CN113603694B - 1, 2-diketone compound and preparation method and application thereof - Google Patents
1, 2-diketone compound and preparation method and application thereof Download PDFInfo
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Abstract
1, 2-diketone compounds and a preparation method and application thereof. The invention develops the aryl-substituted imidazole compound with novel structure, the preparation method thereof and the application thereof in preparing anti-tumor drugs, and the process has mild reaction conditions, convenient operation, low cost and wide industrial application prospect, and the product purity reaches more than 97 percent. The aryl-substituted imidazole compound provided by the invention shows a certain antitumor activity, lays a foundation for screening and developing new drugs, and has a good practical value.
Description
(I) technical field
The invention relates to a 1, 2-diketone compound and a preparation method and application thereof.
(II) background of the invention
1, 2-diketone compounds are important organic synthesis intermediates which are widely applied to synthesis of pesticides, medicines and the like, and meanwhile, the compounds also have various biological activities, and are one of hot spots of research in recent years. The traditional 1, 2-diketone compounds are mainly prepared by oxidation of alkyne, alkene or diol compounds, but have many defects to limit application. Therefore, the preparation of the novel 1, 2-diketone compound has important theoretical significance and practical application value.
Disclosure of the invention
The invention aims to provide a 1, 2-diketone compound, a preparation method thereof and application thereof in preparing antitumor drugs
In order to achieve the purpose, the invention adopts the following technical scheme:
1, 2-diketones of formula (I):
in the formula (I), R1Or R2Each independently is C1～C10Alkyl, or R1、R2Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8The heterocyclic ring of (4); r is3Is C4～C8Heteroaryl, phenyl or by C1～C10Alkyl radical, C1～C10Alkoxy or halogen substituted phenyl.
Further, said R1Or R2Each independently preferably being methyl, ethyl, or R1、R2Linked to form a ring and combined with the N between the two to form a pyrrolidine ring, a piperidine ring or a morpholine ring.
Further, said R3Preferably furyl, thienyl, phenyl or phenyl substituted by methyl, methoxy, fluoro, chloro or bromo.
Most preferably, the 1, 2-diketones of formula (I) are one of the following:
the invention provides a preparation method of a 1, 2-diketone compound shown in a formula (I), which comprises the following steps:
mixing a triazine compound shown in a formula (II) and a ketone compound shown in a formula (III), adding the mixture into a solvent, stirring and reacting for 5-20 hours at the temperature of 80-150 ℃ under an oxygen atmosphere, and after the reaction is finished, obtaining a reaction liquid and carrying out post-treatment to obtain a 1, 2-diketone compound shown in a formula (I); the mass ratio of the triazine compound shown in the formula (II) to the ketone compound shown in the formula (III) is 1: 2.4 to 3.0; the solvent is halogenated aromatic hydrocarbon or amide compounds;
r in formula (II) or formula (III)1、R2、R3Each as defined above.
Further, copper salt is added into the solvent before reaction, and the mass ratio of the triazine compound shown in the formula (II) to the copper salt is 1: 0 to 0.2(0 means infinitely close to 0 but not 0), and the amount of the copper salt is not 0.
Preferably, the cupric salt is cuprous chloride, cuprous bromide, cupric chloride, cupric bromide or cupric acetate.
Still further, before the reaction, halogen is added into the solvent, and the mass ratio of the triazine compound shown in the formula (II) to the halogen is 1: 0 to 3.0(0 means infinitely close to 0 but not 0), and the amount of the halogen is not 0.
Preferably, the halogen is iodine.
Furthermore, an oxidant is added into the solvent before the reaction, and the quantity ratio of the triazine compound shown in the formula (II) to the halogen is 1: 0 to 1.4(0 means infinitely close to 0 but not 0), the amount of the substance of the oxidizing agent being not 0; the oxidant is m-chloroperoxybenzoic acid, K2S2O4Or bis-trifluoroacetyliodobenzene.
Preferably, the oxidizing agent is m-chloroperoxybenzoic acid.
