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Preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid

A technology of dihydroisoxazole and isoxazole is applied in the directions of organic chemical methods, chemical instruments and methods, organic racemization, etc., and achieves the effects of high reaction yield and easy operation.

Active Publication Date: 2021-06-08
SHANGHAI TIANYE CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the existing published patents or documents, there is less research on this compound, so it is necessary to (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid Carry out in-depth research on the synthesis process and provide relatively suitable preparation methods to meet the growing market demand

Method used

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  • Preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid
  • Preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid
  • Preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0025]

[0026] Under nitrogen protection, 104 g (0.5 mol) of 3-chloro-2-fluoro-o-chlorobenzaldoxime and 500 mL of dichloromethane were put into the reaction flask. The material was dissolved under stirring at room temperature, cooled to 10°C, 77.5 g (0.9 mol) of methyl acrylate was added, and 83.7 g (0.55 mol) of DBU was added dropwise. After the addition was completed, the temperature was slowly raised to room temperature for 8 hours, and the raw material was detected by HPLC at 0.9% .

[0027] Add saturated ammonium chloride aqueous solution to quench, separate layers, extract the aqueous phase once with dichloromethane, combine the organic phases, wash the organic phase with 0.5N hydrochloric acid and saturated brine, concentrate the organic phase until it is stagnant, add 300 mL of absolute ethanol . The material was dissolved under stirring at room temperature, cooled to 5°C, and 134.6 g (0.673 mol) of 20% sodium hydroxide aqueous solution was slowly added dropwise, ...

Embodiment 2

[0029]

[0030] Under nitrogen protection, 104 g (0.5 mol) of 3-chloro-2-fluoro-o-chlorobenzaldoxime and 500 mL of 2-methyltetrahydrofuran were put into the reaction flask. The material was dissolved under stirring at room temperature, cooled to 10°C, 102.7 g (0.9 mol) of isopropyl acrylate was added, 83.7 g (0.55 mol) of DBU was added dropwise, and after the addition was completed, the temperature was slowly raised to room temperature for 8 hours of reaction. %.

[0031] Add saturated ammonium chloride aqueous solution to quench, separate layers, extract the aqueous phase once with 2-methyltetrahydrofuran, combine the organic phases, wash the organic phase with 0.5N hydrochloric acid and saturated brine, cool the organic phase to 5 °C, slowly add 20 % sodium hydroxide aqueous solution 134.6g (0.673mol), after the dropwise addition was completed, the temperature was slowly raised to room temperature for reaction for 4 hours, and 0.2% of the raw material was detected by HPLC...

Embodiment 3

[0033]

[0034] Under nitrogen protection, 104 g (0.5 mol) of 3-chloro-2-fluoro-o-chlorobenzaldoxime and 500 mL of diethoxymethane were put into the reaction flask. The material was dissolved under stirring at room temperature, cooled to 10°C, 90 g (0.9 mol) of ethyl acrylate was added, and 83.7 g (0.55 mol) of DBU was added dropwise. After the addition was completed, the temperature was slowly raised to room temperature for 8 hours of reaction, and 0.2% of the raw material was detected by HPLC.

[0035] Add saturated ammonium chloride aqueous solution to quench, separate layers, extract the aqueous phase once with diethoxymethane, combine the organic phases, wash the organic phase with 0.5N hydrochloric acid and saturated brine, cool the organic phase to 5 ° C, slowly add 20 % sodium hydroxide aqueous solution 188.8g (0.673mol), after the dropwise addition was completed, the temperature was slowly raised to room temperature for reaction for 4 hours, and 0.2% of the raw mate...

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Abstract

The invention discloses a preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: taking 3-chloro-2-fluoro-o-chlorobenzaldoxime as a raw material, and reacting with acrylate in the presence of organic alkali to obtain 3-(3-chloro-2-fluorophenyl)-4, 5-dihydro-isoxazole-5-carboxylate; then, carrying out alkaline hydrolysis to obtain a 3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid racemate; using (R)-alpha-phenylethylamine for salt formation resolution and separation, and obtaining (R)-3-(3-chloro-2-fluorobenzene)-4, 5-dihydroisoxazole-5-carboxylic acid. The method is easy and convenient to operate and high in reaction yield, the purity of the obtained product is larger than 99.0% and larger than or equal to 99.5% ee, the single impurity content is smaller than 0.2%, and potential industrial amplification prospects are achieved.

Description

technical field [0001] The invention relates to a preparation method of (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid, belonging to the technical field of pharmaceutical intermediates. Background technique [0002] As an important class of heterocyclic compounds, isoxazole compounds have unique chemical structures and important pharmacological activities, and have attracted extensive attention from chemical and medicinal chemistry researchers in recent years. This type of compound has a wide range of biological activities such as relaxing cardiovascular, regulating calcium ions, treating Alzheimer's disease, antibacterial, etc., and exhibits excellent activities in pesticides and herbicides. [0003] (R)-3-(3-Chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid, as an important isoxazole intermediate, is a selective factor XIa inhibitor or FXIa An important intermediate of dual inhibitors of plasma kallikrein and plasma kallikrein. [00...

Claims

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Application Information

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IPC IPC(8): C07B57/00C07D261/04
CPCC07B57/00C07D261/04C07B2200/07
Inventor 薛峰高峰刘洪强田贝贝
Owner SHANGHAI TIANYE CHEM
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