| Pyrrole is the basic structure unit of many biologically active natural products and active pharmaceutical ingredients,the most classic synthesis of pyrrole is the Paal-Knorr reaction.In this project,the Paal-Knorr reaction was optimized and its kinetics was studied in a microchannel reactor.The synthesis for 1-?2-hydroxyethyl?-2,5-dimethylpyrrole is analyzed qualitatively and quantitatively by gas chromatography?GC?,while the 2,5-hexanedione and ethanolamine are used as raw materials,methanol is used as solvent and methanol hydrochloride solution is used as quencher.Furthermore,the reaction conditions are also optimized,the optimum reaction condition is as following:temperature 100°C,retention time 74.2 s.Then the reaction kinetics was fitted under optimum reaction condition and the conclusion is confirmed that reaction is a second order reaction under75°C,which is consistent with the batch reaction order,and the reaction rate constant is0.0302 L·mol-1·s-1.Lesinurad is the first marketed urate reabsorption transporter?URAT1?inhibitor in the world which is developed by AstraZeneca.In order not to infringe the patents of AstraZeneca,the project designed a synthetic route which is eco-friendly,raw material readily available,high yield and easily industrialized.Lesinurad was synthetised by thiourea,elimination,cyclization,alkylation,bromination and hydrolysis and aminoguanidine hydrochloride is as raw material.The industrial production route was established through continuous optimization base on the laboratory experiment,and pilot scale is 500 g.By preliminary exploration of the impurities generated in the experiment during the optimization process,there are 6 impurities founded.Two of them are new compounds,others have been reported.At the same time,after inferring the cause of the impurity,the control method and synthesis of these impurity are developed in this project. |
PDF Full Text Request