CN110981869A - Synthesis method of 1, 8-bis-azachromone and application of 1, 8-bis-azachromone in antidiabetic drugs - Google Patents
Synthesis method of 1, 8-bis-azachromone and application of 1, 8-bis-azachromone in antidiabetic drugs Download PDFInfo
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Abstract
The invention relates to a method for synthesizing 1, 8-dinitrogen chromone compounds, which specifically comprises the steps of taking 3-substituted pyridine or quinoline nitrogen oxide I as a raw material, triethylamine as an alkali, 1, 2-dichloroethane as a solvent, reacting under the condition of 25-30 ℃ under the condition of tripyrrolidinyl phosphonium bromide hexafluorophosphate (PyBrop) to obtain a compound II, and cyclizing the compound II under the condition of refluxing of 2M hydrochloric acid and tetrahydrofuran solution to obtain the 1, 8-dinitrogen chromone compounds.
Description
Technical Field
The invention belongs to the field of organic synthesis and the field of pharmaceutical application, and relates to a 1, 8-dinitrodiazochromone compound, which comprises synthesis, evaluation and application.
Technical Field
The chromone compound has various biological activities and pharmaceutical activities, including antibacterial, anticancer, antioxidant, hypoglycemic, anti-inflammatory and other activities. The 1, 8-bis-azachromone is an isostere of chromone and has better water solubility because the structure contains two nitrogen atoms. At present, various medicines with 1, 8-diazepine chromone parent nucleus structures, such as anfonaftate, enoxacin, trovafloxacin and the like, exist in the market, so that the synthesis research of the 1, 8-diazepine chromone compounds is very significant.
However, few reports are reported on the synthesis of such compounds, which suggests that methods for the synthesis of such compounds may present major challenges. In 2012, Viktor o.iaroshenko et al reported a synthesis method of such a compound, but this method requires the use of a plurality of metal catalysts, and the reaction temperature is high, which increases the raw material cost and the risk factor of the reaction; in addition, the starting material used in this process is a 2-halo substituted pyridine, which greatly limits the substrate applicability of this process. Therefore, the development of a simple and efficient general synthetic method for 1, 8-dinitrochromone is significant.
Disclosure of Invention
The invention aims to provide a synthesis method of 1, 8-bis-azachromone, which comprises the steps of taking 3-substituted pyridine or quinoline nitrogen oxide I as a raw material, taking triethylamine as an alkali, taking dichloroethane as a solvent, reacting under the condition of 25-30 ℃ under the condition of tripyrrolidinyl phosphonium bromide hexafluorophosphate (PyBrop) to obtain a compound II, and cyclizing the compound II under the condition of refluxing of 2M hydrochloric acid and tetrahydrofuran solution to obtain the 1, 8-bis-azachromone compound.
The purpose of the invention is realized by the following technical scheme:
the structure of the 1, 8-dinitro-chromone compound has the following general formula:
wherein R is1Hydrogen, hydroxyl, halogen, nitro, aryl, carboxyl, trifluoromethyl, amido, ester, alkyl or alkoxy which are substituted at one or more positions 4, 5 and 6 of the pyridine ring; r2Is alkyl, cycloalkyl, substituted benzyl, allyl, propargyl; r3Is substituted alkenyl, aryl, alkyl; r4Hydrogen atom or substituted phenyl, alkyl.
The 1, 8-bis-azachromone is obtained by the following synthetic route:
the reaction takes 3-substituted pyridine or quinoline nitrogen oxide I as a raw material, triethylamine as alkali, dichloroethane as a solvent, and under the condition of 25-30 ℃, under the condition of tripyrrolidinyl phosphonium bromide hexafluorophosphate (PyBrop), a compound II is obtained, and then the compound II is cyclized under the reflux condition of 2M hydrochloric acid and tetrahydrofuran solution to obtain the 1, 8-dinitrodiazochromone compound.
The nomenclature and structure of the synthesized 1, 8-dinitrochromone compounds are shown in table 1:
TABLE 11 nomenclature and Structure of 8-dinitrochromone Compounds
The invention has the advantages and positive effects that:
1. the invention adopts cheap and easily available nitrogen oxides as raw materials, and the reaction method has the remarkable advantages of high position selectivity, wide substrate applicability and the like.
2. The method has the advantages of mild reaction conditions, simple and convenient operation, no high-temperature high-pressure reaction, safe reaction conditions and suitability for large-scale production and development.
3. The method has good substrate applicability, and can synthesize the 1, 8-dinitrochromone compounds with different substituents.
