药物Safinamide(沙芬酰胺)合成检索总结报告

药物Safinamide（沙芬酰胺）合成检索总结报告

一、Safinamide（沙芬酰胺）简介

Safinamide（沙芬酰胺）于2017年3月在美国上市，主要与左旋多巴或卡比多巴合用，用于治疗帕金森病。Safinamide（沙芬酰胺）常见的不良反应有运动障碍、跌倒、恶心和失眠。

Safinamide（沙芬酰胺）分子结构式如下:

CAS:133865-89-1CAS:202825-46-5

英文名称：Safinamide英文名称：Safinamide mesylate

中文名称：沙芬酰胺中文名称：沙芬酰胺甲磺酸盐

本文主要对Safinamide（沙芬酰胺）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。

二、Safinamide（沙芬酰胺）合成路线

Safinamide （沙芬酰胺）关键中间体13最简便合成方法如下：

三、Safinamide （沙芬酰胺）合成检索总结报告

(一)Safinamide （沙芬酰胺）中间体2

的合成合成方法

实验步骤参考文献操作方法

一

I 2(4.8g,19.02mmol)was added to a stirred solution of Ph 3P (4.15g,15.85mmol)and imidazole (1.1g,15.85mmol)in anhyd CH 2Cl 2(20mL)at 0°C,and the solution was stirred for 5min.A solution of alcohol 1(2g,15.85mmol)in CH 2Cl 2(5mL)was added drop-wise over 10min,and the mixture was stirred for 1h with exclusion of light.When the reaction was complete (TLC),the reaction was quenched with 1M aq Na 2S 2O 3(15mL),and the mixture was extracted with CH 2Cl 2(2×20mL).The organic layers were combined,washed with brine (2×10mL),dried (Na 2SO 4),filtered,and concentrated under reduced pressure.Purification of the crude residue by column chromatography [silica gel,PE-EtOAc,(95:5)]gave a colorless oil 2;yield:3.5g (95%).Synthesis ;vol.46;nb.13;(2014);p.1751-1756;操作方法

二To a stirred solution of triphenyl phosphine (4.15g,15.85mmol),imidazole (1.1g,15.85mmol)in dry dichloromethane (20mL),iodine (4.8g,19.02mmol)at 0°C was added and the solution was stirred for 5min.To this,3-fluoro benzyl alcohol (compound 1)(2g,15.85mmol)dissolved in dichloromethane (5mL)was added drop wise over 10min and the stirring was continued for 1hour with exclusion of light.After completion of the reaction (indicated by TLC),the reaction mixture was quenched by addition of an aqueous Na 2S 2O 3solution (15mL),then extracted with dichloromethane (2×20mL).The combined organic layers were washed with brine solution,dried over anhydrous Na 2SO 4,filtered,and concentrated under reduced

WO2014/178083;(2014);(A1)English

pressure.Purification of the crude residue was

done by column chromatography (silica gel,petroleum ether/EtOAc,95:5)to yield compound 2as a colorless oil (3.5g,95%).

(二)Safinamide （沙芬酰胺）中间体4的合成方法一合成方法

实验步骤参考文献操作方法

一

A solution of the iodide 2(3

g,12.7mmol)in MeCN was added slowly to a stirred solution of 4-(hydroxymethyl)-phenol 3(1.57g,12.7mmol)and K 2CO 3(8.8g,63.55mmol)in anhyd MeCN (25mL),and the mixture was heated at 70°C for 6h.When the reaction was complete (TLC),H 2O (20mL)was added and the mixture was extracted with EtOAc (3×20mL).The organic layers were combined,washed with brine (2×10mL),dried (Na 2SO 4),filtered,and concentrated under reduced pressure.Purification of the crude residue by column chromatography [silica gel,PE ：EtOAc (70:30)]gave a colorless solid 4;yield:2.7g (91%);mp 63-65°C.Synthesis ;vol.46;nb.13;(2014);p.1751-1756操作方法

二To a stirred solution of 4-(hydroxymethyl)phenol 3(1.57g,12.7mmol)and K 2CO 3(8.8g,63.55mmol)in dry acetonitrile (25mL),compound 2(3g,12.7mmol)in acetonitrile was slowly added and the reaction mixture was heated at 70°C for 6hours.After completion of the reaction (indicated by TLC),water (20mL)was added to the reaction mixture,then extracted with ethylacetate (3×20mL).The combined organic layers were washed with brine solution,dried over anhydrous Na 2SO 4,filtered,and concentrated under reduced pressure.Purification of the crude residue was done by column chromatography (silica gel,petroleum ether/EtOAc,70:30)to yield compound 4as a colorless solid (2.7g,91%);mp 63-65°C.WO2014/178083;(2014);(A1)English

(三)Safinamide （沙芬酰胺）中间体4的合成方法二①Safinamide （沙芬酰胺）中间体7的合成