CN113105468A - Polycyclic spiroindolone compound containing benzopyrone and preparation method and application thereof - Google Patents
Polycyclic spiroindolone compound containing benzopyrone and preparation method and application thereof Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of pharmaceutical chemicals, and discloses a polycyclic spiroindolone compound containing benzopyrone and a preparation method and application thereof. The structure of the compound is shown in the following formula I, and the polycyclic spiroindolone compound containing benzopyrone has good biological activity and is expected to become a novel antimalarial drug. The invention also discloses a preparation method of the polycyclic spiroindolone compound containing benzopyrone. The preparation method of the benzopyrone-containing polycyclic spiroindolone compound has the advantages of simple and easily obtained raw materials and catalysts, wide substrate range applicability, excellent selectivity, mild reaction conditions and moderate to excellent yield for a series of benzopyrone-containing polycyclic spiroindolone compounds.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a polycyclic spiroindolone compound containing benzopyrone, and a preparation method and application thereof.
Background
In the research of medicinal chemistry, polycyclic spiroindolone structural units are an important dominant framework. Research shows that the polycyclic spiroindolone compound generally has wide biological activity and good pharmaceutical activity, shows biological activity such as anti-inflammatory, anti-HIV, antifungal, antitumor, antiviral and the like, and has certain inhibiting effect on tuberculosis. As shown below, NITD609 is an antimalarial drug that attacks multiple plasmodium proteins and kills the two most common plasmodium species; the natural product Citrinadin B has strong anti-tumor activity; gelsemine alkaloid has hypnotic and anti-injury effects, and can effectively relieve chronic pain.
Disclosure of Invention
In order to overcome the disadvantages and shortcomings of the prior art, the invention provides a polycyclic spiroindolone compound containing benzopyrone.
The invention also aims to provide a preparation method of the benzopyrone-containing polycyclic spiroindolone compound.
The invention further aims to provide application of the benzopyrone-containing polycyclic spiroindolone compounds.
The purpose of the invention is realized by the following scheme:
a polycyclic spiroindolone compound containing benzopyrone has a chemical structure general formula shown in formula I:
wherein R is1Represents a substituent on the benzene ring to which it is attached, and is selected from any one of H, alkyl, halogen and alkoxy;
R2representsOne or more substituents on the benzene ring to which they are attached, wherein when a plurality of substituents are represented, the plurality of substituents may be linked to form a ring or may be independent of each other, and when R represents a ring2When represents one substituent or a plurality of independent substituents on the corresponding benzene ring, a plurality of R2The same or different is selected from one of H, alkyl, halogen and alkoxy; when R is2When a plurality of substituents which can form a ring on the corresponding benzene ring are represented, the ring formed is preferably a benzene ring (for example, the following formula I-8). (ii) a
R3Any one selected from alkyl, benzyl and allyl.
Preferably, the benzopyrone-containing polycyclic spiroindolone compound has a chemical structure of one of the following structural formulas:
more preferably, the benzopyrone-containing polycyclic spiroindolone compound has a chemical structure of one of the following structural formulas:
the preparation method of the polycyclic spiroindolone compound containing benzopyrone comprises the following steps: under the protection of nitrogen, uniformly mixing a catalyst, a compound shown as a formula II, a compound shown as a formula III and a solvent, stirring at a reaction temperature of-80-100 ℃ until the reaction is finished, and separating to obtain the compound shown as the formula I.
Wherein R is1Represents a substituent on the benzene ring to which it is attached, and is selected from any one of H, alkyl, halogen and alkoxy;
R2represents one or more substituents on the phenyl ring to which it is attachedWhen a plurality of substituents are represented, the plurality of substituents may be linked to form a ring or may be independent of each other, and when R represents a group2When represents one substituent or a plurality of independent substituents on the corresponding benzene ring, a plurality of R2The same or different is selected from one of H, alkyl, halogen and alkoxy; when R is2When a plurality of substituents which can form a ring on the corresponding benzene ring are represented, the ring formed is preferably a benzene ring;
R3any one selected from alkyl, benzyl and allyl.
The compound shown in the formula II and the compound shown in the formula III are used in the following amount: the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1.2-1.6: 1, preferably 1.5: 1.