4. The compound has hypoglycemic activity, can be used for preparing medicines for treating diabetes, and has stronger inhibition activity on α -glucosidase by the compounds 29 and 30 discovered through actual detection.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound 3 in deuterated trichloromethane;
FIG. 2 is a nuclear magnetic carbon spectrum of compound 3 in deuterated trichloromethane;
FIG. 3 is a nuclear magnetic hydrogen spectrum of compound 13 in deuterated trichloromethane;
FIG. 4 is a nuclear magnetic carbon spectrum of compound 13 in deuterated trichloromethane;
FIG. 5 is a nuclear magnetic hydrogen spectrum of compound 30 in deuterated trichloromethane;
fig. 6 is a nuclear magnetic carbon spectrum of compound 30 in deuterated trichloromethane;
Detailed Description
For understanding the present invention, the present invention will be further described with reference to the following examples: the following examples are illustrative and not intended to be limiting, and are not intended to limit the scope of the invention.
The general structural formula of the 1, 8-dinitrogen variegated ketone compound is shown as the following formula
The specific nomenclature and structure are shown in table 1 above.
The 1, 8-dinitrochromone compounds are synthesized by the following general synthesis method:
pyridine nitrogen oxide I (1.0 eq.), 1, 2-dichloroethane (0.25M), amine (2.5eq.), triethylamine (3.0eq.), and/or pyridine,
Molecular sieves (same weight as pyridine nitrogen oxide), PyBrop (1.3 eq.). The reaction was then stirred at room temperature and followed by TLC until the reaction was complete. Filtering the reaction solution, adding ethyl acetate and water into the mother solution, separating the water phase with ethyl acetate for three times, combining organic phases, washing with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, concentrating, taking petroleum ether and ethyl acetate as mobile phases of 100: 1-50: 1, and performing column chromatography to obtain a compound II.
A round-bottom flask was charged with Compound II (1.0eq), tetrahydrofuran (0.25M), and then an aqueous hydrochloric acid solution (2M, 2.0eq) was added, and the mixture was heated under reflux until the reaction was complete. Extracting with ethyl acetate, mixing organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain the compounds shown in Table 1 with a yield of 34-66%.
The following examples are intended to illustrate the present invention.
Example 1
The synthesis method of example 1 is the same as the above synthesis method.
1-benzyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 42%; a white solid;1H NMR(400MHz，CDCl3)δ8.74(dd，J＝8.0，2.0Hz，1H)，8.67(dd， J＝4.4，1.6Hz，1H)，7.33(dd，J＝8.0，4.4Hz，1H)，7.32-7.25(m，3H)，7.04-7.02(m，2H)，6.30 (s，1H)，5.84(s，2H)，2.43(s，3H).13C NMR(100MHz，CDCl3)δ177.8，152.6，152.1，151.0， 136.8，135.9，129.0，127.5，125.8，120.9，119.7，112.8，47.7，21.5.HRMS(+ESI-TOF)m/z： [M+H]+Calcd for C16H15N2O 251.1179；Found 251.1182.
example 2
The synthesis method of example 2 is the same as the general synthesis method described above.
1-ethyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 33%; a white solid;1H NMR(400MHz，CDCl3)δ8.73-8.67(m，2H)，7.33-7.29(m，1H)，6.25(s，1H)，4.55(q，J＝7.2Hz，2H)，2.54(s，3H)，1.38(t，J＝7.2Hz，3H).13C NMR(100MHz，CDCl3)δ177.7，151.9，151.8，150.3，135.6，121.1，119.3，112.4，40.2，21.1，14.5.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C11H13N2O 189.1022；Found 189.1023.
example 3
The synthesis method of example 3 is the same as the general synthesis method described above.
2-methyl-1-propyl-1，8-naphthyridin-4(1H)-one
Yield: 36 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.68(dd，J＝4.4，2.4Hz，1H)，8.65(dd，J＝8.0，1.6Hz，1H)，7.28(dd，J＝8.0，4.4Hz，1H)，6.22(s，1H)，4.38(t，J＝7.6Hz，2H)，2.50(s， 3H)，1.80-1.71(m，2H)，1.00(t，J＝7.6Hz，3H).13C NMR(100MHz，CDCl3)δ177.5，151.9， 151.7，150.4，135.4，120.9，119.2，112.2，46.6，22.5，21.3，11.1.HRMS(+ESI-TOF)m/z：[M +H]+Calcd for C12H15N2O 203.1179；Found 203.1181.
example 4
The synthesis method of example 4 is the same as the above synthesis method.
1-butyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 84%; a white solid;1H NMR(400MHz，DMSO-d6)δ8.80(dd，J＝4.4，2.0Hz，1H)，8.47 (dd，J＝7.6，2.0Hz，1H)，7.43(dd，J＝8.0，4.4Hz，1H)，6.14(s，1H)，4.41(t，J＝8.0Hz，2H)，2.53 (s，3H)，1.69-1.61(m，2H)，1.41-1.36(m，2H)，0.93(t，J＝7.6Hz，3H).13CNMR(100MHz， DMSO-d6)δ175.9，152.8，152.1，150.2，134.9，120.4，119.5，111.4，44.3，30.7，20.6，19.6， 13.6.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C13H17N2O 217.1335；Found217.1338.
example 5
The synthesis method of example 5 is the same as the general synthesis method described above.
