Continuous Hydrogenation In A Micro-Packed Bed Reactor To Remove Benzyl-Type Protecting Groups

In the process of drug synthesis,due to the complicated reaction route and the existence of a large number of functional groups on the substrate,it is often necessary to protect the amino and hydroxyl functional groups on the substrate by using protection and deprotection strategies.Benzyl is widely used in the protection of amino and hydroxyl functional groups due to its stability and ease of installation.Compared with the direct reduction method and the transfer catalytic hydrogenation method,the direct catalytic hydrogenation method using high-pressure hydrogen as the raw material and the noble metal palladium as the catalyst has the characteristics of better atomic economy and high efficiency and environmental protection.The high-pressure hydrogenation batch commonly used for hydrogenation has the advantages of simple structure,but also has the problems of slow reaction speed,tedious operation and poor safety.Therefore,a safe,efficient,economic and environmentally friendly hydrogenation method is urgently needed in the field of pharmaceutical synthesis.In this dissertation,N-diphenylmethylazetidin-3-ol?a pharmaceutical intermediate for the synthesis of antibiotics and antibacterial agents?was used as the model to perform continuous hydrogenolysis of N-diphenylmethyl in a micro-packed bed reactor.The effects of catalysts,solvents and the acidity and alkalinity of solvents on the reaction rate were studied.The results showed that the catalytic activity per unit mass of Pd?OH?₂ was twice that of Pd catalyst;the rate of hydrogenolysis reaction was higher when methanol or ethyl acetate was used as the solvent,tetrahydrofuran solvents had a certain toxic effect on Pd?OH?₂ catalyst;acidic conditions favor hydrogenolysis of N-diphenylmethyl,while basic conditions inhibit hydrogenolysis of N-diphenylmethyl.The rate of hydrogenolysis of N-diphenylmethyl in a micro-packed reactor was compared with that in a conventional batch reactor.The experimental results showed that within a unit time and a unit reactor volume,the material handling capacity in the micro-packed bed reactor is 100 times that of the reactor,which illustrates the excellent hydrogenation performance of the micro-packed bed continuous reactor.In addition,the results of long-period experiments in the micro-packed bed reactor found that the hydrogenolysis rate of the feedstock can be maintained above 99.5%within 190 h.After eliminating the effect of internal and external mass transfer resistance in a micro-packed bed reactor,the intrinsic reaction kinetics catalyzed by Pd?OH?₂/Al₂O₃was studied,and the orders of reaction and activation energy were obtained.The results showed that the reaction order of N-diphenylmethylazetidin-3-ol is 0.53,the reaction order of hydrogen is 0.31,and the activation energy is 18.6 k J/mol.Through the establishment of an adsorption kinetic model,it was found that the surface reaction step is the rate-determining step of the hydrogenolysis reaction;the adsorption type of hydrogen on Pd?OH?₂/Al₂O₃ catalyst is dissociation adsorption,and the adsorption type of N-diphenylmethylazetidin-3-ol and hydrogen on Pd?OH?₂/Al₂O₃ catalyst is non-competitive adsorption.