Chiral 7-azaindoline amide compounds, methods of synthesis thereof, and uses thereof

Abstract

The application discloses a kind of chiral 7-azaindoline amide compounds, its synthesis method and application, belong to organic chemistry synthesis and medical technology field, the compound has with N-[3-phenyl-3-(diphenyl phosphoryl) propionyl] Substituted 7-azaindoline as basic skeleton Structural characteristics;Its synthesis method is: under room temperature condition, copper salt is dissolved in organic solvent with chiral ligand (L) Stirring mixing, then sequentially adding α, β-unsaturated 7-azaindoline amide (I), diphenyl phosphine (II) And base, after stirring reaction, the target product is obtained by separation and purification;The compound provided by the application can be efficiently converted into other novel 7-azaindoline derivatives by simple reaction, and has potential application value in the field of medicinal chemistry and asymmetric catalysis;The synthesis method provided by the application has the advantages of simple operation, mild reaction condition, wide substrate applicability, high yield and high enantioselectivity.

Description

Technical Field

[0001] This invention relates to the fields of organic chemical synthesis and pharmaceutical technology, and particularly to chiral 7-azaindolineamide compounds, their synthesis methods, and their applications. Background Technology

[0002] 7-azaindoline is an important class of nitrogen-containing heterocyclic skeletons, and its derivatives are widely found in a variety of biologically active molecules, showing particular value in the development of kinase inhibitor antitumor drugs (RSC Med. Chem., 2024, 15, 3180; Future Medicinal Chemistry, 2023, 15, 2309). However, the structural modifications of 7-azaindoline derivatives disclosed in the prior art are mostly concentrated on aromatic ring or alkyl substitution, resulting in relatively conservative structures. There is still room for optimization in terms of biological activity, kinase selectivity, or drug-likeness.

[0003] Therefore, developing a class of novel, easily synthesized, and potentially bioactive chiral 7-azaindoline derivatives is of great significance for expanding the structural diversity of this type of lead compound and exploring its applications in medicine and other fields. Summary of the Invention

[0004] One of the objectives of this invention is to provide a class of chiral 7-azaindolineamide compounds to solve the above-mentioned problems.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a chiral 7-azaindolineamide compound, wherein the compound has the structure shown in the following structural formula (Ⅲ):

[0006] ,

[0007] In the above structural formula, R 1 The substituent is selected from one of aryl, alkyl, alkoxy, alkylthio, halogen, ester, amino, cyano, nitro, sulfonyl, phosphono, and hydrogen; R 2 The substituent is selected from one of alkyl, alkoxy, aryl, ester, and hydrogen; R 3 The substituent is selected from alkyl, alkoxy, ester, aryl, and hydrogen.

[0008] This invention provides a class of high optical purity chiral 7-azaindolineamide compounds, which have a 7-azaindoline core structural unit with a 3-phenyl-3-(diphenylphosphoyl)propionyl side chain containing a tertiary carbon chiral center on the nitrogen atom.

[0009] This invention not only synthesizes chiral 7-azaindoline derivatives with a single configuration through asymmetric catalysis, but also starts from the source by structurally modifying chiral N-[3-phenyl-3-(diphenylphospho)propionyl]7-azaindoline to improve the pharmacological properties of this type of compound, thereby facilitating the discovery of new drugs.

[0010] The application value of the compounds of this invention lies in two aspects: First, this molecule innovatively combines the advantageous drug skeleton of 7-azaindoline with a diphenylphosphinoyl functional group through a propionyl chain, creating a completely new chemical skeleton. Its unique "7-azaindoline-phosphoryl" structure is expected to bring high activity and good drug-like properties, providing a sufficient source of compounds for the development of novel kinase inhibitors and other anti-tumor drugs. Second, the phosphorus atom and chiral center in the molecule make it potential for further modification, developing into novel chiral ligands or organic catalysts for asymmetric catalytic reactions, thus promoting the development of synthetic chemistry.

[0011] A second objective of this invention is to improve a method for synthesizing the above-mentioned chiral 7-azaindolineamide compounds, comprising the following steps:

[0012] At room temperature, copper salt and chiral ligand (L) are stirred in an organic solvent for 0.5–2.0 h, then α,β-unsaturated 7-azaindolineamide (I), diphenylphosphine (II) and base are added sequentially, and the reaction is stirred at -20–70 °C for 12–72 h. After the reaction is complete, the mixture is directly separated and purified to obtain the final product.