Specifically, the invention provides a preparation method of the 1, 2-diketone compound shown in the formula (I), which specifically comprises the following steps:
mixing a triazine compound shown in a formula (II) and a ketone compound shown in a formula (III), adding the mixture into a solvent, stirring and reacting for 5-20 hours at 80-150 ℃ under the action of copper salt, halogen and an oxidant and under an oxygen atmosphere, and after the reaction is finished, obtaining a reaction liquid and carrying out post-treatment to obtain a 1, 2-diketone compound shown in a formula (I); the amount ratio of the triazine compound shown in the formula (II), the ketone compound shown in the formula (III), the copper salt, the halogen and the oxidant is 1: 2.4-3.0: 0-0.2: 0 to 3.0: 0 to 1.4; the solvent is halogenated aromatic hydrocarbon or amide compounds; the oxidant is m-chloroperoxybenzoic acid and K2S2O4Or bistrifluoroacetyliodobenzene;
r in formula (II) or formula (III)1、R2、R3Each at willAs defined above.
Further, the solvent is preferably chlorobenzene, 1, 2-dichlorobenzene, 1,2, 4-trichlorobenzene or DMF.
Further, the volume of the solvent is 4-8 mL/mmol based on the amount of the triazine compound represented by formula (II).
In the preparation method of the invention, the post-treatment of the reaction solution can adopt the following method: after the reaction is finished, adding a 10% sodium thiosulfate aqueous solution into the obtained reaction solution, extracting with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, concentrating, performing column chromatography separation by using dichloromethane to ethyl acetate as an eluent in a volume ratio of 25:1, collecting eluent containing a target compound, and performing reduced pressure evaporation to remove a solvent and drying to obtain the 1, 2-diketone compound shown in formula (I); the volume of the aqueous sodium thiosulfate solution is 60mL/mmol based on the amount of the triazine compound represented by the formula (II).
The invention also provides application of the 1, 2-diketone compound in preparing antitumor drugs.
Furthermore, the tumor is human liver cancer cell (HEPG2) or human breast cancer cell (T47D).
Furthermore, when the tumor is human liver cancer cell (HEPG2), the compound (I-12) or (I-16) has better anti-tumor activity, and the compound (I-1), (I-3), (I-7), (I-8) or (I-14) has certain anti-tumor activity; when the tumor is a human breast cancer cell (T47D), the compounds (I-7), (I-8) or (I-16) have better anti-tumor activity, and the compounds (I-1), (I-2), (I-3) or (I-12) have certain anti-tumor activity.
Compared with the prior art, the invention has the beneficial effects that:
the invention develops the aryl substituted imidazole compound with novel structure and the preparation method thereof, and the process has mild reaction conditions, convenient operation, low cost, high product purity of more than 97 percent and wide industrial application prospect. The aryl-substituted imidazole compound provided by the invention shows a certain antitumor activity, lays a foundation for screening and developing new drugs, and has a good practical value.
(IV) detailed description of the invention
The invention will now be further illustrated by the following examples, without limiting the scope of the invention thereto. The raw material formula (II) compound used by the invention is prepared by reacting ester and biguanide under the action of sodium methoxide at room temperature; specific synthetic methods are described in the literature (Bioorganic & Medicinal Chemistry Letters,19(2009), 5644-.
Example 1: preparation of Compound (I-1)
2-amino-4-dimethylamino-1, 3, 5-triazine (69.9mg, 0.5mmol), acetophenone (162.7mg, 1.4mmol), iodine (254.4mg, 1.0mmol), cuprous chloride (9.6mg,0.1mmol), and m-chloroperoxybenzoic acid (132.0mg,0.6mmol) were added to a reaction vessel, mixed in 1,2, 4-trichlorobenzene (4mL), and reacted in an oil bath at 150 ℃ under an oxygen atmosphere for 8 hours with stirring; after completion of the reaction, 30mL of a 10% aqueous solution of sodium thiosulfate was added, extraction was performed with dichloromethane (30mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, column-chromatographed (dichloromethane: ethyl acetate ═ 25:1, v: v), distilled under reduced pressure, and dried to give the objective compound (I-1) in a yield of 144.5mg, and the yield was 78%.
