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CN118638038B - N-axis chiral indole amide compound and synthesis method thereof - Google Patents

N-axis chiral indole amide compound and synthesis method thereof Download PDF

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CN118638038B
CN118638038B CN202410720170.0A CN202410720170A CN118638038B CN 118638038 B CN118638038 B CN 118638038B CN 202410720170 A CN202410720170 A CN 202410720170A CN 118638038 B CN118638038 B CN 118638038B
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CN118638038A (en
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李天真
陈群
石枫
张宇辰
吴淑芳
王大华
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Abstract

The application discloses an N-axis chiral indole amide compound and a synthesis method thereof, and belongs to the technical field of indole compounds. The N-N axis chiral indole amide compound is obtained by a synthesis method that indole derivative amide and anhydride are used as reaction raw materials, the reaction raw materials are added into an organic solvent, stirring reaction is carried out at-20-0 ℃ under the catalysis of chiral isothiourea, TLC tracking reaction is carried out until the reaction is complete, and the compound is obtained after filtration, concentration and purification. The N-axis chiral indole amide compound synthesized by the application has higher sensitivity and strong cytotoxic activity to human hepatoma cell Hep G2 through biological activity test. The method has the advantages of more conventional reaction conditions, mild and simple reaction process, low cost, suitability for industrial production, and high yield and corresponding selectivity, and can obtain products with various structures by using a plurality of types of substrates as reactants.

Description

N-axis chiral indole amide compound and synthesis method thereof
Technical Field
The application belongs to the technical field of indole compounds, and particularly relates to an N-N axis chiral indole amide compound and a synthesis method thereof.
Background
The axial chiral indole compounds are widely applied to anticancer drug molecules and natural products, and have wide application prospects in the field of life science. However, currently widely existing axial chiral indoles focus on axial chiral N-aryl indoles, axial chiral 3-aryl indoles, axial chiral 2-aryl indoles, axial chiral 5-aryl indoles, axial chiral N-pyrrolyl indoles, 3-bisindoles, N-axial chiral bisindoles. No study on N-axis chiral indole amide compounds and report on cytotoxicity of human hepatoma cell Hep G2 are seen.
Disclosure of Invention
The application aims to provide an N-axis chiral indole amide compound, which expands the variety range of the axial chiral indole compound, and the N-axis chiral indole amide compound is found to have good sensitivity and cytotoxic activity on human liver cancer cell Hep G2 through researches.
The second purpose of the application is to provide a synthesis method of the N-axis chiral indole amide compound, which has the advantages of mild reaction process, simplicity, safety, easiness in operation, high enantioselectivity, low cost and high yield.
In order to achieve the above purpose, in one aspect, the present application provides an N-axis chiral indoleamide compound, which has a chemical structural formula as follows:
Wherein R is independently selected from one of phenyl, halogen substituted phenyl, diphenyl phosphine substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl and cycloalkyl, R 1 is independently selected from one of hydrogen, halogen, methyl and methoxy, R 2 is independently selected from one of hydrogen, methyl and halogen, R 3 is independently selected from one of methyl ester group, ethyl group, phenyl, camphoryl and furanosyl, R 4 is independently selected from one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroaryl ethyl, C1-C6 alkyl, cycloalkyl, allyl and phenyl.
On the other hand, the application also provides a synthesis method of the N-N axis chiral indole amide compound, which comprises the specific steps of adding indole derivative amide and anhydride serving as reaction raw materials into an organic solvent, stirring and reacting for 12-30 hours at minus 20-0 ℃ under the presence of a dehydrating agent and alkali under the catalysis of chiral isothiourea, carrying out TLC tracking reaction until the reaction is complete, and filtering, concentrating and purifying to obtain the N-N axis chiral indole amide compound;
the indole derivative amide has the structural formula: Wherein R is selected from one of phenyl, halogen substituted phenyl, diphenylphosphine substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl and cycloalkyl, R 1 is selected from one of hydrogen, halogen, methyl and methoxy, R 2 is selected from one of hydrogen, methyl and halogen, R 3 is selected from one of methyl ester group, ethyl ester group, phenyl, camphoryl and furanosyl;
the structural formula of the anhydride is as follows: Wherein R 4 is selected from one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroaralkylethyl, C1-C6 alkyl, cycloalkyl, allyl and phenyl;
The molar ratio of the indole-derived amide to the anhydride is 1:1.5, and the molar ratio of the indole-derived amide to the chiral isothiourea is (1-4): 0.2.
