Chiral indolinoquinazolinone polycyclic compound containing dihydronaphthofuran structure, preparation method and use thereof

Abstract

The present invention discloses a chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure, having a structure as shown in formula (I), and belonging to the fields of organic synthetic chemistry and medicine. A preparation method is also disclosed, comprising dissolving tryptanthrin imine (II) and naphthol (III) in an organic solvent, then adding a molecular sieve and a chiral catalyst, and reacting at room temperature with stirring. After the reaction, separation and purification are performed to obtain the chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure. The polycyclic compound provided by the present invention has dihydronaphthofuran and indolinoquinazolinone substructures. The present invention also discloses the use of such compounds in the development of anti-tumor drugs, showing great potential in anti-tumor drug research. Furthermore, the preparation method of the present invention has the advantages of novelty, simplicity of operation, mild reaction conditions, high yield, and high stereoselectivity.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure, a preparation method and use thereof. Background Art

[0002] Tryptanthrin is a representative indolin-quinazolinone alkaloid found in many traditional Chinese medicines, including Radix Isatidis, Indigo Naturalis, Polygonum indigo, and Indigofera odorata. Furthermore, tryptanthrin has been detected in the metabolites of certain microorganisms. Studies have shown that tryptanthrin exhibits multiple pharmacological activities, including antibacterial, antiviral, antitumor, anti-inflammatory, and cardiovascular protective activities. It exhibits high medicinal value in the treatment of bacterial infections, tumors, inflammatory damage, and viral invasion, and its safety has been demonstrated in cytotoxicity and mouse toxicity studies (Bioadhesion Biofilm Res. 2019, 35, 1093; Arch. Pharmacal. Res. 2018, 41, 419; Appl. Magn. Reson. 2015, 46, 781; J. China Pharm. 2013, 22, 7). In addition, many tryptanthrin-derived indolin-oquinazolinone alkaloids also have good antibacterial and antitumor biological activities, such as Cruciferane, Phaitanthrin A / B / D, and Candidine (J. Med. Chem. 2013, 56, 8321-8331; Med. Sci. Monit. 2018, 24, 5668; Bioorganic Med. Chem. Lett. 2015, 25, 3867; J. Nat. Prod. 2008, 71, 1275). Therefore, the development of tryptanthrin-derived indolin-oquinazolinone alkaloids is of great significance and is a hot topic in drug research and development.

[0003] It has been shown that tryptanthrin ketone imine is a class of highly active and readily available organic synthons, which react with the aza-Friedel-Crafts reaction of indole and pyrrole to synthesize a large number of indole- or pyrrole-containing indole and quinazolinone derivatives (Org.Chem.Front.2023,10,5421). Through in vitro biological activity evaluation experiments, it was demonstrated that such indole- or pyrrole-containing indole and quinazolinone derivatives have good activity against human leukemia cells and lung cancer cells. In view of the high efficiency of the aforementioned tryptanthrin ketone imine in the synthesis of indole and quinazolinone alkaloids, and the huge potential of indole and quinazolinone alkaloids in new drug research and development, the development of structurally diverse indole and quinazolinone alkaloids has important practical significance and economic value. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a novel class of chiral indolinone and quinazolinone polycyclic compounds containing a dihydronaphthofuran structure, thereby providing sufficient and reliable candidate molecules for the development of new drugs.

[0005] The chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure provided by the present invention has a structure shown in the following structural formula (I), and contains a core structural unit of dihydronaphthofuran and indolinoquinazolinone:

[0006]

[0007] 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; R 4 The substituent is selected from one or more of aryl, alkyl, hydrogen, halogen, alkoxy, cyano, nitro, ester, carbonyl, alkylthio, and amino.