1-isopropyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 55 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.68-8.66(m，2H)，7.29-7.26(m，1H)，6.21(s，1H)，4.76(s，1H)，2.53(s，3H)，1.77(s，6H).13C NMR(100MHz，CDCl3)δ177.9，152.2，151.5，150.6，135.5，122.0，119.2，113.0，52.8，22.8，21.2.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C12H15N2O 203.1179；Found 203.1182.
example 6
The synthesis method of example 6 is the same as the general synthesis method described above.
1-cyclopropyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 57 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.74(dd，J＝4.4，2.0Hz，1H)，8.64(dd，J＝8.0，2.0Hz，1H)，7.30(dd，J＝8.0，4.4Hz，1H)，6.23(s，1H)，3.23-3.18(m，1H)，2.64(s，3H)， 1.43-1.38(m，2H)，0.98-0.93(m，2H).13C NMR(100MHz，CDCl3)δ178.2，155.0，152.5， 151.2，135.4，121.2，119.4，112.5，29.7，29.1，21.9，11.7.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C12H13N2O 201.1022；Found 2001.1025.
example 7
The synthesis method of example 7 is the same as the general synthesis method described above.
1-cyclopentyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 56 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.65-8.63(m，2H)，7.24(dd，J＝7.6，4.8Hz，1H)，6.20(s，1H)，5.03-4.94(m，1H)，2.52(s，3H)，2.49-2.42(m，2H)，2.21-2.12(m， 2H)，1.93-1.88(m，2H)，1.72-1.62(m，2H).13C NMR(100MHz，CDCl3)δ177.9，152.8，150.8， 150.4，135.6，122.1，119.1，113.0，60.2，30.3，26.1，23.0.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C14H17N2O 229.1335；Found 229.1338.
example 8
The synthesis method of example 8 is the same as the general synthesis method described above.
1-cyclohexyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 66 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.80-8.57(m，2H)，7.28(s，1H)，6.24 (s，1H)，4.29-4.23(m，1H)，3.13-3.09(m，2H)，2.53(s，3H)，2.11(s，2H)，1.98-1.88(m，2H)， 1.77-1.74(m，2H)，1.38(s，3H).13C NMR(100MHz，CDCl3)δ178.0，152.4，151.7，150.5， 135.5，121.9，119.3，113.0，62.1，30.4，27.0，25.4，23.1.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C15H19N2O 243.1492；Found 243.1492.
example 9
The synthesis of example 9 was performed as described above.
1-(4-methoxybenzyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 51 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.73(dd，J＝8.0，2.0Hz，1H)，8.69(dd，J＝4.8，2.0Hz，1H)，7.33(dd，J＝8.0，4.4Hz，1H)，6.97(d，J＝8.4，2H)，6.82(d，J＝8.4，2H)，6.29 (s，1H)，5.77(s，2H)，3.76(s，3H)，2.44(s，3H).13C NMR(100MHz，CDCl3)δ177.8，159.0， 152.6，152.1，151.0，135.8，128.7，127.2，120.9，119.7，114.3，112.8，55.3，47.2，21.5. HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C17H17N2O2281.1285；Found281.1285.
example 10
The synthesis method of example 10 is the same as the above synthesis method.
1-(4-fluorobenzyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 49 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.72(dd，J＝8.0，2.0Hz，1H)，8.66(dd， J＝4.4，2.0Hz，1H)，7.33(dd，J＝8.0，4.8Hz，1H)，7.03-6.96(m，4H)，6.29(s，1H)，5.78(s，2H)， 2.42(s，3H).13C NMR(100MHz，CDCl3)δ177.9，162.2(d，J＝245.0Hz)，152.4(d，J＝5.0Hz)， 152.2(d，J＝3.0Hz)，151.0(d，J＝3.0Hz)，136.0，132.6(d，J＝4.0Hz)，127.7(d，J＝8.0Hz)， 121.0，119.9(d，J＝3.0Hz)，116.0(d，J＝21.0Hz)，113.0，47.2，21.5(d，J＝4.0Hz).HRMS (+ESI-TOF)m/z：[M+H]+Calcd for C16H14FN2O 269.1085；Found269.1085.
example 11
The synthesis of example 11 was performed as described above.
1-(4-bromobenzyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 45 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.72(dd，J＝8.0，2.0Hz，1H)，8.65(dd， J＝4.4，2.0Hz，1H)，7.42(d，J＝8.0Hz，2H)，7.34(dd，J＝8.0，4.8Hz，1H)，6.91(d，J＝8.0Hz， 2H)，6.29(s，1H)，5.76(s，2H)，2.41(s，3H).13C NMR(100MHz，CDCl3)δ177.7，152.3，152.1， 150.8，135.9，135.8，132.0，127.6，121.3，120.8，119.8，112.8，47.2，21.4.HRMS(+ESI-TOF) m/z：[M+H]+Calcd for C16H14BrN2O 329.0284；Found 329.0283.
example 12
The synthesis method of example 12 is the same as the general synthesis method described above.
