Preparation method of 3-substituted phenyl-4,5-dihydroisoxazole derivative and application and intermediate thereof

A technology of dihydroisoxazole and derivatives, applied in the direction of organic chemistry and the like, can solve the problems of poor bromination reaction selectivity and unavoidable side reactions, and achieve the effects of safe and controllable production, product quality assurance, and avoidance of by-products.

Active Publication Date: 2019-08-30
HEBEI MEDICAL UNIVERSITY
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0020]4. In the first method, the selectivity of the bromination reaction is poor, and side reactions are inevitable

Method used

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  • Preparation method of 3-substituted phenyl-4,5-dihydroisoxazole derivative and application and intermediate thereof
  • Preparation method of 3-substituted phenyl-4,5-dihydroisoxazole derivative and application and intermediate thereof
  • Preparation method of 3-substituted phenyl-4,5-dihydroisoxazole derivative and application and intermediate thereof

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preparation example Construction

[0071] In the preparation method of the 3-substituted phenyl-4,5-dihydroisoxazole derivatives provided by the present invention, the route and steps are as follows:

[0072]

[0073] (1) The compound of formula V undergoes hydroxylamination reaction to generate the compound of formula VII;

[0074] (2) the compound of formula VII generates the compound of formula VIII through diazotization and halogenation;

[0075] (3) the compound of formula VIII generates the compound of formula IX through dipolar cycloaddition;

[0076] Where: A is selected from H, Cl, Br, I, CO 2 R; R is selected from H, C1-C4 alkyl; X is selected from Cl, Br or I; n is selected from 0, 1 or 2.

[0077] Concrete reaction condition is as follows:

[0078] step 1):

[0079]

[0080] n=0,1,2A=-Cl,-Br,-I,-CO 2 H,-CO 2 Me,-CO 2 Et et al.

[0081] The reaction is carried out under the following conditions: the solvent used is a protic solvent such as: water, methanol, ethanol, propanol, isopropano...

Embodiment 1

[0103] Synthesis of 2-methyl-6-methylthiobenzonitrile

[0104]

[0105] Add 2-methyl-6-nitrobenzonitrile (2.49g, 15.36mmol), toluene 40mL, 20% sodium methyl mercaptide solution (5.38g, 15.37mmol) successively to a one-necked bottle equipped with a magnetic stirring bar, TBAB 0.30g. After stirring at room temperature for 4 hours, it was detected by thin layer chromatography that the reaction was complete. Add 50 mL of distilled water, shake, let stand, and separate the toluene phase. Wash with saturated aqueous sodium chloride (10 mL×3), and dry over anhydrous sodium sulfate. After precipitation under reduced pressure, the crude product was purified by column chromatography to obtain white crystals (2.09 g, 83.4%). ESI-MS(m / z):164[M+H] + , 186[M+Na] + , 202[M+K] + .

Embodiment 2

[0107] Synthesis of 3-bromo-2-methyl-6-methylthiobenzonitrile

[0108]

[0109] Add 2-methyl-6-methylthiobenzonitrile (0.41 g, 2.51 mmol), iron tribromide (0.95 g, 3.21 mmol) and 10 mL of dichloromethane into a 25 mL two-necked flask equipped with a thermometer to dissolve. After cooling down to -5-0°C, magnetic stirring was started, and liquid bromine (0.95 g, 5.93 mmol) was added dropwise. After 1 hour, it was detected by thin-layer chromatography that the reaction was complete. Add 10 mL of distilled water to quench, extract with dichloromethane (10 mL×3), wash the organic phase with 3% aqueous sodium hydroxide solution (10 mL×3), and then wash with distilled water until neutral. The organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure and purified by column chromatography to obtain white crystals (0.55 g, 90.4%). ESI-MS(m / z):242[M+H] + , 264[M+Na] + , 280[M+K] + .

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Abstract

The invention relates to a preparation method of a 3-substituted phenyl-4,5-dihydroisoxazole derivative and application and an intermediate thereof. A cyano compound (V) is converted into an N-hydroxybenzimidium compound (VII), and then 3-substituted phenyl-4,5-dihydroisoxazole intermediate (IX) is synthesized through a diazotization chlorination reaction and a dipolar cycloaddition reaction; a reaction condition is mild and controllable, the reaction selectivity in each step is good, the yield is relatively high, production of some byproducts is avoided, the product quality is guaranteed, andindustrialization of a whole technological route is easy to implement.

Description

technical field [0001] The invention relates to a preparation method of 3-substituted phenyl-4,5-dihydroisoxazole derivatives, its use and intermediates. Background technique [0002] Currently, 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) inhibitors are new herbicide targets identified in the 1990s by inhibiting 4-hydroxyphenylpyruvate dioxygenase in plastoquinone biosynthesis Oxidase (4-HPPD), which indirectly affects the synthesis of carotenoids, interferes with the synthesis and function of chloroplasts under light, and eventually leads to the death of weeds. The mechanism of action of 4-HPPD inhibitors in animals and plants is different, and it is safe for mammals. So far, the HPPD inhibitor herbicides that have been developed are still one of the herbicide species with the least toxicity to mammals. Therefore, this is a class of herbicides with good development prospects. [0003] Topramezone (topramezone) is a kind of p-hydroxyphenylpyruvate dioxygenase (4-HPPD) in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/04C07D413/10C07C323/62C07C317/44
CPCC07D261/04C07D413/10C07C323/62C07C317/44Y02P20/55
Inventor 李林邢瑞娟刘兰张云李媛媛孟静何瑞红律涛王亚博王磊张恺石晓伟谷建敏郭冉刘异凡
Owner HEBEI MEDICAL UNIVERSITY
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