Preparation method of Firocoxib intermediate

A technology of firocoxib and intermediates, which is applied in the field of preparation of firocoxib intermediates, can solve the problems of failure to meet environmental requirements, respiratory tract damage, etc., and achieve the effects of increased yield, improved purity, and easy separation

Active Publication Date: 2018-03-09
YANGZHOU TIANHE PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional synthesis method of 2-methyl-1-[4-(methylsulfonyl)phenyl]propan-1-one is: using thioanisole as the reaction raw material, then introducing isobutyryl through Friedel-Crafts reaction, and then through Oxidation reaction forms sulfone compounds, but the reaction raw material thioanisole in this method has a strong pungent smell, which is easy to cause damage to the human respiratory tract, and cannot meet the environmental requirements in the industrial production process

Method used

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  • Preparation method of Firocoxib intermediate

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Experimental program
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Effect test

Embodiment 1

[0025] Under air or oxygen atmosphere, add 2mL dimethylsulfoxide to the reactor, then add 68.25mg 1-(4-iodophenyl)-2-methylpropan-1-one, 25.03mg acetylacetone, 3.58mg Cuprous oxide, 2.8mg of palladium acetate and 84mg of potassium tert-butoxide were mixed and stirred evenly, the temperature of the system was raised to 100°C, and the reaction was refluxed for 20h. After the reaction was completed, 20mL of deionized water was added to the solution, and then 20mL of ethyl acetate was added to carry out After multiple extractions, the organic phases were collected and combined, then dried by adding anhydrous sodium sulfate, and finally the solvent was removed by vacuum evaporation and chromatographic separation to obtain 2-methyl-1-[4-(methylsulfonyl)phenyl] Propan-1-one, 58% yield.

[0026] Adding a catalyst to the reaction system greatly increases the reaction rate, when the amount of palladium salt catalyst is less than 0.001 equivalent of the amount of halogenated aromatic hyd...

Embodiment 2

[0034] Under air or oxygen atmosphere, add 2mL dimethylsulfoxide to the reactor, then add 68.25mg 1-(4-iodophenyl)-2-methylpropan-1-one, 65.50mg triphenylphosphine, 3.58mg of cuprous oxide, 2.8mg of palladium acetate and 84mg of potassium tert-butoxide, mix and stir evenly, raise the temperature of the system to 100°C, reflux for 20h, add 20mL of deionized water to the solution after the reaction, and then add 20mL of ethyl acetate The ester was extracted several times, after collecting and combining the organic phases, adding anhydrous sodium sulfate for drying, and finally removing the solvent by evaporation under reduced pressure and chromatographic separation to obtain 2-methyl-1-[4-(methylsulfonyl)benzene Base] propan-1-one, the yield was 27%.

Embodiment 3

[0036] Under air or oxygen atmosphere, add 2mL dimethylsulfoxide to the reactor, then add 68.25mg 1-(4-iodophenyl)-2-methylpropan-1-one, 25.03mg acetylacetone, 3.58mg Cuprous oxide, 2.8 mg of palladium acetate and 51 mg of sodium ethoxide, mixed and stirred evenly, the temperature of the system was raised to 100 ° C, and the reaction was refluxed for 20 hours. After the reaction was completed, 20 mL of deionized water was added to the solution, and then 20 mL of ethyl acetate was added for several times. After extraction, the combined organic phases were collected, dried by adding anhydrous sodium sulfate, and finally evaporated under reduced pressure to remove the solvent and chromatographically separated to obtain 2-methyl-1-[4-(methylsulfonyl)phenyl]propane- 1-Kone in 38% yield.

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Abstract

The invention discloses a preparation method of a Firocoxib intermediate. The preparation method belongs to the technical field of chemical synthesis. The preparation method comprises the steps: adding isobutyryl-containing aryl halide, a catalyst, a ligand and thin alkali into an organic solvent at an air or oxygen atmosphere, raising the temperature to carry out a reaction for 10-20h, and then,carrying out aftertreatment to prepare 2-methyl-1-[4-(methylsulfonyl)phenyl]propane-1-ketone. According to the preparation method, isobutyryl-containing aryl halide is used as a reaction raw material,so that a high-yield target product can be obtained; in addition, compound raw materials such as thioether or sulfoxide capable of generating great environmental hazards are avoided from being adopted, so that the production is environment-friendly, meanwhile, few reaction steps are required, few side reactions are generated, and the purity and yield of a product are high.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a firocoxib intermediate. Background technique [0002] Firocoxib is an important coxi-type non-steroidal anti-inflammatory drug, which mainly produces antipyretic, analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins mediated by cyclooxygenase-2 (COX-2) , Approved by the FDA, firocoxib can currently be used to treat equine osteoarthritis and acute and chronic pain and inflammation caused by clinical operations, while 2-methyl-1-[4-(methylsulfonyl)phenyl ] Propan-1-one is an important intermediate in the synthesis of firocoxib. The traditional synthesis method of 2-methyl-1-[4-(methylsulfonyl)phenyl]propan-1-one is: using thioanisole as the reaction raw material, then introducing isobutyryl through Friedel-Crafts reaction, and then through The oxidation reaction forms sulfone compounds, but the reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C315/00C07C317/24
CPCC07C315/00C07C317/24
Inventor 杨南松陆华平王小龙赵云德仇香
Owner YANGZHOU TIANHE PHARM CO LTD
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