1-(3-bromobenzyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 41 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.72(dd，J＝8.0，2.0Hz，1H)，8.65(dd， J＝4.4，2.0Hz，1H)，7.38(d，J＝8.0Hz，1H)，7.34(dd，J＝8.0，4.8Hz，1H)，7.21(s，1H)，7.15(t，J ＝8.0Hz，1H)，6.91(d，J＝8.0Hz，1H)，6.29(s，1H)，5.78(s，2H)，2.41(s，3H).13C NMR(100MHz， CDCl3)δ177.8，152.2，152.1，150.8，139.2，135.9，130.7，130.5，129.0，124.4，123.1，120.8， 119.8，112.9，47.1，21.4.HRMS(+ESI-TOF)m/z：[M+H]+Calcdfor C16H14BrN2O 329.0284； Found 329.0282.
example 13
The synthesis method of example 13 is the same as the general synthesis method described above.
1-cyclopropyl-2，6-dimethyl-1，8-naphthyridin-4(1H)-one
Yield: 42%; a white solid;1H NMR(400MHz，CDCl3)δ8.56(d，J＝2.4Hz，1H)，8.43(d，J＝1.6Hz，1H)，6.20(s，1H)，3.22-3.16(m，1H)，2.62(s，3H)，2.44(s，3H)，1.41-1.36(m，2H)，0.96 -0.91(m，2H).13C NMR(100MHz，CDCl3)δ178.3，154.7，152.1，150.8，134.8，129.0，120.7， 112.2，29.1，21.8，17.9，11.6.HRMS(+ESI-TOF)m/z：[M+Na]+Calcd for C13H14N2ONa237.0998；Found 237.1000.
example 14
The synthesis method of example 14 is the same as the above synthesis method.
1-cyclopropyl-2，7-dimethyl-1，8-naphthyridin-4(1H)-one
Yield: 40 percent; white solidA body;1H NMR(400MHz，CDCl3)δ8.48(d，J＝8.0Hz，1H)，7.13(d，J＝8.0Hz，1H)，6.17(s，1H)，3.18-3.12(m，1H)，2.65(s，3H)，2.60(s，3H)，1.36(q，J＝6.8Hz，2H)， 0.95-0.91(m，2H).13C NMR(100MHz，CDCl3)δ178.3，161.2，154.4，152.1，135.4，119.5， 118.9，112.4，29.1，25.3，21.8，11.8.HRMS(+ESI-TOF)m/z：[M+H]+Calcd forC13H15N2O 215.1179；Found 215.1179.
example 15
The synthesis of example 15 was performed as described above.
1-allyl-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 36 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.70(s，1H)，8.69(dd，J＝6.4，0.8Hz，1H)，7.34-7.30(m，1H)，6.28(s，1H)，6.06-5.97(m，1H)，5.20-5.17(m，3H)，4.91(d，J＝17.6， 1H)，2.51(s，3H).13C NMR(100MHz，CDCl3)δ178.0，152.5，152.1，150.6，135.9，132.7， 121.0，119.7，116.6，112.6，46.8，21.2.HRMS(+ESI-TOF)m/z：[M+H]+Calcd forC12H13N2O 201.1022；Found 201.1023.
example 16
The synthesis method of example 16 is the same as the general synthesis method described above.
2-methyl-1-(prop-2-yn-1-yl)-1，8-naphthyridin-4(1H)-one
Yield: 15 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.74(dd，J＝4.4，2.0Hz，1H)，8.68(dd，J＝8.0，2.0Hz，1H)，7.34(dd，J＝7.6，4.4Hz，1H)，6.28(s，1H)，5.35(d，J＝2.4Hz，2H)，2.65(s， 3H)，2.30(t，J＝2.4Hz，1H).13C NMR(100MHz，CDCl3)δ177.9，152.0，151.8，150.1，136.0，121.1，119.8，112.9，78.3，72.7，34.0，21.1.HRMS(+ESI-TOF)m/z：[M+H]+Calcd forC12H11N2O 199.0866；Found 199.0867.
example 17
The synthesis of example 17 was performed as described above.
1-cyclopropyl-2-isopropyl-1，8-naphthyridin-4(1H)-one
Yield: 50 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.75(dd，J＝4.4，2.0Hz，1H)，8.62(dd，J＝8.0，2.0Hz，1H)，7.30(dd，J＝8.0，4.8Hz，1H)，6.32(s，1H)，3.93-3.86(m，1H)，3.26-3.20 (m，1H)，1.45-1.32(m，2H)，1.34(s，3H)，1.32(s，3H)，0.88-0.84(m，2H).13C NMR(100MHz， CDCl3)δ178.7，165.1，152.9，151.3，135.2，121.2，119.4，108.9，30.1，28.3，23.0，12.2. HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C14H17N2O 229.1335；Found 229.1338.
example 18
The synthesis of example 18 was performed as described above.
