Novozhilov Yuri V, Dorogov Mikhail V, Blumina Maria V, Smirnov Alexey V, Krasavin Mikhail
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000 Russian Federation.
Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof, 198504 Russian Federation.
Chem Cent J. 2015 Feb 13;9:7. doi: 10.1186/s13065-015-0082-7. eCollection 2015.
If literature protocols are followed, conversion of an advanced ketal ester intermediate (available in kilogram quantities via a published Paal-Knorr synthesis) to cholesterol-lowering drug atorvastatin calcium is hampered by several process issues, particularly at the final stage where the hemi-calcium salt is obtained.
We developed a high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities by introducing the following key improvements: i. isolating the pure product of the ketal deprotection step as crystalline solid, and ii. using a convenient ethyl acetate extraction procedure to isolate the pure atorvastatin calcium at the ester hydrolysis and counter-ion exchange step.
The convenient and operationally simple conversion of an advanced intermediate of atorvastatin to the clinically used hemi-calcium salt form of the drug that is superior to the methods obtainable from the literature is now available to facilitate the production of atorvastatin calcium on industrial scale. Graphical abstractStepwise ketal and tert-butyl ester group hydrolysis and a modified work-up protocol lead to a more convenient preparation of API-grade atorvastatin calcium.
如果遵循文献中的方法，将一种高级缩酮酯中间体（可通过已发表的帕尔-克诺尔合成法以千克量获得）转化为降胆固醇药物阿托伐他汀钙会受到几个工艺问题的阻碍，特别是在获得半钙盐的最后阶段。
我们开发了一种7千克规模的阿托伐他汀钙盐高产合成方法，通过引入以下关键改进措施，产品纯度达到>99.5%：i. 将缩酮脱保护步骤的纯产物分离为结晶固体，ii. 在酯水解和反离子交换步骤中使用简便的乙酸乙酯萃取程序分离纯阿托伐他汀钙。
现在已有一种简便且操作简单的方法，可将阿托伐他汀的高级中间体转化为临床上使用的半钙盐形式的药物，该方法优于文献中可得的方法，有助于在工业规模上生产阿托伐他汀钙。图形摘要逐步进行缩酮和叔丁酯基团水解以及改进的后处理方案可更方便地制备原料药级阿托伐他汀钙。
