A Simple And Low-cost Synthesis Of (3R,4R)-2-amino-1-Hydroxy-4-methyl Pyrrolidin-2-one(L-687,414)

N-methyl-D-aspartate (NMDA) receptor antagonists are a classof central nervous system drugs and is an essential treatment forepilepsy and other neurological diseases and prevention ofneurodegenerative disorders.(3R,4R)-2-Amino-1-hydroxy-4-methyl pyrrolidin-2-one (L-687,414) is an antago-nistacting at the glycine site of the NMDA receptor.L-687414was first discovered and synthesized by the MerckSharp and Dohme, but so far no suitable route for large scaleproduction has been reported. This thesis describes theimprovements of a route initially reported by Roche. This optimizedsynthesis is practical for producing up to kilograms of L-687414atlower cost. L-687,414is prepared in5steps starting from diethyloxalate, including Grignard reaction, cyclization, reduction, saltpurification, and hydrogenation reduction. The key steps are theenamine reduction and chiral compounds separation, which werethe limiting steps for large scale production of L-687414: 1. Reducing the key intermediate enamine with sodiumborohydride in the presence of Lewis acid instead of the expensivemetal catalyst such as platinum oxide.2. Avoiding the isomers separation with chiral preparativeHPLC, several kinds of TM salts such as HCl, TsOH, tartaric acidetc. were tried to recrystallize in several solvents since there isamino group in this structure.This process procedure has many advantages, such as easyoperation and low cost, which can be practical for scale-up.