[0013] The α,β-unsaturated 7-azaindolineamide (Ⅰ) has the following structure:

[0014] ;

[0015] The diphenylphosphine(II) has the following structure:

[0016] .

[0017] As a preferred technical solution, the organic solvent is selected from one or more of the following: toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, dichlorobenzene, hexafluorobenzene, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, N,N-dimethylformamide, and dimethyl sulfoxide.

[0018] As a preferred technical solution: the copper salt is selected from at least one of cuprous chloride, cuprous bromide, cuprous iodide, copper tetraacetonitrile hexafluorophosphate, cuprous trifluoromethanesulfonate, cuprous acetate, cuprous oxide, cuprous thiophene-2-carboxylate, copper tetraacetonitrile tetrafluoroborate, copper bromide, copper acetate, copper sulfate, copper trifluoromethanesulfonate, and copper acetylacetonate; the minimum amount of the copper salt is 10 mol of α,β-unsaturated 7-azaindolineamide (I).

[0019] Cuprous acetate was further preferred as a copper salt catalyst because it yielded the highest reaction rate and exhibited the best stereoselectivity.

[0020] As a preferred technical solution: the chiral ligand is a chiral ferrocene bisphosphine ligand, and the minimum amount of the chiral ligand is 12 mol of α,β-unsaturated 7-azaindolineamide (I).

[0021] The chiral ligand of the catalyst in the above synthetic route is preferably one of the chiral ligands shown in the box below.

[0022]

[0023] It should be noted that the “chiral ligand 1”, “chiral ligand 2”, “chiral ligand 3”, “chiral ligand 4”, “chiral ligand 5”, “chiral ligand 6”, “chiral ligand 7” and “chiral ligand 8” mentioned in the following embodiments correspond to the compounds L1, L2, L3, L4, L5, L6, L7 and L8 in the above boxes, respectively.

[0024] As a preferred technical solution, the minimum amount of diphenylphosphine (II) is 100 mol of α,β-unsaturated 7-azaindolineamide (I).

[0025] A further preferred amount is 1.5 equivalents because it results in a higher reaction yield and better stereoselectivity.

[0026] As a preferred technical solution: the separation and purification method is one or more of recrystallization, column chromatography and plate chromatography; the solvent for separation and purification is selected from toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, dichlorobenzene, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, n-butyl ether, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, petroleum ether, n-hexane, methanol, ethanol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, or a mixture of one or more of these.

[0027] Further preferred materials include n-hexane, petroleum ether, tert-butyl methyl ether, dichloromethane, and ethyl acetate, because these produce products with higher purity.

[0028] As a preferred technical solution: the alkali is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine, N,N-diisopropylethylamine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, tetramethylguanidine, and triethylamine.

[0029] 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was further preferred as the base for the reaction because it resulted in higher yields and better stereoselectivity.

[0030] A third objective of this invention is to provide an application of the above-mentioned compound in the synthesis of organic compounds. Specifically, a 3-(diphenylphosphoyl)propionic acid derivative (Ⅳ) obtained by further derivatization of the above-mentioned compound has the following structure:

[0031] .

[0032] The fourth objective of this invention is to provide a method for synthesizing the above-mentioned 3-(diphenylphospho)propionic acid derivative (Ⅳ), specifically: dissolving compound (Ⅲ) in an organic solvent, then adding a catalyst, stirring the reaction at reflux temperature for 1 to 8 h, and after the reaction is complete, directly separating and purifying to obtain compound (Ⅳ) with a 3-(diphenylphospho)propionic acid skeleton.

[0033] .

[0034] As a preferred technical solution, the catalyst is selected from at least one or a mixture of multiple of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and boron trifluoride ether.

[0035] Trifluoroacetic acid was further preferred because it yielded the highest reaction rate.

[0036] As a preferred technical solution, the minimum amount of catalyst used is 20 mol%.

[0037] As a preferred technical solution, the separation and purification method is one or more of pulping, recrystallization, and column chromatography separation.

[0038] Column chromatography separation is further preferred because it yields higher product purity.

[0039] The fifth objective of this invention is to provide an application of the above-mentioned compound in the preparation of kinase inhibitor antitumor drugs.

