Practical synthesis of tetrahydrofolate by highly efficient catalytic hydrogenation in continuous flow

Hundred-gram scale of highly selective catalytic hydrogenation of folic acid has been developed, which is adopted continuous-flow technology with Raney Ni as a catalyst. Through optimization of the reaction condition, a high conversion rate of folic acid (> 99%) and a high selectivity (99%) of tetrahydrofolate have been achieved. Additionally, a high-purity calcium-6 S -5-methyltetrahydrofolate (6 S -5-MTHF.Ca) has been synthesized from tetrahydrofolate obtained by continuous hydrogenation through chiral resolution, methylation, salting and recrystallization (purity: 99.5%, de : 97.6%). Compared to known methods, this method provides a feasible procedure using simple, inexpensive, and readily available reagents, making it a step-economical and cost-effective alternative strategy for production of tetrahydrofolate and its active derivatives. Graphical Abstract For Table of Contents Only