2-cyclohexyl-1-cyclopropyl-1，8-naphthyridin-4(1H)-one
Yield: 46 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.74(dd，J＝4.4，2.0Hz，1H)，8.61(dd， J＝7.6，1.6Hz，1H)，7.29(dd，J＝8.0，4.4Hz，1H)，6.29(s，1H)，3.52-3.47(m，1H)，3.25-3.19 (m，1H)，2.02-1.85(m，4H)，1.81(s，2H)，1.47-1.38(m，6H)，0.88-0.83(m，2H).13C NMR(100 MHz，CDCl3)δ178.7，163.8，152.8，151.3，135.2，121.2，119.4，109.8，40.9，33.5，28.4，26.7， 25.9，12.0.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C17H21N2O 269.1648；Found 269.1650.
example 19
The synthesis method of example 19 is the same as the above synthesis method.
(E)-1-cyclopropyl-2-styryl-1，8-naphthyridin-4(1H)-one
Yield: 40 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.78(dd，J＝4.4，2.0Hz，1H)，8.65(dd， J＝7.6，1.6Hz，1H)，7.60-7.53(m，2H)，7.48-7.35(m，4H)，7.33(dd，J＝8.0，4.4Hz，1H)，7.27- 7.23(m，1H)，6.62(s，1H)，3.41-3.36(m，1H)，1.43-1.38(m，2H)，0.92-0.87(m，2H).13C NMR (100MHz，CDCl3)δ178.5，153.4，152.5，151.8，135.8，135.7，135.4，129.5，129.1，127.5， 122.8，121.7，119.6，109.1，29.5，12.0.HRMS(+ESI-TOF)m/z：[M+H]+Calcdfor C19H17N2O 289.1335；Found 289.1337.
example 20
The synthesis method of example 20 is the same as the general synthesis method described above.
1-cyclopropyl-2-(4-fluorophenyl)-1，8-naphthyridin-4(1H)-one
Yield: 48 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.83(dd，J＝4.4，2.0Hz，1H)，8.69(dd，J＝8.0，2.0Hz，1H)，7.64-7.50(m，2H)，7.38(dd，J＝8.0，4.4Hz，1H)，7.20(t，J＝8.4Hz，2H)， 6.31(s，1H)，3.40-3.35(m，1H)，1.01-0.96(m，2H)，0.50-0.46(m，2H).13C NMR(100MHz， CDCl3)δ178.3，163.3(d，J＝249.0Hz)，155.4，153.0，152.0，135.5，132.6(d，J＝3.0Hz)， 130.2(d，J＝8.0Hz)，121.5，119.8，115.8(d，J＝22.0Hz)，113.8，31.9，12.6.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C17H14FN2O 281.1085；Found 281.1086.
example 21
The synthesis method of example 21 was the same as the above synthesis method.
1-cyclopropyl-2-(4-methoxyphenyl)-1，8-naphthyridin-4(1H)-one
Yield: 43 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.82(dd，J＝4.4，2.0Hz，1H)，8.68(dd， J＝8.0，2.0Hz，1H)，7.49(d，J＝8.8Hz，2H)，7.36(dd，J＝8.0，4.8Hz，1H)，7.01(d，J＝8.4Hz， 2H)，6.33(s，1H)，3.89(s，3H)，3.43-3.37(m，1H)，1.00-0.95(m，2H)，0.49-0.44(m，2H).13C NMR(100MHz，CDCl3)δ178.4，160.6，156.5，153.2，151.9，135.5，129.9，129.0，121.6， 119.7，114.0，113.5，55.5，32.1，12.7.HRMS(+ESI-TOF)m/z：[M+H]+Calcd forC18H17N2O2293.1285；Found 293.1286.
example 22
The synthesis of example 22 was performed in the same manner as described above.
1-cyclopropyl-2-(4-methoxyphenyl)-3-methyl-1，8-naphthyridin-4(1H)-one
Yield: 44%; a white solid;1H NMR(400MHz，DMSO-d6)δ8.84(s，1H)，8.51(d，J＝7.2Hz，1H)，7.46-7.43(m，3H)，7.09(d，J＝8.0Hz，2H)，3.84(s，3H)，3.16(s，1H)，1.78(s，3H)，0.77(d，J ＝5.6Hz，2H)，0.50(s，2H).13C NMR(100MHz，CDCl3)δ159.7，152.9，152.0，151.5，135.5， 130.6，128.0，119.2，113.8，55.4，32.1，13.1，12.8.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C19H19N2O2307.1441；Found 307.1442.
example 23
The synthesis of example 23 was performed as described above.