1H NMR(500MHz,CDCl3)δ10.02(s,1H),7.76(d,J＝7.7Hz,2H),7.58(t,J＝7.7Hz,1H),7.41(t,J＝7.7Hz,2H),7.35(d,J＝7.7Hz,2H),7.28(t,J＝7.7Hz,1H),7.10(t,J＝7.7Hz,2H),3.40(s,3H),3.34(s,3H)
Example 2:
the procedure of example 1 was otherwise identical except for changing 1,2, 4-trichlorobenzene to o-dichlorobenzene (2mL), giving a yield of 61.5mg and a yield of 33%.
Example 3:
the procedure of example 1 was otherwise the same except that 1,2, 4-trichlorobenzene was changed to N, N-dimethylformamide, thereby giving a yield of 34.6mg and an yield of 18%. .
Example 4:
the procedure of example 1 was otherwise the same except that 1,2, 4-trichlorobenzene was changed to chlorobenzene at a temperature of 80 ℃ to give a yield of 14.0mg and a yield of 8%.
Example 5:
the m-chloroperoxybenzoic acid was changed to bistrifluoroacetyliodobenzene (PIFA) (245.6mg, 0.6mmol), and the other operations were the same as in example 1, yielding 26.9mg and 15% yield.
Example 6:
changing m-chloroperoxybenzoic acid to potassium persulfate (K)2S2O8) (152.3mg, 0.6mmol), the same procedures as in example 1 were repeated except that the yield was 42.9mg, which was found to be 23%.
Example 7:
the operation was carried out in the same manner as in example 1 except for changing the amount of m-chloroperoxybenzoic acid to (175.9mg, 0.7mmol), thereby obtaining a yield of 126.8mg and a yield of 68%.
Example 8:
the same procedure as in example 1 was carried out except that m-chloroperoxybenzoic acid was not added, whereby the yield was 53.6mg and 28% was obtained.
Example 9:
the amount of iodine was changed to (381.5mg, 1.5mmol), and the other operations were performed as in example 1, yielding 120.6mg in 64% yield.
Example 10:
the procedure of example 1 was otherwise the same as in example 1 except that iodine was not added, and yield was 65.0mg, i.e., 34%.
Example 11:
the same procedure as in example 1 was carried out without adding cuprous chloride, yielding 98.5mg and 52% yield.
Example 12:
cuprous chloride was changed to cuprous bromide (14.4mg, 0.1mmol) and the other operations were the same as in example 1, yielding 114.2mg and 61% yield.
Example 13:
the procedure of example 1 was otherwise the same as in example 1 except that cuprous chloride was changed to cupric chloride (13.4mg, 0.1mmol), yielding 99.8mg and 53% yield.
Example 14:
the procedure of example 1 was otherwise identical except that cuprous chloride was changed to cupric bromide (22.5mg, 0.1mmol), yielding 131.7mg and 71% yield.
Example 15:
the procedure of example 1 was otherwise identical except that cuprous chloride was changed to cupric acetate (20.8mg, 0.1mmol), yielding 120.0mg and 65% yield.
Example 16:
the reaction time was shortened to 5 hours, and the other operations were the same as in example 1, yielding 106.3mg and 57% yield.
Example 17:
the amount of acetophenone was changed to (180.8mg, 1.5mmol), and the other operations were performed as in example 1 to yield 116.2mg of acetophenone, i.e., 63% yield.
Example 18:
the amount of acetophenone was changed to (144.6mg, 1.2mmol), and the other operations were performed as in example 1 to yield 98.5mg and 53% yield.
Example 19: preparation of Compound (I-2)
The operation was as in example 1 except that acetophenone was changed to p-methoxyacetophenone (216.7mg,1.4mmol), yield was 53.9mg, yield was 25%.
1H NMR(500MHz,CDCl3)δ10.01(s,1H),7.79(d,J＝8.9Hz,2H),7.35(d,J＝8.7Hz,2H),6.90(d,J＝8.9Hz,2H),6.64(d,J＝8.7Hz,2H),3.89(s,3H),3.76(s,3H),3.38(s,3H),3.33(s,3H)
Example 20: preparation of Compound (I-3)
The operation was carried out as in example 7 except that acetophenone was changed to p-methylacetophenone (180.9mg,1.4mmol), and the reaction was carried out for 20 hours to give a yield of 129.8mg in 65% yield.