Alternatively, the chiral isothiourea is selected from compounds of formulae (4 a) - (4 g):
Wherein the compounds of formulas (4 a) - (4 d) have the structural formula: Wherein R is selected from one of isopropyl, tert-butyl, benzyl and phenyl, wherein R is isopropyl, marked as formula (4 a), R is tert-butyl, marked as formula (4 b), R is benzyl, marked as formula (4 c), and R is phenyl, marked as formula (4 d);
the structural formula of the compound of the formula (4 e) is
The structural formula of the compound of the formula (4 f) is
The structural formula of the compound of the formula (4 g) is
Preferably, the chiral isothiourea is the compound of formula (4 d).
Optionally, the organic solvent is selected from one of acetonitrile, acetone, ethyl acetate, 1, 2-dichloroethane, toluene, tetrahydrofuran, chloroform, carbon tetrachloride and dichloromethane, and the ratio of the volume of the organic solvent to the molar amount of the indole-derived amide is (5-60 mL): 1mmol.
Alternatively, the organic solvent is methylene chloride, and the ratio of the volume of the organic solvent to the molar amount of the indole-derived enamine compound of formula 1 is 5 ml/1 mmol.
Alternatively, the dehydrating agent is selected fromMolecular sieve, magnesium sulfate, sodium sulfate.
Preferably, the dehydrating agent isMolecular sieves.
Optionally, the base is selected from one of sodium carbonate, lithium carbonate, potassium bicarbonate, potassium phosphate, triethylamine, N-dimethylethylenediamine.
Preferably, the base is sodium carbonate and the molar ratio of the indole-derived enamine to the sodium carbonate is 1:2.
The application has at least the following beneficial effects:
(1) The N-axis chiral indole amide compound is successfully synthesized, and biological activity tests show that the derivative has higher sensitivity and strong cytotoxic activity to human pre-liver cancer cell Hep G2, so that the N-axis chiral indole amide compound synthesized by the application is expected to be applied to the field of medicines;
(2) The synthesis method of the N-axis chiral indole amide compound provided by the application has the advantages of more conventional reaction conditions, mild and simple reaction process, easiness in operation, low cost, suitability for industrial mass production and good industrialization prospect, and the method uses a plurality of types of substrates as reactants to obtain products with various and complex structures, and has high yield and high enantioselectivity.
Drawings
The accompanying drawings are included to provide a further understanding of the application, and are incorporated in and constitute a part of this specification, illustrate the application and together with the description serve to explain, without limitation, the application. In the drawings:
FIG. 1 is a synthetic route diagram of an N-axis chiral indoleamide of example 1 of the present application;
FIG. 2 is a synthetic route diagram of an N-axis chiral indoleamide of example 2 of the present application;
FIG. 3 is a synthetic route for N-N axis chiral indoleamides of exemplary embodiments 3-14 of the present application;
FIG. 4 is a synthetic route for N-axis chiral indoleamides of illustrative examples 15-34 of the present application.
Detailed Description
The chemical structural formula of the N-axis chiral indoleamide compound in the specific embodiment of the application is shown in formula 3:
In the formula 3, R is independently selected from one of phenyl, halogen substituted phenyl, diphenyl phosphine substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl and cycloalkyl; R 1 is independently selected from one of hydrogen, halogen, methyl and methoxy, R 2 is independently selected from one of hydrogen, methyl and halogen, R 3 is independently selected from methyl ester group, R 4 is independently selected from one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroaralkylethyl, C1-C6 alkyl, cycloalkyl, allyl and phenyl. By way of illustration, when R is phenyl, R 1 can be any of hydrogen, halogen, methyl, methoxy, R 2 can be any one of hydrogen, methyl and halogen, and R 3 can be methyl ester group, ethyl ester group, phenyl group, camphoryl group, Any one of furanosyl groups, R 4 can be any one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroarylethyl, C1-C6 alkyl, cycloalkyl, allyl and phenyl, it being understood that when R is any one of halogen substituted phenyl, diphenylphosphine substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl and cycloalkyl, R 1 can be hydrogen, Halogen, methyl, methoxy, R 2 is any one of hydrogen, methyl, halogen, R 3 is any one of methyl ester group, ethyl ester group, phenyl, camphora, furanosyl, R 4 is benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroaralkylethyl, C1-C6 alkyl, cycloalkyl, allyl, phenyl. It follows that the species of the R, R 1、R2、R3、R4 groups are not constrained by each other and are free to combine.
