Asymmetric Synthesis of Bortezomib Prodrug

Example 8

The asymmetric synthesis of bortezomib-prodrug (FIG. 13) may involve the preparation of intermediate-1 (N-sulfinyl α-amino boron pinacolato complex) by following published methods. Selective removal of the N-sufinyl group under mild acidic conditions may produce the amine hydrochloride (intermediate 2), which may then be coupled with N-Boc-L-phenylalanine by a TBTU/DIPEA mediated reaction protocol. Intermediate-3 (amine hydrochloride) may then undergo coupling with the commercially available 3-am inopyrazine-2-carboxylic acid to produce the pinacol boronate of bortezomib. This may subsequently be hydrolyzed under biphasic conditions utilizing iso-butylboronic acid as a pinacol sequestering agent. Finally the intermediate-4 may undergo a sodium cyanoborohydride mediated reductive amination with ALDO (PC) in presence of catalytic amounts of TFA to produce bortezomib prodrug.