Preparation method of trifluoromethyl hydroxylated derivatives of isoindolinone

A technology of trifluoromethyl hydroxy and isoindolinone, applied in the direction of organic chemistry and the like, can solve the problems of complex reaction conditions, poor reaction selectivity, cumbersome steps, etc., and achieves simple reaction operation and post-treatment process, mild reaction conditions, The effect of easy availability of raw materials

Active Publication Date: 2018-08-24
SUZHOU UNIV
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Problems solved by technology

[0008] So far, there have been no reports on the trifluoromethyl hydroxylation of the double bond of isoindolinones. 3 SO 2 The reports of Na as a trifluoromethyl source have disadvantages such as poor reaction selectivity, complex reaction conditions, and cumbersome steps.
In the above existing synthetic techniques of trifluoromethyl hydroxylated derivatives, there are deficiencies such as high operational technical requirements, and the reaction scale cannot be too large.

Method used

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  • Preparation method of trifluoromethyl hydroxylated derivatives of isoindolinone
  • Preparation method of trifluoromethyl hydroxylated derivatives of isoindolinone
  • Preparation method of trifluoromethyl hydroxylated derivatives of isoindolinone

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Embodiment one: the synthesis (2a) of 3-hydroxyl-2-phenyl-3-(2,2,2-trifluoro-1-phenylethyl) isoindol-1-one

[0038]

[0039] (1) Weigh 3-benzylidene-2-phenylisoindol-1-one 1a (0.297g, 1mmol), sodium trifluoromethanesulfinate (0.468g, 3mmol), cuprous chloride (0.020g, 0.2mmol), potassium persulfate (1.081g, 4mmol) was dissolved in 9mL of acetonitrile aqueous solution (acetonitrile: water = 2:1). The mixture was stirred and reacted at 25°C, and the reaction was followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:6) to obtain compound 2a. Isolated yield was 60%.

[0040] (2) Weigh 3-benzylidene-2-phenylisoindol-1-one 1a (0.297g, 1mmol), sodium trifluoromethanesulfinate (0.468g, 3mmol), cuprous iodide (0.038g, 0.2mmol), potassium persulfate (1.081g, 4mmol) was dissolved in 9mL of acetonitrile aqueous solution (acetonitrile:water=2:1). Th...

Embodiment 2

[0057] Embodiment two: the synthesis of 3-hydroxyl-2-(4-fluorophenyl)-3-(2,2,2-trifluoro-1-phenylethyl)isoindol-1-one (2b) synthesis

[0058]

[0059] Weigh 3-benzylidene-2-(4-fluorophenyl)isoindol-1-one 1b (0.316g, 1mmol), sodium trifluoromethanesulfinate (0.468g, 3mmol), bromide Cuprous (0.028g, 0.2mmol), potassium persulfate (1.081g, 4mmol) were dissolved in 9mL of acetonitrile aqueous solution (acetonitrile:water=2:1). The mixture was stirred and reacted at 25°C, and the reaction was followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:6) to obtain compound 2b. Isolated yield was 67%.

[0060] 2b: Pale yellow solid, 67% yield; 1 H NMR (400MHz, DMSO-d6) δ: 8.00 (s, 1H), 7.93 (d, J = 7.5Hz, 1H), 7.87–7.83 (m, 1H), 7.72 (d, J = 6.8Hz, 1H) ,7.68(d,J=7.2Hz,1H),7.37(dd,J=8.6,5.1Hz,2H),7.29(d,J=9.8Hz,1H),7.26–7.22(m,2H),7.07( t, J=7.6Hz, 2H),...

Embodiment 3

[0061] Example Three: 3-Hydroxy-2-(4-methoxyphenyl)-3-(2,2,2-trifluoro-1-phenylethyl)isoindol-1-one (2c) synthesis

[0062]

[0063] Weigh 3-benzylidene-2-(4-methoxyphenyl)isoindol-1-one 1c (0.327g, 1mmol), sodium trifluoromethylsulfinate (0.468g, 3mmol), Cuprous bromide (0.028g, 0.2mmol), potassium persulfate (1.081g, 4mmol) were dissolved in 9mL of acetonitrile aqueous solution (acetonitrile:water=2:1). The mixture was stirred and reacted at 25°C, and the reaction was followed by TLC until the reaction was completely completed. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:6) to obtain compound 2c. Isolated yield was 78%.

[0064] 2c: Pale yellow solid, 78% yield; 1 H NMR (400MHz, DMSO-d6) δ: 7.89(d, J=7.4Hz, 1H), 7.85(s, 1H), 7.69–7.63(m, 2H), 7.24(dd, 4H), 7.07(t, J=7.7Hz, 2H), 6.98(d, J=9.0Hz, 2H), 6.46(d, J=7.5Hz, 2H), 4.05(q, J=10.5Hz, 1H), 3.80(s, 3H) ; 13 C NMR (101MHz, DMSO-d6) δ: ...

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Abstract

The invention relates to a preparation method of trifluoromethyl hydroxylated derivatives of isoindolinone. The method comprises steps as follows: a substituted N-phenyl-3-benzalisoindole-1-one derivative shown as the formula (1) and sodium trifluoromethanesulfinate are subjected to a reaction in a solvent at 10-80 DEG C under the catalytic action of copper salt and oxidizing action of an oxidizing agent, the trifluoromethyl hydroxylated derivatives of isoindolinone shown as the formula (2) are obtained, and the reaction route is shown in the description, wherein R<1>, R<2>, R<3>, R<4>, R<5>,R<6>, R<7>, R<8>, R<9>, R<10>, R<11> and R<12> are independently selected from hydrogen, alkyl, alkoxy or halogen. With adoption of the method, multiple trifluoromethyl hydroxylated derivatives of N-phenyl-3-benzalisoindole-1-one can be obtained with high yield; reaction conditions are mild, operation and aftertreatment processes are simple, and the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of a trifluoromethyl hydroxylated derivative of isoindolinone. Background technique [0002] Nitrogen-containing heterocyclic compounds are an important class of organic compounds with biological activity and medicinal value. Especially 3-hydroxy-isoindol-1-one derivatives are important pharmaceutical intermediates and structural units of natural products. It has been reported in the literature that N-phenyl-3-benzylidene isoindol-1-one derivatives have anesthetic and sedative effects. On the other hand, trifluoromethylation has become the focus of research in the field of organic synthesis. Organic compounds containing trifluoromethyl have been widely valued in the fields of medicine, pesticides, and material science. This is because trifluoromethyl has a peculiar Metabolic stability, electronegativity, lipophilicity and bioavailability. It can be predict...

Claims

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Application Information

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IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 曾润生王清施鹏
Owner SUZHOU UNIV
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