Synthesis Of Lacosamide

Lacosamide is a new broad-spectrum antiepileptic drug with good tolerability and low drug interactions. Antiepileptic drugs used in China are mainly oral preparations with relatively less injection preparation form. Its injection preparation form will fill this gap showing good prospect of clinical application.This paper mainly studied the synthesis process of Lacosamide with methyl acrylate as raw material. Firstly, synthesize2-bromo-3-methoxy methyl propionate and2-bromo-3-methoxypropionic acid according to reference methods, and then get Lacosamide through amidation, amination, resolution and acetylation in sequence.This paper mainly studied the following aspects:(1) Studied on the influencing factors of amidation through mixed carbonic anhydride method to get2-bromo-N-benzyl-3-methoxy propionamide and optimized the process conditions. In addition, exploratory research was conducted on the direct condensation of the ester with benzyl amine.(2) Studied the resolution of2-amino-N-benzyl-3-methoxy propanamide and obtained R-(-)-2-amino-N-benzyl-3-methoxypropanamide in a simple and efficient manner.(3) Studied on the racemization of the (R/S)-2-amino-N-benzyl-3-methoxy propionamide in the mother liquor of resolution which was rich in S isomer.(4) Studied on the acetylation of R-(-)-2-amino-N-benzyl-3-methoxypropanamide to get Lacosamide.In the study of the amidation step through mixed anhydride method, the paper speculated the reaction mechanism through the impurity separation and structure identification. Based on the understanding of mechanism, we obtained the optimized conditions, solved the problem of transient temperature rise, reduced the impurity formation and improved the yield. One of the impurities is3-methoxy-2-bromo isopropyl propionate which has not been reported in any literature.For the direct condensation of2-bromo-3-methoxy methyl propionate with benzyl amine, the reaction machnism was explored briefly through impurity analysis. The reaction conditions were optimized, thus simplified separation step and improved the reaction yield from51.26%to85.8%with the purity of95.94%. Studied on the new resolution process of2-amino-N-benzyl-3-methoxy propionamide and obatained R-(-)-2-amino-N-benzyl-3-methoxy propionamide-D-(+)-tartaric acid salt with high optical purity through one chemical resolution step and one solvent system. This process largely increased the one-way resolution yield. The chiral salt has not been reported in any literature.Thermal racemization method with water as solvent was employed in the racemization process. The product was almost completely racemized with yield up to90.4%. The racemic product could recycled to resolving again and raised the total yield of resolution.With appropriate acid or alkali catalyst, acetylation was conducted with R-(-)-2-amino-N-benzyl-3-methoxy propanamide oxalic acid salt and acetylation agent directly to obtain the title compound. The process solved the the existing technical problem that R-(-)-2-amino-N-benzyl-3-methoxy propanamide is unstable and tends to produce impurities difficult to remove and side reactions would occur during the purification.This route shows great industrial value since it is low-cost, mild, environmentally friendly and yield-high.