Application Of Silica Gel Catalyzed Rearrangement Reaction In Synthesis Of α-Aryl Propionic Acid

Naproxen and tiprofenicacid areα-arylpropionic acid nonsteroidal anti-inflammatory drugs（NSAIDs）.They are widely used clinically for antipyretic,analgesic and anti-inflammatory,and have a large market and development prospects.Therefore,it is of great significance to study their synthesis process to reduce environmental pollution and production cos ts.Silica gel is an environment-friendly,non-toxic,non-corrosive equipment and reusable solid acid.It can catalyze rearrangement reactions,oxidation reactions,and reduction reactions with high efficiency and high selectivity under mild conditions.This thesis focuses on the synthesis process of silica gel-catalyzed rearrangement of epoxy compounds into aldehydes,and appli cation of this method to the synthesis of naproxen and tiprofenicacid.The following research results are obtained（the yield calculation of the following steps are based on the starting material aryl ethyl ketone）:（1）Epoxidation reaction:Trimethylsulfonium sulfide is prepared from dimethyl sulfide,sulfuric acid and methanol under 20℃for 6 h,and the optimum molar ratio of the material is ndimethyl sulfide:nconcentrated sulfuric acid:nmethanol=3:2.1:1.The prepared trimethylsulfonium hydrogen sulfate is directly used in the epoxidation reaction.In the presence of sodium hydroxide,6-methoxy-2-acetylnaphthalene reacts with trimethylsulfonium bisulfate at 30℃for 3 h to obtain2-（6-methoxynaphthyl）-1,2-propylene oxide,the yield is 99.1%,the molar ratio of material is n_{6-methoxy-2-acetylnaphthalene}:n_methanol:n_{Na OH}=2:3:15.Under the same conditions,2-acetylthiophene and trimethylsulfonium bisulfate undergo epoxidation to obtain2-methyl-2-（2-thienyl）ethylene oxide.（2）Rearrangement reaction:2-（6-methoxynaphthyl）-1,2-propylene oxide rearrange to 2-（6-methyloxy-2-naphthyl）propionaldehyde,using silica gel as the catalyst and A as solvent,and reacting at 80℃for 3 h,the yield is 87.1%.The dosage of catalyst is m_{silica gel}:m_{6-methoxy-2-acetylnaphthalene}=15%;Silica gel as the catalyst,B as the solvent,reacting at 30℃for 2.5 h,2-methyl-2-（2-thienyl）ethylene oxide rearrange to 2-（2-thienyl）propanal.the dosage of catalyst is m_{silica gel}:m_{2-acetylthiophene}=20%;Silica gel can be recycled 3 times.（3）Oxime reaction:2-（6-methoxy-2-naphthyl）propanal or 2-（2-thienyl）propionaldehyde with hydroxylamine hydrochloride react at 90℃for 1 h to obtain2-（6-methoxy-2-naphthyl）propoxime or 2-（2-thienyl）propoxime,the dosage of catalyst is n6-methoxy-2-acetylnaphthalene or 2-acetylthiophene:n NH2OH·HCl:n KOH=1:1.5:1.1;2-（6-Methoxy-2-naphthyl）propoxime is synthesized in one step from the epoxy compound through rearrangement reaction and oxime reaction,and the yield is 80.8%.（4）Hydrolysis reaction:In the presence of potassium hydroxide,2-（6-methoxy-2-naphthyl）propoxime react at 120℃for 7 h to obtain 2-（6-methoxy-2-Naphthyl）propionic acid with a yield of 73.7%,the mass concentration of potassium hydroxide solution is 50%,and the molar ratio of material is n_KOH:n_{6-methoxy-2-acetylnaphthalene}=5:1;In the presence of potassium hydroxide,2-（2-thienyl）propion oxime react at 120℃for 8 h to obtain 2-（2-thienyl）propionic acid with a yield of 71.3%,the mass concentration of potassium hydroxide solution is50%,and the molar ratio of material is n_KOH:n_{6-methoxy-2-acetylnaphthalene}=4:1.（5）"One-pot" synthesis of racemic naproxen,using 6-methoxy-2-acetylnaphthalene as the raw material,through epoxidation reaction,silica gel catalytic rearrangement reaction,oximation and hydrolysis reaction to synthesize 2-（6-methoxy-2-naphthyl）propionic acid with a total yield of 73.9%and a purity of 97.4%.This route has the advantages of simple synthesis method,mild reaction conditions,easy post-processing operation and reduction of"three wastes"emissions,and is more suitable for industrial production.（6）"One-pot"synthesis of 2-（2-thienyl）propionic acid,using 2-acetylthiophene as the raw material,through epoxidation reaction,silica gel catalytic rearrangement reaction,oximation and hydrolysis reaction to synthesize 2-（2-thienyl）propionic acid with a total yield of 71.3%and a purity of 97.5%.Compared with other synthetic routes,it has the advantages of simple operation,safe reagents,high yield and low cost.No literature has reported that use this route to synthesis 2-（2-thienyl）propionic acid,which has a certain novelty.