrate range, provides a green synthesis method for efficient construction of a high-steric-hindrance nitrile compound skeleton, and is convenient for preparation of the high-steric-hindrance nitrile compound and application of the high-steric-hindrance nitrile compound in the field of drug preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a bulky nitrile compound, a preparation method thereof and an application thereof. Background Art

[0002] Cyano groups are widely present in various natural products, bioactive molecules and drug molecules. Complex cyano-containing molecules have received extensive attention due to their use as synthetic intermediates for the formation of amines, ketones, carboxylic acids, aldehydes, etc. Among them, molecules containing quaternary carbon centers are more important because quaternary carbon centers have special properties that can prevent oxidation at the α-position, thereby avoiding the release of biologically toxic cyanides. The synthesis of bulky nitrile compounds with such properties has high value. For example, anastrozole is an aromatase inhibitor used to treat breast cancer; piritramide is a synthetic opioid used to treat postoperative pain; verapamil is a calcium channel antagonist used in the treatment of angina pectoris with anti-arrhythmic drugs, and the effect of its methoxy derivative gallopamil is ten times stronger. The structural formulas of the above bulky nitrile compounds are as follows:

[0003]

[0004] For traditional methods for synthesizing bulky nitrile compounds, one is the nucleophilic substitution of secondary nitriles or the difunctionalization of primary nitriles, but controlling the position of substituents remains a challenge; the other is the cyanation reaction of tertiary alcohols or halides, and transition metal-catalyzed cyanation reactions are also an option. However, these methods usually require the use of cyanide salts and cyanation reagents such as acetonitrile, trimethylsilyl cyanide, acetone cyanohydrin and 4-cyanopyridine, and their use under stoichiometric conditions poses potential risks. Therefore, it is of great significance to research and develop a method for synthesizing bulky nitrile compounds with a simple preparation method, mild reaction conditions and safety. Summary of the Invention

[0005] In view of the deficiencies in the prior art, the present invention provides a bulky nitrile compound, a preparation method thereof and an application thereof. A novel bulky nitrile compound is prepared by a multi-component one-pot method. The preparation method is simple, the reactants are safe and stable, the reaction conditions are mild, which is conducive to the production and application of bulky nitrile compounds.

[0006] To solve the above technical problems, on the one hand, the present invention provides a bulky nitrile compound, and the general structural formula of the bulky nitrile compound is shown in Formula III:

[0007]

[0008] Wherein, R 1 and R 2Independently selected from one of H, halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0009] Furthermore, the structural formula of the bulky nitrile compound is selected from one of Formula III-1 to III-16:

[0010]

[0011] In the second aspect of the present invention, there is provided a method for preparing the bulky nitrile compound described in the first aspect. The compound shown in Formula I and the compound shown in Formula II are reacted in the presence of a metal salt catalyst, a phenylphosphine ligand, and a solvent to obtain the bulky nitrile compound;

[0012] The general structural formulas of the compound shown in Formula I and the compound shown in Formula II are as follows:

[0013]

[0014] Wherein, R 1 and R 2 Independently selected from one of H, halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0015] The present invention uses the indole carbonate shown in Formula I and the benzyl isocyanide shown in Formula II as reactants, and a novel nitrile compound with a bulky quaternary carbon center of Formula III is prepared by a one-pot method, providing a more step-economic, atom-economical, easy-to-post-treat, fast and efficient nitrile compound with a bulky quaternary carbon center; it is constructed in one step using simple raw materials, the raw materials are cheap and easily available, the conditions are simple and mild, the atom economy is high, the yield is excellent, and at the same time it also has the advantage of a wide substrate range, providing a green synthesis method for the efficient construction of the nitrile compound skeleton with a bulky quaternary carbon center.

[0016] Furthermore, the molar ratio of the compound shown in Formula I to the compound shown in Formula II is (0.1-20):10, preferably (1-5):5.

[0017] Furthermore, the molar ratio of the metal salt catalyst to the compound shown in Formula II is (0.1-200):100, preferably (1-40):100.

[0018] Furthermore, the temperature of the reaction is 60-120 °C, and the time is 1-12 h.

[0019] Furthermore, the metal salt catalyst is selected from one or more of palladium acetate (Pd(OAc)2), palladium chloride, dichlorobis(acetonitrile)palladium, and tetrakis(triphenylphosphine)palladium.

