The invention relates to a preparation method of (2R, 5R)-1, 2, 5-trimethylpiperazine. The preparation method comprises the following steps: sequentially adding Boc-N-methyl-D-
alanine, D-
alanine methyl
ester hydrochloride, EDC.HCl, HOBT and DMF (
Dimethyl Formamide) into a reaction flask, stirring for dissolving, activating
carboxylic acid, and dropwise adding N-methylmorpholine; after the reaction is finished, adding
ethyl acetate to dilute a
reaction system, adding 1M
hydrochloric acid for washing, layering and reserving an organic phase, and adding a saturated
sodium bicarbonate solution for washing, layering and reserving an organic phase; adding saturated
salt water for washing, layering, leaving an organic phase, and concentrating the organic phase; adding
formic acid; adding sec-butyl
alcohol and methylbenzene to neutralize the
alkalinity in the crude product; dissolving with methylbenzene, dropwise adding a red aluminum solution, neutralizing, washing, layering, concentrating an organic phase to obtain a crude product, and purifying the crude product to obtain a finished product. The preparation method has the advantages that BOC-N-methyl-D-
alanine and D-
alanine methyl ester hydrochloride are taken as initial raw materials, the (2R, 5R)-1, 2, 5-trimethylpiperazine is obtained through the steps of condensation, cyclization and reduction, and the chiral purity of the (2R, 5R)-1, 2, 5-trimethylpiperazine is improved.