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A chiral tetrahydrofuroxazine fused benzimidazole-4,7-dione derivative and its preparation method and use

A technology of tetrahydrofuran and benzimidazole is applied in the field of benzimidazole-4,7-dione derivatives and their preparation, and achieves the effects of good antitumor activity, simple synthesis method and easy operation

Active Publication Date: 2022-03-04
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no relevant literature report on the synthesis of benzimidazole-4,7-dione analogues from sugars

Method used

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  • A chiral tetrahydrofuroxazine fused benzimidazole-4,7-dione derivative and its preparation method and use
  • A chiral tetrahydrofuroxazine fused benzimidazole-4,7-dione derivative and its preparation method and use
  • A chiral tetrahydrofuroxazine fused benzimidazole-4,7-dione derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: the synthesis of compound 3

[0040] Under the condition of ice bath, add 1,4-dimethoxybenzene (10 g, 0.072 mol) in batches to 60 mL of concentrated nitric acid, stir mechanically, remove the ice bath after 1 h, react at room temperature for 1 h, and then heat up to 80 °C, continue to react for 2h. Cool down, pour the reaction mixture into ice water, filter, and dry the filter cake to obtain Compound 1 as a yellow solid.

[0041] Dissolve the yellow solid 1 (12 g, 0.053 mol) in 60 mL of absolute ethanol, add 0.72 g of palladium carbon, replace with hydrogen 3 times, continuously feed hydrogen, react at room temperature for 2 h, filter, and concentrate under reduced pressure, the obtained black solid is Compound 2.

[0042] Dissolve the black solid 2 (8g, 0.048mol) and 1,4:3,6-dihydro-D-fructose (8.3g, 0.058mol) in 100mL of ethanol, under nitrogen protection, heat to 65°C for 3h, wait for the reaction After completion, the solvent was distilled off under...

Embodiment 2

[0043] Embodiment 2: the synthesis of compound 4

[0044] Compound 3 (5g, 0.017mol) was added to a mixed solvent of 20mL water and 20mL acetonitrile, stirred at room temperature, bis(trifluoroacetoxy)iodobenzene (11g, 0.026mol) was added, reacted for 2h, concentrated under reduced pressure, Silica gel column chromatography (EA:MeOH=20:1) gave 4 as a yellow solid. 1 H NMR (400MHz, DMSO-d 6)δ6.74(s,2H),6.01(s,1H),5.47(d,J=6.7Hz,1H),5.13(d,J=16.0Hz,1H),4.81(d,J=16.0Hz, 1H), 4.57(m, 1H), 4.28(s, 1H), 4.01(t, J=7.3Hz, 1H), 3.73(t, J=8.4Hz, 1H).

Embodiment 3

[0045] Example 3: Compounds QIF-1a and QIF-1b (general formula 1, R is an aromatic amino group, and the amino group is substituted at the 8-position and 9-position respectively; general formula 5, R 3 for the synthesis of hydrogen)

[0046] (In the compound QIF number, a is 8-position substitution, b is 9-position substitution, the same below.)

[0047] Compound 4 (500mg, 1.91mmol) was dissolved in 35mL of methanol, aniline (174μL, 1.91mmol) was added, stirred at room temperature for 15min, concentrated under reduced pressure, separated by column chromatography (DCM:MeOH=30:1), and purple was obtained in turn Solid compounds QIF-1a and QIF-1b.

[0048] QIF-1a: 1 H NMR (400MHz, DMSO-d 6 )δ9.18(s,1H),7.43(t,J=7.6Hz,2H),7.37(d,J=7.8Hz,2H),7.21(t,J=7.1Hz,1H),6.04(s, 1H), 5.67(s, 1H), 5.45(d, J=6.7Hz, 1H), 5.09(d, J=15.7Hz, 1H), 4.79(d, J=15.7Hz, 1H), 4.62–4.48( m, 1H), 4.26(s, 1H), 3.98(t, J=7.3Hz, 1H), 3.71(dd, J=8.9, 8.1Hz, 1H).

[0049] QIF-1b: 1H NMR (400MHz, DMSO-d6) δ9...

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Abstract

The invention discloses a chiral tetrahydrofuranoxazine fused benzimidazole-4,7-diketone derivative, a preparation method and application thereof, and belongs to the fields of sugar chemistry and medicinal chemistry. It has the structure shown in the following general formula: (R is an amino group) using 1,4:3,6-dihydrated fructose and o-phenylenediamine as raw materials, through condensation, oxidation and ring expansion, one-pot multi-step reaction stereoselective Chiral tetrahydrofuroxazine fused benzimidazole derivatives were obtained, and then a series of benzimidazole-4,7-dione derivatives were obtained through oxidation reaction and substitution reaction of different amine compounds. This kind of derivative has good biological activity, can be used as antitumor drug or the lead of antitumor drug, and has the value of further research and development.

Description

technical field [0001] The invention belongs to the fields of sugar chemistry and medicinal chemistry, and in particular relates to benzimidazole-4,7-dione derivatives and a preparation method thereof. Background technique [0002] Benzimidazoles are nitrogen-containing heterocyclic compounds with special structures, reactivity and physiological activities, and are important mother nuclei of many active compounds. On the basis of benzimidazole, benzimidazole-4,7-dione compounds can be obtained through further structural modification. Benzimidazole-4,7-dione compounds have a wide range of biological activities, and the substituents on the quinone ring play an important role in biological activity. Most of the biologically active benzimidazole-4,7-diones The substitution position of the compound is at the 2, 5, or 6 position. [0003] [0004] Synthesis of new benzimidazole-4,7-dione derivatives is an effective way to discover new drugs. The preparation method of benzimi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/14A61P35/00
CPCC07D498/14A61P35/00
Inventor 刘丰五王海霞霍翔宇季书杰
Owner ZHENGZHOU UNIV