拉科酰胺原料药中有关物质的合成

Synthesis of related substances of lacosamide

目的研究拉科酰胺原料药中有关物质的来源及合成方法,为产品质量控制提供依据和杂质对照品。方法在参考拉科酰胺原料药相关合成方法的基础上,以Boc-D-丝氨酸为原料,经多步反应分别制得拉科酰胺的6种有关物质:(R)-2-氨基-N-苄基-3-羟基丙酰胺(A)、(R)-2-乙酰胺基-N-苄基-3-羟基丙酰胺(B)、(2R)-2-(乙酰胺基)-3-(乙酰氧基)-N-(苯甲基)丙酰胺(C)、N-[(1R)-1-(甲氧基甲基)-2-氧代-2-[(苯基甲基)氨基]乙基]-2-甲基丙酯(D)、(R)-N-苄基-2-(3-苄基脲基)-3-甲氧基丙酰胺(E)、(R)-N-苄基-3-甲氧基-2-(N-甲基乙酰氨基)丙酰胺(F)。结果与结论合成的6种拉科酰胺有关物质的结构经1H-NMR、13C-NMR、HR-MS谱确证,可作为拉科酰胺原料药的杂质对照品,其中有关物质E和F为新化合物。

To improve the quality control of lacosamide,six related substances were synthesized.(R)-2-Amino-N-benzyl-3-hydroxypropanamide(A),(R)-2-acetamido-N-benzyl-3-hydroxypropanamide(B)and(2R)-2-(acetamido)-3-(acetyloxy)-N-(phenylmethyl)propanamide(C)were synthesized based on the use of Boc-D-serine as raw material.N-[(1R)-1-(methoxymethyl)-2-oxo-2-[(phenylmethyl)amino]ethyl]-2-methylpropyl ester(D),(R)-N-benzyl-2-(3-benzylureido)-3-methoxypropanamide(E)and(R)-N-benzyl-3-methoxy-2-(N-methylacetamido)propanamide(F)were synthesized from(R)-2-amino-N-benzyl-3-methoxyproplonamide.In addition,impurity E and impurity F were new compounds,the structures of them were characterized by 1H-NMR,13C-NMR and HR-MS.The purities of impurity A,B,C,D,E,and F was 95.3%,99.6%,99.9%,98.4%,99.7%,and 99.7%,respectively by HPLC analysis which can be used as reference substances for the lacosamide.