Tryptanthrin imine compounds and their derivatives, synthesis methods and applications thereof

Abstract

The invention discloses a tryptanthrin imine compound and a derivative thereof, belonging to the field of organic chemical synthesis and medicine. The structure of the compound comprises an imine functional group and an indole and quinazolinone skeleton. The synthesis method comprises the following steps: dissolving tryptanthrin (I) in an organic solvent and stirring at room temperature, then adding an aza ylide reagent (II), heating and stirring for reaction, and separating and purifying the compound after the reaction is completed. The invention also discloses a product of the reaction of the compound with indole or pyrrole, namely, 6-amino-6-(3-indolyl) indole and quinazolinone or 6-amino-6-(2-pyrrolyl) indole and quinazolinone derivatives. The invention also discloses the application of the derivative in the preparation of compounds for treating leukemia and lung cancer. The compound of the invention has a wide range of applications, has great application value in asymmetric synthesis, and particularly shows broad application prospects in new drug research and development. The synthesis method has the advantages of simple operation, mild reaction conditions, good substrate universality, high yield, and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to tryptanthrin imine compounds and derivatives thereof, and synthesis methods and applications thereof. Background Art

[0002] Tryptanthrin is a natural indolequinazolinone alkaloid and one of the main ingredients of many traditional Chinese medicines, including Radix Isatidis, Indigo Naturalis, Polygonum tinctorium, and Indigofera ovata. In addition, tryptanthrin can also be detected in the metabolites of certain microorganisms. Studies have shown that tryptanthrin has multiple pharmacological activities such as antibacterial, antiviral, antitumor, anti-inflammatory, and cardiovascular protection; it has shown high medicinal value in bacterial infection, tumor treatment, inflammatory damage, and viral invasion, and both cytotoxicity tests and mouse toxicity tests have confirmed that it has good safety ( Appl. Magn. Reson. 2015, 46 , 781; Arch. Pharmacal. Res. 2018, 41 , 419; J. Bioadhesion Biofilm Res. 2019, 35 , 1093; China Pharm. 2013, 22 , 7). In addition, many derivatives of tryptanthrin also have good antibacterial and antitumor biological activities, such as Candidine, Phaitanthrin A / B / D, Cruciferane, etc. ( Med. Sci. Monit. 2018, 24 ,5668; J. Med. Chem. 2013, 56 , 8321–8331; J. Nat. Prod. 2008, 71 , 1275; Bioorganic Med. Chem. Lett. 2015, 25 , 3867). Therefore, the development of various types of tryptanthrin derivatives has aroused great interest among synthetic chemists and medicinal chemists and has become a hot spot in drug research and development.

[0003] Imines are a very important class of organic synthons with advantages such as high activity and easy availability. Asymmetric reactions involving imines have always been a hot topic in the field of organic synthesis. Adv. Synth. Catal. 2018, 360 , 3614; Tetrahedron 2016, 72 , 4449; Chem. Rev. 2011, 111 , 2626; Beilstein J. Org. Chem. 2018, 14 , 1349; Chem. Rev. 2020, 120 , 3721; Adv. Synth. Catal. 2021, 363 ,3655;). Moreover, imines have been successfully used in the synthesis of many important biologically active compounds, including amino acids, β -lactam, 3-aminomethylindole derivatives, etc. ( Acc. Chem. Res. 2003, 36 , 10; ACS Med. Chem. Lett. 2014, 5, 199 ; Eur. J. Med. Chem. 2015, 96 , 196; Eur. J. Org. Chem. 2007, 2007 , 5797; Acc. Chem. Res. 2004, 37 , 102;). Therefore, developing novel imine compounds and studying their applications in organic synthesis are of great practical significance and have also attracted widespread attention from organic chemists and medicinal chemists.