Adding indole derivative amide and anhydride serving as reaction raw materials into an organic solvent, stirring and reacting for 12-30 hours at minus 20-0 ℃ in the presence of a dehydrating agent and alkali under the catalysis of chiral isothiourea, tracking the reaction to completion by TLC, filtering, concentrating and purifying to obtain the N-N axis chiral indole amide compound;
the indole derivative amide has a structural formula of formula 1:
Wherein R is independently selected from one of phenyl, halogen substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl and cycloalkyl, R 1 is independently selected from one of hydrogen, halogen, methyl and methoxy, R 2 is independently selected from one of hydrogen, methyl and halogen, R 3 is independently selected from one of methyl, ethyl, phenyl, camphoryl and furanosyl, R 1 can be any one of hydrogen, halogen, methyl and methoxy, R 2 can be any one of hydrogen, methyl and halogen, R 3 can be any one of methyl, ethyl, phenyl, camphoryl and furanosyl, R 1 can be any one of hydrogen, halogen, methyl, methoxy, R 2 can be any one of hydrogen, methyl and 62, and phenyl, and furanosyl can be any one of methyl, 62, methyl, 62 and 62. It follows that the species of the R, R 1、R2、R3 groups are not constrained by each other and are free to combine.
The structural formula of the anhydride is shown as formula 2: Wherein R 4 is selected from one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, naphthylethyl, heteroaralkylethyl, C1-C6 alkyl, cycloalkyl, allyl and phenyl;
the alkali is selected from any one of sodium carbonate, lithium carbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, triethylamine and N, N-dimethyl ethylenediamine, in an alternative specific embodiment, the alkali is sodium carbonate, the molar ratio of the indole-derived enamine to the sodium carbonate is 1:2, in other alternative embodiments, the alkali can also be lithium carbonate, potassium bicarbonate, potassium phosphate, potassium carbonate, triethylamine and N, N-dimethyl ethylenediamine, and the molar ratio of the indole-derived enamine to the alkali except sodium carbonate is 1:2.
The molar ratio of the indole-derived amide to the anhydride is 1:1.5, and the molar ratio of the indole-derived amide to the chiral isothiourea is (1-4): 0.2. It will be appreciated that the molar ratio of the indole-derived amide to the chiral isothiourea may be 1:0.2,2:0.2,3:0.2,4:0.2, provided that any ratio within the range of (1-4): 0.2 can achieve the object of the present application.
The specific embodiment of the application relates to a synthesis method of an N-axis chiral indole amide compound, wherein chiral isothiourea is selected from compounds of formulas (4 a) - (4 g):
Wherein the compounds of formulas (4 a) - (4 d) have the structural formula: Wherein R is selected from one of isopropyl, tert-butyl, benzyl and phenyl, wherein R is isopropyl, marked as formula (4 a), R is tert-butyl, marked as formula (4 b), R is benzyl, marked as formula (4 c), and R is phenyl, marked as formula (4 d);
the structural formula of the compound of the formula (4 e) is
The structural formula of the compound of the formula (4 f) is
The structural formula of the compound of the formula (4 g) isIllustratively, in some specific embodiments, the chiral isothiourea is selected (4 d)In other specific embodiments, the chiral isothiouronium may also be of the formula (4 a), (4 b), (4 c), (4 e), (4 f).
The synthesis method of the N-axis chiral indole amide compound has the advantages of more conventional reaction conditions, mild, simple and convenient reaction process, easy operation, low cost, suitability for industrial mass production and good industrialization prospect, and the method uses a plurality of types of substrates as reactants to obtain products with various and complex structures, and has high yield and high enantioselectivity.
