氨噻肟酸结晶过程优化及工艺设计.docxVIP

PAGE 36 氨噻肟酸结晶过程优化及工艺设计 摘要：在头孢菌素这一大浪潮的推动之下，我国药物中间体的产量较前大幅增加，由此在颇多药物中间体供应国之中独占鳌头，成为世界第一。当下生产需求量最大的四种抗生素侧链中间体分别为三嗪环、D-对羟基苯甘氨酸及其邓钾盐以及氨噻肟酸。作为多种后代头孢菌素的侧链中间体，氨噻肟酸通常由乙酰乙酸乙酯经过10个步骤才可最终得到能够直接合成头孢药物或者AE-活性酯的无水氨噻肟酸，分别为肟化-醚化-溴化-蒸馏-环合-水解-结晶生成含水氨噻肟酸-脱水-过滤-干燥。生产质量管理规范明确指出，药物中间体的质量直接决定成品质量，所以其质量需进一步提高以达到更高要求。尽管我国氨噻肟酸的产量大幅增加，但成品质量及技术工艺上存在的问题依旧令人担忧。所以，以理论为基础，通过实验的方法研究氨噻肟酸制备过程中的重要技术以努力实现减少成本并保障质量的双赢局面。尽管氨噻肟酸的合成技术已得到充分完善的研究，但其脱水重结晶及反应结晶技术尚未得到足够的研究和报道。但不可否认的是，结晶技术的好坏对成品的收率和质量起决定作用，因此它在整个生产过程中的作用可见一斑。 关键词：氨噻肟酸；医药中间体；AE-活性酯；抗生素 Optimization of crystallization process and process design of aminothiaxamic acid Abstract: Driven by the big wave of cephalosporin, the production of drug intermediates in China has increased significantly compared with the previous one, so it has become the first in the world among the suppliers of many drug intermediates. Currently, the intermediates of the side chains of the four antibiotics with the greatest demand are triazine ring, d-p-hydroxyphenylglycine and its potassium salt, and aminothiamic acid. As a variety of side chain of cephalosporin intermediates, ammonia thiamethoxam oxime acid are usually made of ethyl acetoacetate after 10 steps to finally be able to direct synthesis of cephalosporin drugs or AE - active ester anhydrous ammonia thiamethoxam oxime acid, respectively oximation - etherification - bromide - distillation - cyclization - hydrolysis - crystallization generated aqueous ammonia thiamethoxam oxime acid - dehydration - filter - dry. The production quality management specification clearly states that the quality of drug intermediates directly determines the quality of finished products, so its quality needs to be further improved to meet higher requirements. Although the production of aminothiamic acid in China has increased greatly, the quality of finished products and the problems in technology are still worrying. Therefore, on the basis of theory, the important technology in the preparation of aminothiamic acid was studied by experi