咪唑并[1,2-b]哒嗪的合成

Synthesis of Imidazo [1,2-b] Pyridazine

咪唑并[1,2-b]哒嗪是第四代头孢类抗生素——头孢唑兰的3位侧链。以马来酸酐为起始原料,通过肼解、卤代、氨解、成环、脱卤合成了咪唑并[1,2-b]哒嗪。采用强酸为反应介质,可使马来酰肼的收率达到96%。采取一锅法合成中间体3,6-二氯哒嗪,产品收率由两步法的74.4%提高至88%。采用微波辅助合成3-氨基-6-氯哒嗪,反应时间从17 h缩短到0.5 h。在咪唑环形成过程中,以乙醇为溶剂,采用价格低廉的氯乙醛,简化了反应后处理过程。在6-氯咪唑并[1,2-b]哒嗪脱氯过程中,使用钯碳作催化剂,在常压下通入氢气即可完成反应。各单步收率均高于80%。

Imidazo [ 1,2-b ] pyridazine is the C-3 side chain of the fourth-generation cephalosporins： cefozopran. In this paper, maleic anhydride was used as the starting material to synthesize imidazo [ 1, 2-hi pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization and dehalogenation. Strong acids were applied as the reaction medium of the first step, and the yield of maleic hydrazide could reach 96%. 3,6-Dichloro-pyridazine was synthesized by a new one-pot method which increased the yield from 74.4% to 88%. 3-Amino-6-chloro pyridazine was synthesized by microwave-assisted ammonolysis,which could shorten the reaction time from 17 h to 0.5 h. During the formation of the imidazole ring, with ethanol as the solvent, the use of low-cost chloroacetaldehyde could simplify the reaction process. In the hydrogenation of the 6-chloro-imidazo [ 1,2-b ] pyridazine, palladium carbon was used as the catalyst, and the reaction could be accomplished at atmospheric pressure. Since each single-step yield was higher than 80% , this synthetic route was considered to be practical in industry.