The N-axis chiral indole amide compound of the specific embodiment of the application shows that the derivative has higher sensitivity and strong cytotoxic activity to human pre-liver cancer cell Hep G2 through biological activity test, and the N-axis chiral indole amide compound synthesized by the specific embodiment of the application is expected to be applied to the field of medicines.
The present application will be described in further detail with reference to examples.
In the examples below, unless otherwise indicated, indole-derived amides, anhydrides, chiral isothiouronimides and other reagents are commercially available or are reported in known literature and the experimental procedure is generally carried out under conventional conditions or conditions recommended by the manufacturer.
The specific reagent types disclosed in some of the exemplary embodiments are not particularly indicated, so long as the reagent types included in the protection scope of the present application can replace the corresponding reagents in the specific embodiments of the present application, and the protection scope of the present application is not limited by the specific reagent types in the specific embodiments.
Example 1
Referring to FIG. 1, in the case of the N-axis chiral indole amide compound of example 1 of the present application, 0.1mmol of indole-derived amide of formula 1a and 0.15mmol of anhydride of formula 2a are added as reactants to a solvent under nitrogen, under the action of 0.02mmol (20 mol% of indole-derived amide) of chiral isothiourea, 100mg of the compound is obtainedMolecular sieve and 0.2mmol sodium carbonate are stirred for reaction for 30 hours at minus 20 ℃, TLC is carried out to finish the reaction, the reaction is filtered and concentrated, and then the reaction is purified and separated by silica gel column chromatography (eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1), thus obtaining the N-axis chiral bisindole compound formula 3aa, and the yield and the enantioselectivity are shown in the table 1.
TABLE 1 influence of different kinds of chiral isothiourea, solvent volume, temperature, dehydrating agent, base on reaction enantioselectivity and yield
Note that ee is the enantiomeric excess in Table 1 and [ a ] reaction time is 30 hours.
From the data in Table 1, it can be seen that the optimal reaction conditions are that the chiral isothiourea is of formula 4d, the solvent is dichloromethane, the volume of the reaction solution is 0.5mL, and the dehydrating agent isThe molecular sieve has a reaction time of 30 hours, the molar ratio of the formula 1a to the formula 2a to the sodium carbonate is 1:1.5:2, and the reaction temperature is-20 ℃.
The structural characterization data of the product formula 3aa obtained from the optimal reaction conditions in example 1 are as follows:
83％yield(27.4mg)as a colorless oil.[α]D 20＝-6.8(c 0.66,Acetone);1H NMR(400MHz,Acetone-d6)δ7.79(d,J＝8.0Hz,1H),7.48–7.38(m,3H),7.30–7.23(m,1H),4.37–4.27(m,2H),3.39–3.25(m,1H),2.73–2.50(m,2H),1.33(t,J＝7.1Hz,3H),1.17(d,J＝6.8Hz,3H),1.12(d,J＝6.8Hz,3H),1.06(t,J＝7.2Hz,3H);13C NMR(100MHz,Acetone-d6)δ178.0,174.9,160.0,138.8,127.8,126.8,124.4,123.0,122.3,111.0,109.3,60.7,34.4,18.8,18.7,13.6,7.8;IR(KBr):2980,1712,1616,1538,1448,1266,1197,1021,761cm-1;ESI FTMS exact mass calcd for(C18H22N2O4+H)+requires m/z 331.1653,found m/z 331.1629;The enantiomeric excess:83％,determined by HPLC(IG,hexane/isopropanol＝90/10,flow rate 1.0mL/min,I＝254nm)tR＝7.716min(major),tR＝9.693min(minor).
Example 2
Referring to FIG. 2, in the case of the N-axis chiral indole amide compound of example 2 of the present application, 0.1mmol of indole-derived amide of formula 1a and 0.15mmol of anhydride of formula 2b were added as reactants to a solvent under nitrogen, under the action of 0.02mmol (20 mol% of indole-derived amide) of chiral isothiourea, 100mg of the compound was obtainedThe molecular sieve and 0.2mmol sodium carbonate are stirred and reacted for 30 hours at 0 ℃, TLC tracks the reaction to the end, and after filtration and concentration, the mixture is purified and separated by silica gel column chromatography (eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1), thus obtaining the N-N axis chiral bisindole compound formula 3ab, and the yield and the enantioselectivity are shown in the table 2.
