Study On The Synthesis Of Intermediates Of Bortezomib

Recently the morbidity of multiple myeloma(MM) has exceed that of acute leukmia, and becomes the second most serious malignant tumor. Bortezomib is the first proteaseme inhibitor developed by Millennium, which had been established to be clinically useful for the treatment of MM. Recent years, research of the synthesis of R-(+)-Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenylalanine-L-leucine boronate which is a key intermediate in the production of Bortezomib gains more attention.The synthesis method of R-(+)-Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenyl alanine-L-leucine boronate are introduced and summarized. In this thesis, the synthe sis procedure is demonstrated including:(1) the formation of R-(+)-Pinanediol-1-ammomium trifluoroacetate-3-methylbutane-l-boronate from2-methylpropyl boronic acid via esterification with (+)-Pinanediol, homologation with LiCHCl2, then nucleo philic substitution with LiN(CH(CH3)2)2and last salification with CF3COOH, the yield is49.9%;(2) the preparation of N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine from pyrazinecarboxylic acid via acylation with L-Phenylalaine methyl ester hydroch loride followed by hydrolyzation with NaOH, the yield is65%;(3) R-(+)-Pinanediol-1-ammomium trifluoroacetate-3-methylbutane-l-boronate acylates with N-(Pyrazine-2-ylcarbonyl)-L-phenylalanine to give R-(+)-Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenylalanine-L-leucine, the yield is86%.The reaction mechanism of each step is studied and the process is optimized in this paper. The total yield of R-(+)-Pinanediol N-(pyrazine-2-ylcarbonyl)-L-phenyl alanine-L-leucine is42.9%.The structure of each product is confirmed by1H-NMR、13CNMR、GC-MS and so on.