盐酸阿齐利特合成工艺的改进

Improved synthesis of Azimilide dihydrochloride

目的改进盐酸阿齐利特的合成工艺。方法以对氯苯胺为原料合成5-对氯苯基-2-糠醛(Ⅱ);Ⅱ与1-氨基海因盐酸盐(Ⅲ)经缩合反应合成1-[5-(对氯苯基)糠叉氨基]海因(Ⅳ);在DMF中,Ⅳ与1,4-化合物二溴丁烷,再与1-甲基哌嗪反应,经盐酸乙醇成盐制得盐酸阿齐利特(Ⅰ)。结果总收率57.1%,纯度99.5%(HPLC),化合物Ⅰ的结构经1HN-MR、13CNMR、MS确证。结论该方法反应条件温和,操作简便,成本约为原工艺的50%,适合规模化生产。

OBJECTIVE To improve the synthesis method of azimilide dihydrochloride. METHODS Azimilide dihydrochloride （ Ⅰ ） was obtained by one -pot reaction of intermediate 1 - [ 5 - （p -chlorophenyl）furfurylideneamino ] hydantoin （ 1V ） with 1,4 - dibromobutane and 1 - methylpiperazine, then by salt formation. The compound IV was obtained by condensation of 1 - aminohydantoin hydrochloride （Ⅲ） with 5 - p - ehlorophenyl - 2 - furfural （ II ）, which were prepared from p - chloro - aniline by diazotization and displacement. RESULTS The total yield is 57.1% （ calculated for p - chloro - aniline）, and the purity is 99.5 % （HPLC）. The chemical structures of the intermediates and target product have been confirmed with 1HNMR, 13 CNMR, and MS. CONCLUSION The procedure developed has several advantages of convenient operation, lower cost and might be applied to scale manufacture.