苯甲酰胺类磷酸二酯酶(Ⅵ)型抑制剂合成工艺优化

Synthesis of Benzoyl Analagues as Phosphodiesterase IV Inhibitors

以N,N-二甲基甲酰胺为溶剂、K2CO3作为催化剂的,3,4-二羟基苯甲醛与氯二氟乙酸甲酯在70℃反应4小时,得到4-二氟甲氧基-3-羟基苯甲醛,产率为64.06%;以二氯甲烷为溶剂,投料摩尔比(DABD∶Ph3P)=1∶1.2,0℃投料后,室温反应2小时,4-二氟甲氧基-3-羟基苯甲醛和3-羟基四氢呋喃醚化合成4-(二氟甲氧基)-3(四氢呋喃-3-基氧基)苯甲醛,产率为86.25%;4-(二氟甲氧基)-3(四氢呋喃-3-基氧基)苯甲醛用高锰酸钾在丙酮和H2O中反应8小时氧化为4-(二氟甲氧基)-3-(四氢呋喃-3-基氧基)苯甲酸,并且收率为89.64%;用二氯亚砜将酸酰氯化后,不经分离在室温下与相应的胺在四氢呋喃中反应0.5小时生成4-(二氟甲氧基)-N-正丁基-3-(四氢呋喃-3-基氧基)苯甲酰胺类磷酸二酯酶(Ⅵ)的抑制剂。实验过程中通过HPLC,1H NMR等进行定性、定量分析和表征。

3,4-Dihydroxybenzaldehyde reacted with methyl chlorodifluoroacetate at 70℃for 4 h in N,N-Dimethylformamidet and K2 CO3 to abtain 4-difluoromethoxy-3-hydroxybenzaldehyde with a productivity of 64.06%.4-difluoromethoxy-3-hydroxybenzaldehyde was etherified to 4-(difluoromethoxy)-3(tetrahydrofuran-3-yloxy)benzaldehyde in dichloromethane at room temperature for 2 h with the yiled of 86.25%under the following condition:molar retio(DABD∶Ph3 P)=1∶1.2,0℃feeding.4-(difluoromethoxy)-3(tetrahydrofuran-3-yloxy)benzaldehyde was then oxidized to 4-(difluoromethoxy)-3-(tetrahydrofuran-3-yloxy)benzoic acid with potassium permanganate in acetone and H2 O at room temperature for 8 h and the yield was 89.64%.The acid was chlorized with thionyl chloride.Without further procession,4-(difluoromethoxy)-3-(tetrahydrofuran-3-methoxyl)benzoyl chloride reacted with various amine in tetrahydrofuran at room temperature for 0.5 h to give the target compound with a yield about 39.2%~49.0%.Qualitatively and quantitatively analysis was processed by HPLC and1 H NMR.