The catalyst is inorganic base or organic base; wherein the organic base is 1,2,2,6, 6-pentamethylpiperidine (PMP), triethylene Diamine (DABCO), sodium tert-butoxide (tBuONa), 1,5, 7-triazabicyclo (4.4.0) dec-5-ene (TBD), potassium tert-butoxide (tBuOK), triethylamine (Et)3N), 1,3, 3-Tetramethylguanidine (TMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0]Dec-5-ene (MTBD), sodium methoxide (MeONa), and 1, 8-diazabicyclo [5.4.0]Any one of undec-7-ene (DBU); the inorganic alkali is potassium hydroxide (KOH) and cesium carbonate (Cs)2CO3) Sodium hydroxide (NaOH) and potassium carbonate (K)2CO3) Any one of them.
The catalyst is used in an amount which satisfies the following conditions: the amount of the catalyst is 0.01 to 1 time the amount of the compound represented by the formula III.
The solvent is at least one of tetrahydrofuran, chlorobenzene, trifluoroethanol, acetone, toluene, 1,2, 2-tetrachloroethane, ethyl acetate, dichloromethane, dimethylformamide, diethyl ether, fluorobenzene, bromobenzene, 1, 2-dichloroethane, nitromethane, 1, 2-trichloroethane, chloroform, 1, 4-dioxane, acetonitrile and methanol.
The dosage of the solvent is such that 0.2-10 mL of solvent is added to 1mmol of the compound shown in the formula III.
The separation is preferably carried out by concentrating the reaction solution and then carrying out direct column chromatography.
The reaction temperature is preferably 35 ℃.
The application of the polycyclic spiroindolone compound containing benzopyrone in preparing antimalarial drugs.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a polycyclic spiroindolone compound with benzopyrone
The compound is a series of novel polycyclic spiroindolone compounds with benzopyrone, and the polycyclic spiroindolone compounds with benzopyrone have good biological activity and are expected to become novel antimalarial drugs.
The invention also discloses a preparation method of the polycyclic spiroindolone compound with benzopyrone. The preparation method has the advantages of simple and easily obtained raw materials and catalysts, wide substrate range applicability, excellent selectivity, mild reaction conditions and moderate to excellent yield of a series of polycyclic spiroindolone compounds with benzopyrone.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
The reagents used in the examples are commercially available without specific reference.
Examples in which the compound represented by the formula II is tert-butyl (3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate or a derivative thereof, can be synthesized according to the following literature methods [ N. -J.Zhong, F.Wei, Q. -Q.Xua, L.Liu, D.Wang, Y. -J.Chen, chem.Commun.2013,49,11071-11073 ]; the compound shown in the formula III is chromone-3-formaldehyde or a derivative thereof.
Example 1
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds represented by formula I-1:
under the protection of nitrogen, tert-butyl (3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate II-1 (109.9mg,0.35mmol), chromone-3-carbaldehyde III-1 (34.8mg,0.20mmol), catalyst (DABCO) triethylenediamine (6.8mg,0.060mmol) and solvent CH were added in this order to a 10mL reaction flask2Cl2(2.0 mL). After the reaction solution was stirred at 0 ℃ for 4 hours, the TLC detected that the reaction of the starting materials was almost completed, and the reaction was stopped. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/5) to obtain 65.0mg of product I-1 yellow solid with the yield of 95%.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-1:1H NMR(500MHz,CDCl3):δ7.72(dd,J＝8.0,2.0Hz,1H),7.53(td,J＝9.0,2.0Hz,1H),7.41(td,J＝8.0,1.5Hz,1H),7.21–7.15(m,3H),7.06–7.02(m,2H),6.93(d,J＝7.5Hz,1H),5.77(dd,J＝7.5,2.5Hz,1H),3.59(d,J＝7.5Hz,1H),3.18(s,3H).13C NMR(125MHz,CDCl3):δ188.83,172.04,159.64,146.30,144.26,136.91,130.36,127.07,126.85,124.43,123.65,122.92,122.31,121.53,118.43,112.48,109.23,80.91,65.78,54.88,26.88.(ESI):Exact mass calcd for C21H14N2NaO3[M+Na]+:365.0895,Found:365.0897.