[0008] The application value of the compound of the present invention is:

[0009] 1. Molecules containing an indolinoquinazolinone backbone often exhibit excellent antibacterial, anti-inflammatory, and anti-tumor activities. For example, Phaitanthrin D (structure shown below) exhibits good binding affinity for both the Nsp9 replicase and the spike protein, and has great potential for inhibiting multiple molecular targets of SARS-CoV-2 (J. Biomol. Struct. Dyn. 2022, 40, 249). Furthermore, compounds containing a dihydronaphthofuran backbone also often exhibit excellent biological activity. For example, dihydronaphthofuran compound IV is a 5-lipoxygenase inhibitor (J. Med. Chem. 1996, 39, 5035), and compound V is an α-chymotrypsin inhibitor (Biochem. Biophys. Acta 1972, 258, 548). Therefore, it can be reasonably predicted that the chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure provided by the present invention has potential multiple biological activities, which can provide a sufficient source of compounds for new drug screening and is an important source for the development of new drugs;

[0010] 2. In vitro activity tests showed that the chiral indolinoquinazolinone polycyclic compounds containing a dihydronaphthofuran structure provided by the present invention all exhibited significant anti-leukemia cell activity. This result supports the prediction that the compounds provided by the present invention have good biological activity and also demonstrates the application potential of the present invention in the field of drug research and development.

[0011]

[0012] A second object of the present invention is to provide a method for synthesizing a chiral indolin-quinazolinone polycyclic compound containing a dihydronaphthofuran structure, the technical scheme of which is as follows: dissolving tryptanthrin imine (II) and naphthol (III) in an organic solvent, then adding a molecular sieve and a chiral catalyst, stirring and reacting at room temperature, and after the reaction is completed, separating and purifying to obtain a chiral indolin-quinazolinone polycyclic compound (I) containing a dihydronaphthofuran structure;

[0013] Wherein, the tryptanthrin imine (II) has the following structure:

[0014]

[0015] The naphthol (III) has the following structure:

[0016]

[0017] The synthetic route is:

[0018]

[0019] The present invention adopts the above-mentioned synthesis method to synthesize a series of novel chiral indolinoquinazolinone polycyclic compounds containing dihydronaphthofuran structure.

[0020] As a preferred technical solution: the organic solvent is selected from one or more of dichloromethane, chloroform, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, hexafluorobenzene, 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.

[0021] Hexafluorobenzene is further preferred as the solvent because it provides the highest reaction yield and best stereoselectivity.

[0022] As a preferred technical solution: the catalyst is selected from various acids, bases, and metal-base systems, including but not limited to sulfonic acid, carboxylic acid, organic phosphoric acid, titanium tetrachloride, boron trifluoride, triethylamine, tertiary amine-thiourea, tertiary amine-squaramide, copper-potassium carbonate, copper-cesium carbonate, scandium-potassium carbonate, and nickel-potassium carbonate; the catalyst is chiral or racemic.

[0023] A more preferred technical solution: the chiral catalyst is a chiral phosphoric acid having the following formula A, B, or C, or a chiral tertiary amine-squaramide having the following formula D or E, that is, the catalyst used is further preferably selected from one of the following:

[0024]

[0025] Catalyst B is further preferred because of its high reaction yield and good stereoselectivity.

[0026] As a preferred technical solution: the minimum usage of the catalyst is 0.1 mol%.

[0027] As a preferred technical solution: the minimum dosage of the naphthol compound is 1.0 equivalent of tryptanthrin imine.

[0028] 1.2 equivalents is further preferred because the reaction yield is high and the stereoselectivity is good.

[0029] As a preferred technical solution: the reaction temperature is any temperature between 0 and 100°C.

[0030] 35° C. is further preferred because the reaction yield is higher and the stereoselectivity is better.

[0031] As a preferred technical solution: the separation and purification method is a combination of one or more of beating, recrystallization, and column chromatography separation.

[0032] Column chromatography separation is further preferred because the purity of the product is high.

[0033] As a preferred technical solution: the separation and purification solvent is selected from one or more 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.

[0034] Petroleum ether, n-hexane, dichloromethane and ethyl acetate are further preferred because the purity of the product is high.

[0035] The third object of the present invention is to provide the use of the above-mentioned compound I in the preparation of anti-tumor drugs.

[0036] Specifically, the application value of the aforementioned Compound I disclosed in this invention lies in the fact that preliminary cell viability experiments have demonstrated that this class of compounds exhibits significant cytotoxicity against human leukemia K562 cells. The results of these cell viability studies are shown in Table 1. Therefore, through further research, this class of compounds is expected to become lead compounds for anti-tumor drugs.

[0037] Specific experimental procedures: 5000 human leukemia K562 cells were seeded into 96-well cell culture plates and allowed to grow for 24 hours. Then, certain concentrations of the above compounds were added, with the anti-tumor drug cisplatin as a control, and the reaction was continued for 48 hours. The average 50% inhibitory concentration (IC) of all compounds was then determined. 50 Each concentration was repeated at least 3 times, and all experiments were repeated 3 times. Some average results are shown in Table 1.