TABLE 2 influence of different kinds of chiral isothiourea, solvent volume, dehydrating agent, base on reaction enantioselectivity and yield
Note that ee is the enantiomeric excess in Table 2 and [ a ] reaction time is 30 hours.
From the data in Table 2, it can be seen that the optimal reaction conditions are that the chiral isothiourea is of formula 4d, the solvent is dichloromethane, the volume of the reaction solution is 0.5mL, and the dehydrating agent isThe molecular sieve has a reaction time of 30 hours, the molar ratio of the formula 1a to the formula 2b to the sodium carbonate is 1:1.5:2, and the reaction temperature is 0 ℃.
The structural characterization data of the product formula 3ab obtained from the optimal reaction conditions in example 2 are as follows:
77％yield(30.2mg)as a colorless oil.[α]D 20＝-20.2(c 0.52,Acetone);1H NMR(400MHz,Acetone-d6)δ7.79(d,J＝8.0Hz,1H),7.48(s,1H),7.43–7.38(m,1H),7.32–7.21(m,5H),7.17–7.12(m,2H),4.31(q,J＝6.8Hz,2H),4.11–4.04(m,1H),3.93–3.85(m,1H),3.35–3.23(m,1H),1.33(t,J＝7.1Hz,3H),1.17(d,J＝6.7Hz,3H),1.11(d,J＝6.9Hz,3H);13C NMR(100MHz,Acetone-d6)δ178.2,172.5,160.0,138.9,133.8,129.7,128.2,128.1,126.9,126.8,124.5,123.0,122.3,111.2,109.4,60.8,42.7,34.4,18.8,18.7,13.6;IR(KBr):2979,1731,1712,1537,1269,1197,1144,1065,747,719cm-1;ESI FTMS exact mass calcd for(C23H24N2O4+H)+requires m/z 393.1809,found m/z 393.1793;The enantiomeric excess:96％,determined by HPLC(IB,hexane/isopropanol＝90/10,flow rate 1.0mL/min,I＝254nm)tR＝6.750min(major),tR＝9.193min(minor).
Examples 3 to 14
The synthesis of examples 3-14 was identical to that of example 2, except that anhydrides of different structures were used as starting materials.
The synthetic route is shown in figure 3, and the products, enantiomeric excess and yields are shown in the following table 3.
TABLE 3 reaction starting materials, products, enantiomeric excess and yields for examples 1-14
[A] The reaction temperature was-20 ℃, formula (b) 1: formula 2=1.5:1, toluene (1 mL), and formula (C) 15 ℃, formula (1) 2=1.5:1, and the solvent was methylene chloride: toluene=1:1 (1 mL).
Examples 15 to 34
The synthesis of examples 15-34 was identical to example 2, except that indole-derived amides of different structures were used as starting materials.
The synthetic route is shown in FIG. 4, and the products, enantiomeric excess and yields are shown in Table 4 below.
TABLE 4 reaction starting materials, products, enantiomeric excess, yields for examples 2 and 15-34
[A] The reaction temperature is 15 ℃, formula 1, formula 2=1.5:1.
As can be seen from tables 3 and 4, the method of the application can realize the synthesis of the N-axis chiral indole amide compound in one step, has extremely high enantioselectivity and excellent yield, has high atomic economy, is environment-friendly and wide in application range, has the advantages of easily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment and diversified product structures, and thus has relatively high implementation value and potential social and economic benefits.
The following examples of the application of N-N axis chiral indole amide compounds, through CCK8 method test some examples of the compounds to human liver cancer cell Hep G2 cytotoxic activity, test results please refer to Table 5, table 6, table 7.
TABLE 5 cytotoxic Activity of the Compounds of the application against human hepatoma cell Hep G2
Note that IC 50 refers to half maximal inhibitory concentration in table 5.
TABLE 6 cytotoxic Activity of the Compounds of the application against human hepatoma cell Hep G2
Note that IC 50 refers to half-maximal inhibitory concentration in table 6.
TABLE 7 cytotoxic Activity of the Compounds of the application against human hepatoma cell Hep G2
Note that IC 50 refers to half maximal inhibitory concentration in table 7.
