医药中间体7-ATCA的合成工艺研究

Study on the synthesis of pharmaceutical intermediate 7-ATCA

目的优化头孢母核(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA.HCl)的合成工艺。方法对三氟化硼络合物催化合成头孢母核7-ATCA.HCl的工艺进行了探索,在现有文献基础上,采用三氟化硼碳酸二甲酯络合物替代传统的三氟化硼乙腈络合物或三氟化硼乙醚络合物催化7-ACA和1-甲基-5-巯基四氮唑合成头孢母核7-ATCA.HCl。结果确定了三氟化硼碳酸二甲酯与7-ACA合适的摩尔比,产品收率>124%,含量>99%。结论该方法制备的7-ATCA.HCl收率高、质量好,易于实现工业化。

Objective To improve the manufacturing process of cephalosporin nucleus （6R,7R）-7-amino- 3-[[（1 -methyl- 1 -H-tetrazol-5-yl）thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid hydrochloride（7-ATCA.HCl ）. Methods Studies were made for the synthesis of cephalosporin nucleus 7-ATCA.HCl catalyzed by boron trifluoride complexes. Boron trifluoride acetonitrile complex or boron trifluoride ethyl ether complex, which were the traditional boron trifluoride complexes, were substituted by boron trifluoride dimethyl carbonate complex to catalyze the reaction of 7-ACA and 5-mercapto-1-methyltetrazole to prepare 7-ATCH.HCI. Results Appropriate mole proportion of boron trifluoride dimethyl carbonate complex and 7-ACA was determined, in which resulting product yield was exceeding 124% and assay was exceeding 99%. Conclusion 7-ATCA,HCl prepared by this method which was obtained with high yield and good quality. In addition this method was suitable for commercial production scales.