甲磺酸沙芬酰胺有关物质的合成

Synthesis of the Related Substance of Safinamide Mesylate

为控制甲磺酸沙芬酰胺产品的质量,本研究合成了有关物质A,即(S)-2-[3-(3-氟苄基)-4-(3-氟苄氧基)苄胺基]-丙酰胺。用对溴苯甲醚(7)与间氟苯甲酰氯(8)在Lewis酸催化下制得(5-溴-2-羟基苯基)(3-氟苄基)甲酮(9)。9经还原后,与间氟溴苄(11)经取代反应生成4-溴-2-(3-氟苄基)-1-(3-氟苄氧基)苯(12),随后经溴锂交换/甲酰化反应,生成3-(3-氟苄基)-4-(3-氟苄氧基)苯甲醛(13)。13与L-丙氨酰胺盐酸盐发生还原胺化得到有关物质A,总收率9.82%(以7计),结构经^(1)H NMR、^(13)C NMR和MS确证,可作为甲磺酸沙芬酰胺质量研究的对照物。

In order to control the quality of safinamide mesylate,the related substance A,named(S)-2-[[3-(3-fluorobenzyl)-4-[(3-fluorobenzyl)oxy]benzyl]amino]propanamide,was synthesized in this study.(5-Bromo-2-hydroxyphenyl)(3-fluorophenyl)methanone(9)was synthesized by the reaction of 4-bromoanisole(7)with 3-fluorobenzoyl chloride(8)catalyzed by Lewis acid.Compound 9 reduced in the presence of Et3SiH/BF_(3)·Et_(2)O,then reacted with 3-fluorobenzyl bromide(11)to give 4-bromo-2-(3-fluorobenzyl)-1-(3-fluorobenzyloxy)benzene(12),followed by lithium bromide exchange/formylation to give 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde(13).Related substance A was synthesized by reductive amination of 13 with L-alanamide hydrochloride,in an overall yield of 9.82%(based on 7).The structure of the product was confirmed by 1H NMR,13C NMR and MS,which could be used as the reference for quality control of safinamide mesylate.