[0040] Specifically, the application value of the above-mentioned compound (III) disclosed in this invention lies in the fact that this type of compound has a novel structure and is expected to act as a selective inhibitor of various key kinases, thereby blocking the proliferation signals of tumor cells. Preliminary cell activity experiments show that this type of compound exhibits good killing effect on human leukemia cells K562, and its activity is comparable to that of the positive control drug cisplatin, suggesting that it may exert its effect by inhibiting related kinases (such as CDK8), and has the potential to be developed into an anti-leukemia drug. Specific activity data are shown in Table 1.

[0041] The specific experimental procedure is as follows: K562 human leukemia cells in the logarithmic growth phase were seeded at a density of 5000 cells per well in a 96-well plate and cultured for 24 hours; then, different concentrations of compounds III-a, III-b, III-c, III-d, III-e, III-f, and III-g prepared in Examples 1 to 7 (described later) were added, with the antitumor drug cisplatin used as a positive control, and the cells were cultured for another 48 hours; subsequently, the half-maximal inhibitory concentration (IC50) of each compound was measured. 50 Each concentration was set up with 3 replicates, and the experiment was repeated 3 times. The average results are shown in Table 1.

[0042] As shown in Table 1, the inhibitory activity of the compounds of this invention against human leukemia cells K562 is comparable to that of cisplatin. This indicates that these compounds hold promise as lead compounds for the treatment of leukemia.

[0043] Table 1: Results of activity tests of different compounds on K562 cells

[0044]

[0045] a IC 50 The value is the average of three independent experiments.

[0046] Compared with existing technologies, the advantages of this invention are as follows: This invention utilizes a copper salt-catalyzed hydrophosphineization reaction of α,β-unsaturated 7-azaindolineamides with diphenylphosphine to synthesize a series of N-[3-phenyl-3-(diphenylphosphoyl)propionyl]7-azaindoline compounds with high yield and high enantioselectivity. Furthermore, this invention also efficiently synthesizes 3-(diphenylphosphoyl)propionic acid compounds through a simple method. This invention enriches the variety of 7-azaindoline and 3-(diphenylphosphoyl)propionic acid compounds, providing ample candidate molecules for new drug development and offering novel chiral ligands or organic catalysts for asymmetric catalytic reactions. This method features mild reaction conditions, commercially available catalysts, simple operation, a wide range of substrate applications and good versatility, high yield (up to 99%), and good enantioselectivity (up to 96% ee). Attached Figure Description

[0047] Figure 1 The 1H NMR spectrum of Ⅲ-a obtained in Example 1;

[0048] Figure 2 The carbon NMR spectrum of Ⅲ-a obtained in Example 1;

[0049] Figure 3 The high performance liquid chromatogram (racemic) of Ⅲ-a obtained in Example 1 is shown.

[0050] Figure 4 The image shows the high-performance liquid chromatogram (chiral) of Ⅲ-a obtained in Example 1. Detailed Implementation

[0051] To explain the technical content, objectives, and effects of the present invention in detail, the following specific embodiments are provided to further illustrate the content of the present invention. However, the content of the present invention is far more than the following examples.

[0052] Example 1

[0053] Synthetic compound (Ⅲ-a)

[0054]

[0055] Synthesis of compound III-a:

[0056] ;

[0057] In a dry reaction tube, a copper source and chiral ligands 1-8 were dissolved in 2 mL of solvent and stirred for 0.5 hours at room temperature under an argon atmosphere. Then, α,β-unsaturated 7-azaindolineamide I-a (0.10 mmol), diphenylphosphine II-a (0.20 mmol), and base (0.5 equiv) were added sequentially. The reaction was then stirred at a certain temperature. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1, v / v) to obtain compound III-a.

[0058] The process and conditions shown in the above reaction equations are illustrated in Table 2, with some different reaction conditions listed below:

[0059] Table 2: Yields and stereoselectivity under different reaction conditions

[0060]

[0061] As can be seen from Table 2, chiral ligands have a significant impact on the stereoselectivity of the reaction, with chiral ligand L8 showing the best effect. In addition, temperature, solvent, and catalyst dosage also have a significant impact on the reaction.