example 2
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds represented by formula I-2:
under nitrogen, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-2 (49.2mg,0.15mmol), chromone-3-carbaldehyde III-1 (17.4mg,0.10mmol), catalyst (MTBD) 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (1.6mg,0.010mmol) and solvent DCE (1.0mL) were added in this order to a 25mL reaction flask. After the reaction solution was stirred at-10 ℃ for 5 hours, the TLC detection showed that the reaction was substantially complete and the reaction was stopped. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/6) to obtain 31.7mg of product I-2 yellow solid with the yield of 89%.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-2:1H NMR(400MHz,CDCl3)δ7.73(dd,J＝8.0,1.6Hz,1H),7.55–7.49(m,1H),7.16–7.10(m,2H),7.06–6.97(m,4H),5.76(dd,J＝8.0,2.8Hz,1H),3.55(d,J＝8.0Hz,1H),3.44(s,3H),2.60(s,3H).13C NMR(100MHz,CDCl3)δ188.96,172.76,159.63,146.11,141.95,136.88,134.10,127.65,126.83,124.69,122.28,121.54,120.86,120.84,118.41,112.55,80.93,65.38,55.25,30.24,18.93.Exact mass calcd for C22H16N2NaO3[M+Na]+:379.1053,Found:379.1056.
example 3
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of formula I-3:
5-fluoro-substituted tert-butyl (3- (1-cyanovinyl) -1-methyl-2-oxoindol-3-yl) carbonate II-3 (49.8mg,0.15mmol), chromone-3-carbaldehyde III-1 (17.4mg,0.10mmol), catalyst (TBD)1,5, 7-triazabicyclo (4.4.0) dec-5-ene (2.8mg,0.020mmol), and solvent THF (1.0mL) were added in this order to a 25mL reaction flask under nitrogen. After the reaction solution was stirred at 10 ℃ for 6 hours, the TLC detected that the reaction of the starting materials was almost completed, and the reaction was stopped. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/6) to obtain 31.0mg of product I-3 yellow solid with the yield of 86%.
Analytical data for benzopyrone-containing polycyclic spiroindolones of formula I-3:1H NMR(400MHz,CDCl3)δ7.72(dd,J＝8.0,1.6Hz,1H),7.57–7.50(m,1H),7.20(d,J＝2.8Hz,1H),7.13(td,J＝8.8,2.8Hz,1H),7.07–7.02(m,2H),6.96(dd,J＝7.2,2.4Hz,1H),6.87(dd,J＝8.8,4.0Hz,1H),5.77(dd,J＝8.0,2.8Hz,1H),3.55(d,J＝8.0Hz,1H),3.17(s,3H)；13C NMR(100MHz,CDCl3)δ188.68,171.77,159.67(d,J＝241Hz),159.64,146.75,140.22,137.10,128.44(d,J＝8.0Hz),126.88,123.83,122.43,121.43,118.47,116.80(d,J＝23Hz),112.26,111.43,111.18,109.96(d,J＝8.0Hz),80.74,65.91,54.81,27.06.Exact mass calcd for C21H13FN2NaO3[M+Na]+:383.0802,Found:383.0810.
example 4
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of formula I-4:
under the protection of nitrogen, 5-methoxy substituted tert-butyl (3- (1-cyanovinyl) -1-methyl-2-oxoindol-3-yl) carbonate II-4 (51.6,0.15mmol), chromone-3-carbaldehyde III-1 (17.4mg,0.10mmol) and catalyst (DBU)1, 8-diazabicyclo [5.4.0] were added in sequence to a 10mL reaction flask]Undec-7-ene (6.1mg,0.040mmol) and solvent CH3CN (1.0 mL). After the reaction solution was stirred at 30 ℃ for 5 hours, the reaction was stopped after the starting material had substantially reacted by TLC. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether ═ 1/5), so that 33.9mg of the product I-4 yellow solid is obtained, and the yield is 91%.
