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Preparation method for sulfur-containing 3-methylene isoindoline-1-one derivative

A methylene isoindoline and derivative technology, applied in the direction of organic chemistry, can solve the problem of thiol catalyst poisoning, etc., and achieve the effects of simple operation, easy product availability, and emission reduction.

Active Publication Date: 2019-02-22
WENZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, N,S-bidentate auxiliaries are rarely used in the synthesis of 3-methyleneisoindolin-1-one derivatives, probably due to poisoning of thiol catalysts (Angew.Chem.2008, 120, 2922)

Method used

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  • Preparation method for sulfur-containing 3-methylene isoindoline-1-one derivative
  • Preparation method for sulfur-containing 3-methylene isoindoline-1-one derivative
  • Preparation method for sulfur-containing 3-methylene isoindoline-1-one derivative

Examples

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Effect test

specific Embodiment 1

[0026] Specific example one: with 0.2mmol N-(2-(methylthio)phenyl)benzamide and 13.5mmol methyl acrylate as substrate, 0.02mmol Pd(OAc) 2 As a catalyst, 0.24 mmol of anhydrous copper acetate was used as an oxidant, and the mixture was placed in a mixture of 1,2-dichloroethane and glacial acetic acid for 24 hours in an oil bath at 110°C. After the reaction was completed, the mixture was neutralized with glacial acetic acid as a solvent with a saturated sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give 42.3 mg of (E)-2-(2-(2-(methylthio)phenyl)-3-oxoisoindol-1-ylidene)acetate as a white solid Esters, yield 65%. m.p.180-182℃. 1 H NMR (500MHz, CDCl 3 )δ9.15(d, J=8.0Hz, 1H), 7.97(d, J=7.5Hz, 1H), 7.76–7.73(m, 1H), 7.67–7.64(m, 1H), 7.50–7.47(m ,1H),7.39(d,J=...

specific Embodiment 2

[0027] Specific Example Two: With 0.2mmol 4-methyl-N-(2-(methylthio)phenyl)benzamide and 13.5mmol methyl acrylate as substrate, 0.02mmol Pd(OAc) 2 As a catalyst, 0.24 mmol of anhydrous copper acetate was used as an oxidant, and the mixture was placed in a mixture of 1,2-dichloroethane and glacial acetic acid for 24 hours in an oil bath at 110°C. After the reaction was completed, the mixture was neutralized with glacial acetic acid as a solvent with a saturated sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by flash column chromatography afforded 45.4 mg of (E)-2-(6-methyl-2-(2-(methylthio)phenyl)-3-oxoisoindole-1- as a white solid Subunit) methyl acetate, yield 67%. m.p.175-177℃. 1 H NMR (400MHz, CDCl 3 )δ8.98(s,1H),7.84(d,J=7.6Hz,1H),7.49–7.45(m,2H),7.36(d,J=7.6Hz,1H),7.31–7.27(m,1H )...

specific Embodiment 3

[0028] Specific Example Three: With 0.2mmol 2-methyl-N-(2-(methylthio)phenyl)benzamide and 13.5mmol methyl acrylate as substrate, 0.02mmol Pd(OAc) 2 As a catalyst, 0.24 mmol of anhydrous copper acetate was used as an oxidant, and the mixture was placed in a mixture of 1,2-dichloroethane and glacial acetic acid for 24 hours in an oil bath at 110°C. After the reaction was completed, the mixture was neutralized with glacial acetic acid as a solvent with a saturated sodium bicarbonate solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by flash column chromatography afforded 35.9 mg of (E)-2-(4-methyl-2-(2-(methylthio)phenyl)-3-oxoisoindole-1- as a white solid Subunit) methyl acetate, yield 53%. m.p.123-125℃. 1 H NMR (400MHz, CDCl 3 )δ9.03(d,J=8.0Hz,1H),7.61–7.58(m,1H),7.49–7.45(m,1H),7.41–7.35(m,2H),7.31–7.27(m,1...

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Abstract

The invention relates to a preparation method for sulfur-containing 3-methylene isoindoline-1-one. The preparation method comprises the steps that N-(2-(methylthio)phenyl) benzamide and methyl acrylate serve as substrates, Pd(OAc)2 serves as a catalyst, anhydrous copper acetate serves as an oxidizing agent, a mixture is put into a mixed solution of 1,2-dichloroethane and glacial acetic acid in anoil bath at 110 DEG C for reaction for 24 hours, after the reaction is ended, a solvent of the glacial acetic acid of the mixture is neutralized by using a sodium bicarbonate saturated solution, thena water layer is extracted by using ethyl acetate, a combined organic layer is dried by using anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and residues are purified through a rapid column chromatography method so as to obtain a required product. The preparation method has the advantages that the raw materials are simple and easy to obtain, a preparation process is novel and simple, the pollution is less, the energy consumption is low, and the yield is high.

Description

technical field [0001] The invention relates to a preparation method of sulfur-containing 3-methylene isoindolin-1-one derivatives. Background technique [0002] 3-methylene isoindolinone is an important structural unit in many drugs and bioactive molecules, you can refer to page 3557 of the 12th issue of "Bioorganic Medicinal Chemistry Communication" in 2002 (Bioorg.Med.Chem.Lett.2002, 12,3557). Some of their analogues can be used as PDE4 inhibitors, you can refer to "Drug Design and Discovery", No. 11, 2014, page 1188 (Lett.Drug.Des.Discov.2014, 11, 1188), anti-tumor drugs, etc., you can refer to "Natural Product Impurities", No. 72, 2009, page 1279 (J.Nat.Prod.2009, 72, 1279). Therefore, the synthesis of 3-methyleneisoindolinone has attracted extensive attention of researchers. [0003] Over the past few decades, major breakthroughs have been made in metal-catalyzed C–H bond activation, which provides important methods for constructing C–C and C–heterobonds. In 2005, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46
CPCC07D209/46
Inventor 张小红李玲张兴国
Owner WENZHOU UNIVERSITY
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