亚叶酸钙合成工艺研究

Research on the synthesis process of leucovorin calcium

提供了一种亚叶酸钙的合成方法,以叶酸为起始原料,经还原反应、甲酰化成盐反应、水解反应及成盐反应及得亚叶酸钙化合物。最佳工艺条件如下:m_((叶酸)):m_((硼氢化钠)):m_((水))=1∶0.8∶5,90℃,反应2 h,合成四氢叶酸;m_((四氢叶酸))∶m _((甲酸))∶m_((三氟乙酸))∶m_((浓盐酸))=1∶3.75∶0.375∶3.75,30℃,反应6 h,合成5,10-亚甲基四氢叶酸盐酸盐;5,10-亚甲基四氢叶酸盐酸盐pH=6~7,100℃,水解6 h得5-甲酰基四氢叶酸;m_((5-甲酰基四氢叶酸))∶m_((无水氯化钙))=1∶0.275,30℃,反应1 h得亚叶酸钙。整个过程收率为40%,经HPLC检测,成品纯度高达99.68%,单杂0.11%,总杂0.79%.

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%.