拉科酰胺原料药中有关物质的合成
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摘要
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、~(13)C-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,~(13)C-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.■
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,~(13)C-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.■
引文
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[5] 马银玲,赵峰,张恺,等.拉科酰胺的合成[J].中国医药工业杂志,2009,40(9):641-643.
[6] 陈一芬,王超,禹艳坤,等.拉科酰胺的合成工艺改进[J].合成化学,2010,18(4):520-522.
[7] 彭海燕,蔡润发,廖祝元,等.拉科酰胺中脲类化合物杂质的合成及结构鉴定[J].赣南师范大学学报,2016,6(6):69-70.
[8] NARSAIAH A,WADAVRAO S,NARIKIMALLI A.A non-infringing route for enantioselective synthesis of antiepileptic agent lacosamide[J].Synthesis,2013,45(22):3383-3386.
[9] MORIEUX P,P STABLES J,KOHN H.Synthesis and anticonvulsant activities of N-benzyl(2R)-2-acetamido-3-oxysubstituted propionamide derivatives[J].Bioorg Med Chem,2008,16(19):8968-8975.
[10] AMINUL I,BUDIDET S R,DANDA S R,et al.An improved process for the preparation of lacosamide:US,2011144983A1[P].2011-05-16.
[2] BEN-MENACHEM E,BITON V,ATUZIS D,et al.Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures[J].Epilepsia,2007,48(7):1308-1317.
[3] BAULAC M,BYRNES W,WILLIAMS P,et al.Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy[J].Acta Neurol Scand,2017,135(4):434-441.
[4] KAMINSKI R,R LIVINGOOD M,ROGAWSKI M.Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice[J].Epilepsia,2004,45(7):864-867.
[5] 马银玲,赵峰,张恺,等.拉科酰胺的合成[J].中国医药工业杂志,2009,40(9):641-643.
[6] 陈一芬,王超,禹艳坤,等.拉科酰胺的合成工艺改进[J].合成化学,2010,18(4):520-522.
[7] 彭海燕,蔡润发,廖祝元,等.拉科酰胺中脲类化合物杂质的合成及结构鉴定[J].赣南师范大学学报,2016,6(6):69-70.
[8] NARSAIAH A,WADAVRAO S,NARIKIMALLI A.A non-infringing route for enantioselective synthesis of antiepileptic agent lacosamide[J].Synthesis,2013,45(22):3383-3386.
[9] MORIEUX P,P STABLES J,KOHN H.Synthesis and anticonvulsant activities of N-benzyl(2R)-2-acetamido-3-oxysubstituted propionamide derivatives[J].Bioorg Med Chem,2008,16(19):8968-8975.
[10] AMINUL I,BUDIDET S R,DANDA S R,et al.An improved process for the preparation of lacosamide:US,2011144983A1[P].2011-05-16.