Analytical data for benzopyrone-containing polycyclic spiroindolones of formula I-4:1H NMR(400MHz,CDCl3)δ7.72(dd,J＝8.0,1.6Hz,1H),7.55–7.49(m,1H),7.17(d,J＝2.7Hz,1H),7.07–7.00(m,2H),6.92(dd,J＝8.8,2.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.79(d,J＝2.4Hz,1H),5.76(dd,J＝7.6,2.8Hz,1H),3.80(s,3H),3.56(d,J＝8.0Hz,1H),3.15(s,3H)；13C NMR(101MHz,CDCl3)δ188.82,171.65,159.62,156.70,146.35,137.58,136.93,128.18,126.85,124.40,122.30,121.45,118.42,114.31,112.49,110.58,109.66,80.87,66.12,55.77,54.86,26.97.Exact mass calcd for C22H16N2NaO4[M+Na]+:395.1002,Found:395.1005.
example 5
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of the formula I-5:
under nitrogen, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-1 (47.1mg,0.15mmol), 6-methyl-3-formylchromone III-2 (18.8mg,0.10mmol), the catalyst triethylamine (3.6mg,0.035mmol), and the solvent EtOAc (1.0mL) were added sequentially to a 10mL reaction flask. After the reaction solution was stirred at 25 ℃ for 1 hour, the reaction was stopped by TLC after the starting material had reacted substantially. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/5) to obtain 32.0mg of product I-5 yellow solid with the yield of 90 percent.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-5:1H NMR(400MHz,CDCl3)δ7.50(d,J＝1.6Hz,1H),7.44–7.38(m,1H),7.33(dd,J＝8.8,2.0Hz,1H),7.19–7.14(m,3H),6.96-6.90(m,2H),5.73(dd,J＝8.0,2.8Hz,1H),3.56(d,J＝8.0Hz,1H),3.18(s,3H),2.28(s,3H)；13C NMR(100MHz,CDCl3)δ188.99,172.09,157.65,146.50,144.20,138.03,131.81,130.31,127.13,126.42.124.22,123.63,122.90,121.11,118.17,112.52,109.20,80.77,65.70,54.86,26.87,20.41.(ESI):Exact mass calcd for C22H16N2NaO3[M+Na]+:379.1053,Found:379.1049.
example 6
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of the formula I-6:
under the protection of nitrogen, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-1 (47.1mg,0.15mmol), 7-bromo-3-formylchromone III-3 (25.3mg,0.10mmol), catalyst (PMP)1,2,2,6, 6-pentamethylpiperidine (7.8mg,0.050mmol) and solvent CHCl were added in this order to a 10mL reaction flask3(1.0 mL). After the reaction solution was stirred at 35 ℃ for 4 hours, the reaction was stopped by TLC after the starting material had reacted substantially. Directly subjecting the reaction solution to column chromatography, eluting with eluent (ethyl acetate)Ester/petroleum ether (1/7) to give product i-6 as a yellow solid 28.1mg, 67% yield.
Analytical data for benzopyrone-containing polycyclic spiroindolones of formula I-6:1H NMR(400MHz,CDCl3)δ7.82(d,J＝2.4Hz,1H),7.59(dd,J＝8.8,2.8Hz,1H),7.46–7.38(m,1H),7.21–7.16(m,2H),7.15(d,J＝2.4Hz,1H),6.96–6.92(m,2H),5.76(dd,J＝7.6,2.8Hz,1H),3.58(d,J＝7.6Hz,1H),3.18(s,3H)；13C NMR(100MHz,CDCl3)δ187.70,171.88,158.48,145.94,144.16,139.53,130.52,129.22,126.68,124.55,123.79,122.93,122.38,120.45,114.95,112.30,109.35,81.09,65.89,54.24,26.92.Exact mass calcd for C21H13BrN2NaO3[M+Na]+:443.0002,Found:442.9993.
