Synthetic Of Bruton’s Tyrosine Kinase Inhibitor (-)-CD055

(-)-CD055, a novel Bruton’s tyrosine kinase inhibitor, is currently in intensive pre-clinical research as a candidate drug for tumor.Starting from pyridine, 3S-amino-N-(6-amino-5-fluorine-pyrimidine)-4S-hydroxy-piperidine, the intermediate 12, was prepared via formation of N-benzyl pyridinium bromide salt, reduction, epoxidation, ring-opening reaction, chemical resolution, hydrogenation, amino nucleophilic addition, reductive amination and ester-amine exchange reaction with 7.11% overall yield; starting from ethyl L-pyroglutamate, ethyl 1-(3-chloro-5-trifluorinemethyl-phenyl)-5-hydroxy-pyrrolidine-2R-formate, the intermediate 13 was obtained via Ullmann reaction and Dibal-H reduction with yield of 67.45%; The aforementioned two intermediates 12 and 13 was applied to offer target molecule (-)-CD055 via condensation, reduction, and intramolecular cyclization with ee% up to 99% and yield of 52%. We have obtained optimized conditions without the application of column chromatography in the whole process. Thus, we have laid the foundation for industrial scale-up.Additionally, in order to determine the chiral purity, (+)-CD055、(+)-L-CD055 and (-)-L-CD055 were also prepared in this work.