[0020] Further, the phenylphosphine ligand is one or more of triphenylphosphine (PPh3), bis(diphenylphosphino)methane, and 1,3-bis(diphenylphosphino)propane.

[0021] Further, the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, 1,2-dichloroethane, and toluene.

[0022] Further, the structural formula of the compound shown in Formula I is selected from one of Formulas I-1 to I-8:

[0023]

[0024] Further, the compound shown in Formula II is selected from one of Formulas II-1 to II-9:

[0025]

[0026] Further, the reaction principle for preparing the compound of Formula III-1 using the compound of Formula I-1 and the compound of Formula II-1 as reactants is as follows:

[0027]

[0028] In the third aspect of the present invention, there is provided the use of the bulky nitrile compound described in the first aspect in the preparation of a drug, wherein the drug is an anti-tumor active drug, and the tumors are melanoma and breast cancer.

[0029] Advantages of the present invention:

[0030] The present invention uses indole carbonate and benzyl isocyanide as reaction raw materials, and prepares a nitrile compound with a bulky quaternary carbon center by a one-pot method, providing a more step-economic, atom-economic, easy-to-post-process, fast and efficient bulky nitrile compound; it is constructed in one step using simple raw materials, and has the advantages of cheap and easily available raw materials, simple and mild conditions, high atom economy, excellent yield, and wide substrate range, providing a green synthesis method for the efficient construction of the bulky nitrile compound skeleton, facilitating the preparation of the bulky nitrile compound and its application in the field of drug preparation. Description of the Drawings

[0031] In order to more clearly illustrate the technical solutions of the present invention, the drawings required for use in the examples will be briefly introduced below. Obviously, the drawings described below are only the embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0032] Figure 11H NMR spectrum of Compound III-1 prepared in Example 1 of the present invention;

[0033] Figure 2 13C NMR spectrum of Compound III-1 prepared in Example 1 of the present invention. Detailed implementation manners

[0034] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts belong to the scope of protection of the present invention.

[0035] Example 1: Synthesis of the compound shown in (III-1)

[0036] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 22 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add the solvent 1,4-dioxane (2 mL). Stir and react at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is evaporated under vacuum and separated by column chromatography (column chromatography separation conditions: the stationary phase is silica gel powder of 200-300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.0428 g of the reaction product is obtained.

[0037] Characterize the above reaction product, and its 1H NMR and 13C NMR spectra are respectively as Figure 1 and Figure 2 shown.

[0038] According to the characterization data, the obtained reaction product is a pure product (purity > 95%), and the product yield is calculated, and the result is 85%.

[0039] Example 2: Synthesis of the compound shown in (III-2)

[0040] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-2, 22 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, then add the solvent 1,4-dioxane (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), obtaining 0.037 g of the reaction product.

[0041] The above reaction product was characterized, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.43 - 7.38 (m, 4H), 7.31 - 7.26 (m, 1H), 7.21 - 7.17 (m, 4H), 7.16 - 7.11 (m, 5H), 7.00 - 6.93 (m, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 1.76 (s, 3H), 1.63 (s, 3H).

[0042] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield was calculated, and the result was 71%.

[0043] Example 3: Synthesis of the compound shown in (III-3)

[0044] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of the compound corresponding to II-3 (22 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), obtaining 0.042 g of the reaction product.

[0045] The above reaction product was characterized, and the results were as follows: 11H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.43 (m, 3H), 7.33 - 7.28 (m, 3H), 7.24 - 7.19 (m, 4H), 7.19 - 7.11 (m, 4H), 7.05 - 6.96 (m, 2H), 2.38 (s, 6H), 1.83 (s, 3H), 1.67 (s, 3H).

[0046] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 82%.

[0047] Example 4: Synthesis of the compound shown in (III-4)

[0048] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of the compound corresponding to II-4 (22 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Purge with nitrogen three times and add 1,4-dioxane as the solvent (2 mL). Stir and react at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.044 g of the reaction product is obtained.

[0049] Characterize the above reaction product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.50 - 7.46 (m, 4H), 7.29 - 7.24 (m, 1H), 7.21 - 7.16 (m, 5H), 7.11 (d, J = 7.8 Hz, 2H), 7.02 - 6.95 (m, 4H), 2.35 (s, 3H), 1.74 (s, 3H), 1.66 (s, 3H).