1H NMR(500MHz,CDCl3)δ10.03(s,1H),7.71(d,J＝8.1Hz,2H),7.29(d,J＝8.1Hz,2H),7.24(d,J＝8.0Hz,2H),6.92(d,J＝8.0Hz,2H),3.40(s,3H),3.34(s,3H),2.45(s,3H),2.29(s,3H)
Example 21: preparation of Compound (I-4)
The operation is as in example 1, except that acetophenone is replaced by p-chloroacetophenone (208.6mg,1.4mmol), giving a yield of 200.0mg in 90%.
1H NMR(500MHz,CDCl3)δ9.99(s,1H),7.74(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.29(d,J＝8.4Hz,2H),7.13(d,J＝8.4Hz,2H),3.41(s,3H),3.35(s,3H)
Example 22: preparation of Compound (I-5)
The operation is as in example 1, except that acetophenone is replaced by p-bromoacetophenone (270.3mg,1.4mmol) and m-chloroperoxybenzoic acid (173.3mg,0.8mmol), giving a yield of 219.5mg and 80%.
1H NMR(500MHz,CDCl3)δ9.97(s,1H),7.65(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),7.29(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),3.40(s,3H),3.34(s,3H)
Example 23: preparation of Compound (I-6)
The operation is as in example 1, except that acetophenone is replaced by p-fluoroacetophenone (186.7mg,1.4mmol), yield 127.0mg, 63%.
1H NMR(500MHz,CDCl3)δ9.99(s,1H),7.81(dd,J＝8.6,5.4Hz,2H),7.34(dd,J＝8.6,5.4Hz,2H),7.12(t,J＝8.6Hz,2H),6.84(t,J＝8.6Hz,2H),3.40(s,3H),3.34(s,3H)
Example 24: preparation of Compound (I-7)
The operation is as in example 1, except that acetophenone is replaced by m-chloroacetophenone (215.7mg,1.4mmol) and m-chloroperoxybenzoic acid (175.1mg,0.8mmol), giving a yield of 161.7mg and a 74% yield.
1H NMR(500MHz,CDCl3)δ9.98(s,1H),7.78–7.74(m,1H),7.70(d,J＝7.9Hz,1H),7.59(dd,J＝7.9,1.1Hz,1H),7.42(t,J＝7.9Hz,1H),7.33–7.29(m,2H),7.27–7.24(m,1H),7.15(t,J＝7.8Hz,1H),3.41(s,3H),3.35(s,3H)
Example 25: preparation of Compound (I-8)
The procedure is as in example 1 except that acetophenone is replaced by m-bromoacetophenone (270.9mg,1.4mmol), yielding 161.4mg in 61% yield.
1H NMR(500MHz,CDCl3)δ9.97(s,1H),7.91(t,J＝1.7Hz,1H),7.77–7.71(m,2H),7.49–7.44(m,1H),7.41–7.36(m,2H),7.36–7.33(m,1H),7.10(t,J＝7.8Hz,1H),3.41(s,3H),3.34(s,3H)
Example 26: preparation of Compound (I-9)
The operation was carried out as in example 1 except that acetophenone was changed to m-methoxyacetophenone (218.2mg,1.5mmol), yield was 131.8mg, yield was 61%.
1H NMR(500MHz,CDCl3)δ10.01(s,1H),7.40(d,J＝7.5Hz,1H),7.33(t,J＝7.8Hz,1H),7.23–7.19(m,1H),7.15–7.11(m,1H),6.99(t,J＝7.8Hz,1H),6.94–6.86(m,2H),6.86–6.81(m,1H),3.80(s,3H),3.57(s,3H),3.40(s,3H),3.34(s,3H)
Example 27: preparation of Compound (I-10)
The operation is as in example 1, except that acetophenone is replaced by o-chloroacetophenone (218.7mg,1.4mmol), yield 117.7mg, 53%.