[0004] Through literature research, the inventors found that the synthesis and application research of imine compounds derived from tryptanthrin have not been reported. In view of the great potential of the aforementioned tryptanthrin derivatives in the development of new drugs and the important position of imine compounds in organic synthesis, it is of great significance and value to design and synthesize a class of tryptanthrin-derived imine compounds and study their use in constructing novel tryptanthrin derivatives. Summary of the invention

[0005] One of the purposes of the present invention is to provide a new type of tryptanthrin imine compounds and their preparation methods and applications, so as to enrich the types of imines and provide sufficient and reliable candidate molecules for the development of new drugs.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is: a new type of tryptanthrin imine compound has a structure shown in the following structural formula (III):

[0007]

[0008] In the above structural formula, R 1 The substituent is selected from one or more of aryl, alkyl, hydrogen, halogen, alkoxy, cyano, nitro, ester, carbonyl, alkylthio, and amino; R 2 The substituent is selected from one or more of aryl, alkyl, hydrogen, halogen, alkoxy, cyano, nitro, ester, carbonyl, alkylthio, and amino; R 3 The substituent is selected from one of acyl, sulfonyl, alkoxycarbonyl and phosphonyl.

[0009] The invention provides a novel tryptanthrin imine compound, which has an imine functional group and the core structural unit of tryptanthrin - indole and quinazolinone.

[0010] The application value of the above-mentioned tryptanthrin ketimine compounds is:

[0011] 1. Imines are a very important class of organic synthons that can be used to construct various useful compounds, such as amino acids, β -lactam, etc. The present invention provides a novel imine compound, which can react with various types of nucleophiles as electrophilic reagents to construct various tryptanthrin derivatives; it enriches the types of imines, provides a novel structure synthon for the field of organic synthesis, and has very important application value.

[0012] 2. Tryptanthrin and its derivatives often have good antibacterial, anti-inflammatory, anti-tumor and other biological activities. For example, Candidine (structure shown in the figure below) has good anti-tumor activity and has inhibitory effects on Lewis lung cancer in mice and melanoma cell line B16 ( Med. Sci. Monit. 2018, 24 , 5668; CN201310194601.6); Phaitanthrin A (structure shown below) has good cytotoxicity to MCF-7, NCI-H460 and SF-268 cell lines, and is also an effective inhibitor of the life cycle of Toxoplasma gondii and has low host cell toxicity ( J. Nat. Prod. 2008, 71 , 1275). The structure of tryptanthrin and its derivatives has the same core skeleton (indole and quinazolinone) as the new compound tryptanthrin imine provided by the present invention. Therefore, it can be reasonably predicted that the various products obtained by the reaction of tryptanthrin imine provided by the present invention also have potential biological activity, which can provide sufficient compound sources for new drug screening and is an important source for the development of new drugs.

[0013] 3. The products of the reaction between tryptanthrin imine and indole or pyrrole, 6-amino-6-(3-indolyl) indole and quinazolinone or 6-amino-6-(2-pyrrolyl) indole and quinazolinone compounds, have significant anti-tumor activity as shown by in vitro activity tests. This result proves that the product obtained by the reaction involving tryptanthrin imine has good biological activity; it also shows the application potential of the present invention in the field of drug research and development.

[0014] .

[0015] The second object of the present invention is to provide a method for synthesizing tryptanthrin imine compounds, the technical scheme adopted is:

[0016] The steps include:

[0017] (1) At room temperature, tryptanthrin (I) is placed in an organic solvent and stirred, and an aza ylide reagent (II) is added, followed by heating and stirring to react for 12-48 h. After the reaction is complete, the tryptanthrin imine compound is directly separated and purified to obtain the compound;

[0018] Wherein, the tryptanthrin (I) has the following structure:

[0019]

[0020] The aza ylide reagent (II) has the following structure:

[0021]

[0022] The synthetic route is:

[0023]

[0024] The present invention adopts the above-mentioned synthesis method to synthesize a series of new tryptanthrin imine compounds.

[0025] As a preferred technical solution: the organic solvent is selected from one or more of dichloromethane, chloroform, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, trifluorotoluene, nitrobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0026] As a preferred technical solution: the minimum amount of the reactant aza ylide (II) is 0.9 molar equivalent of tryptanthrin (I).

[0027] As a preferred technical solution: the reaction temperature is any temperature between 25 and 200°C.

[0028] As a preferred technical solution: the separation and purification method is a combination of one or more of pulping, recrystallization, and column chromatography separation.

[0029] As a preferred technical solution: the separation and purification solvent is selected from one or a mixture of petroleum ether, n-hexane, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0030] The third object of the present invention is to provide an application of the above compound (III) in chemical synthesis, the technical scheme adopted is:

[0031] The tryptanthrin imine (III) is placed in an organic solvent, and then a catalyst and an aromatic ring compound (V) are added in sequence, and then stirred at a certain temperature for 0.5-48 hours. After the reaction is completed, the 6-amino-6-aryl indole and quinazolinone compound (IV) is directly separated and purified.

