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Synthetic method of 3-benzylidene isoindoline-1-ketone derivative

A technology of benzylidene isoindoline and a synthesis method, which is applied in the field of pharmaceutical chemical intermediates and related chemical synthesis, can solve the problems of poor substrate applicability, harsh reaction conditions, restricted application and the like, and achieves cost reduction and good universality. Effect

Active Publication Date: 2019-06-21
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction is carried out in two steps, and the raw materials need to be prepared in advance and the reaction conditions are harsh, which limits the application of this type of method [W.-D.Lu et al., Tetrahedron, 2002,58,7315-7319]
Subsequent studies have been improved, and the one-pot reaction has the intermolecular ring-forming reaction of amide halides and phenylacetylene [Hellal, K., Cuny, G.D., Tetrahedron Letters, 2011, 52, 5508-5511], which requires The precious metal palladium and ligands are used as catalysts, and the reaction is carried out under microwave and high temperature conditions. From the perspective of cost, the reaction conditions have certain limitations for industrial applications.
In addition, the coupling reaction of carboxylic acid iodide and alkynoic acid is also an effective means of synthesizing isoindolin-1-one. This method uses cuprous iodide as a catalyst, and the equivalent ammonium acetate and cesium carbonate are heated at high temperature. The reaction is carried out, but the substrate suitability is poor [Irudayanathan, F.M., Noh, J., Choi, J., Lee, S., Advanced Synthesis and Catalysis, 2014, 16, 3433-3442]

Method used

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  • Synthetic method of 3-benzylidene isoindoline-1-ketone derivative
  • Synthetic method of 3-benzylidene isoindoline-1-ketone derivative
  • Synthetic method of 3-benzylidene isoindoline-1-ketone derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Synthesis of (3-(benzylidene)isoindolin-1-one)

[0040] In a 25mL reactor, add o-bromoaniline (0.034g, 0.2mmol), cuprous iodide (0.004g, 0.02mmol) and potassium tert-butoxide (0.045g, 0.4mmol), replace nitrogen with vacuum three times and then add benzene Acetylene (0.031g, 0.3mmol) and water (0.011g, 0.6mmol) were added to anhydrous 1,4-dioxane 1.5mL and stirred at 100°C for 12h. Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether: ethyl acetate = 5:1) obtained 0.028 g of 3-(benzylidene)isoindolin-1-one with a yield of 64%.

[0041]

[0042] white solid, 1 H NMR (500MHz, CDCl 3 )δ8.40(s,1H),7.90(d,J=7.6,1H),7.82(d,J=7.7Hz,1H); 7.66(t,J=7.6Hz,1H),7.54(t,J =7.5Hz,1H),7.51-7.42(m,4H),7.37-7.31(m,1H),6.58(s,1H). 13 CNMR (125MHz, CDCl 3)δ169.0, 138.2, 135.0, 133.1, 132.3, 129.2, 129.1, 128.7, 128.5, 127.7, 123.6, 119.8, 105.9.

Embodiment 2

[0044] Synthesis of (3-(3-bromobenzylidene)isoindolin-1-one)

[0045] In a 25mL reactor, add o-bromoaniline (0.034g, 0.2mmol), cuprous iodide (0.004g, 0.02mmol) and potassium tert-butoxide (0.045g, 0.4mmol), replace nitrogen with vacuum three times and then add 3 -Bromophenylacetylene (0.054g, 0.3mmol) and water (0.015g, 0.8mmol), add anhydrous 1,4-dioxane 1.5mL, and stir at 110°C for 16h. Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether: ethyl acetate = 5:1) obtained 0.042 g of 3-(3-bromobenzylidene) isoindolin-1-one, the yield 70%.

[0046]

[0047] Pale yellow solid, 1 H NMR (500MHz, DMSO) δ10.90(s, 1H), 8.04(d, J=7.8Hz, 1H), 7.86-7.67(m, 3H); 7.67-7.54(m, 2H), 7.46(d, J=8.0Hz, 1H), 7.36(d, J=15.7Hz, 1H), 6.74(s, 1H). 13 CNMR (125MHz, DMSO) δ174.4, 143.7, 142.3, 138.8, 137.6, 136.4, 135.9, 135.0, 134.7, 133.5, 133.2, 127.9, 127.4, 125.7, 109.3.

Embodiment 3

[0049] Synthesis of (3-(4-Propylbenzylidene)isoindolin-1-one)

[0050] The operation was the same as in Example 1, and 0.041 g of 3-(4-propylbenzylidene)isoindolin-1-one was obtained by reacting o-bromobenzonitrile and 4-propylphenylacetylene, with a yield of 77%.

[0051]

[0052] white solid, 1 H NMR (500MHz, CDCl 3 )δ8.33(s,1H),7.90(d,J=7.6Hz,1H),7.80(d,J=7.8Hz,3H),7.69-7.61(m,1H),7.53(t,J=7.4 Hz,1H),7.40(d,J=8.1Hz,1H),7.27(d,J=8.2Hz,2H),6.56(s,1H),2.68-2.60(t,J=8.0Hz,2H), 1.69(m,2H),0.99(t,J=7.3Hz,3H). 13 C NMR (125MHz, CDCl 3 )δ168.9, 142.6, 138.3, 132.5, 132.4, 129.4, 129.0, 128.7, 128.4, 123.6, 119.7, 106.2, 37.8, 24.4, 13.8.

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Abstract

The invention belongs to the fields of pharmaceutical chemical intermediates and related chemical technologies, and provides a synthetic method of a 3-benzylidene isoindoline-1-ketone derivative. Thesynthetic method is characterized in that bromobenzonitrile and phenylacetylene which are simple, cheap and easy to obtain are taken as raw materials, copper salt is taken as a catalyst, and 3-benzylidene isoindoline-1-ketone and the derivative thereof are synthesized in an anhydrous organic solvent under the combined action of a catalytic amount of water and alkali. The preparation method of the3-benzylidene isoindoline-1-ketone derivative, provided by the invention, has the benefits that reaction steps are few, the raw materials are low in cost, reaction conditions are mild, and the operation is convenient; the obtained product is high in yield and high in purity and fully meets the quality requirements as a drug intermediate, and favorable conditions are provided for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical and chemical intermediates and related chemical synthesis, and specifically relates to a synthesis method of novel 3-benzylidene isoindoline-1-one derivatives. Background technique [0002] 3-Benzylidene isoindolin-1-one derivatives are an important class of heterocyclic compounds, whose structures are commonly found in natural products and drug molecules, and have good biological activities. Currently used in the synthesis of anti-anxiety, hypotensive, anesthetic drugs [Botero, H.M., Trankle, C., Baumann, K., Pick, R., Mies-Klomfas s, E., Kostenis, E., Mohr, K ., Holzgrabe, U., J. Med. Chem., 2000, 43, 2155]. In view of the importance of 3-benzylidene isoindolin-1-one and its derivatives, how to efficiently synthesize 3-benzylidene isoindoline-1-one and its derivatives has attracted widespread attention. [0003] The synthesis of 3-benzylidene isoindolin-1-one derivatives reported so far...

Claims

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Application Information

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IPC IPC(8): C07D209/46
Inventor 包明李鹏程张胜王万辉
Owner DALIAN UNIV OF TECH
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