[0038] Table 1: Some results of cell viability assay

[0039]

[0040] 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 these compounds are expected to become lead compounds for the treatment of leukemia.

[0041] The advantages of the present invention are that, through the asymmetric [3+2] tandem cyclization reaction of tryptanthrin imine and naphthol, a series of novel chiral indolinoquinazolinone polycyclic compounds containing a dihydronaphthofuran structure are synthesized for the first time. These compounds possess both the advantageous skeletons of dihydronaphthofuran and indolinoquinazolinone and contain two consecutive chiral centers, providing a novel source for the screening and discovery of lead compounds and drug candidate molecules. Furthermore, in vitro cell activity experiments demonstrated that these compounds exhibited a potent inhibitory effect against human leukemia K562 cells, suggesting their potential as lead compounds for anti-leukemia drugs. Furthermore, the present method possesses the advantages of mild reaction conditions, readily available raw materials and catalysts, simple operation, and excellent stereoselectivity (>20:1 dr, 99% ee). BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the H NMR spectrum of compound Ⅰ-c obtained in Example 3;

[0043] Figure 2 This is the carbon NMR spectrum of compound Ⅰ-c obtained in Example 3;

[0044] Figure 3 This is the HPLC chromatogram of compound Ⅰ-c prepared in Example 3 (racemic);

[0045] Figure 4 This is the HPLC chromatogram (chirality) of compound Ⅰ-c obtained in Example 3;

[0046] Figure 5 This is the H NMR spectrum of I-h prepared in Example 8;

[0047] Figure 6This is the carbon NMR spectrum of I-h prepared in Example 8;

[0048] Figure 7 This is the HPLC chromatogram of compound I-h prepared in Example 8 (racemic);

[0049] Figure 8 This is the HPLC chromatogram (chirality) of compound I-h prepared in Example 8;

[0050] Figure 9 This is the single crystal structure diagram of Ⅰ-h prepared in Example 8. DETAILED DESCRIPTION

[0051] The present invention will be further described below with reference to the accompanying drawings.

[0052] The raw materials, solvents, catalysts, molecular sieves, etc. used in the present invention are all commercially available.

[0053] Example 1:

[0054] Synthesis of compound Ⅰ-a

[0055]

[0056] Synthesis of compound Ia:

[0057] In a dry reaction tube, tryptanthrin imine II-a (0.1 mmol), 2-naphthol III-a (0.12 mmol), molecular sieves (50 mg), solvent (2 mL), and chiral catalysts A / B / C / D / E (5 mol%) were added in sequence. The reaction was then allowed to proceed at 35°C. After completion of the reaction, the solvent was evaporated under reduced pressure. The crude product residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-a. The different reaction conditions are shown in Table 1. The specific reaction process is as follows:

[0058]

[0059] Table 1 Optimization results of some reaction conditions

[0060]

[0061] Note: The time in Table 1 is the time it takes for compound II-a to completely disappear.

[0062] As can be seen from Table 1, the Molecular sieve, catalyst B, and 4 mL of hexafluorobenzene as solvent are more preferred.

[0063] Compound Ia is a light yellow solid with a yield of 99%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 97% (ee); [α]D 20 =+299.44(c=2.0g / 100mL, CH2Cl2);

[0064] The ee value was determined by HPLC using a Chiralpak IC column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =8.9min,t minor =13.0min;

[0065] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=7.6Hz,2H),8.38(d,J=8.1Hz,1H),8.09(d,J=7.8Hz,1H),7.94(d,J=8.2Hz,1H ),7.87-7.68(m,3H),7.56(t,J=7.5Hz,1H),7.41(dt,J=23.4,7.6Hz,2H),7.30-6.66(m,5H),1.47-0.57(m,9H). 13 C NMR(101MHz,DMSO-d6)δ159.0,155.0,154.6,143.1,141.0,134.5,132.2,130.8,129.8,129.4,129.1,127.7,127.6 ,125.0,123.6,122.1,119.9,117.7,116.3,115.8,114.1,113.2,112.0,79.3,72.5,27.6.HRMS(ESI-TOF)m / z[M+H] + calcd.for C 30 H 26 N3O4492.1918, found 492.1926.