[0032] Wherein, the tryptanthrin imine compound (III) has the following structure:

[0033] .

[0034] The 6-amino-6-aryl indole and quinazolinone compound (IV) has the following structure:

[0035] .

[0036] The synthetic route is:

[0037] .

[0038] The present invention adopts the above-mentioned synthesis method to synthesize a series of novel 6-amino-6-aryl indole and quinazolinone compounds.

[0039] As a preferred technical solution: the organic solvent is selected from one or more of dichloromethane, chloroform, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, trifluorotoluene, nitrobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0040] As a preferred technical solution: the catalyst is selected from at least one of silver oxide, silver nitrate, silver acetate, silver hexafluoroantimonate, silver tetrafluoroborate, silver bis(trifluorosulfonyl)imide, gold chloride, triphenylphosphine gold chloride, tri(pentafluorophenyl)phosphine gold chloride, tricyclohexylphosphine gold chloride, and tri(2,4-di-tert-butylphenoxy)phosphine gold chloride, or a mixture of more.

[0041] As a preferred technical solution: the aromatic ring compound ArH (V) is selected from one of indole, pyrrole, benzene, pyridine, thiophene, furan, benzothiophene, benzofuran, quinoline and isoquinoline.

[0042] As a preferred technical solution: the catalyst is selected from various organic acids, including but not limited to sulfonic acid, carboxylic acid, and organic phosphoric acid.

[0043] As a preferred technical solution: the catalyst is chiral or racemic.

[0044] As a preferred technical solution: the minimum dosage of the aromatic ring compound is 1.0 molar equivalent of tryptanthrin imine.

[0045] As a preferred technical solution: the minimum usage of the catalyst is 0.1 mol %.

[0046] As a preferred technical solution: the reaction temperature is any temperature in the range of 0 to 100°C.

[0047] As a preferred technical solution: the separation and purification method is a combination of one or more of recrystallization and column chromatography separation.

[0048] As a preferred technical solution: the separation and purification solvent is selected from one or a mixture of petroleum ether, n-hexane, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0049] The present invention synthesizes a series of novel 6-amino-6-aryl indole and quinazolinone compounds containing two advantageous skeletons (indole and quinazolinone and indole / pyrrole) with high yield and high stereoselectivity, enriching the application of tryptanthrin and the types of tryptanthrin derivatives, thereby providing sufficient compound sources for the screening of lead compounds and drug candidate molecules. The method has the advantages of mild reaction conditions, commercially available catalysts, simple operation, high yield (up to 99%), and high stereoselectivity (up to 99% ee).

[0050] A fourth object of the present invention is to provide the use of the above compound (IV) in the preparation of anti-tumor drugs.

[0051] Specifically, the application value of the above compound (IV) disclosed in the present invention is that: through preliminary cell activity experiments, it is shown that this type of compound has a good killing effect on human leukemia cells K562, and the results of cell activity research are shown in Table 1. Therefore, through further research, this type of compound is expected to become a lead compound for anti-tumor drugs.

[0052] The advantages of the present invention are that a series of novel tryptanthrin imine compounds are synthesized for the first time by a simple method. The imine compounds are good electrophilic reagents and can react with various types of nucleophilic reagents to synthesize various tryptanthrin derivatives, thereby providing sufficient compound sources for the screening of lead compounds and drug candidate molecules. In addition, in vitro cell activity experiments show that the product of the reaction of the tryptanthrin imine of the present invention with indole has good anti-leukemia cell activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1This is the hydrogen nuclear magnetic resonance spectrum of III-a prepared in Example 1;

[0054] Figure 2 This is the carbon NMR spectrum of III-a prepared in Example 1;

[0055] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of IV-a prepared in Example 2;

[0056] Figure 4 is the carbon NMR spectrum of IV-a obtained in Example 2;

[0057] Figure 5 is the HPLC chromatogram (racemic) of IV-a obtained in Example 2;

[0058] Figure 6 This is the HPLC chromatogram (chirality) of IV-a obtained in Example 2. Implementation