[0062] The results showed that using cuprous acetate as the copper source, chiral ligand L8 as the ligand, 10 mol% catalyst, tert-butyl methyl ether as the solvent, and a reaction temperature of 25℃ was a more preferred scheme.

[0063] Under the above optimal scheme, the obtained Ⅲ-a was a white solid with a yield of 96%; the enantiomeric excess percentage was 93% (ee); [α] D 20 = +94.97 (c = 1.0 g / 100 mL, CH2Cl2);

[0064] The ee value was determined by HPLC: Chiralpak IB column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 13.2 min, t minor = 11.5min.

[0065] Structural assessment: 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 5.1 Hz, 1H), 8.03 –7.96 (m, 2H), 7.52 – 7.44 (m, 5H), 7.36 – 7.29 (m, 4H), 7.26 – 7.20 (m, 2H),7.14 – 7.04 (m, 3H), 6.84 – 6.79 (m, 1H), 4.57 – 4.39 (m, 2H), 3.90 – 3.81(m, 2H), 3.50 – 3.38 (m, 1H), 2.94 – 2.81 (m, 2H); e.g. Figure 1 As shown;

[0066] 13C NMR (101 MHz, CDCl3) δ 170.00 (d, J = 16.0 Hz), 155.70, 146.36,136.14 (d, J = 5.8 Hz), 133.33, 132.52 (d, J = 52.6 Hz), 131.79 (d, J = 2.6Hz), 131.69 (d, J = 8.6 Hz), 131.31 (d, J = 2.6 Hz), 131.16 (d, J = 8.7 Hz), 130.26 (d, J = 5.7 Hz), 128.73 (d, J = 11.0 Hz), 128.13, 128.06 (d, J = 8.5Hz), 126.89 (d, J = 2.6 Hz), 125.74, 118.12, 45.69, 42.34 (d, J = 69.1 Hz), 36.80, 24.14; For example Figure 2 As shown.

[0067] 31 P NMR (162 MHz, CDCl3) δ 33.71;

[0068] HRMS (ESI) m / z: [M + H] + calcd. for C 28 H 25 N2O2P 453.1726, found453.1718.

[0069] The high-performance liquid chromatograms of racemic III-a and chiral III-a obtained in Example 1 are as follows: Figure 3 and Figure 4 As shown.

[0070] The 1H NMR spectrum, 1C NMR spectrum, and HPLC spectrum of Ⅲ-a are shown below. Figure 1-4 As shown.

[0071] Example 2

[0072] Synthetic compound (Ⅲ-b)

[0073]

[0074] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide Ib (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and base (0.5 equiv) were added sequentially. The reaction was then stirred at 25 °C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-b.

[0075] Compound III-b was a white solid in 96% yield; enantiomeric excess was 93% (ee); [α] D 20 = +122.00 (c = 1.0 g / 100 mL, CH2Cl2);

[0076] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 33.7 min, t minor = 23.5min.

[0077] Structural assessment: 1 H NMR (400 MHz, CDCl3) δ 8.15 – 8.08 (m, 1H), 8.03 – 7.93 (m, 2H), 7.55 – 7.45 (m, 5H), 7.38 – 7.31 (m, 2H), 7.30 – 7.27 (m, 1H), 7.25– 7.17 (m, 3H), 6.95 – 6.89 (m, 2H), 6.85 – 6.80 (m, 1H), 4.54 – 4.33 (m,2H), 3.95 – 3.80 (m, 2H), 3.50 – 3.38 (m, 1H), 2.94 – 2.84 (m, 2H), 2.20 (s, 3H);

[0078] 13C NMR (101 MHz, CDCl3) δ 170.10 (d, J = 16.2 Hz), 155.77, 146.40,136.45 (d, J = 2.8 Hz), 133.34, 132.94 (d, J = 5.8 Hz), 132.65 (d, J = 43.8Hz), 132.43, 131.77 - 131.68 (m), 131.69 (d, J = 38.3 Hz), 131.34 - 131.22(m), 130.09 (d, J = 5.7 Hz), 128.91 (d, J = 2.2 Hz), 128.82, 128.73 (d, J =11.4 Hz), 128.13 (d, J = 11.7 Hz), 125.79, 118.12, 45.73, 41.81 (d, J = 69.4Hz), 36.85, 24.19, 21.18;

[0079] 31 P NMR (162 MHz, CDCl3) δ 33.93;

[0080] HRMS (ESI) m / z: [M + H] + calcd. for C 29 H 27 N2O2P 467.1883, found467.1886.

