Study On Synthesis Of Ibuprofen By A New Process Of Isobutyrylation-hydrogenation-Carbonylation

Ibuprofen is a non-steroidal anti-inflammatory drug.It is konw as"Four Diamonds"of antipyretic analgesia together with paracetamol,aspirin and analgin.Its antipyretic and analgesic effect are obvious and its adverse reactions are small.In response to the country's call for“clean production”,there is an urgent need for a new process for synthesis of ibuprofen.Ibuprofen was synthesized from isobutylbenzene by Friedel Crafts acylation,hydrogenation reduction and carbonylation.Compared with the five-step reaction of the Boots process,the BHC process is a typical atomic economy reaction.Therefore,it is necessary to carry out the research on the BHC process for ibuprofen synthesis and industrial upgrading.In this thesis,a new clean synthesis process of isobutylbenzene to p-isobutylacetophenone via Friedel Crafts acylation,p-isobutylacetophenone catalytic hydrogenation to p-isobutylphenylethanol andp-isobutylphenylethanolcarbonylationtoibuprofenhasbeenstudied systematically and comprehensively.The main contents and results are as follows:?1?The synthesis process of p-isobutylacetophenone from isobutylbenzene by Friedel Crafts acylation was studied,The process was optimized through the investigation of single factor and the control of experimental conditions,and the optimal molar ratio of reactants was determined to be aluminum trichloride:acetyl chloride:iso-butylbenzene=M₁:M₂:1;The best reaction temperature is 0 to 10?;The order of titration of reactants is aluminum chloride?dichloromethane??acetylchloride?isobutylbenzene;In the subsequent hydrolysis reaction of hydrolysis temperature for 15 to 20?;To ensure the quality of target product,the acceleration should be accelerated as far as possible,the yield of p-isobutylacetophenone can reach more than 97%under the above conditions.?2?Pd/C catalyzed hydrogenation of isobutylacetophenone was used to study the synthesis process of isobutylacetophenone.The process was optimized through the investigation of single factor in the experiment,and the optimal reaction conditions were determined as follows:30 g of isobutylacetophenone,m?isobutylacetophenone?:m?methanol?=1:3;T=30?;P=0.8 MPa;M?5%Pd/C?=2.4 g;M?30%NaOH?=X₁ g,and the yield of p-isobutylphenylethanol could reach over 96%under the above conditions.In a certain range of experimental conditions,the primary and secondary order of influencing factors for hydrogenation reaction was determined by orthogonal experiment:the amount of catalyst>the amount of NaOH>hydrogen pressure.Nitrogen adsorption desorption,TEM,XRD characterization analysis were carried out on Pd/C catalyst before and after the reaction to determine the reasons for the decreased activity of the catalyst in the reaction process.?3?The synthesis process of p-iso-butyl phenyl alcohol carbonylation to ibuprofen was studied.The optimal reaction system was determined to be PdCl₂?PPh₃?₂-TsOH-NCl-CuCl₂&PdCl₂-H₂O-1,4-dioxane by single factor investigation and orthogonal experiment.Better reaction conditions as follows:m?p-isobutylbenzene ethanol?=22.25 g,m?p-toluene sulfonic acid?=4.27 g,m?NCl?=0.98 g,V?1,4-dioxane?=78 ml,V?H₂O?=6 ml,T=110?,P?CO?=5.5 MPa,completed by under the condition of the reaction yield can reach 82%of ibuprofen.In a certain range of conditions,the order of influence factors of carbonylation was determined by orthogonal experiment:temperature>pressure>the type of catalyst>the type of solvent.