1H NMR(500MHz,CDCl3)δ9.98(s,1H),7.58(dd,J＝7.8,1.6Hz,1H),7.44(td,J＝7.8,1.6Hz,1H),7.37–7.34(m,1H),7.30(dd,J＝7.6,1.4Hz,1H),7.26–7.23(m,2H),7.23–7.21(m,1H),7.07(td,J＝7.6,1.4Hz,1H),3.40(s,3H),3.34(s,3H)
Example 28: preparation of Compound (I-11)
The procedure is as in example 7, except that acetophenone is replaced by o-bromoacetophenone (278.6mg,1.4mmol), and the reaction is carried out for 9 hours to give an yield of 169.7mg, 64%.
1H NMR(500MHz,CDCl3)δ9.99(s,1H),7.61–7.54(m,2H),7.48–7.43(m,1H),7.35(td,J＝7.6,1.8Hz,1H),7.32-7.28(m,2H),7.17–7.13(m,2H),3.40(s,3H),3.35(s,3H)
Example 29: preparation of Compound (I-12)
The operation was as in example 1 except that acetophenone was changed to 2-acetylthiophene (180.4mg,1.4mmol), m-chloroperoxybenzoic acid (176.0mg,0.8mmol), and the yield was 110.4mg, 58%.
1H NMR(500MHz,CDCl3)δ9.91(s,1H),7.82–7.80(m,1H),7.79–7.75(m,1H),7.44(d,J＝4.8Hz,1H),7.20(d,J＝4.3Hz,1H),7.17(t,J＝4.3Hz,1H),6.89(t,J＝4.8Hz,1H),3.39(s,3H),3.34(s,3H)
Example 30: preparation of Compound (I-13)
The operation is as in example 1, except that acetophenone is replaced by 2-acetylfuran (160.0mg,1.5mmol), yield 46.8mg, 26%.
1H NMR(500MHz,CDCl3)δ9.90(s,1H),7.76-7.73(m,1H),7.39(d,J＝3.4Hz,1H),7.26(d,J＝3.4Hz,1H),7.19-7.16(m,1H),6.65(dd,J＝3.6,1.6Hz,1H),6.49(dd,J＝3.6,1.6Hz,1H),3.38(s,3H),3.33(s,3H)
Example 31: preparation of Compound (I-14)
The operation was carried out as in example 1 except that 2-amino-4-dimethylamino-1, 3, 5-triazine was changed to 2-amino-4-diethylamino-1, 3, 5-triazine (84.6mg,0.5mmol), and the yield was 161.0mg and 80%.
1H NMR(500MHz,CDCl3)δ10.03(s,1H),7.75(dd,J＝8.2,1.1Hz,2H),7.60–7.55(m,1H),7.40(t,J＝7.8Hz,2H),7.37–7.34(m,2H),7.30–7.28(m,1H),7.10(t,J＝7.8Hz,2H),3.80(q,J＝7.1Hz,2H),3.77(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H),1.29(t,J＝7.1Hz,3H)
Example 32: preparation of Compound (I-15)
The operation was carried out in the same manner as in example 1 except that 2-amino-4-dimethylamino-1, 3, 5-triazine was replaced with 2-amino-4-morpholinyl-1, 3, 5-triazine (84.6mg,0.5mmol), whereby the yield was 99.6mg and 48%.
1H NMR(500MHz,CDCl3)δ10.04(s,1H),7.78–7.74(m,2H),7.61–7.57(m,1H),7.44–7.40(m,2H),7.37–7.33(m,2H),7.32–7.28(m,1H),7.13–7.09(m,2H),4.09–4.02(m,4H),3.84–3.80(m,4H)
Example 33: preparation of Compound (I-16)
The operation was carried out as in example 1 except that 2-amino-4-dimethylamino-1, 3, 5-triazine was changed to 2-amino-4-pyrrolidinyl-1, 3, 5-triazine (83.0mg,0.5mmol), whereby the yield was 132.3mg and 66%.