[0081] Example 3

[0082] Synthetic compound (Ⅲ-c)

[0083]

[0084] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide Ic (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and base (0.5 equiv) were added sequentially. The reaction was then stirred at 25 °C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-c.

[0085] Compound III-c was a white solid in 86% yield; enantiomeric excess was 95% (ee); [α] D 20 = +133.57 (c = 1.0 g / 100 mL, CH2Cl2);

[0086] The ee value was determined by HPLC: Chiralpak IB column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 17.8 min, t minor = 14.0min.

[0087] Structural assessment: 1 H NMR (400 MHz, DMSO-d6) δ 8.10 – 8.05 (m, 1H), 8.04 – 7.96 (m, 2H), 7.76 – 7.68 (m, 2H), 7.58 – 7.51 (m, 3H), 7.51 – 7.46 (m, 1H), 7.39– 7.29 (m, 3H), 7.29 – 7.23 (m, 2H), 6.93 – 6.87 (m, 1H), 6.70 – 6.62 (m,2H), 4.66 – 4.56 (m, 1H), 4.26 – 4.12 (m, 1H), 3.76 – 3.66 (m, 2H), 3.57 (s, 3H), 3.19 – 3.07 (m, 1H), 2.89 – 2.73 (m, 2H);

[0088] 13C NMR (101 MHz, DMSO-d6) δ 168.59 (d, J = 16.3 Hz), 157.88 (d, J =1.8 Hz), 155.26, 145.62, 133.92, 133.18 (d, J = 29.0 Hz), 132.23 (d, J = 35.0Hz), 131.73 (d, J = 2.6 Hz), 131.29 (d, J = 2.8 Hz), 130.93 - 130.84 (m), 130.86 (d, J = 22.6 Hz), 128.80 (d, J = 10.9 Hz), 128.25 (d, J = 11.7 Hz),128.12, 126.41, 118.25, 113.23, 54.80, 45.61, 39.93 (d, J = 69.8 Hz), 36.42,23.47;

[0089] 31 P NMR (162 MHz, DMSO-d6) δ 34.00;

[0090] HRMS (ESI) m / z: [M + H] + calcd. for C 29 H 27 N2O3P 483.1832, found483.1834.

[0091] Example 4

[0092] Synthetic compound (Ⅲ-d)

[0093]

[0094] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide Id (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and a base (0.5 equiv) were added sequentially. Then, at 25 °C... o The reaction was stirred at C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-d.

[0095] Compound III-d was a white solid in 88% yield; enantiomeric excess was 96% (ee); [α] D 20 = +138.86 (c = 0.5 g / 100 mL, CH2Cl2);

[0096] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 23.7 min, t minor = 18.4min.

[0097] Structural assessment: 1 H NMR (400 MHz, DMSO-d6) δ 8.10 – 8.04 (m, 1H), 7.97 – 7.87(m, 2H), 7.61 – 7.51 (m, 4H), 7.51 – 7.42 (m, 3H), 7.38 – 7.32 (m, 1H), 7.31– 7.22 (m, 2H), 7.07 – 6.99 (m, 1H), 6.97 – 6.90 (m, 1H), 6.83 – 6.76 (m,1H), 6.67 – 6.60 (m, 1H), 5.17 – 5.07 (m, 1H), 4.09 – 3.94 (m, 1H), 3.75 –3.57 (m, 2H), 3.42 – 3.30 (m, 4H), 2.90 – 2.77 (m, 2H);

[0098] 13C NMR (101 MHz, DMSO-d6) δ 168.52 (d, J = 15.5 Hz), 156.50 (d, J =5.7 Hz), 155.24, 145.57, 133.86, 132.96 (d, J = 4.2 Hz), 132.02 (d, J = 2.2Hz), 131.78 - 131.76 (m), 131.17 - 131.16 (m), 130.99 (d, J = 8.6 Hz), 130.48(d, J = 8.8 Hz), 129.34 (d, J = 4.4 Hz), 128.77 (d, J = 10.9 Hz), 127.92 -127.90 (m), 127.71 (d, J = 11.5 Hz), 126.31, 124.23 (d, J = 5.7 Hz), 119.94-119.92 (m), 118.16, 110.34, 55.04, 45.58, 35.72, 32.35 (d, J = 68.6 Hz),23.47;

[0099] 31 P NMR (162 MHz, DMSO-d6) δ 32.52;

[0100] HRMS (ESI) m / z: [M + H] + calcd. for C 29 H 27 N2O3P 483.1832, found483.1835.