2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 66 percent; a white solid;1H NMR(400MHz，DMSO-d6)δ12.07(s，1H)，8.70(dd，J＝4.4，1.6 Hz，1H)，8.39(dd，J＝8.0，1.6Hz，1H)，7.36(dd，J＝8.0，4.4Hz，1H)，5.98(s，1H)，2.35(s，3H).13C NMR(100MHz，DMSO-d6)δ177.1，152.7，151.3，150.8，134.4，119.5，118.9，109.2，19.4. HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C9H9N2O 161.0709；Found 161.0711.
example 24
The synthesis of example 24 was performed in the same manner as described above.
2-methyl-1-phenyl-1，8-naphthyridin-4(1H)-one
Yield: 61%; a white solid;1H NMR(400MHz，CDCl3)δ8.71(dd，J＝8.0，2.0Hz，1H)，8.55(dd，J＝4.4，2.0Hz，1H)，7.62-7.55(m，3H)，7.30-7.26(m，3H)，6.36(s，1H)，2.11(s，3H).13CNMR (100MHz，CDCl3)δ178.3，152.5，152.4，152.3，139.0，135.6，130.0，129.3，129.0，120.6， 119.7，112.1，22.6.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C15H13N2O 237.1022；Found 237.1026.
example 25
The synthesis of example 25 was performed in the same manner as described above.
1-(4-methoxyphenyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 40 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.71(dd，J＝8.0，2.0Hz，1H)，8.58(dd，J＝4.4，2.0Hz，1H)，7.30-7.27(m，1H)，7.17-7.15(m，2H)，7.09-7.06(m，2H)，6.35(s，1H)， 3.90(s，3H)，2.12(s，3H).13C NMR(100MHz，CDCl3)δ178.1，159.7，152.9，152.5，152.2， 135.4，131.3，129.8，120.5，119.5，115.0，111.9，55.5，22.5.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C16H15N2O2267.1128；Found 267.1129.
example 26
The synthesis method of example 26 was the same as the above synthesis method.
1-(4-fluorophenyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 35 percent; a white solid;1H NMR(400MHz，DMSO-d6)δ8.57(dd，J＝4.4，2.0Hz，1H)，8.50 (dd，J＝7.6，2.0Hz，1H)，7.51-7.46(m，2H)，7.43-7.38(m，3H)，6.29(s，1H)，2.06(s，3H).13C NMR(100MHz，DMSO-d6)δ176.6，161.8(d，J＝245.0Hz)，152.7，152.1，152.0，134.9，134.9， 134.7，131.4(d，J＝9.0Hz)，119.8(d，J＝6.0Hz)，116.4(d，J＝22.0Hz)，111.1，21.9.HRMS (+ESI-TOF)m/z：[M+H]+Calcd for C15H12FN2O 255.0928；Found 255.0929.
example 27
The synthesis of example 27 was performed as described above.
1-(4-bromophenyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 37 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.69(dd，J＝8.0，2.0Hz，1H)，8.53(dd， J＝4.4，2.0Hz，1H)，7.73-7.70(m，2H)，7.29(dd，J＝8.0，4.8Hz，1H)，7.16-7.13(m，2H)，6.34 (s，1H)，2.11(s，3H).13C NMR(100MHz，CDCl3)δ178.1，152.1，151.8，137.9，135.5，133.2，130.7，123.4，120.5，119.8，112.2，22.5.HRMS(+ESI-TOF)m/z：[M+H]+Calcdfor C15H12BrN2O 315.0128；Found 315.0129.
example 28
The synthesis of example 28 was performed in the same manner as described above.
1-(2，4-difluorophenyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 41 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.68(dd，J＝8.0，2.0Hz，1H)，8.52(dd， J＝4.4，2.0Hz，1H)，7.33-7.27(m，2H)，7.11-7.05(m，2H)，6.36(s，1H)，2.14(s，3H).13C NMR (100MHz，CDCl3)δ178.4，163.2(dd，J＝251，11Hz)，158.7(dd，J＝252，13Hz)，152.4，152.0， 151.9，135.7，131.8(dd，J＝10，1Hz)，122.7(dd，J＝14，5Hz)，120.5，120.1，112.6(dd，J＝23， 5Hz)，112.5，105.6(dd，J＝26，24Hz)，21.8.HRMS(+ESI-TOF)m/z：[M+H]+Calcd for C15H11F2N2O 273.0834；Found 273.0834.
example 29
The synthesis of example 29 was performed as described above.
1-(2-hydroxyethyl)-2-methyl-1，8-naphthyridin-4(1H)-one
Yield: 41 percent; a white solid;1H NMR(400MHz，CDCl3)δ8.66(dd，J＝4.4，1.6Hz，1H)，8.44(dd， J＝7.6，1.6Hz，1H)，7.24(dd，J＝8.0，4.4Hz，1H)，6.00(s，1H)，4.63(t，J＝4.8Hz，2H)，4.10(t，J ＝4.8Hz，2H)，2.57(s，3H).13C NMR(100MHz，CDCl3)δ177.5，153.8，151.7，150.8，135.7，121.0，119.6，112.4，61.6，48.1，22.5.HRMS(+ESI-TOF)m/z：[M+H]+Calcdfor C11H13N2O2205.0972；Found 205.0966.
example 30
The synthesis of example 30 was performed as described above.
