Process For The Preparation Of Cunninghamia Lanceolata Carbon Supported FeO(OH) Nanoparticles And Its Application

It was well-known that aromatic amines are key intermediates widely present in the pharmaceuticals and functional materials.The main approaches for the synthesis of aromatic amines are Fe/acid reduction and Pd/C hydrogenation pathways in the industry.The Fe/acid reduction pathway uses low-cost Fe powder,however,a large amount of iron oxides would be generated as by-products,this pathway fails to meet green chemistry requirement.The Pd/C catalyst has a good catalytic activity and can be reused in the Pd/C hydrogenation pathway,but the following scientific issues could be pointed out,such as excess amount of high-pressure H₂,strict equipment requirements and production of heterocyclic hydrogenation byproducts.Hence,the development of a low-cost carbon-supported iron catalyst for the hydrogenation of nitroarenes with vantages of Fe/acid reduction and Pd/C hydrogenation pathways instead of these two pathways is of highly significance,which has important academic and application value.In this thesis,we proposed and designed a heterogeneous catalyst cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles according to these reported articles.This heterogenous catalyst own a graphited structure surrounding the FeO（OH）,which can improve iron atom electron conductivity and structure stability.These nanoparticles can efficiently catalyze nitro reduction and hydrazine substitution.Meanwhile,using the prepared nanoparticles,we systematically studied the reaction of nitro reduction,applying to the synthesis of EGFR T790M mutant inhibitor Osimetinib key amine intermediate,and using synthesized amines for deeply application study,including total synthesis of Osimertinib and its derivatives,indazoles,and phthalazinones.The in vitro bioactivity study of Osimertinib derivatives was also proceeded.In this dissertation,the main results were as follows:（1）A series of activated carbons-supported iron oxide hydroxide particles were prepared using commercially available carbon sources,and the best heterogeneous catalyst cunninghamia lanceolata carbon-supported iron particles was screened using2-nitrobenzen as the substrate.The HRTEM、XPS、BET、XRD、and EDX mapping characterization of cunninghamia lanceolata carbon-supported iron particles showed the iron catalyst has a FeO（OH）structure,with size 30-40 nm.The screening and characterization results indicated that the carbon graphitization is important for the best catalytic activity of hydrogenation,which can improve the electron conductivity,and promote nitro reduction.（2）Based on the prepared cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles,the catalyzed hydrogenation of nitro aromatic compounds to corresponding amine compounds in the presence of 80%hydrazine hydrate was studied.The study indicated that this protocol has good substrate applicability to nitrobenzenes and nitro heterocyclic compounds.Then the catalyst was successfully applied in the formation of key anti-cancer drug intermediates.Meanwhile,the result showed that this catalyst can hydrogenate chiral afatinib nitro compound to the corresponding amine intermediate without racemization.At last,on the basis of previous literatures and control experiments,a possible mechanism for cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles catalyzed nitro reduction was proposed:Hydrazine hydrate was completely and incompletely decomposed to produce H^*on the surface of FeO（OH）/C nanoparticles,the H^*reacted with nitro products to obtain nitroso intermediates,then azanol intermediates and lastly amine compounds were produced.（3）The reported synthetic routes of Osimertinib have a few disadvantages,such as low yield,high cost,and not environmentally-friendly.To overcome these shortcomings,an improved method for total synthesis of Osimertinib was developed in six steps with 50.9%yield in kilogram-scale.Most importantly,in the key step of nitro reduction,the prepared cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles were used to catalyze the hydrogenation of nitro compound to the corresponding amine compound in high yield using 80%hydrazine hydrate as the hydrogen source.Recycle experiments showed that this catalyst can be reused for at least 8 times.Furthermore,a series of Osimertinib derivatives were synthesized,and their biological activities were also studied using human lung cancer cells A549 cells and H1975 cells.The best inhibitor compound 23d was screened with IC₅₀values of4.7μM and 11.6μM,respectively.（4）The cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles were employed to catalyse the selective hydrazine substitution of p-nitro-aryl fluorides with hydrazine hydrate.The results showed that the hydrazine substitution of p-nitro-aromatic fluorides containing electron-withdrawing groups efficiently proceeded in high yield and selectivity;while p-nitro-aromatic fluorides contain electron-withdrawing groups,the p-nitro-aromatic fluorides tended to produce hydrazine substituted products.Furthermore,with these prepared aryl hydrazines in hand,some indazoles and phthalazinones which may be used as the skeleton of potential pharmaceuticals were synthesized successfully in high yields.At last,on the basis of previous literatures and control experiments,a possible mechanism for cunninghamia lanceolata carbon-supported FeO（OH）nanoparticles catalyzed hydrazine substitution was proposed:hydrazine hydrate was decomposed to N₂H₃^-and H⁺on the surface of FeO（OH）/C nanoparticles.When p-nitro-aromatic fluorides bearing electro-withdrawing groups,it is easy to form aryl carbocation,the p-nitro-aromatic fluorides are apt to produce hydrazine substituted products via C-N coupling.However,when p-nitro-aromatic fluorides contain electron-donating groups,it is difficult to form aryl carbocation,the p-nitro-aromatic fluorides are apt to generate nitro reduced products.