[0059] The present invention will be further described below in conjunction with the accompanying drawings, wherein the chiral phosphoric acid structure involved is as follows:

[0060] . Example

[0061] Synthesis of compound III-a:

[0062] ;

[0063] At room temperature, tryptanthrin (5 mmol), toluene (20 mL), BocN=PPh 3 (10 mmol), then heated to reflux for 24 hours, after the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane = 15:1:1~10:1:1) to obtain compound III-a as a bright yellow solid with a yield of 62%;

[0064] Structure identification: 1 H NMR (300 MHz, DMSO- d 6 ) δ 8.71 – 8.39 (m, 1H), 8.33 (d, J =7.9 Hz, 1H), 8.02 – 7.67 (m, 3H), 7.67 – 7.41 (m, 2H), 7.33 (t, J = 7.7 Hz,1H), 1.71 (s, 9H). 13C NMR (75 MHz, DMSO- d 6 ) δ 160.0, 158.3, 153.2, 146.7,143.3, 142.1, 135.5, 134.8, 129.5, 127.4, 126.9, 124.1, 124.1, 123.0, 117.4,83.8, 28.3. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 20 H 17 N 3 O 3 Na 370.1162, found370.1169.

[0065] The H NMR spectrum and C NMR spectrum of Ⅲ-a are shown as Figure 1 , Figure 2 shown.

[0066] Example 2: Synthesis of compound (IV-a)

[0067] ;

[0068] At room temperature, in a dry reaction tube, tryptanthrin III-a (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and indole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-a.

[0069] Compound IV-a is a white solid with a yield of 97%; the purity detected by HPLC is >99% and the enantiomeric excess is 98% (ee); [α] D 20 = -197.46 ( c = 2.3 g / 100mL, CH 2 Cl 2 ).

[0070] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 70 / 30 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 10.2 min, t minor =14.4 min. The results are as follows Figure 5 , Figure 6 shown.

[0071] Structure identification: 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.19 (s, 1H), 8.64 – 8.50 (m, 1H), 8.29 (dd, J = 7.8, 1.5 Hz, 2H), 7.82 (t, J = 7.6 Hz, 1H), 7.68 (d, J =8.2 Hz, 1H), 7.64 – 7.49 (m, 4H), 7.43 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 8.3Hz, 1H), 7.16 – 7.01 (m, 2H), 6.94 (t, J = 7.6 Hz, 1H), 1.05 (brs, 9H). 13 CNMR (75 MHz, DMSO- d 6 ) δ 160.9, 159.3, 154.2, 147.1, 138.9, 137.0, 134.9,134.8, 129.2, 127.5, 127.1, 126.8, 126.4, 124.4, 123.8, 121.5, 120.8, 120.7,118.9, 115.9, 112.4, 111.8, 78.9, 63.4, 27.6. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 28 H 24 N 4 O 3 Na 487.1741, found 487.1744.

[0072] The hydrogen and carbon nuclear magnetic resonance spectra of IV-a are shown as follows: Figure 3 , Figure 4 Shown

[0073] Example 3: Synthesis of compound (IV-b)

[0074] ;

[0075] At room temperature, in a dry reaction tube, tryptanthrin III-a (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and 5-chloroindole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-b.

[0076] Compound IV-b is a white solid with a yield of 98%; the purity detected by HPLC is >99% and the enantiomeric excess is 98% (ee); [α] D 20 = -324.7 ( c = 1.0 g / 100mL, CH 2 Cl 2 ).

[0077] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 80 / 20 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 10.5 min, t minor =7.1 min.

[0078] Structure identification: 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.33 (s, 1H), 8.75 – 8.10 (m,3H), 8.09 – 7.77 (m, 2H), 7.72 – 7.53 (m, 4H), 7.48 (t, J = 7.4 Hz, 1H), 7.37(d, J = 8.6 Hz, 1H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H), 6.93 (s, 1H), 1.27 –0.75 (m, 9H). 13 C NMR (75 MHz, DMSO- d 6) δ 160.6, 159.2, 154.1, 146.9, 138.8,135.6, 134.8, 134.2, 129.4, 127.3, 127.1, 126.8, 126.4, 126.3, 125.7, 123.8,123.4, 121.5, 120.9, 120.7, 116.0, 113.3, 112.1, 78.9, 63.1, 27.6. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 28 H 23 C1N 4 O 3 Na 521.1351, found 521.1352.

