新药Difamilast（地法米司特）合成检索总结报告
一、Difamilast（地法米司特）简介
Difamilast（地法米司特）适应于治疗中至重度特异反应性皮炎。2020年3月26日宣布在两项针对成人和儿科患者的新型非甾体磷酸二酯酶IV（PDE4）MM36治疗轻度至中度特应性皮炎局部的两项日本3期临床试验中取得了积极成果。产假可以提前多久休
Difamilast（地法米司特）分子结构式如下:
CAS：937782-05-3现代诗简短
南轩松
英文名称：Difamilast使命召唤9汉化补丁
中文名称：地法米司特
本文主要对Difamilast（地法米司特）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、Difamilast（地法米司特）合成路线
三、Difamilast （地法米司特）合成检索总结报告(一)Difamilast （地法米司特）中间体2
的合成
合成方法
实验步骤性能英语
参考文献操作方法一
In a
50ml flask 3-(cyclopropylmethoxy)-4-(difluorometh-oxy)-benzonitrile 1(0.5g,2.7mmol),was dissolved in MeOH (3ml),and the homogeneous solution was stirred at room temperature.91%Aqueous H 2SO 4(1ml)was slowly added drop wi and the solution was warmed at 50°C.for a week.The solution was cooled to 0to 5°C.,and water (10ml)was added,and the obtained suspension was stirred at low temperature for 1hour.The suspension was filtered on a gooch funnel.The product was obtained as a white solid (yield 78%).
US2015/111931;(2015);(A1)English;WO2015/59050;(2015);(A1)English
(二)Difamilast （地法米司特）中间体3的合成
合成方法
实验步骤
参考文献
操作方法一
To 60mL
of N,N-dimethylformamide were added methyl 4-(difluoromethoxy)-3-hydroxybenzoate 2(5.0g,22.94mmol),potassium carbonate (6.33g,45.88mmol)and benzyl bromide (3.3mL,27.53mmol).
The whole mixture was stirred at 60o C for 4.5hours.To the reaction mixture was added water (40mL)and the resulting mixture was extracted with ethyl acetate (50mL ×3).The combined organic layers were dried over anhydrous sodium sulfate,and the solvent was removed.The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)5/1)to give a white solid 3(6.99g).
WO2015/161830;(2015);(A1)English;WO2016/34134;(2016);(A1)English.
(三)Difamilast （地法米司特）中间体4的合成温馨小屋
合成方法
实验步骤
参考文献操作方法一
To a mixed
solvent of ethanol (60mL)and water (30mL)were added methyl 3-(benzyloxy)-4-(difluoromethoxy)
benzoate 3(6.99g,22.69mmol)and sodium hydroxide (2.27g,56.74mmol).The mixture was stirred at 60o C for 1.5hours,then ethanol was removed.To the residue was added hydrochloric acid (1M)to adjust the pH to 1.The mixture was extracted with ethyl acetate (50mL ×3).The organic layers were combined,dried over anhydrous sodium sulfate,and the solvent was removed to give a white solid 4(6.70g).
WO2015/161830;(2015);(A1)English;WO2016/34134;(2016);(A1)English
(四)Difamilast （地法米司特）中间体5的合成
合成方法
实验步骤
参考文献
操作方法一
A 2g quantity of 3-benzyloxy-4-difluoromethoxybenzoic acid 4was suspended in 40ml of dichloromethane,and one drop of dimethylformamide was added.A 0.7ml quantity of oxalyl chloride
was added dropwi with ice-cooling and stirring.After 2hours,the reaction mixture was concentrated under reduced pressure.The residue was dissolved in 5ml of acetone and the resulting solution was added dropwi to 28%aqueous ammonia with ice-cooling and stirring.The obtained mixture was stirred for 1hour and the precipitated crystals were collected by filtration and dried under reduced pressure to give 1.9g of white powdery
3-benzyloxy-4-difluoromethoxybenzamide 5.红星照耀中国读后感
WO2007/58338;(2007);(A2)English
(五)Difamilast （地法米司特）中间体7的合成
合成方法
实验步骤
参考文献
操作方法一
归口管理部门
A 1.8g quantity of 3-benzyloxy-4-difluoromethoxy-benzamide 5was suspended in 50ml of isopropanol,and 1.17g of 1,3-dichloro-2-propanone 6was added.The mixture was heated and refluxed overnight.The reaction mixture was concentrated,and the resulting residue was purified by silica gel column chromatography
WO2007/58338;(2007);(A2)English
