Research On The Mechanochemical Condensation And Its Application In The Synthesis Of Intermediate Of Prils

This dissertation consists of two parts.Partâ… is the research progress on the solid-state mechanochemistry used in condensation reaction.In Chapter one,the solid-state mechanochemistry in organic synthesis,as well as its applications in pharmaceutical industry has been reviewed.Close attention has also been paid to the prospects of the applications.In the Chapter two of Partâ… ,a facile amination of solid 1,3-dicarbonyl compounds with ammonium salts or amines in solid state has been achieved by mechanochemical grinding in the presence of KHSO₄/SiO₂.Most of the reactions proceed smoothly at room temperature under solid-state condition and give their correspondingβ-imino-derivatives in high yields.The method has the advantage of simple manipulation,mild conditions.In the Chapter one,Partâ…¡,research on the synthesis of ethyl 2-oxo-4-phenylbutyrate（EOPB）which is an intermediate of Angiotansin Converting Enzyme Inhibitor（ACEI）was reviewed.In the Chapter two,Partâ…¡,Grignard reaction to prepare EOPB was explored,usingβ-chloroethyl benzene orβ-bromoethyl benzene（β-BEB） as starting material,in which the latter was synthesized by anti-Markovnikov addition of hydrogen bromide to styrene under the optimum reaction conditions.In the Chapter three,Partâ…¡,an intermediate for Prils was synthesized using hypnone as a starting material in three steps:（a） condensing hypnone with diethyl oxalate with≥95%yield of 4-dioxo-4-phenylbut-2-enoate（2）;（b）mechanochemical grinding to prepare ethyl 2-amino-4-oxo-4-phenyl-but-2-enoate（3）in 99%yield;（c） catalytical hydrogenation of 3 afforded quantificationally 2-amino-4-phenylbutanoic acid（4’）which is also an important intermediate of EOPB and prils.Compare to the corresponding result of Grignard reaction method,this route afford higher yield of the product in higher purity.In conclusion,the method of mechanochemical grinding in preparing drugs has the advantage of efficiency,“green”,simple manipulation,mild conditions.