[0079] Example 4: Synthesis of compound (IV-c)

[0080] ;

[0081] At room temperature, in a dry reaction tube, tryptanthrin III-a (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and 5-bromoindole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-c.

[0082] Compound IV-c is a white solid with a yield of 99%; the purity detected by HPLC is >99% and the enantiomeric excess is 98% (ee); [α] D 20 = -232.4 ( c = 0.8 g / 100mL, CH 2 Cl 2 ).

[0083] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 70 / 30 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 7.4 min, t minor = 5.3min.

[0084] Structure identification: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.35 (s, 1H), 8.53 (d, J = 7.4Hz, 1H), 8.46 – 7.96 (m, 3H), 7.85 (t, J = 7.1 Hz, 1H), 7.66 – 7.47 (m, 5H), 7.34 – 7.26 (m, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.90 (s, 1H), 1.02 (d, J =94.1 Hz, 9H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 160.6, 159.2, 154.2, 146.9, 138.9,135.8, 135.0, 134.2, 129.5, 127.3, 127.2, 126.9, 126.5, 126.4, 126.3, 124.1,123.8, 120.8, 116.0, 113.8, 112.0, 111.5, 79.0, 63.1, 27.6. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 28 H 23 Bn 4 O 3 Na 567.0830, found 567.0831.

[0085] Example 5: Synthesis of Compound IV-d

[0086] ;

[0087] At room temperature, in a dry reaction tube, tryptanthrin III-a (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and 7-methylindole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-d.

[0088] Compound IV-d is a white solid with a yield of 99%; the purity detected by HPLC is >99% and the enantiomeric excess is >99% (ee); [α] D 20 = -176.9 ( c = 1.3 g / 100mL, CH 2 Cl 2 ).

[0089] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 80 / 20 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 11.7 min, t minor =29.9 min.

[0090] Structure identification: 1 H NMR (300 MHz, DMSO- d 6 ) δ 11.19 (s, 1H), 8.55 (d, J = 7.8Hz, 1H), 8.29 (d, J = 7.7 Hz, 2H), 7.84 – 7.76 (m, 1H), 7.69 – 7.52 (m, 4H), 7.48 – 7.36 (m, 1H), 7.20 (s, 2H), 6.90 – 6.74 (m, 2H), 2.38 (s, 3H), 1.24 –0.67 (m, 9H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 161.0, 159.4, 154.3, 147.1, 139.0,136.4, 135.0, 134.9, 129.3, 127.5, 127.2, 126.9, 126.4, 124.1, 123.9, 121.9,121.0, 120.8, 119.2, 117.9, 116.0, 112.8, 79.0, 63.4, 27.7, 16.7. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 29 H 26 N 4 O 3Na 501.1897, found 501.1902.

[0091] Example 6: Synthesis of Compound IV-e

[0092] ;

[0093] At room temperature, in a dry reaction tube, 2-chlorotryptanthranone (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and indole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-e.

[0094] Compound IV-e is a white solid with a yield of 65%; the purity detected by HPLC is >99% and the enantiomeric excess is 99% (ee); [α] D 20 = -216.4 ( c = 1.0 g / 100mL, CH 2 Cl 2 ).

[0095] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 85 / 15 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 20.4 min, t minor =30.0 min.

[0096] Structure identification: 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.19 (d, J = 2.8 Hz, 1H), 8.74 –7.91 (m, 3H), 7.83 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 – 7.49 (m, 4H), 7.46 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.2 Hz, 2H), 6.95 (t, J= 7.6 Hz, 1H), 1.25 – 0.74 (m, 9H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 161.4, 158.2,154.0, 145.8, 138.6, 137.0, 134.9, 131.4, 129.7, 129.4, 127.1, 125.4, 124.6,124.5, 123.9, 122.1, 121.5, 120.9, 119.0, 116.0, 112.0, 111.8, 79.0, 63.4,27.6. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 28 H 23 C1N 4 O 3 Na 521.1351, found 521.1358.

[0097] Example 7: Synthesis of Compound IV-f

[0098] ;

[0099] At room temperature, in a dry reaction tube, 4-methyltryptanthrin (0.1 mmol) and chiral phosphoric acid (0.002 mmol) were dissolved in 2 mL of dichloromethane, and indole (0.12 mmol) was added. The reaction was continued to stir at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and the crude product residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain compound IV-f.