2-methyl-1-phenylbenzo[b][1，8]naphthyridin-4(1H)-one
Yield: 66 percent; a white solid;1H NMR(400MHz，CDCl3)δ9.26(s，1H)，8.00(d，J＝8.0Hz，1H)， 7.73-7.65(m，2H)，7.63-7.54(m，3H)，7.49-7.45(m，1H)，7.32-7.30(m，2H)，6.31(s，1H)， 2.16(s，3H).13C NMR(100MHz，CDCl3)δ179.2，154.3，151.2，149.0，139.3，137.2，131.9， 129.7，129.4，129.2，128.9，128.5，125.6，125.4，119.9，109.8，23.1.HRMS(+ESI-TOF)m/z： [M+H]+Calcd for C19H15N2O 287.1179；Found 287.1180.
in vitro α -glucosidase inhibitory Activity assay for Compounds 3, 10, 21, 29 and 30
(a) Preparation of phosphate buffer solution
Accurately weighing potassium dihydrogen phosphate (KH) by using an analytical balance2PO4) Dipotassium hydrogen phosphate (K)2HPO4) 13.68g and 22.69g respectively; dissolving a small amount of distilled water, introducing into a 500mL volumetric flask, and diluting to a constant volume to a scale mark with the distilled water to prepare a buffer solution with the concentration of 0.4M; measuring 62.5mL, pouring into a 500mL volumetric flask, metering to the volume with distilled water to a scale mark, fully and uniformly mixing, and adding a proper amount of phosphoric acid to adjust the pH value to 6.8 to obtain the final required buffer solution with the concentration of 50 mM.
(b) α preparation of glucosidase
Preparation of enzyme stock solution α -glucosidase powder (100U) from Saccharomyces cerevisiae, preparing 100U/mL enzyme solution with 1mL of the above phosphate buffer (50mM, pH 6.8), diluting the enzyme, diluting 20 times to 5U/mL, subpackaging in small EP tubes, and storing at-80 deg.C in refrigerator for use.
The preparation of the enzyme test solution comprises the steps of taking α -glucosidase with the concentration of 5U/mL in a small EP tube, diluting the α -glucosidase into α -glucosidase solution with the concentration of 0.04U/mL according to the proportion of 8/992mL (enzyme/buffer solution) for later use.
(c) Preparing the required substrate solution
Preparation of a substrate stock solution, namely, 211mg of 4-nitrophenol- α -D-glucopyranoside (p-NPG) is precisely weighed by an analytical balance, 70mL of 50mM phosphate buffer solution (50mM, pH 6.8) is added, and the mixture is dissolved and uniformly mixed to prepare 10mM substrate (p-NPG) stock solution, and the 10mM substrate (p-NPG) stock solution is preserved at the temperature of minus 20 ℃ in a dark place for standby.
Preparation of a substrate solution: a10 mM substrate (p-NPG) solution is diluted into a 0.5mM substrate (p-NPG) solution, and the solution is prepared in situ.
(d) Dissolving the desired compound
Preparation of positive control stock solution: acarbose was selected as a positive control in this experiment. Acarbose powder was precisely weighed using an analytical balance, dissolved in dimethyl sulfoxide (DMSO), sufficiently dissolved and uniformly mixed to prepare a 10mM acarbose mother liquor, which was stored in a refrigerator at 4 ℃. The test concentrations were diluted with 10mM acarbose stock solution.
Preparation of test compound stock solutions: all inhibitors were dissolved in dimethyl sulfoxide (DMSO) to prepare 10mM test solutions.
(e) α -glucosidase inhibitory activity test system
The test systems were specifically grouped into Blank group, Control group, compound Blank group and compound group, which were:
(1) blank group: buffer (170 μ L) +0.5mM substrate (30 μ L);
(2) control group: buffer (140. mu.L) + DMSO (10. mu.L) +0.04U/mL enzyme (20. mu.L) +0.5mM substrate (30. mu.L);
(3) group of compounds: buffer (160 μ L) + test compound (10 μ L) +0.5mM substrate (30 μ L);
(4) compound Blank group: buffer (140 μ L) + test compound (10 μ L) +0.04U/mL enzyme (20 μ L) +0.5mM substrate (30 μ L);
in the experiment process, firstly adding a buffer solution and a compound to be detected into a 96-well plate, then adding 0.04U/mL enzyme (20 mu L), incubating at 37 ℃ and slightly shaking for 5min, finally adding 0.5mM substrate (30 mu L), further incubating for 30min under the same condition, placing an ELISA plate on an ELISA reader, setting the wavelength to be 405nm, reading the absorbance value (OD), and calculating the inhibition rate as follows:
wherein OD4Is the absorbance, OD, of the compound group in the presence of an inhibitor3Is the absorbance, OD, of the inhibitor in the Blank group of compounds2Is the absorbance, OD, of the Control group, i.e., without the effect of the test compound1The absorbance of the blank control, i.e., buffer. And (4) carrying out three parallels in each experiment, setting multiple holes for each concentration, and calculating an average value to obtain an error value SD between each group of data.