[0101] Example 5

[0102] Synthetic compound (Ⅲ-e)

[0103]

[0104] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide Ie (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and base (0.5 equiv) were added sequentially. The reaction was then stirred at 25 °C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-e.

[0105] Compound III-e was a white solid in 96% yield; the enantiomeric excess was 93% (ee); [α] D 20 = +187.87 (c = 1.0 g / 100mL, CH2Cl2);

[0106] The ee value was determined by HPLC: Chiralpak IB column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 13.1 min, t minor = 10.5min.

[0107] Structural assessment: 1 H NMR (400 MHz, CDCl3) δ 8.21 – 8.17 (m, 1H), 8.11 – 8.03(m, 2H), 7.64 – 7.56 (m, 5H), 7.49 – 7.42 (m, 2H), 7.39 – 7.34 (m, 4H), 7.20– 7.14 (m, 2H), 6.95 – 6.90 (m, 1H), 4.62 – 4.45 (m, 2H), 4.04 – 3.89 (m,2H), 3.55 – 3.42 (m, 1H), 3.06 – 2.93 (m, 2H);

[0108] 13C NMR (101 MHz, CDCl3) δ 169.80 (d, J = 15.8 Hz), 155.64, 146.38,134.81 (d, J = 5.8 Hz), 133.47, 132.83 (d, J = 3.2 Hz), 132.49, 131.97,131.94, 131.68, 131.59 - 131.52 (m), 131.11 (d, J = 8.8 Hz), 131.02, 128.84 (d, J = 11.2 Hz), 128.35 - 128.24 (m), 125.81, 118.28, 45.72, 41.86 (d, J =69.0 Hz), 36.75, 24.17;

[0109] 31 P NMR (162 MHz, CDCl3) δ 33.30;

[0110] HRMS (ESI) m / z: [M + H] + calcd. for C 28 H 24 ClN2O2P 487.1337, found487.1340.

[0111] Example 6

[0112] Synthetic compound (Ⅲ-f)

[0113]

[0114] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide If (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and base (0.5 equiv) were added sequentially, and the reaction was stirred at 25 °C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-f.

[0115] Compound III-f was a white solid in 85% yield; enantiomeric excess was 95% (ee); [α] D 20 = +182.00 (c = 1.0 g / 100 mL, CH2Cl2);

[0116] The ee value was determined by HPLC: Chiralpak IB column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 15.2 min, t minor = 12.9min.

[0117] Structural assessment: 1 H NMR (400 MHz, DMSO-d6) δ 8.14 – 8.04 (m, 3H), 7.89 (s,1H), 7.82 – 7.73 (m, 2H), 7.73 – 7.65 (m, 2H), 7.65 – 7.60 (m, 1H), 7.60 –7.51 (m, 4H), 7.48 – 7.42 (m, 1H), 7.39 – 7.31 (m, 2H), 7.31 – 7.22 (m, 3H), 6.94 – 6.86 (m, 1H), 4.91 – 4.81 (m, 1H), 4.44 – 4.30 (m, 1H), 3.71 – 3.57(m, 2H), 3.35 – 3.22 (m, 1H), 2.81 – 2.62 (m, 2H);

[0118] 13 C NMR (101 MHz, DMSO-d6) δ 168.50 (d, J = 16.3 Hz), 155.21, 145.61,134.35 (d, J = 5.8 Hz), 133.87, 133.17, 132.53 (d, J = 1.9 Hz), 132.24,131.83 - 131.77 (m), 131.34, 130.89 (dd, J = 20.1 Hz, 8.7 Hz), 128.85 (d, J =11.2 Hz), 128.47 - 128.34 (m), 128.21 (d, J = 11.4 Hz), 127.40 (d, J = 12.4Hz), 127.01, 126.36, 125.78 (d, J = 26.9 Hz), 118.25, 45.54, 41.14 (d, J =68.0 Hz), 36.36, 23.38;

[0119] 31P NMR (162 MHz, DMSO-d6) δ 31.92;

[0120] HRMS (ESI) m / z: [M + H] + calcd. for C 32 H 27 N2O2P 503.1883, found503.1884.