[0100] Compound IV-f is a white solid with a yield of 95%; the purity detected by HPLC is >99% and the enantiomeric excess is 82% (ee); [α] D 20 = -21.1 ( c = 0.1 g / 100mL, CH 2 Cl 2 ).

[0101] The ee value was determined by HPLC: Chiralpak AD-H column; mobile phase: 70 / 30 n-hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major = 8.9 min, t minor= 5.2min.

[0102] Structure identification: 1 H NMR (600 MHz, DMSO- d 6 ) δ 11.11 (s, 1H), 8.53 (d, J = 8.0Hz, 1H), 8.51 – 8.25 (m, 1H), 8.25 – 8.09 (m, 1H), 8.09 – 8.04 (m, 1H), 7.77– 7.55 (m, 3H), 7.50 (s, 1H), 7.42 – 7.27 (m, 2H), 7.19 – 7.02 (m, 2H), 6.74– 6.63 (m, 1H), 2.55 (s, 3H), 1.30 – 0.62 (m, 9H). 13 C NMR (151 MHz, DMSO- d 6 )δ 159.6, 154.6, 145.7, 138.9, 137.2, 135.3, 135.1, 129.3, 126.7, 126.4,124.7, 124.5, 124.0, 123.9, 122.6, 121.7, 120.6, 118.5, 116.0, 112.4, 111.8,78.7, 63.2, 28.0, 17.2. HRMS (ESI-TOF) m / z [M + Na] + calcd. for C 29 H 26 N 4 O 3 Na501.1897, found 501.1904.

[0103] Physiological activity test of the compounds prepared in Examples 2-7 above:

[0104] Specific experimental operation: 5000 human leukemia K562 cells were inoculated into 96-well cell culture plates and allowed to grow for 24 hours. Then a certain concentration of the above compounds was added, with the anti-tumor drug cisplatin as a control, and the reaction was continued for 48 hours. Then the average 50% inhibition concentration (IC 50 Each concentration was repeated at least 3 times, and all experiments were repeated 3 times. The average results are shown in Table 1.

[0105] Table 1: Cell viability assay results

[0106] Compound Ⅳ-a Ⅳ-b Ⅳ-c Ⅳ-d Ⅳ-e Ⅳ-f Cisplatin <![CDATA[IC 50 ( u M) a ]]> 31.45 29.064 27.178 27.398 22.767 20.982 23.735

[0107] As can be seen from Table 1, some compounds of the present invention have anti-K562 activity comparable to or even better than that of cisplatin, indicating that such compounds are expected to become leading compounds for the treatment of leukemia.

[0108] The above descriptions are only some embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A tryptanthrin imine compound, characterized in that: It has the structure shown in the following structural formula (III-a):

2. The method for preparing the tryptanthrin imine compound according to claim 1, characterized in that: The steps include: At room temperature, tryptanthrin (I) is placed in an organic solvent and stirred, and an aza ylide reagent (II) is added, followed by heating and stirring to react for 12-48 hours. After the reaction is completed, it is directly separated and purified to obtain; Wherein, the tryptanthrin (I) has the following structure: The aza ylide reagent (II) has the following structure: Among them, R 1 and R 2 For H, R 3 For Boc.

3. The preparation method according to claim 2, characterized in that: The organic solvent is selected from one or more of dichloromethane, chloroform, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, trifluorotoluene, nitrobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide; The amount of the reactant aza ylide (II) used is at least 0.9 molar equivalents of tryptanthrin (I); The reaction temperature is 25-200°C.

4. A 6-amino-6-aryl indole quinazolinone compound prepared by using the compound according to claim 1, characterized in that: It has the structure shown in the following structural formula:

5. The preparation method according to claim 2, characterized in that: The separation and purification method is a combination of one or more of recrystallization and column chromatography.

6. The preparation method according to claim 5, characterized in that: The separation and purification solvent is selected from one or a mixture of petroleum ether, n-hexane, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

7. Use of the compound according to claim 1 in organic synthesis, characterized in that: The synthesized compound has the structure shown in the following structural formula:

8. Use of the compound according to claim 4 in the preparation of anti-leukemia drugs.

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