咪喹莫特合成工艺的改进

Improvement of Synthesis Procedure of Imiquimod

以2,4-二羟基喹啉为起始原料经过硝化、氯代、胺解、硝基还原、环化、苄胺化和脱苄基等七步反应合成了目标产物咪喹莫特.通过7次循环使用硝化反应的母液使2,4-二羟基-3-硝基喹啉(Ⅱ)的平均收率达99%;在95%的乙醇中使用铁粉和盐酸还原4-(2-甲基丙胺基)-2-氯-3-硝基喹啉(Ⅳ),反应完成后添加适量的无水碳酸钾使铁的氧化物容易经过滤与产物分离,得到76%收率的4-(2-甲基丙胺基)-3-氨基-2-氯喹啉(Ⅴ).通过对各个反应条件的改进,硝化、胺解、硝基还原、环化、苄胺化反应的中间产物可不经重结晶直接用于下一步反应,简化了合成工艺,使七步反应总收率超过45%.

Imiquimod was synthesized from raw material 2,4-dihydroxyquinoline via 7 reaction steps including nitration, chlorination, amination, reduction of nitro group, cyclization, benzylamination and debenzylation. The average yield of 2,4-dihydroxy-3-nintroquinoline （Ⅱ） reached 99% by reusing the mother liquid of nitration for 7 times. 4- （ 2-methylpropylamino ） -2-chloro-3-nitroquinoline （Ⅳ） was reduced to 4- （ 2-methylpropylamino ） -3-amino-2-chloroquinoline （Ⅴ） by iron powder and hydrochloric acid in 95% ethanol, anhydrous K2CO3 with proper quantity was added to the reaction mixture to make the byproduct ferric oxide easy to filtrate off from the solution of Ⅴ, the yield of Ⅴ was 76%. With the improved synthesis procedure, the intermediates obtained from the nitration, the amination, the reduction of nitro group, the cyclization and the benzylamination were pure enough to be directly used in the next reaction without further purification, thus simplifying the synthesis procedure with an overall imiquimod yield of more than 45 %.