[0050] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 83%.

[0051] Example 5: Synthesis of the compound shown in (III-5)

[0052] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-5, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with a mesh size of 200 - 300, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), to obtain 0.046 g of the reaction product.

[0053] Characterize the above reaction product, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 9.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.58 - 7.51 (m, 3H), 7.32 (d, J = 8.3 Hz, 1H), 7.29 (s, 2H), 7.21 - 7.09 (m, 5H), 6.95 - 6.91 (m, 1H), 6.77 (s, 1H), 6.53 (s, 2H), 6.29 (s, 1H), 2.38 (s, 3H), 1.57 (s, 3H), 0.96 (s, 3H).

[0054] According to the characterization data, it can be known that the prepared reaction product is a pure product (purity > 95%); calculate the product yield, and the result is 85%.

[0055] Example 6: Synthesis of the compound shown in (III-6)

[0056] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-6, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with a mesh size of 200 - 300, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), to obtain 0.042 g of the reaction product.

[0057] The above reaction product was characterized, and the results were as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.49 (m, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 - 7.27 (m, 4H), 7.24 - 7.18 (m, 4H), 7.16 (s, 1H), 7.09 (d, J = 7.8 Hz, 2H), 7.02 - 6.96 (m, 2H), 2.37 (s, 3H), 1.78 (s, 3H), 1.67 (s, 3H).

[0058] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the result was 78%.

[0059] Example 7: Synthesis of the compound shown in (III-7)

[0060] 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-7, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) were weighed into a 20 mL reaction tube. Nitrogen was evacuated and replaced three times, and 1,4-dioxane was added as the solvent (2 mL). The reaction was stirred at 100 °C in an oil bath for 12 hours. After the reaction was completed, the reaction solution was subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase was silica gel powder with 200 - 300 mesh, the mobile phase was petroleum ether (A) and ethyl acetate (B), and the mobile phase change program was A:B = 20:1), and 0.046 g of the reaction product was obtained.

[0061] The above reaction product was characterized, and the results were as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.69 - 7.43 (m, 5H), 7.41 - 7.11 (m, 10H), 7.03 (s, 2H), 2.39 (s, 3H), 1.77 (s, 3H), 1.67 (s, 3H).

[0062] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the result was 85%.

[0063] Example 8: Synthesis of the compound shown in (III-8)

[0064] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-8, 22 μL, 150 mol%), 0.010 mmol of Pd(OAc)₂ (0.0018 g, 10 mol%), and 0.020 mmol of PPh₃ (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.042 g of the reaction product is obtained.

[0065] The above reaction product was characterized, and the results were as follows: 1 H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.49 - 7.40 (m, 5H), 7.30 (t, J = 7.3 Hz, 1H), 7.24 - 7.20 (m 5H), 7.09 (d, J = 7.7 Hz, 2H), 6.99 (d, J = 4.2 Hz, 2H), 2.37 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0066] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield was calculated, and the result was 74%.

[0067] Example 9: Synthesis of the compound shown in (III-9)

[0068] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-1, 0.0464 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-9, 22 μL, 150 mol%), 0.010 mmol of Pd(OAc)₂ (0.0018 g, 10 mol%), and 0.020 mmol of PPh₃ (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.043 g of the reaction product is obtained.

[0069] The above reaction product was characterized, and the results were as follows: 11H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.93 - 7.70 (m, 6H), 7.56 (q, J = 6.2 Hz, 2H), 7.44 - 7.08 (m, 7H), 7.00 (q, J = 7.7 Hz, 4H), 6.64 (d, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.90 (s, 3H), 1.73 (s, 3H).

[0070] According to the characterization data, the obtained reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 78%.

[0071] Example 10: Synthesis of the compound shown in (III-10)

[0072] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-2, 0.0497 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and add 1,4-dioxane as the solvent (2 mL). Stir and react at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.042 g of the reaction product is obtained.

[0073] Characterize the above reaction product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 1H), 7.62 (s, 2H), 7.44 (d, J = 6.5 Hz, 2H), 7.32 (d, J = 8.0 Hz, 3H), 7.17 - 7.08 (m, 2H), 7.07 - 6.96 (m, 4H), 6.93 - 6.86 (m, 2H), 6.79 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H).