example 7
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of formula I-7:
under nitrogen protection, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-1 (47.1mg,0.15mmol), 7-benzyloxy-3-formylchromone III-4 (28.0mg,0.10mmol), cesium carbonate as a catalyst (3.3mg,0.010mmol), and toluene as a solvent (1.0mL) were added in this order to a 10mL reaction flask. After the reaction solution was stirred at 40 ℃ for 2 hours, the reaction was stopped by TLC after the starting material had reacted substantially. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether-1/7) to obtain 37.2mg of product I-7 yellow solid with the yield of 83 percent.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-7:1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.8Hz,1H),7.44–7.33(m,7H),7.20–7.13(m,3H),6.92(d,J＝7.6Hz,1H),6.66(dd,J＝8.8,2.4Hz,1H),6.54(d,J＝2.4Hz,1H),5.75(dd,J＝7.7,2.8Hz,1H),5.09(s,2H),3.53(d,J＝8.0Hz,1H),3.18(s,3H)；13C NMR(100MHz,CDCl3)δ186.77,171.98,165.95,161.70,146.31,144.24,135.68,130.31,128.74,128.37,127.52,127.08,124.55,123.65,122.92,115.30,112.53,111.47,109.20,102.07,81.20,70.43,65.61,54.50,26.90.Exact mass calcd for C28H20N2NaO4[M+Na]+:471.1315,Found:471.1316.
example 8
Synthesizing a benzopyrone-containing polycyclic spiroindolone compound shown in formula I-8:
under nitrogen protection, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-1 (47.1mg,0.15mmol), 4-oxo-4H-benzo chromene-3-amino carboxaldehyde III-5 (22.4mg,0.10mmol), catalyst NaOH (1.2mg,0.030mmol) and solvent bromobenzene (1.0mL) were added sequentially to a 10mL reaction flask. After the reaction solution was stirred at 50 ℃ for 3 hours, the reaction was stopped by TLC after the starting material had reacted substantially. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether ═ 1/7), and 25.9mg of product I-8 yellow solid is obtained, with the yield of 66%.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-8:1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.0Hz,1H),7.78(d,J＝8.4Hz,1H),7.69(d,J＝8.8Hz,1H),7.66–7.61(m,1H),7.59–7.52(m,1H),7.45–7.37(m,2H),7.33(d,J＝2.4Hz,1H),7.25–7.16(m,2H),6.93(d,J＝8.0Hz,1H),5.95(dd,J＝8.0,2.8Hz,1H),3.70(d,J＝8.0Hz,1H),3.16(s,3H)；13C NMR(100MHz,CDCl3)δ187.92,171.93,158.03,146.15,144.26,137.93,130.38,130.10,127.86,127.01,126.42,124.79,124.73,123.88,123.68,122.98,121.87,121.21,115.86,112.52,109.25,81.59,65.85,54.48,26.88.Exact mass calcd for C25H16N2NaO3[M+Na]+:415.1053,Found:415.1055.
example 9
Synthesizing a benzopyrone-containing polycyclic spiroindolone compound shown in formula I-9:
under nitrogen protection, tert-butyl (3- (1-cyanovinyl) -1, 7-dimethyl-2-oxoindol-3-yl) carbonate II-1 (47.1mg,0.15mmol), 6-chloro-7-methyl-4-oxo-4H-chromene-3-carbaldehyde III-6 (22.2mg,0.10mmol), catalyst KOH (2.3mg,0.040mmol) and solvent fluorobenzene (1.0mL) were added in this order to a 10mL reaction flask. After the reaction solution was stirred at 60 ℃ for 5 hours, the reaction was stopped by TLC after the starting material had substantially reacted. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/7) to obtain 28.1mg of product I-9 as a yellow solid with the yield of 72 percent.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-9:1H NMR(400MHz,CDCl3)δ7.67(s,1H),7.44–7.38(m,1H),7.21–7.14(m,3H),6.96–6.90(m,2H),5.75(dd,J＝8.0,2.8Hz,1H),3.54(d,J＝7.6Hz,1H),3.17(s,3H),2.38(s,3H)；13C NMR(100MHz,CDCl3)δ187.40,171.88,157.87,146.34,146.13,144.20,130.47,128.46,126.79,126.51,124.55,123.77,122.94,120.39,120.07,112.39,109.31,81.03,65.80,54.25,26.91,20.95.Exact mass calcd for C22H15ClN2NaO3[M+Na]+:413.0663,Found:413.0659.