The CCK8 method of the embodiment of the application comprises the specific process of inoculating a human liver cancer cell line (Hep G2) into a 96-well plate with the density of 5000 cells per 100 mu L per well. After 24 hours of adhesion, the medium was changed to DMEM without FBS. The selected N-axis chiral indoleamide of example 1 was added to the medium at a concentration of 12.5. Mu.g/mL, 25. Mu.g/mL, 50. Mu.g/mL, 100. Mu.g/mL, 200. Mu.g/mL, and the cells were further cultured for 24 hours.
The selected N-axis chiral indoleamides of example 15 and example 20 were added to the medium at concentrations of 3.125. Mu.g/mL, 6.25. Mu.g/mL, 12.5. Mu.g/mL, 25. Mu.g/mL, 50. Mu.g/mL, and the cells were cultured for an additional 24 hours.
The selected N-N axis chiral indoleamides of examples 11, 25, 28 and 29 were added to the medium at concentrations of 6.25. Mu.g/mL, 12.5. Mu.g/mL, 25. Mu.g/mL, 50. Mu.g/mL, 100. Mu.g/mL and the cells were cultured for an additional 24 hours. Cells not exposed to the examples served as controls, and wells with medium alone served as blanks. At the end of compound stimulation, the supernatant was removed and 100 μl DMEM containing 10 μ LCCK was added to each well for an additional 1 hour at 37 ℃. The plates were then shaken for 5 seconds and the Optical Density (OD) values were read at 450 nm. The IC 50 values for the corresponding examples on Hep G2 cells were then calculated by GraphPad software. The test results are shown in tables 5, 6 and 7. The results show that the compound synthesized by the application has higher cytotoxic activity on human hepatoma cell Hep G2.
The foregoing is only a preferred embodiment of the present application, but the scope of the present application is not limited thereto, and any person skilled in the art, who is within the scope of the present application, should make equivalent substitutions or modifications according to the technical scheme and the concept of the present application, and should be covered by the scope of the present application.

Claims (8)

1.一种N-N轴手性吲哚酰胺类化合物，其特征在于，其化学结构式为：1. An N-N axial chiral indoleamide compound, characterized in that its chemical structural formula is: 其中，R独立地选自苯基、卤素取代的苯基、萘基、杂芳基、C1-C6烷基中的一种；R1独立地选自氢、卤素、甲基、甲氧基中的一种；R2独立地选自氢、甲基、卤素中的一种；R3独立地选自甲酯基、乙酯基中的一种；R4独立地选自苄基、甲基取代苄基、甲氧基取代苄基、卤素取代苄基、C1-C6烷基中的一种。Wherein, R is independently selected from one of phenyl, halogen-substituted phenyl, naphthyl, heteroaryl, and C1-C6 alkyl; R1 is independently selected from one of hydrogen, halogen, methyl, and methoxy; R2 is independently selected from one of hydrogen, methyl, and halogen; R3 is independently selected from one of methyl ester and ethyl ester; R4 is independently selected from one of benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, and C1-C6 alkyl. 2.根据权利要求1所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，包括：以吲哚衍生酰胺与酸酐作为反应原料加入到有机溶剂中，在手性异硫脲的催化下，在脱水剂及碱存在的条件下，-20～0℃搅拌反应12-30小时，TLC跟踪反应至完全，过滤、浓缩、纯化后，获得所述N-N轴手性吲哚酰胺类化合物；2. The method for synthesizing N-N axial chiral indoleamide compounds according to claim 1, characterized in that it comprises: adding indole derivative amide and acid anhydride as reaction raw materials into an organic solvent, stirring and reacting at -20 to 0° C. for 12 to 30 hours under the catalysis of chiral isothiourea, in the presence of a dehydrating agent and a base, tracking the reaction by TLC until completion, filtering, concentrating, and purifying to obtain the N-N axial chiral indoleamide compounds; 所述吲哚衍生酰胺结构式为：其中，R独立地选自苯基、卤素取代的苯基、萘基、杂芳基、C1-C6烷基中的一种；R1独立地选自氢、卤素、甲基、甲氧基中的一种；R2独立地选自氢、甲基、卤素中的一种；R3独立地选自甲酯基、乙酯基中的一种；The