Continuous Flow Synthesis of 5-Methyltetrahydrofolate from Folic Acid

5-Methyltetrahydrofolate (5-MTHF) is an active form of folic acid (FA) and an essential micronutrient preventing anemia and numerous other adverse health conditions such as cardiovascular disease and cancer. Herein, a continuous flow sequence synthesis of 5-MTHF from FA was developed, involving three elementary steps: catalytic hydrogenation of FA to tetrahydrofolic acid (THFA), methylenation of THFA with formaldehyde, and hydrogenation of the methylenation intermediates to 5-MTHF. This process features an expeditious synthesis of 5-MTHF in an integrated flow platform with water as the sole solvent and without any intermediate purification. The overall yield of this three-step flow process was up to 53.54% in a total residence time of 71.4 min. The separated yield of 5-MTHF reached 49.3%.