[0066] Example 2:

[0067] Synthesis of compound Ⅰ-b

[0068]

[0069] In a dry reaction tube, tryptanthrin imine II-b (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was completed by spot plate monitoring, the solvent was evaporated under reduced pressure. The crude product residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-b;

[0070] Compound Ib is a light yellow solid with a yield of 99%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 99% (ee); [α] D 20 =+286.0(c=1.1g / 100mL, CH2Cl2);

[0071] The ee value was determined by HPLC using a Chiralpak IB column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =7.9min,t minor =11.6min;

[0072] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.91-8.53(m,2H),8.28(d,J=8.1Hz,1H),7.93(d,J=8.2Hz,1H),7.82(d,J=8.7 Hz,1H),7.78-7.66(m,3H),7.52-7.41(m,2H),7.40-7.33(m,1H),7.29-6.73(m,4H),1.38-0.81(m,9H). 13 C NMR(101MHz,DMSO-d6)δ158.0,156.0(d,J=237.6Hz,1C),154.5,140.5,139.8,130.9,129.8,129.4,129.0(d,J=7.8Hz,1C),127.7,125.3,123.5 ,122.3(d,J=23.7Hz,1C),117.8,117.5,116.2,114.7,114.6,113.1,112.6(d,J=23.9Hz,1C),112.0,79.3,72.5,27.6.HRMS(ESI-TOF)m / z[M+H] + calcd.forC 30 H 25 FN3O4510.1824, found 510.1845.

[0073] Example 3:

[0074] Synthesis of compound Ⅰ-c

[0075]

[0076] In a dry reaction tube, tryptanthrin imine II-c (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was complete, the solvent was evaporated under reduced pressure. The crude product residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-c.

[0077] Compound I-c is a light yellow solid with a yield of 99%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 97% (ee); [α] D 20 =+284.75(c=1.6g / 100mL, CH2Cl2);

[0078] The ee value was determined by HPLC using a Chiralpak IC column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =7.0min,t minor =16.9min;

[0079] HPLC racemic and chiral chromatograms are shown in Figure 3 and Figure 4 ;

[0080] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.90-8.45(m,2H),8.34-8.25(m,1H),8.01(d,J=7.8Hz,1H),7.94(d,J=8.2Hz,1H),7.84(d,J=8.8 Hz,1H),7.77-7.69(m,1H),7.59-7.49(m,2H),7.48-7.40(m,1H),7.27-7.18(m,1H),7.18-6.66(m,4H),1.44-0.72(m,9H). 13CNMR(101MHz,DMSO-d6)δ159.1(d,J=242.4Hz,1C),158.7,154.8,154.7,143.0,137.3,134.6,131.2,129.8,129.4,128.9,128.0,127 .5,123.7,122.2,119.9,117.4(d,J=8.1Hz,1C),116.8,115.7,113.8,113.3,112.0,110.6,79.5,72.3,27.5.HRMS(ESI-TOF)m / z[M+H] + calcd.for C 30 H 25 FN3O4510.1824, found 510.1835; hydrogen spectrum and carbon spectrum are as follows Figure 1 and Figure 2 shown.

[0081] Example 4:

[0082] Synthesis of compound Ⅰ-d

[0083]

[0084] In a dry reaction tube, tryptanthrin imine II-d (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was complete, the solvent was evaporated under reduced pressure. The crude product residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-d.

[0085] Compound I-d is a light yellow solid with a yield of 98%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 99% (ee); [α] D 20 =+255.31(c=2.6g / 100mL, CH2Cl2);

[0086] The ee value was determined by HPLC using a Chiralpak IC column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =6.9min,t minor =13.6min.

[0087] Structure identification: 1H NMR (400MHz, DMSO-d6) δ8.89-8.44(m,2H),8.30(d,J=8.7Hz,1H),8.02(d,J=7.8Hz,1H),7.95(d,J=8.2Hz,1H),7.8 4(d,J=8.8Hz,1H),7.79-7.65(m,2H),7.59-7.50(m,1H),7.49-7.40(m,2H),7.21-6.93(m,4H),1.45-0.73(m,9H). 13 C NMR(101MHz,DMSO-d6)δ158.9,154.9,154.7,143.2,139.8,134.8,131.3,129.8,129.5,129.2,128.9,128.5,128.0,12 7.6,123.8,123.1,122.2,120.0,117.6,116.7,115.8,113.7,113.1,112.0,79.6,72.3,27.6.HRMS(ESI-TOF)m / z[M+H] + calcd.forC 30 H 25 ClN3O4526.1528,found526.1534.

