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Continuous production of aprepitant chiral intermediate by immobilized amidase in a packed bed bioreactor

Lin, Chao-Ping, Wu, Zhe-Ming, Tang, Xiao-Ling, Hao, Chang-Ling, Zheng, Ren-Chao, Zheng, Yu-Guo
Bioresource technology 2019 v.274 pp. 371-378
amidase, biocatalysts, bioprocessing, bioreactors, catalytic activity, chemical bonding, epoxides, half life, moieties, space and time, thermal stability
To develop a highly efficient method for aprepitant chiral intermediate (S)-4-fluorophenylglycine, a continuous reaction system was established in packed bed bioreactor using amidase covalently immobilized on epoxy resin as biocatalyst. The epoxy resin was firstly modified by metal-chelate method and functional groups (Cu2+-IDA) generated were able to rapidly adsorb amidases, which were further covalently bound onto the modified resin with 90.1% immobilization yield and 80.2% activity recovery. The immobilized amidase exhibited excellent thermal stability with the longest half-life of 1456.8 h at 40 °C ever reported. (S)-4-fluorophenylglycine was continuously produced using the reaction system with 49.9% conversion, 99.9% ee, and an outstanding space-time yield of 5.29 kg L−1 d−1. Moreover, the efficient reaction system exhibited a high operational stability and retained 86.3% catalytic activity after 25-day continuous operation. This efficient continuous bioprocess presents great industrial potential for large-scale production of (S)-4-fluorophenylglycine.