[0121] Example 7

[0122] Synthetic compound (Ⅲ-g)

[0123]

[0124] In a dry reaction tube, cuprous acetate (0.010 mmol) and chiral ligand 8 (0.012 mmol) were dissolved in 2 mL of solvent. After stirring for 0.5 hours at room temperature under an argon atmosphere, α,β-unsaturated 7-azaindolineamide Ig (0.10 mmol), diphenylphosphine II-a (0.15 mmol), and base (0.5 equiv) were added sequentially. The reaction was then stirred at 25 °C. After the reaction was complete, an oxidant was added to oxidize the product. After complete oxidation, the solvent was removed by vacuum distillation. The crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to give compound III-g.

[0125] Compound III-e is a white solid in 99% yield; enantiomeric excess is 90% (ee); [α] D 20 = +38.73 (c = 0.5 g / 100 mL, CH2Cl2);

[0126] The ee value was determined by HPLC: Chiralpak IB column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 25.0 min, t minor = 22.0min.

[0127] Structural assessment: 1H NMR (400 MHz, DMSO-d6) δ 8.09 – 8.05 (m, 1H), 8.04 – 7.96(m, 2H), 7.81 – 7.74 (m, 2H), 7.57 – 7.52 (m, 3H), 7.52 – 7.48 (m, 1H), 7.44– 7.33 (m, 3H), 7.21 – 7.17 (m, 1H), 6.95 – 6.88 (m, 2H), 6.79 – 6.74 (m,1H), 5.06 – 4.99 (m, 1H), 4.22 – 4.10 (m, 1H), 3.81 – 3.68 (m, 2H), 3.24 –3.13 (m, 1H), 2.89 – 2.80 (m, 2H);

[0128] 13 C NMR (101 MHz, DMSO-d6) δ 168.08 (d, J = 15.4 Hz), 155.19, 145.61,138.17 (d, J = 6.6 Hz), 133.93, 132.53 (d, J = 8.6 Hz), 131.90 (d, J = 2.8Hz), 131.64, 131.53, 131.50, 131.03 - 130.81 (m), 128.85 (d, J = 11.0 Hz), 128.28 (d, J = 11.7 Hz), 127.24 (d, J = 6.6 Hz), 126.42, 126.39, 125.22 (d, J= 2.7 Hz), 118.28, 45.62, 37.39, 36.69 (d, J = 70.4 Hz), 23.47;

[0129] 31 P NMR (162 MHz, DMSO-d6) δ 32.82;

[0130] HRMS (ESI) m / z: [M + H] + calcd. for C 26 H 23 N2O2PS 459.1291, found459.1294.

[0131] Example 8

[0132] Synthetic compound IV

[0133]

[0134] In a dry reaction tube, compound IV (0.1 mmol) was dissolved in 2 mL of tetrahydrofuran, and then trifluoroacetic acid was added. The mixture was refluxed at 90 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound IV.

[0135] Compound IV was a white solid in 98% yield; enantiomeric excess was 92% (ee); [α] D 20 = +70.78(c = 1.740 g / 100 mL, CH2Cl2);

[0136] The ee value was determined by HPLC: Chiralpak AD column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 26.8 min, t minor = 13.3min.

[0137] Structural assessment: 1 H NMR (400 MHz, CDCl3+CD3OD) δ 7.94 – 7.84 (m, 2H), 7.63 –7.50 (m, 3H), 7.42 – 7.30 (m, 3H), 7.28 – 7.21 (m, 2H), 7.21 – 7.15 (m, 2H),7.15 – 7.07 (m, 3H), 4.67 (s, 1H), 4.19 – 4.09 (m, 1H), 3.10 – 2.97 (m, 1H),2.88 – 2.76 (m, 1H);