example 10
Synthesis of benzopyrone-containing polycyclic spiroindolone Compounds of formula I-10:
under nitrogen protection, 1-benzyl- (3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonic acid tert-butyl ester II-5 (58.5mg,0.15mmol), chromone-3-carbaldehyde III-1 (17.4mg,0.10mmol), catalyst potassium tert-butoxide (3.4mg,0.030mmol) and solvent acetone (1.0mL) were added in this order to a 10mL reaction flask. After the reaction solution was stirred at 70 ℃ for 2 hours, the reaction was stopped by TLC after the starting material had substantially reacted. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/5) to obtain the product I-10 as a yellow solid 36.0mg with 86% yield.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-10:1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.8Hz,1H),7.54-7.48(m,1H),7.33-7.28(m,2H),7.27-7.22(m,4H),7.20-7.13(m,2H),7.12-7.07(m,1H),7.05-7.00(m,2H),6.71(d,J＝8.0Hz,1H),5.76(dd,J＝8.0,2.8Hz,1H),4.91-4.80(m,2H),3.63(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ188.68,172.28,159.62,146.36,143.24,136.97,134.64,130.24,128.75,127.63,127.01,126.99,126.83,124.46,123.01,122.28,121.47,118.38,110.38,112.52,80.93,65.85,54.77,44.38.Exact mass calcd for C27H18N2NaO3[M+Na]+:441.1210,Found:441.1207.
example 11
Synthesis of benzopyrone-containing polycyclic spiroindolone compounds of formula I-11:
under nitrogen protection, 1-allyl- (3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonic acid tert-butyl ester II-6 (51.0mg,0.15mmol), chromone-3-carbaldehyde III-1 (17.4mg,0.10mmol), sodium tert-butoxide as a catalyst (1.0mg,0.010mmol) and methanol as a solvent (1.0mL) were added in this order to a 10mL reaction flask. After the reaction solution was stirred at 80 ℃ for 5 hours, the reaction was stopped after the starting material had substantially reacted by TLC. The reaction solution is directly subjected to column chromatography and eluent (ethyl acetate/petroleum ether: 1/5) to obtain 31.3mg of product I-11 yellow solid with the yield of 85 percent.
Analytical data for benzopyrone-containing polycyclic spiroindolone compounds of formula I-11:1H NMR(400MHz,CDCl3)δ7.73(dd,J＝8.0,2.0Hz,1H),7.55–7.49(m,1H),7.37(td,J＝7.6,1.6Hz,1H),7.22–7.13(m,3H),7.06–7.01(m,2H),6.90(d,J＝8.0Hz,1H),5.81–5.71(m,2H),5.30–5.17(m,2H),4.37–4.21(m,2H),3.61(d,J＝7.6Hz,1H)；13C NMR(100MHz,CDCl3)δ188.70,171.87,159.62,146.28,143.37,136.93,130.24,130.24,127.01,126.84,124.46,123.64,123.00,122.29,121.51,118.38,117.67,112.49,110.20,80.92,65.78,54.81,42.77.Exact mass calcd for C23H16N2NaO3[M+Na]+:391.1053,Found:391.1054.
example 12
Antimalarial activity test of polycyclic spiroindolone compounds containing benzopyrone:
in view of the fact that the polycyclic spiroindolone compound containing benzopyrone synthesized by us has important elements of spiroindolone. To examine the utility of this class of compounds, the compounds of examples 1-11 were tested for antimalarial activity.
The prior art describes that NITD609 is an antimalarial drug, and the benzopyranone-containing polycyclic spiroindolone compounds synthesized by the method have certain similarity, so that the present example tests the antimalarial activity of 11 compounds shown in the following table by taking NITD609 as a reference substance. The in vitro culture method is adopted, and the specific implementation steps are as follows:
dissolving the compounds with numbers 1-12 in Table 1 in 70% ethanol, diluting with sterile water to obtain 125nM solution, implanting 50 μ L hemin (1mmol/L in DMSO; Sigma, USA) and 80 μ L acetate buffer solution (4mmol/L, pH 5.0) into 96-well plate, mixing, adding the solution into the plate at 100 μ L, and placing 96-well plate in sealed wet CO at 50 deg.C2And incubating for 5 hours in an incubator in a dark place. Subsequently, 200. mu.L of pyridine-HEPES solution (20mmol/L, pH 7.5) was added to each well, and the mixture was incubated at room temperature for 20 hours in a chamber. The absorbance at 450nm was measured on a microplate reader. Obtaining the concentration of unreacted hemin from the hemin standard curve, and calculating the Inhibitory Concentration (IC) of the compound to the formation of beta-hemin50)[K.K.Ncokazi,T.J.Egan,Anal.Biochem.2005,338,306-319.]. The test results are shown in Table 1.