[0074] According to the characterization data, the obtained reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 78%.

[0075] Example 11: Synthesis of the compound shown in (III-11)

[0076] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-3, 0.0541 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with a mesh size of 200 - 300, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.044 g of the reaction product is obtained.

[0077] The above reaction product was characterized, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.64 - 7.53 (m, 2H), 7.42 - 7.35 (m, 5H), 7.35 - 7.29 (m, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.18 - 7.14 (m, 4H), 7.12 (d, J = 1.9 Hz, 1H), 2.39 (s, 3H), 1.79 (s, 3H), 1.65 (s, 3H).

[0078] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield was calculated, and the result was 76%.

[0079] Example 12: Synthesis of the compound shown in (III-12)

[0080] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-4, 0.0481 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with a mesh size of 200 - 300, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), and 0.043 g of the reaction product is obtained.

[0081] The above reaction product was characterized, and the results were as follows:1 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 9.1, 4.5 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.47 (d, J = 6.7 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.27 - 7.23 (m, 4H), 7.21 - 7.09 (m, 3H), 7.04 - 7.01 (m, 3H), 6.81 (td, J = 8.9, 2.6 Hz, 1H), 6.53 (dd, J = 9.4, 2.6 Hz, 1H), 2.26 (s, 3H), 1.67 (s, 3H), 1.54 (s, 3H).

[0082] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 82%.

[0083] Example 13: Synthesis of the compound shown in (III-13)

[0084] Weigh 0.1 mmol of indole carbonate 5 (the compound corresponding to the number (I-5), 0.0497 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to the number (II-1), 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and add 1,4-dioxane as the solvent (2 mL). Stir and react at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: the stationary phase is silica gel powder of 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program (A:B) is 20:1), and 0.039 g of the reaction product is obtained.

[0085] Characterize the above reaction product, and the results are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.71 (s, 1H), 7.58 (s, 2H), 7.43 - 7.38 (m, 5H), 7.34 - 7.31 (m, 1H), 7.24 - 7.14 (m, 6H), 7.00 - 6.88 (m, 2H), 2.40 (s, 3H), 1.80 (s, 3H), 1.67 (s, 3H).

[0086] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield is calculated, and the result is 73%.

[0087] Example 14: Synthesis of the compound shown in (III-14)

[0088] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-6, 0.0493 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1) to obtain 0.032 g of the reaction product.

[0089] The above reaction product was characterized, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.1 Hz, 1H), 7.65 (s, 1H), 7.57 - 7.51 (m, 2H), 7.37 - 7.32 (m, 5H), 7.26 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 8.6 Hz, 4H), 6.78 (dd, J = 9.0, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 3.46 (s, 3H), 2.34 (s, 3H), 1.77 (s, 3H), 1.66 (s, 3H).

[0090] According to the characterization data, the prepared reaction product is a pure product (purity > 95%); the product yield was calculated, and the result was 60%.

[0091] Example 15: Synthesis of the compound shown in (III-15)

[0092] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-7, 0.0477 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), obtaining 0.040 g of the reaction product.

[0093] Characterize the above reaction product, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.62 (s, 1H), 7.55 (d, J = 6.5 Hz, 2H), 7.42 - 7.31 (m, 5H), 7.27 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.6 Hz, 2H), 7.16 - 7.10 (m, 4H), 6.86 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 8.3, 1.5 Hz, 1H), 2.36 (d, J = 2.5 Hz, 6H), 1.78 (s, 3H), 1.65 (s, 3H).

[0094] According to the characterization data, the obtained reaction product is a pure product (purity > 95%); calculate the product yield, and the result is 78%.

