Synthesis Of Thiophene Derivatives And Construction Of Microchannel Reactors

The bromination reaction play an important role in the synthesis of pharmaceutical intermediates,but there are many problems with it.such as the safety of bromine,low utilization of bromine atoms,and low product yields.So we explored a green bromination method to solve the problems.At the same time,through the study of the bromination mechanism and the feasibility analysis of the microchannel reaction,we finally use microchannel reactor to do the bromination reaction.Utilizing their unique advantages to achieving safe production of bromination reactions and increasing the selectivity of target products.We choose thiophene as the bromination object to study the bromination of heterocyclic compounds,then combining a green bromination method and microrochannelreactorforthesynthesisof2-bromothiophene.2-thiophenecarboxylic acid is an importan intermediate for the synthesis of Raltitrexed,an anticancer drug.In addition,it also has unique application value in new materials and coloring agents.The previous work of this group has explored a new method for the synthesis of 2-thiophenecarboxylic acid.At the same time,We combining the new method and microrochannel reactor for the synthesis of 2-thiophenecarboxylic acid.?1?Through comparing direct bromination with oxidation bromination,we choose oxidation bromination from the aspects of bromine addition method,bromine addition time,device construction method and safety.The optimum reaction conditions was obtained through investigating the material ratio,reaction temperature,stirring time,and solvent.The best results show that:n?thiophene?:n?HBr?:n?H₂O₂?=1:1.1:1.3,the reaction process without solvent,the reaction temperature was-15°C.After stirring was complete for 1 h,the mixture was warmed to 0°C and stirred for 1 h.The final thiophene conversion was 92%,the yield of 2-bromothiophene was 88%,and the bromine atom utilization was 86%.?2?Through analyzing the traditional limiting conditions for the synthesis of2-bromothiophene,we conducted a feasibility study which is using Corning G1microreactor for industrial scale-up.Firstly,the reaction mechanism of synthesis of 2-bromothiophene is discussed.Secondly,the total reaction heat of oxidation process and bromination process is theoretically calculated.Comparing with the power consumption of cold and hot integrated machine,we estimated the heat transfer efficiency.Then,analyzing the anti-corrosion performance of various components of the microreactor system,we select the appropriate components;Finally,according to the purpose of the reaction,we design the installation sequence of the reaction plates and prepare to carry out the reaction.?3?Using the Corning G1 microchannel reactor to do industrial scale-up experiments.The optimum reaction conditions was obtained through investigating the material ratio,residence time,reaction temperature and other factors.The best results show that:At 25?,n?thiophene?:n?HBr?:n?H₂O₂?=0.8:1:1.1 and the residence time was 30s.At this time,the conversion of2-bromothiophene was 90%.Thiophene selectivity is 79.9%.?4?We combining the new method and microrochannel reactor for the synthesis of 2-thiophenecarboxylic acid.After dropwise addition of 2-thiophenecarboxaldehyde in a conventional manner,the reaction solution is introduced into the microchannel reaction plate via a peristaltic pump to enhance mass transfer and finally returned to the reaction vial.The experimental results showed that at 25°C,n?2-thiophenecarboxaldehyde?:n?H₂O₂?n?NaOH?:=1:5:1.5and the reaction time was 6 hours.At this time,the conversion rate of 2-thiophenecarboxaldehyde was 95%.The yield of 2-thiophenecarboxylic acid was 88%.?5?We investigated the influence of inert gas,a self-made static micromixer,and increasing the system pressure on the yield of 2-bromothiophene.Several methods for enhancing the mass transfer under microchannel reaction conditions are summarized.