Synthesis Of Proteasome Inhibitor MLN9708 And An Intermediate Of Bortezomib

Bortezomib(Velcade)as a drug is used for the treatment of replased multiple myeloma(MM).R-Pinanediol-1-a-mmonium trifluoroacetate-3-methylbutane-1-boronate is an important intermediate for the synthesis of bortezomib.As a new generation of proteasome inhibitors,MLN9708 is also a new drug for the treatment of MM,and now being in clinical trials.The main work in this thesis can be summarized as follows:(1)Synthesis of MLN9708: Using 2,5-dichlorobenzoic acid as a raw material,MLN9708 is prepared by a series of reactions,including N-acylation,hydrolysis in alkaline condition,N-acylation,hydrolysis in acidic conditions and esterification.For the technology of preparation,the factors influencing the yield such as reaction temperature,feeding mode,condensing agent,are discussed respectively,and the technology route is also optimized.The molecular structure of product is confirmed by 1H NMR spectrum and the purity is up to 99.7% by HPLC analysis.We also enhance the total yield significantly from 8.57% to 12.55% compared with the reference.(2)Synthesis of R-Pinanediol-1-ammonium trifluoroacetate-3-methylbutane-1-boronate: levalyl boronic acid pinacol ester hydrochloride is employed as raw material.In dry DCM and at room temperature(25 ?),the amino group of levalyl boronic acid pinacol ester hydrochloride is protected by(Boc)2O,and then the transesterification reaction with pinanendiol is carried out in chloroform at room temperature.Finally,deprotection of amino group is finished with TFA.The total yield is 56.6%.The structures of product and several intermediates are confirmed by 1H NMR spectra.