TABLE 1NITD609 and data for antimalarial Activity tests of benzopyrone-containing polycyclic spiroindolone Compounds described in examples 1-11
aThe data in the table are the average of three tests;bIC50the concentration representing half of the maximal inhibition produced by the test compound.
As can be seen from the data in Table 1, the compounds I-1 to 11 all have antimalarial activity, the inhibition ability of the compounds is different due to different substituents in each compound, the preliminary results of the antimalarial activity resistance of the compounds I-1, I-3, I-4, I-8, I-10 and I-11 are better than that of NITD609, and the antimalarial activity resistance of other compounds is slightly worse than that of NITD 609. In general, the activity test data in table 1 indicate that the benzopyrone-containing polycyclic spiroindolone compounds of the present invention have antimalarial activity, and are expected to be developed into a novel class of antimalarial drugs.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A polycyclic spiroindolone compound containing benzopyrone is characterized in that the chemical structure general formula is shown as formula I:
wherein R is1Represents a substituent on the benzene ring to which it is attached, and is selected from any one of H, alkyl, halogen and alkoxy;
R2represents one or more substituents on the benzene ring to which it is attached, and when representing a plurality of substituents, the plurality of substituents are linked to form a ring or are independent of each other, and when R is2When represents one substituent or a plurality of independent substituents on the corresponding benzene ring, a plurality of R2The same or different is selected from one of H, alkyl, halogen and alkoxy; when R is2Represents that when a plurality of substituents on the corresponding benzene ring are connected to form a ring, the ring is a benzene ring;
R3any one selected from alkyl, benzyl and allyl.
2. The benzopyrone-containing polycyclic spiroindolone compound according to claim 1, characterized in that the chemical structure thereof is one of the following structural formulae:
3. the benzopyrone-containing polycyclic spiroindolone compound according to claim 1, characterized in that the chemical structure thereof is one of the following structural formulae:
4. a method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to any one of claims 1 to 3, characterized by comprising the steps of: under the protection of nitrogen, uniformly mixing a catalyst, a compound shown as a formula II, a compound shown as a formula III and a solvent, stirring at a reaction temperature of-80-100 ℃ until the reaction is finished, and separating to obtain a compound shown as a formula I;
the specific reaction route is as follows:
wherein R is1、R2、R3As defined in claim 1 or 2 or 3.
5. The method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to claim 4, wherein:
the compound shown in the formula II and the compound shown in the formula III are used in the following amount: the molar ratio of the compound shown in the formula II to the compound shown in the formula III is 1.2-1.6: 1.
6. the method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to claim 4, wherein:
the catalyst is organic base or inorganic base.
7. The method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to claim 6, wherein:
the organic base is any one of 1,2,2,6, 6-pentamethylpiperidine, triethylene diamine, sodium tert-butoxide, 1,5, 7-triazabicyclo (4.4.0) dec-5-ene, potassium tert-butoxide, triethylamine, 1,3, 3-tetramethylguanidine, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, sodium methoxide and 1, 8-diazabicyclo [5.4.0] undec-7-ene; the inorganic base is any one of potassium hydroxide, cesium carbonate, sodium hydroxide and potassium carbonate.
8. The method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to claim 4, wherein:
the catalyst is used in an amount which satisfies the following conditions: the amount of the catalyst is 0.01 to 1 time the amount of the compound represented by the formula III.
9. The method for preparing benzopyrone-containing polycyclic spiroindolone compounds according to claim 4, wherein:
the solvent is at least one of tetrahydrofuran, chlorobenzene, trifluoroethanol, acetone, toluene, 1,2, 2-tetrachloroethane, ethyl acetate, dichloromethane, dimethylformamide, diethyl ether, fluorobenzene, bromobenzene, 1, 2-dichloroethane, nitromethane, 1, 2-trichloroethane, chloroform, 1, 4-dioxane, acetonitrile and methanol.
10. Use of the benzopyrone-containing polycyclic spiroindolone compounds according to any one of claims 1 to 3 for the preparation of antimalarial drugs.
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