3-hydroxy isoindole-1-ketone derivative and preparation method thereof

A technology for hydroxyisoindoles and derivatives, which is applied in the field of 3-hydroxyisoindol-1-one derivatives and their preparation, can solve the problems of transition metal increasing reaction cost, harsh reaction conditions, metal residues in products, and the like. The effect of green processing, easy post-processing and mild reaction conditions

Active Publication Date: 2017-10-24
XIAMEN HUAXIA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The traditional synthesis of 3-hydroxyisoindol-1-one compounds is mainly obtained through the addition reaction of phthalimide and Grignard reagent, which has the disadvantages of harsh reaction conditions and poor regioselectivity
In the method for the synthesis of 3-hydroxyisoindol-1-one by transition metal-catalyzed cyclization reaction developed in recent years, the use of transition metals increases the reaction cost on the one hand, and easily causes the problem of product metal residues on the other hand, making it Limited use in mass production applications

Method used

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  • 3-hydroxy isoindole-1-ketone derivative and preparation method thereof
  • 3-hydroxy isoindole-1-ketone derivative and preparation method thereof
  • 3-hydroxy isoindole-1-ketone derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Preparation of N,N-dibenzyl-2-fluorobenzamide

[0044]

[0045] Put 10mmol of dibenzylamine, 12mmol of triethylamine, and 30mL of dichloromethane in an ice bath at 0°C and stir, slowly add 10mmol of 2-fluorobenzoyl chloride dropwise, remove the ice bath, and react at room temperature for 2h. An appropriate amount of water was added to stop the reaction. The reaction solution was diluted with dichloromethane, washed three times with water, and the organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate, and recrystallize from dichloromethane / petroleum ether to obtain 3.03 g of the target product with a yield of 95%.

Embodiment 2

[0047] Preparation of N,N-dibenzyl-2-fluoronicotinamide

[0048]

[0049] Dibenzylamine 10mmol, 2-fluoronicotinic acid 12mmol, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) 12mmol, 1-hydroxybenzotriazole (HOBT ) 12mmol, diisopropylethylamine 20mmol were dissolved in 20mL N,N-dimethylformamide, and stirred at room temperature for 24h. Add appropriate amount of water or sodium chloride solution to stop the reaction. The reaction solution was diluted with ethyl acetate, washed three times with water, and the organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate, and purify by column chromatography to obtain 2.75 g of the target product with a yield of 86%.

Embodiment 1-13

[0050] The following examples 1-13 are the preparation methods of 3-hydroxyisoindol-1-one derivatives

[0051] Example 1

[0052] Preparation of 2-Benzyl-3-phenyl-3-hydroxyisoindol-1-one

[0053]

[0054] Put 0.5mmol of N,N-dibenzyl-2-bromobenzamide (1a), 1mmol of potassium hydroxide, and 10mL of dimethylsulfoxide in an oil bath at 100°C for 5h. Add appropriate amount of water or sodium chloride solution to stop the reaction, and cool to room temperature. The reaction solution was diluted with ethyl acetate, washed three times with water, and the organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate, and purify by column chromatography to obtain 127.6 mg of the target product with a yield of 81%. The NMR characterization of this compound is as follows: 1 H NMR (400MHz, CDCl 3 )δ7.77(dd, J=6.1,1.8Hz,1H),7.49–7.41(m,2H),7.32(dd,J=6.8,3.0Hz,2H),7.25(dd,J=6.5,2.0Hz ,4H),7.22–7.00(m,5H),4.69(dd,J=15.0,6.9Hz,1H),4.06(d,J=15.0Hz,1H),3.29(s,1H); 13 C NM...

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PUM

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Abstract

The invention discloses a preparation method of a 3-hydroxy isoindole-1-ketone derivative (formula 2). A compound as shown by formula (1) is used for carrying out substitution reaction in a solvent in the presence of alkali and air to obtain the 3-hydroxy isoindole-1-ketone derivative. According to the method disclosed by the invention, the oxygen in the air is taken as an oxygen source, the used raw materials are easy to obtain, the yield is high, the reaction condition is mild, the substrate range is wide, the reaction specificity is strong, and the post-processing is simple, convenient and green.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to 3-hydroxyisoindol-1-one derivatives and a preparation method thereof. Background technique [0002] 3-Hydroxyisoindol-1-one derivatives are an important class of nitrogen-containing heterocyclic compounds with a wide range of biological activities. The natural product chilenine, the diuretic chlorthalidone (chlortalidone), and the hypnotic eszopiclone ( eszopiclone), and anti-tumor small molecule MDM2-p53 inhibitor NU8231 and other molecules all contain 3-hydroxyisoindol-1-one structure. Therefore, the research on new synthetic methods of 3-hydroxyisoindol-1-one compounds and their analogues has important application value and has attracted the attention of researchers in related fields. [0003] The traditional synthesis of 3-hydroxyisoindol-1-one compounds is mainly obtained through the addition reaction of phthalimide and Grignard reagent, which has the d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07D405/04C07D401/04
Inventor 沈金海游其华傅奇赵晶庄峙厦
Owner XIAMEN HUAXIA UNIV
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