[0088] Example 5:

[0089] Synthesis of compound Ⅰ-e

[0090]

[0091] In a dry reaction tube, tryptanthrin imine II-e (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was completed by plate monitoring, the solvent was evaporated under reduced pressure. The crude product residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-e;

[0092] Compound Ie is a light yellow solid with a yield of 98%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 97% (ee); [α] D 20 =+267.22(c=1.7g / 100mL, CH2Cl2);

[0093] The ee value was determined by HPLC using a Chiralpak IB column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =8.6min,t minor =10.8min.

[0094] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.89-8.43(m,2H),8.07-7.98(m,2H),7.94(d,J=8.2Hz,1H),7.83(d,J=8.8Hz ,1H),7.78-7.65(m,2H),7.59-7.51(m,1H),7.48-7.40(m,1H),7.19-6.74(m,5H),1.46-0.72(m,9H). 13 C NMR(101MHz,DMSO-d6)δ162.4(d,J=244.4Hz,1C),159.1,154.9,154.5,1 43.2,142.1,134.9,131.0,129.8,129.4,128.9,127.8,127.6,124.8,123 .7,122.1,120.0,117.4,115.9,113.6,113.5,112.0,111.7(d,J=22.2Hz ,1C),103.7(d,J=29.3Hz,1C),79.4,72.0,27.6.HRMS(ESI-TOF)m / z[M+H] + calcd.for C 30 H 25 FN3O4510.1824, found 510.1826.

[0095] Example 6:

[0096] Synthesis of compound Ⅰ-f

[0097]

[0098] In a dry reaction tube, add tryptanthrin imine II-f (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was completed by spot plate monitoring, the solvent was evaporated under reduced pressure. The crude product residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound I-f;

[0099] Compound I-f is a light yellow solid with a yield of 98%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 98% (ee); [α] D 20 =+320.83(c=0.6g / 100mL, CH2Cl2);

[0100] The ee value was determined by HPLC using a Chiralpak IB column; mobile phase: 95 / 5 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =11.3min,t minor =17.6min;

[0101] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.95-8.45(m,2H),8.33-8.27(m,1H),8.01(d,J=7.8Hz,1H),7.95(d,J=8.2Hz,1H),7.85(d,J=8.8 Hz,1H),7.79-7.66(m,2H),7.60-7.52(m,1H),7.49-7.41(m,1H),7.25-7.18(m,1H),7.17-6.67(m,4H),1.43-0.73(m,9H). 13 CNMR(101MHz,DMSO-d6)δ159.1,154.9,154.6,143.2,142.0,134.9,133.5,131.2,129.8,129.4,128.9,127.9,1 27.6,124.9,123.7,122.2,120.0,117.0,115.9,113.5,113.2,112.0,79.5,72.1,27.5.HRMS(ESI-TOF)m / z[M+H] + calcd.for C 30 H 25 ClN3O4526.1528,found526.1537.

[0102] Example 7:

[0103] Synthesis of compound Ⅰ-g

[0104]

[0105] In a dry reaction tube, tryptanthrin imine II-a (0.1 mmol), 2-naphthol III-b (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After the reaction was complete, the solvent was evaporated under reduced pressure. The crude product residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound Ig;

[0106] Compound I-g is a light yellow solid with a yield of 99%; the diastereomeric ratio is >20:1, and the enantiomeric excess is 95% (ee); [α] D 20 =+143.43(c=0.7g / 100mL, CH2Cl2);

[0107] The ee value was determined by HPLC using a Chiralpak IC column; mobile phase: 90 / 10 n-hexane / ethanol; flow rate: 0.8 mL / min; detection wavelength λ = 254 nm; retention time t major =8.3min,t minor =11.7min;

[0108] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ8.85-8.41(m,2H),8.29(d,J=8.1Hz,1H),8.22(s,1H),8.01(d,J=7.8Hz,1H),7.90- 7.77(m,2H),7.74-7.64(m,1H),7.58-7.50(m,1H),7.41-7.31(m,1H),7.29-6.95(m,5H),1.40-0.61(m,9H). 13 C NMR(101MHz,DMSO-d6)δ158.9,154.9,143.0,140.8,134.6,131.0,131.0,130.5,130.0,129.3,127.6,127.5,125.1,12 4.4,123.5,119.9,118.0,116.3,116.2,115.8,113.9,113.5,113.4,113.2,79.3,72.2,27.5.HRMS(ESI-TOF)m / z[M+H] + calcd.for C 30 H 25 BrN3O4570.1023, found 570.1029.

