咪唑并[1,2-b]哒嗪的合成

Study On Synthesis Of Imidazo [1,2-b] pyridazine

摘要:

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。本文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，产品收率由二步法的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小时缩短到0.5小时之内。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, 使用钯炭作催化剂, 在常压下通入氢气即可完成反应。由于各单步收率均高于80%，具有相当的工业实用价值。

Abstract:

Imidazo [1,2-b] pyridazine is the C-3 side chain of the fourth-generation cephalosporins: Cefozopran. This paper used maleic anhydride as the starting material, synthesized imidazo [1, 2-b] pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization and dehalogenation. Strong acids were applied as the reaction medium of the first step, the yield of maleic hydrazide can be reached up to 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 hours to 0.5 hours. 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, 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.