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Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride

A technology of isoxazolecarbonyl and a synthesis method is applied in the field of synthesis of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride, which can solve the reaction High requirements for equipment sealing, prominent environmental problems, and difficulties in the treatment of three wastes, etc., achieve the effect of large implementation value, social and economic benefits, production safety, and elimination of potential safety hazards.

Active Publication Date: 2009-03-11
浙江遂昌利民科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Phosphorus oxychloride, as a chlorinated reagent, severely corrodes equipment, and a large amount of phosphorous-containing waste water in the product obtained by the process is difficult to treat, causing serious pollution problems and prominent environmental problems.
The tail gas of the thionyl chloride process contains a large amount of asphyxiating sulfur dioxide (one of the six indicators strictly controlled by the national environmental protection on the atmosphere), and the treatment of the three wastes is difficult and expensive
In addition, the transportation and use of thionyl chloride are strictly controlled, requiring high sealing performance of the reaction equipment, and the investment is relatively large.
Poor production safety and long reaction cycle

Method used

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  • Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride
  • Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.33:0.02 (mol ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 9.80g (33mmol), the amount of catalyst is 0.232g (2mmol), and the amount of toluene is 10 times of the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid .

[0020] Add 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and toluene into the reaction kettle, stir evenly, within 45 minutes at room temperature Add the toluene solution of bis(trichloromethyl)carbonate dropwise, open the hydrogen chloride absorption system at the same time, then raise the temperature to 110°C, and reflux the reaction for 2 hours. The fraction at ℃ solidifies under refrigeration.

[0021] 26.22 g of the product was obtained, the yield was 95.7%, the...

Embodiment 2

[0023] 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mol ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 14.85g (50mmol), catalyst consumption is 0.116g (1mmol), dichlorobenzene consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 5 times.

[0024] 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and dichlorobenzene were added to the reaction kettle, after stirring evenly, at room temperature for 45 Add the dichlorobenzene solution of bis(trichloromethyl)carbonate dropwise within 1 minute, open the hydrogen chloride absorption system at the same time, then raise the temperature to 115-120°C, keep the temperature for 1 hour, and recover the dichlorobenzene by distillation under reduced pressure after the reaction is compl...

Embodiment 3

[0027] 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mol ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity It is 14.85g (50mmol), and the amount of catalyst is 0.116g (1mmol), and the amount of dichlorobenzene reclaimed in Example 2 is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4- 5 times the mass of isoxazole formic acid 3.

[0028] 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and dichlorobenzene were added to the reaction kettle, after stirring evenly, at room temperature for 45 Add dropwise the dichlorobenzene solution of two (trichloromethyl) carbonates in minutes, and the others are the same as example 2.

[0029] 26.24 g of the product was obtained, the yield was 95.8%, the melting point was 48-52°C, and the content (GC) was 99.0%. 1 H-NMR (CDCl ...

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Abstract

The invention discloses a chemical synthesizing method of 3-(2'-chlorine-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride as key intermediate of antibiotic sodium flucloxacillin, which is characterized by the following: adopting di-(trichloromethyl) carbonate and 3-(2'-chlorine-6'-fluorophenyl)-5-methyl-4-isooxazole formic acid as raw material; dissolving the mass into organic solvent acted by organic amide under 0-120 deg.c for 1-20h; recycling organic solvent to obtain the product with high receiving rate; eliminating safe hidden danger; saving manufacturing cost effectively.

Description

(1) Technical field [0001] The invention relates to a chemical synthesis method of the key intermediate 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride of the antibiotic flucloxacillin sodium, in particular to a A kind of two (trichloromethyl) carbonate [bis (trichloro-methyl) carbonate] replaces thionyl chloride, phosphorus oxychloride directly with 3-(2'-chloro-6'-fluorophenyl)-5- A chemical synthesis method for preparing 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride by reacting methyl-4-isoxazolecarboxylic acid. (2) Background technology [0002] Before the present invention provides, the chemical synthesis method of existing 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride is mostly based on 3-(2' -Chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid and thionyl chloride or phosphorus oxychloride and other reagents can be prepared by chlorination. For example, in WO2004058732A1, 422 mg of 3-(2'-chloro-6'-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/18
Inventor 陈志卫苏为科闫伟华李峰赖晓春濮发祥
Owner 浙江遂昌利民科技有限公司
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