Abstract： A synthesis method of leucovorin calcium was provided with folic acid as the starting material, through reduction reaction, formyl into salt reaction, hydrolysis reaction and salt into reaction and leucovorin calcium compounds. The optimal process conditions are as follows: m (folic acid)∶ m(sodium borohydride)∶m(water) =1∶0.8∶5, 90 ℃, Reaction for 2 h, Synthetic tetrahydrofolic acid; of m(tetrahydrofolic acid)∶m(formic acid)∶m(trifluoroacetic acid)∶m(concentrated hydrochloric acid) =1∶3.75∶0.375∶3.75, 30 ℃; Reaction for 6 h; Synthesis of the 5, 10-Methylene-tetrahydrofolate hydrochloride; 5,10-Methylenetetrahydrofolate hydrochloride pH=6 ~ 7, 100 ℃, 5-formyl-tetrahydrofolic acid was obtained by 6h of hydrolysis; m(5-formyl tetrahydrofolate)∶ m(anhydrous calcium chloride) =1∶0.275, 30 ℃, Linovorin calcium reaction for 1 h. The yield of the whole process was 40%, and according to the HPLC test, the purity of the finished product was as high as 99.68%, single impurity 0.11%, and total impurity 0.79%.
