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• A novel triphasic system was constructed for bioresolution of (S)-2-chlorophenylglycine methyl ester ((S)- 1). • Optically pure (S)- 1 was prepared via one-step direct bioresolution by the triphasic system. • The triphasic system consisted of the immobilized Protease 6SD on NH 2 -MWCNT, aqueous and MTBE phases. (S)-2-chlorophenylglycine methyl ester ((S)- 1) is a key chiral building block of clopidogrel, which is a widely administered antiaggregatory and antithrombotic drug. Herein, Protease 6SD was covalently immobilized on multi-walled carbon nanotubes (MWCNT), and the as-prepared immobilizate P-6SD@NH 2 -MWCNT was applied in the enantioselective resolution of (R,S)- 1 to yield (S)- 1. In order to overcome the poor solubility of (R,S)- 1 in aqueous solution, a novel triphasic reaction system constituting P-6SD@NH 2 -MWCNT, aqueous phase and methyl tert -butyl ether (MTBE) as the organic phase was constructed, which simultaneously improved the substrate solubility and the immobilizate recyclability. Under the optimized reaction conditions, P-6SD@NH 2 -MWCNT catalyzed 10 mM (R,S)- 1 for 2 h, yielding optically pure (S)- 1 (>99.0 % ee s) with 70.74 % conversion of the (R,S)- 1. Moreover, P-6SD@NH 2 -MWCNT can be reused for 15 batches, displaying an exquisite recycling performance. It is for the first time that enantiomerically pure (S)- 1 was successfully synthesized by protease-catalyzed one-step resolution. [ABSTRACT FROM AUTHOR]