[0095] Example 16: Synthesis of the compound shown in (III-16)

[0096] Weigh 0.1 mmol of indole carbonate (the compound corresponding to I-8, 0.0493 g), 0.15 mmol of benzyl isocyanide (the compound corresponding to II-1, 23 μL, 150 mol%), 0.010 mmol of Pd(OAc)2 (0.0018 g, 10 mol%), and 0.020 mmol of PPh3 (0.0056 g, 20 mol%) into a 20 mL reaction tube. Evacuate and refill with nitrogen three times, and then add 1,4-dioxane as the solvent (2 mL). Stir the reaction mixture at 100 °C in an oil bath for 12 hours. After the reaction is completed, the reaction solution is subjected to vacuum evaporation and column chromatography separation (column chromatography separation conditions: the stationary phase is silica gel powder with 200 - 300 mesh, the mobile phase is petroleum ether (A) and ethyl acetate (B), and the mobile phase change program is A:B = 20:1), obtaining 0.023 g of the reaction product.

[0097] The above reaction product was characterized, and the results were as follows: 1 H NMR(400MHz,CDCl3)δ7.62 - 7.48(m,3H),7.43 - 7.31(m,6H),7.29(d,J=7.2Hz,1H),7.19(t,J=7.6Hz,2H),7.14(d,J=7.6Hz,4H),6.85(d,J=8.9Hz,1H),6.60(dd,J=8.9,2.4Hz,1H),3.77(s,3H),2.36(s,3H),1.77(s,3H),1.65(s,3H).

[0098] According to the characterization data, the prepared reaction product was a pure product (purity > 95%); the product yield was calculated, and the result was 44%.

[0099] Test example: Biological activity test

[0100] According to the relevant reference (Chemico - Biological Interactions 2018, 284, 12–23.), in this test example, the compound prepared in the above - mentioned example was selected to compare the biological activity with betulinic acid BA. Taking the betulinic acid inhibitor as the reference standard, the carbonic anhydrase inhibitory activity of this compound was measured. The results are shown in the table, where the values represent the mean ± standard error of three independent detections.

[0101] Table 1

[0102]

[0103]

[0104] As shown in Table 1, the results after 96 hours of exposure of each compound to 518A2 (melanoma cancer) cells and MCF7 (breast cancer) cells are shown. It can be seen that betulinic acid BA has an inhibitory effect on various malignant tumor cells such as melanoma and breast cancer, and can block the tumor cell cycle; at the same time, the compounds prepared in the examples such as III - 5, III - 6, III - 7, III - 9, III - 10, III - 12, etc. have excellent inhibitory activity and can be prepared into drugs for the treatment of related tumors in the future.

[0105] The present invention has been described in detail above in combination with specific embodiments and exemplary examples, but these descriptions should not be construed as limiting the present invention. Those skilled in the art understand that without departing from the spirit and scope of the present invention, various equivalent substitutions, modifications or improvements can be made to the technical solutions of the present invention and their implementation manners, and these all fall within the scope of the present invention. The protection scope of the present invention is subject to the appended claims.

Claims

1. A bulky hindered nitrile compound, characterized in that: The general structural formula of the bulky hindered nitrile compound is shown in Formula III: Among them, R 1 and R 2 Independently selected from one of H, halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

2. The bulky hindered nitrile compound according to claim 1, characterized in that: The structural formula of the bulky hindered nitrile compound is selected from one of Formulas III-1 to III-16:

3. A method for preparing a bulky hindered nitrile compound according to any one of claims 1 to 2, characterized in that: The compound represented by formula I and the compound represented by formula II are reacted in the presence of a metal salt catalyst, a phenylphosphine ligand and a solvent to obtain the large sterically hindered nitrile compound; The general structural formula of the compound represented by Formula I and the compound represented by Formula II is as follows: Among them, R 1 and R 2 Independently selected from one of H, halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

4. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The molar ratio of the compound represented by formula I to the compound represented by formula II is (0.1-20):

10.

5. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The reaction temperature is 60-120° C. and the reaction time is 1-12 hours.

6. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The metal salt catalyst is selected from one or more of palladium acetate, palladium chloride, acetonitrile palladium dichloride, and tetrakistriphenylphosphine palladium.

7. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The phenylphosphine ligand is one or more of triphenylphosphine, bis(diphenylphosphino)methane and 1,3-bis(diphenylphosphino)propane.

8. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The structural formula of the compound represented by Formula I is selected from one of Formulas I-1 to I-8:

9. The method for preparing a large hindered nitrile compound according to claim 3, characterized in that: The compound represented by formula II is selected from one of formulas II-1 to II-9:

10. Use of the bulky hindered nitrile compound according to any one of claims 1 to 2 in the preparation of medicines.

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