indole-derived amide structural formula is: Wherein, R is independently selected from one of phenyl, halogen-substituted phenyl, naphthyl, heteroaryl, C1-C6 alkyl; R1 is independently selected from one of hydrogen, halogen, methyl, methoxy; R2 is independently selected from one of hydrogen, methyl, halogen; R3 is independently selected from one of methyl ester and ethyl ester; 所述酸酐的结构式为：其中，R4独立地选自苄基、甲基取代苄基、甲氧基取代苄基、卤素取代苄基、C1-C6烷基中的一种；The structural formula of the anhydride is: Wherein, R 4 is independently selected from benzyl, methyl substituted benzyl, methoxy substituted benzyl, halogen substituted benzyl, C1-C6 alkyl; 所述吲哚衍生酰胺与所述酸酐的摩尔比为1：1.5，所述吲哚衍生酰胺与所述手性异硫脲的摩尔比为(1-4)：0.2；The molar ratio of the indole derivative amide to the acid anhydride is 1:1.5, and the molar ratio of the indole derivative amide to the chiral isothiourea is (1-4):0.2; 所述手性异硫脲选自式(4a)、(4c)、(4d)、(4e)、(4f)化合物：The chiral isothiourea is selected from the compounds of formula (4a), (4c), (4d), (4e), and (4f): 其中，所述式(4a)化合物的结构式为： Wherein, the structural formula of the compound of formula (4a) is: 所述(4c)化合物的结构式为： The structural formula of the compound (4c) is: 所述(4d)化合物的结构式为： The structural formula of the compound (4d) is: 所述式(4e)化合物的结构式为： The structural formula of the compound of formula (4e) is: 所述式(4f)化合物的结构式为： The structural formula of the compound of formula (4f) is: 所述的脱水剂选自分子筛中的一种。The dehydrating agent is selected from A type of molecular sieve. 3.根据权利要求2所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述的手性异硫脲为所述式(4d)的化合物。3. The method for synthesizing N-N axial chiral indoleamide compounds according to claim 2, characterized in that the chiral isothiourea is a compound of formula (4d). 4.根据权利要求2所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述的有机溶剂选自乙腈、丙酮、乙酸乙酯、1,2-二氯乙烷、甲苯、四氢呋喃、氯仿、四氯化碳、二氯甲烷中的一种；所述的有机溶剂体积与所述吲哚衍生酰胺的摩尔量的比例为(5-60mL):1mmol。4. The method for synthesizing N-N axial chiral indole amide compounds according to claim 2, characterized in that the organic solvent is selected from one of acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, tetrahydrofuran, chloroform, carbon tetrachloride, and dichloromethane; and the ratio of the volume of the organic solvent to the molar amount of the indole derivative amide is (5-60 mL): 1 mmol. 5.根据权利要求4所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述的有机溶剂为二氯甲烷，所述的有机溶剂体积与所述的吲哚衍生酰胺的摩尔量的比例为5mL:1mmol。5. The method for synthesizing N-N axial chiral indole amide compounds according to claim 4, characterized in that the organic solvent is dichloromethane, and the ratio of the volume of the organic solvent to the molar amount of the indole derivative amide is 5 mL:1 mmol. 6.根据权利要求2所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述脱水剂为分子筛。6. The method for synthesizing NN-axis chiral indoleamide compounds according to claim 2, characterized in that the dehydrating agent is Molecular sieve. 7.根据权利要求2所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述碱选自碳酸钠、碳酸锂、碳酸氢钾、磷酸钾、三乙胺、N,N-二甲基乙二胺中的一种。7. The method for synthesizing N-N axial chiral indoleamide compounds according to claim 2, characterized in that the base is selected from one of sodium carbonate, lithium carbonate, potassium bicarbonate, potassium phosphate, triethylamine, and N,N-dimethylethylenediamine. 8.根据权利要求7所述的N-N轴手性吲哚酰胺类化合物的合成方法，其特征在于，所述碱为碳酸钠，所述吲哚衍生酰胺与所述碳酸钠的摩尔比为1：2。8. The method for synthesizing N-N axial chiral indole amide compounds according to claim 7, characterized in that the base is sodium carbonate, and the molar ratio of the indole derivative amide to the sodium carbonate is 1:2.
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