[0138] 13C NMR (101 MHz, CD3OD+CDCl3) δ 173.55 (d, J = 17.9 Hz), 134.93 (d, J= 5.8 Hz), 132.99 (d, J = 2.8 Hz), 132.39 (d, J = 2.8 Hz), 131.65 (d, J = 9.2Hz), 131.37 (d, J = 9.2 Hz), 131.08, (d, J = 24.9 Hz), 130.19 - 130.00 (m), 129.59 (d, J = 11.6 Hz), 128.72 (d, J = 11.9 Hz), 128.70 (d, J = 2.2 Hz),127.86 (d, J = 2.7 Hz), 43.00 (d, J = 67.0 Hz), 34.78;

[0139] 31 P NMR (162 MHz, CD3OD+CDCl3) δ 36.26;

[0140] HRMS (ESI) m / z: [M + H] + calcd. for C 21 H 19 O3P 351.1145, found 351.1143.

[0141] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A chiral 7-azaindolineamide compound, characterized in that, The compound has the structure shown in the following structural formula (Ⅲ): ， In the above structural formula, R 1 The substituent is selected from one of aryl, alkyl, alkoxy, alkylthio, halogen, ester, amino, cyano, nitro, sulfonyl, phosphono, and hydrogen; R 2 The substituent is selected from one of alkyl, alkoxy, aryl, ester, and hydrogen; R 3 The substituent is selected from alkyl, alkoxy, ester, aryl, and hydrogen.

2. The method for synthesizing chiral 7-azaindolineamide compounds according to claim 1, characterized in that, Includes the following steps: At room temperature, copper salt and chiral ligand (L) are stirred in an organic solvent for 0.5–2.0 h, then α,β-unsaturated 7-azaindolineamide (I), diphenylphosphine (II) and base are added sequentially, and the reaction is stirred at -20–70 °C for 12–72 h. After the reaction is complete, the mixture is directly separated and purified to obtain the final product. The α,β-unsaturated 7-azaindolineamide (Ⅰ) has the following structure: ； The diphenylphosphine(II) has the following structure: 。 3. The synthesis method according to claim 2, characterized in that: The organic solvent is selected from one or a mixture of more than one of toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, dichlorobenzene, hexafluorobenzene, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, N,N-dimethylformamide, and dimethyl sulfoxide.

4. The synthesis method according to claim 2, characterized in that: The copper salt is selected from at least one of cuprous chloride, cuprous bromide, cuprous iodide, copper tetraacetonitrile hexafluorophosphate, cuprous trifluoromethanesulfonate, cuprous acetate, cuprous oxide, cuprous thiophene-2-carboxylate, copper tetraacetonitrile tetrafluoroborate, copper bromide, copper acetate, copper sulfate, copper trifluoromethanesulfonate, and copper acetylacetonate; the minimum amount of the copper salt used is 10 mol of α,β-unsaturated 7-azaindolineamide (I).

5. The synthesis method according to claim 2, characterized in that: The chiral ligand is a chiral ferrocene bisphosphine ligand, and the minimum amount of the chiral ligand is 12 mol of α,β-unsaturated 7-azaindolineamide (I).

6. The synthesis method according to claim 2, characterized in that: The separation and purification method is one or a combination of recrystallization, column chromatography, and plate chromatography; the solvent for separation and purification is selected from one or a mixture of toluene, xylene, mesitylene, fluorobenzene, chlorobenzene, dichlorobenzene, acetonitrile, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, n-butyl ether, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, petroleum ether, n-hexane, methanol, ethanol, ethyl acetate, methyl acetate, isopropyl acetate, and ethyl butyrate.

7. The synthesis method according to claim 2, characterized in that: The alkali is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine, N,N-diisopropylethylamine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, tetramethylguanidine, and triethylamine.

8. A 3-(diphenylphosphoyl)propionic acid derivative (Ⅳ) further derived from the compound of claim 1, characterized in that, It has the following structure: 。 9. The method for synthesizing the 3-(diphenylphospho)propionic acid derivative (Ⅳ) according to claim 8, characterized in that, Compound (III) was dissolved in an organic solvent, and then a catalyst was added. The mixture was stirred at reflux temperature for 1–8 h. After the reaction was complete, the mixture was directly separated and purified to obtain compound (IV) with a 3-(diphenylphosphoyl)propionic acid skeleton. The catalyst was selected from at least one or a mixture of multiple of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and boron trifluoride ether.

10. The use of the compound of claim 1 in the preparation of kinase inhibitor antitumor drugs.

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