In order to overcome the difficulty to separate and purify the intermediate, solve the problem of quaternary ammonium salt removal，the synthesis of (2S,4S)-N-tert-butoxycarbonyl-4-fluoroproline which is a key intermediate of polypeptides and peptidomimetic drug is studied. The target compound is synthesized from (2S,4R)-4-hydroxyproline via esterification, amino protection, and hydroxyl activation-fluorination-hydrolysis tandem reaction. Hydroxyl activation, S_N2 fluorine substitution and ester hydrolysis reaction are completed as a tandem reaction. After the hydrolysis reaction, the product is precipitated from the aqueous solution during the process of adjusting the pH, and the target compound can be directly obtained through filtration. The reaction factors and parameters are optimized, The optimized conditions are as follows: in esterification reaction, n(SOCl₂)∶n(substrate)=1.2∶1.0; in amino protection reaction, n((Boc)₂O)∶n(compound 1)=1.2∶1.0; in trifluoromethyl sulfonylation reaction, n((Tf)₂O)∶n(compound 2)=1.1∶1.0,n(pyridine)∶n(compound 2)=1.2∶ 1.0. The total yield rate is 57.9% after optimization, and the purity is 98.3%. The structure of target compound is confirmed by ¹H-NMR and ¹³C-NMR. This protocol has advantages of mild reaction conditions and simple operation, and is suitable for industrial production.