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Novel synthetic method of key intermediate2-anisacetone of loxoprofen

A technology of tolylpropionic acid and synthesis method, applied in the direction of organic chemistry, nitrile preparation, etc., can solve the problems of unstable quality, poor purity, affecting the purity and efficiency of loxoprofen, etc.

Inactive Publication Date: 2012-11-07
ANHUI HERYI CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2-p-tolylpropionic acid (also known as 2-(4-methylphenyl)propionic acid, 2-(p-toluene)propionic acid) is the key intermediate for the synthesis of loxoprofen, and the current production process is mainly Using toluene as the starting material, the synthesis of 2-p-tolylpropionic acid is carried out through acylation, ketal, rearrangement, hydrolysis and other steps. This process has many steps, long process, low overall yield and huge amount of waste water. Shortcoming, the content of the obtained 2-p-tolylpropionic acid product is between 85-95%, and the purity is poor and the quality is not stable enough, which affects the purity and efficiency of further synthesizing loxoprofen
There are few research reports about the new synthetic method of 2-p-tolylpropionic acid in the prior art

Method used

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  • Novel synthetic method of key intermediate2-anisacetone of loxoprofen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Synthesize 2-p-tolylpropionic acid as follows:

[0072] Put 104kg of p-tolueneacetonitrile, 540kg of dimethyl carbonate, and 280kg of potassium hydroxide into a stainless steel reactor for α-methylation reaction; raise the temperature to 175°C, and control the pressure to 18kg / cm 2 , insulation 8h, generate α-methyl-p-toluene acetonitrile; be cooled to normal temperature, filter out potassium carbonate solid, reclaim dimethyl carbonate, obtain the mother liquor that leaves α-methyl-p-toluene acetonitrile; Add 400kg concentration to be 15wt% sodium hydroxide aqueous solution, heated to 110°C for reflux for 8 hours; cooled to 60°C, added 200kg of toluene to extract and remove organic matter, moved the water layer into a clean reaction kettle; added dropwise 15wt% hydrochloric acid to adjust the pH value to 1-2; cool to 5°C, stir and filter, and the obtained off-white solid crystal is 2-p-tolylpropionic acid.

[0073] It was determined that 158kg of 2-p-tolylpropionic aci...

Embodiment 2

[0075] Synthesize 2-p-tolylpropionic acid as follows:

[0076] Put 100kg of p-tolueneacetonitrile, 500kg of dimethyl carbonate, and 250kg of potassium hydroxide into a stainless steel reactor for α-methylation reaction; raise the temperature to 180°C, and control the pressure to 16kg / cm 2 , keep warm for 8.5h to generate α-methyl-p-tolueneacetonitrile; cool to normal temperature, filter out potassium carbonate solid, recycle dimethyl carbonate, and obtain the mother liquor with α-methyl-p-tolueneacetonitrile; add 440kg concentration 16wt% sodium hydroxide aqueous solution, heated to 108°C for 7h under reflux for hydrolysis; cooled to 58°C, added 240kg of toluene to extract and remove organic matter, moved the water layer into a clean reaction kettle; added dropwise 20wt% hydrochloric acid to adjust the pH value to 1-2; cooled to 6 ° C, stirred, filtered, the obtained off-white solid crystal is 2-p-tolylpropionic acid.

[0077] It was determined that 156kg of 2-p-tolylpropioni...

Embodiment 3

[0079] Synthesize 2-p-tolylpropionic acid as follows:

[0080] Put 100kg of p-tolueneacetonitrile, 450kg of dimethyl carbonate, and 200kg of potassium hydroxide into a stainless steel reactor for α-methylation reaction; raise the temperature to 165°C, and control the pressure to 15kg / cm 2 , insulation 7h, generate α-methyl-p-tolueneacetonitrile; be cooled to normal temperature, filter out potassium carbonate solid, reclaim dimethyl carbonate, obtain the mother liquor that leaves α-methyl-p-tolueneacetonitrile; Add 350kg concentration to be 18wt% sodium hydroxide aqueous solution, heated to 105°C for reflux hydrolysis for 6 hours; cooled to 55°C, added 150kg of toluene to extract and remove organic matter, moved the water layer into a clean reaction kettle; added dropwise 10wt% hydrochloric acid to adjust the pH value to 1-2; cool to 2°C, stir and filter, and the obtained off-white solid crystal is 2-p-tolylpropionic acid.

[0081] It was determined that 155kg of 2-p-tolylprop...

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Abstract

The invention relates to a synthetic method for loxoprofen, in particular to a novel synthetic method of key intermediate2-anisacetone of loxoprofen. The method comprises the following steps: taking methylbenzyl cyanide as an initial material to generate alpha-methylation with dimethyl carbonate in an alkaline environment so as to generate alpha-methyl-methyl phenylacetonitrile, and hydrolyzing the alpha-methyl-methyl phenylacetonitrile in alkaline water to obtain the 2-anisacetone. The method provided by the invention has the advantages of simplicity, easiness in control and small waste water amount. Moreover, the synthesized 2-anisacetone is high in purity and stable in quality, which lays a good foundation for synthesizing the high-purity loxoprofen.

Description

technical field [0001] The invention relates to a synthetic method of loxoprofen, in particular to a novel synthetic method of a key intermediate of loxoprofen, 2-p-tolylpropionic acid. Background technique [0002] Loxoprofen is a non-steroidal anti-inflammatory analgesic drug (NSAIDS) developed by Japan Sankyo Company, which has significant analgesic, anti-inflammatory and antipyretic effects, especially the analgesic effect is significantly better than other propionic acid drugs; At the same time, loxoprofen is a prodrug, which is converted into an active metabolite after being absorbed by the digestive tract to play a role. Compared with other NSAIDS, it causes less damage to the gastrointestinal mucosa. 2-p-tolylpropionic acid (also known as 2-(4-methylphenyl)propionic acid, 2-(p-toluene)propionic acid) is the key intermediate for the synthesis of loxoprofen, and the current production process is mainly Using toluene as the starting material, the synthesis of 2-p-tolyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/30C07C51/08
Inventor 董来山
Owner ANHUI HERYI CHEM
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