[0109] Example 8

[0110] Synthesis of compound Ⅰ-h

[0111]

[0112] In a dry reaction tube, tryptanthrin imine II-h (0.1 mmol), 2-naphthol III-a (0.12 mmol), Molecular sieves (50 mg), hexafluorobenzene (4 mL) and chiral phosphoric acid (5 mol%) of the aforementioned structural formula B were reacted at 35°C. After completion of the reaction, the solvent was evaporated under reduced pressure. The crude product residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 6:1) to obtain compound Ih.

[0113] Compound I-h was a light yellow solid with a yield of 98%; the diastereomeric ratio was >20:1, and the enantiomeric excess was 92% (ee); [α] D 20 = +294.25 (c = 1.0 g / 100 mL, CH2Cl2); HPLC racemic and chiral chromatograms are shown in Figures 1 and 2. Figure 7 and Figure 8 , single crystal structure such as Figure 9 The single crystal structure data are shown in Table 2.

[0114] Table 2 Single crystal structure data of compound I-h

[0115]

[0116] The ee value was determined by HPLC using a Chiralpak IB column; mobile phase: 80 / 20 hexane / ethanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =5.9min,t minor =7.7min;

[0117] Structure identification: 1 H NMR (400MHz, DMSO-d6) δ9.25-8.65(m,1H),8.64-8.48(m,1H),8.27(d,J=8.0Hz,1H),8.00(d,J=8.4Hz,1H),7.93(d,J=8.2Hz,1H), 7.82(d,J=8.7Hz,1H),7.77-7.60(m,2H),7.49-7.40(m,1H),7.40-7.32(m,1H),7.27(s,1H),7.19-6.75(m,4H),1.47-0.71(m,9H). 13C NMR(101MHz,DMSO-d6)δ158.2,154.7,154.4,144.3,140.5,139.1,130.9,129.8,129.5,129.4,129.0,127.7,125.3 ,123.6,122.4,120.1,117.4,117.3,116.2,115.2,112.8,112.7,111.9,79.3,72.5,27.6.HRMS(ESI-TOF)m / z[M+H] + calcd.forC 30 H 25 ClN3O4526.1528, found 526.1531; the H NMR spectrum and C NMR spectrum of Ⅰ-h are as follows Figure 5-6 shown.

[0118] 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 scope of protection of the present invention.

Claims

1. A chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure, characterized in that: Has the following structure: ， ， ， ， ， ， ， 。 2. A method for preparing a chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure as claimed in claim 1, characterized in that: Tryptanthrin imine (II) and naphthol compound (III) are dissolved in an organic solvent, and then molecular sieves and a chiral catalyst are added, and the mixture is stirred at room temperature for reaction. After the reaction is completed, the mixture is separated and purified to obtain the product; Wherein, the tryptanthrin imine (II) has the following structure: ； The naphthol (III) has the following structure: ； The R 1 、R 2 、R 3 、R 4 The substituents are selected from the substituents corresponding to the compound according to claim 1; The chiral catalyst is selected from one of the following compounds: 。 3. The preparation method according to claim 2, wherein: The organic solvent is selected from at least one of dichloromethane, chloroform, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, trifluorotoluene, hexafluorobenzene, 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.

4. The preparation method according to claim 3, wherein: The organic solvent is selected from hexafluorobenzene.

5. The preparation method according to claim 2, wherein: The molecular sieve is selected from one of the molecular sieves with different pore sizes, including Type molecular sieve.

6. The preparation method according to claim 2, wherein: The minimum amount of the naphthol compound (III) is 1.0 equivalent of the tryptanthrin imine (II); and the minimum amount of the catalyst is 0.1 mol%.

7. 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 separation methods; the separation and purification solvent is selected from one or more 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.

8. Use of the compound according to claim 1 in the preparation of a medicament for treating leukemia.

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