The test results are shown in table 2.
TABLE 2 α -glucosidase inhibitory Activity test results
The compounds 29 and 30 related to the invention have stronger inhibitory activity to α -glucosidase and hypoglycemic activity, and can be used for preparing medicines for treating diabetes.
Claims (7)
1. A novel 1, 8-dinitro-chromone compound is characterized in that: the structure is as follows:
2. a synthetic method for preparing the novel 1, 8-diazacyclochromone compound of claim 1, wherein: the method comprises the following steps B: reacting compound II to form 1, 8-bis-azachromone:
wherein R is1Hydrogen, aryl or alkyl substituted at one or more positions 4, 5, 6 of the pyridine ring; r2Is alkyl, cycloalkyl, substituted benzyl, allyl or propargyl; r3Is substituted alkenyl, aryl or alkyl; r4Is a hydrogen atom, a substituted phenyl group or an alkyl group.
3. The method of synthesis according to claim 2, characterized in that: the compound II generates 1, 8-bis-azachromone through cyclization under the reflux condition of 2M hydrochloric acid and tetrahydrofuran solution.
4. The method of synthesis of claim 2, wherein the method further comprises step a: reacting compound I to form compound II:
wherein R is1，R2，R3，R4Is as defined in claim 2.
5. The method of synthesis according to claim 4, characterized in that: the compound I and different types of amine compounds generate a compound II under the action of tripyrrolidinyl phosphonium bromide hexafluorophosphate and alkali.
6. The method according to claim 2 or 4, wherein the method comprises the steps of:
7. the use of a class of 1, 8-diazacyclo-chromone compounds according to claim 1 in the preparation of a medicament for the treatment of diabetes.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN115536653A (en) * | 2022-09-30 | 2022-12-30 | 五邑大学 | Chromone thiazole diketone compound and preparation method, pharmaceutical composition and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992007468A1 (en) * | 1990-10-25 | 1992-05-14 | Imperial Chemical Industries Plc | Herbicides |
| CN1083063A (en) * | 1992-08-21 | 1994-03-02 | 山东新华制药厂 | 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives |
| CN1578781A (en) * | 2001-09-26 | 2005-02-09 | 拜尔药品公司 | 1,8 naphthyridine derivatives and their use to treat diabetes and related disorders |
| CN101679427A (en) * | 2007-06-13 | 2010-03-24 | 赛诺菲-安万特 | Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics |
| CN108329325A (en) * | 2017-07-20 | 2018-07-27 | 天津科技大学 | A kind of synthetic method of 8- azepines chromone |
| CN108484595A (en) * | 2018-02-27 | 2018-09-04 | 天津科技大学 | A kind of succinct synthetic method of asthmatic medicament Fevipiprant |
-
2019
- 2019-12-10 CN CN201911255280.XA patent/CN110981869A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992007468A1 (en) * | 1990-10-25 | 1992-05-14 | Imperial Chemical Industries Plc | Herbicides |
| CN1083063A (en) * | 1992-08-21 | 1994-03-02 | 山东新华制药厂 | 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives |
| CN1578781A (en) * | 2001-09-26 | 2005-02-09 | 拜尔药品公司 | 1,8 naphthyridine derivatives and their use to treat diabetes and related disorders |
| CN101679427A (en) * | 2007-06-13 | 2010-03-24 | 赛诺菲-安万特 | Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics |
| CN108329325A (en) * | 2017-07-20 | 2018-07-27 | 天津科技大学 | A kind of synthetic method of 8- azepines chromone |
| CN108484595A (en) * | 2018-02-27 | 2018-09-04 | 天津科技大学 | A kind of succinct synthetic method of asthmatic medicament Fevipiprant |
Non-Patent Citations (2)
| Title |
|---|
| HAOJIE MA等: "Transition-metal-free oxidative intermolecular cyclization reaction: synthesis of 2-aryl-4-quinolones", 《NEW JOURNAL CHEMISTRY》 * |
| JUN TODA等: "SYNTHESIS OF 2-AROXMETHYLQUINOLIN-4-ONES VIA THE ADDITION REACTION OF ORTHO-NITROBENZOYLKETENE TO 1-ARK-1-TRIMETHYLSILYLOXYETHYLENES", 《HETEROCYCLES》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN111533700B (en) * | 2020-05-20 | 2023-03-28 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN115536653A (en) * | 2022-09-30 | 2022-12-30 | 五邑大学 | Chromone thiazole diketone compound and preparation method, pharmaceutical composition and application thereof |
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