Flow Synthesis of L-α-Glycerylphosphorylcholine: Studies on Synthetic Routes Applicable to a Flow Reactor and Optimization of Reaction Conditions

초록

L-alpha-Glycerylphosphorylcholine (L-alpha-GPC) has mainly been produced by two methods: extraction from plants rich in phosphatidylcholine and chemical synthesis. However, production through extraction involves difficult processes, such as fermentation, extractions and ripening, and conventional chemical synthesis methods with high-cost reactants and a batch reactor. These methods are not ideal for large-quantity production. Thus, it is important to develop a simple production method of L-alpha-GPC, which is suitable for mass production without the need for expensive reactants. Here, we studied synthetic L-alpha-GPC methods that are applicable to a flow synthesis system, which can provide selectivity, reproducibility, scalability, and a high yield in short reaction time using inexpensive starting materials. We developed a two-step synthetic route to produce L-alpha-GPC, including the synthesis of phosphoryl choline using choline chloride and phosphoryl oxychloride (POCl3) as a first step and synthesis of L-alpha-GPC by reacting phosphoryl choline with (R)-(-)-3-chloro-1,2-propanediol (CPD) as a second step under basic conditions. Both steps were separately performed in a customized flow reactor, and reaction conditions were optimized. Finally, phosphoryl choline and L-alpha-GPC, the products first and second reactions, were successfully synthesized with high conversion yields of 97% and 79%, respectively.

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