1H NMR(500MHz,CDCl3)δ10.04(s,1H),7.77(d,J＝7.4Hz,2H),7.58(t,J＝7.4Hz,1H),7.41(t,J＝7.4Hz,2H),7.36(d,J＝7.6Hz,2H),7.28(t.,J＝7.6Hz,1H),7.10(t,J＝7.6Hz,2H),3.79(t,J＝6.6Hz,2H),3.75(t,J＝6.6Hz,2H),2.10–2.05(m,4H)
Example 34: preparation of Compound (I-17)
The operation is as in example 1, except that 2-amino-4-dimethylamino-1, 3, 5-triazine is replaced with 2-amino-4-piperidinyl-1, 3, 5-triazine (90.2mg,0.5mmol), giving a yield of 146.4mg and 71%.
1H NMR(500MHz,CDCl3)δ10.00(s,1H),7.75(d,J＝7.4Hz,2H),7.58(t,J＝7.4Hz,1H),7.41(t,J＝7.4Hz,2H),7.35(d,J＝6.8Hz,2H),7.29(t,J＝6.8Hz,1H),7.11(t,J＝6.8Hz,2H),4.04-3.95(m,4H),1.78-1.66(m,6H)
Example 35: in vitro activity test method of anti-human liver cancer cell (HEPG2) or human breast cancer cell (T47D) in vivo activity test method of anti-human liver cancer cell (HEPG2) or human breast cancer cell (T47D): MTT method
The experimental steps are as follows:
1) preparation of samples: for soluble samples, each 1mg was dissolved in 20. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of culture medium to a concentration of 100. mu.g/mL, and then serially diluted with culture medium to the use concentration.
2) Culture of cells
2.1) preparation of culture medium, wherein each 1000mL of culture medium contains 80 million units of penicillin, 1.0g of streptomycin and 10% of inactivated fetal calf serum.
2.2) culture of cells: inoculating tumor cells into culture medium, placing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
3) Determination of the inhibition of tumor cell growth by samples
The cells were digested with EDTA-trypsin digest and diluted to 1X 10 with medium5PermL, 100 uL/well in 96-well cell culture plates, 37 ℃, 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of medium diluted samples were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2The culture in the incubator, after 72h, adds 5mg/mL MTT to the cell culture wells, 10. mu.L per well, incubate at 37 ℃ for 4h, add DMSO, 150. mu.L per well, shake with a shaker, completely solubilize the formazan, and color with a microplate reader at a wavelength of 570 nm. The inhibition rate of the sample on the tumor cells was calculated by using cells cultured in the medium containing no sample and the same concentration of DMSO as a control under the same conditions, and the results are shown in Table 1. The inhibition effect of 8 samples of the compounds (I-1), (I-2), (I-3), (I-7), (I-8), (I-12), (I-14) and (I-16) on the growth of liver cancer cells or human breast cancer cells in vitro was determined by taking human liver cancer cells (HEPG2) or human breast cancer cells (T47D) as models (the results are detailed in Table 1).
TABLE 1.60 μmol/L inhibition ratio of each compound to human hepatoma cell (HepG2) or human breast cancer cell (T47D)%
The compound (IV) was prepared according to the literature method (Org. Biomol. chem.,2017,15, 5564-5570).
Claims (10)
1. 1, 2-diketones of formula (I):
in the formula (I), R1Or R2Each independently is C1～C10Alkyl, or R1、R2Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8The heterocyclic ring of (4); r3Is C4～C8Heteroaryl, phenyl or by C1～C10Alkyl radical, C1～C10Alkoxy or halogen substituted phenyl.
