利用HPLC法监控反应过程优化丁苯酞合成工艺

发布时间：2018-10-04 20:03

【摘要】：目的建立简便的监控合成过程的HPLC方法,用于优化丁苯酞的合成工艺,为大规模生产和过程监控奠定基础。方法首次建立涵盖本品合成涉及的原料、各步中间体及产物的HPLC检测方法,并以该法实时监控合成过程,为优化反应条件和后处理方法奠定基础。以廉价易得的邻苯二甲酸酐为起始原料,将其与溴代正丁烷的格氏试剂反应,再以硼氢化钠还原,经酸化环合,完成丁苯酞粗品的合成,最后经减压蒸馏纯化。结果整个合成工艺只使用四氢呋喃一种有机溶剂,利于终产品的溶剂限量控制;格氏试剂与邻苯二甲酸酐摩尔比为1.2∶1.0时结果较为理想;借助建立的HPLC法监控反应过程,还对还原反应与环合反应进行了优化,采用1.0倍量的硼氢化钠、6 h内即可完成还原反应,还原之后经酸化至p H 2.0~3.0,搅拌3 h即可完全环合形成丁苯酞。本方法总收率达50~55%,纯度质量分数达到了99.0%以上。结论该合成工艺可用于工业化生产。
[Abstract]:Objective to establish a simple HPLC method for monitoring the synthesis process and to optimize the synthesis process of butylphthalide so as to lay a foundation for mass production and process monitoring. Methods for the first time, a HPLC detection method covering the raw materials, intermediates and products involved in the synthesis of the product was established, and the method was used to monitor the synthesis process in real time, which laid a foundation for optimizing reaction conditions and post-processing methods. The raw material of phthalic anhydride, which is cheap and easy to be obtained, was reacted with Grignard reagent of bromo-n-butane, then reduced by sodium borohydride, then synthesized by acidizing cyclization, and then purified by vacuum distillation. Results only one organic solvent of tetrahydrofuran was used in the whole synthesis process, which was advantageous to the limit control of the solvent of the final product. The results were ideal when the molar ratio of Grignard reagent and phthalic anhydride was 1.2: 1.0. The reaction process was monitored by the established HPLC method. The reduction reaction and cyclization reaction were optimized. The reduction reaction could be completed within 6 h by using 1.0 times amount of sodium borohydride. After reduction, the reaction was acidified to pH 2.0 ~ 3.0 and stirred for 3 h to form butadiphthalein. The total yield of the method was 50 ~ 55 and the purity was over 99.0%. Conclusion the synthetic process can be used in industrial production.
【作者单位】：沈阳药科大学制药工程学院;沈阳医学院;
【基金】：“辽宁省高等学校优秀科技人才支持计划”项目 “沈阳药科大学药物化学学科建设课题”的经费资助
【分类号】：R914.5;O657.72

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