2. The 1, 2-diketones according to formula (I) according to claim 1, characterized in that the 1, 2-diketones according to formula (I) are one of the following:
3. a process for the preparation of 1, 2-diketones of formula (I) according to claim 1, characterized in that the process comprises:
mixing a triazine compound shown in a formula (II) and a ketone compound shown in a formula (III), adding the mixture into a solvent, stirring and reacting for 5-20 hours at the temperature of 80-150 ℃ under an oxygen atmosphere, and after the reaction is finished, obtaining a reaction liquid and carrying out post-treatment to obtain a 1, 2-diketone compound shown in a formula (I); the mass ratio of the triazine compound shown in the formula (II) to the ketone compound shown in the formula (III) is 1: 2.4 to 3.0; the solvent is halogenated aromatic hydrocarbon or amide compounds;
wherein R is1Or R2Each independently is C1～C10Alkyl, or R1、R2Are connected into a ring and are combined with N between the two to form C containing N or N, O4～C8The heterocyclic ring of (1); r is3Is C4～C8Heteroaryl, phenyl or by C1～C10Alkyl radical, C1～C10Alkoxy or halogen substituted phenyl.
4. A process for the preparation of 1, 2-diketones of formula (I) according to claim 3, characterized in that: before the reaction, copper salt is added into the solvent, and the mass ratio of the triazine compound shown in the formula (II) to the copper salt is 1: 0-0.2, and the amount of the copper salt is not 0.
5. A process for the preparation of 1, 2-diketones of formula (I) according to claim 3, characterized in that: before the reaction, halogen is also added into the solvent, and the mass ratio of the triazine compound shown in the formula (II) to the halogen is 1: 0 to 3.0, and the amount of the halogen is not 0.
6. A process for the preparation of 1, 2-diketones of formula (I) according to claim 3, characterized in that: before the reaction, an oxidant is added into the solvent, and the quantity ratio of the triazine compound shown in the formula (II) to the halogen is 1: 0 to 1.4, wherein the amount of the oxidant is not 0; the oxidant is m-chloroperoxybenzoic acid, K2S2O4Or bis-trifluoroacetyliodobenzene.
7. A process for the preparation of 1, 2-diketones of formula (I) according to claim 3, characterized in that: the solvent is chlorobenzene, 1, 2-dichlorobenzene, 1,2, 4-trichlorobenzene or DMF; the volume of the solvent is 4-8 mL/mmol based on the amount of the triazine compound represented by the formula (II).
8. The process for preparing 1, 2-diketones of formula (I) according to claim 3, characterized in that the post-treatment of the reaction solution is: after the reaction is finished, adding a sodium thiosulfate aqueous solution with the mass fraction of 10% into the obtained reaction liquid, extracting with dichloromethane, combining organic layers, drying with anhydrous sodium sulfate, concentrating, performing column chromatography separation by using dichloromethane and ethyl acetate as eluent in the volume ratio of 25:1, collecting eluent containing the target compound, performing reduced pressure evaporation to remove the solvent, and drying to obtain the 1, 2-diketone compound shown in the formula (I); the volume of the aqueous sodium thiosulfate solution is 60mL/mmol based on the amount of the triazine compound represented by the formula (II).
9. Use of the 1, 2-diketones of formula (I) according to claim 1 for the preparation of an antitumor medicament.
10. The use according to claim 9, wherein the tumor is human liver cancer or human breast cancer.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005099824A1 (en) * | 2004-03-30 | 2005-10-27 | Synta Pharmaceuticals, Corp. | 1-glyoxylamide indolizines for treating lung and ovarian cancer |
| CN101090720A (en) * | 2004-11-08 | 2007-12-19 | 巴克斯特国际公司 | Nanoparticulate compositions of tubulin inhibitor compounds |
| WO2010139982A1 (en) * | 2009-06-02 | 2010-12-09 | The University Of Sheffield | Indole derivatives for the stimulation of stem cell proliferation |
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| CN1568324A (en) * | 2001-09-13 | 2005-01-19 | Sbr制药公司 | 1-glyoxylamide indolizines for treating cancer |
| WO2005099824A1 (en) * | 2004-03-30 | 2005-10-27 | Synta Pharmaceuticals, Corp. | 1-glyoxylamide indolizines for treating lung and ovarian cancer |
| CN101090720A (en) * | 2004-11-08 | 2007-12-19 | 巴克斯特国际公司 | Nanoparticulate compositions of tubulin inhibitor compounds |
| WO2010139982A1 (en) * | 2009-06-02 | 2010-12-09 | The University Of Sheffield | Indole derivatives for the stimulation of stem cell proliferation |
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