文章摘要
林 辉,王正泽,王 晓.匹伐他汀钙及其中间体非对映异构体的合成[J].药学与临床研究,2022,30(2):107~110
匹伐他汀钙及其中间体非对映异构体的合成
Synthesis of Pitavastatin Calcium and its Diastereoisomeric Intermediates
投稿时间:2021-07-07  修订日期:2021-08-02
DOI:
中文关键词: 匹伐他汀钙  非对映异构体  合成
英文关键词: Pitavastatin calcium  Diastereoisomers  Synthesis
基金项目:
作者单位邮编
林 辉 南京长澳医药科技有限公司 210038
王正泽 南京长澳医药科技有限公司 
王 晓 南京长澳医药科技有限公司 
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中文摘要:
      目的:为控制匹伐他汀钙的质量,合成匹伐他汀钙及其中间体非对映异构体中的C-5位差向异构体。方法:以(3R,5S,6E)-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基庚-6-烯酸叔丁酯(2)为原料经脱缩酮、氧化、反立体选择性还原得(3R,5R,6E)-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-6-庚烯酸叔丁酯(5)。5水解成盐得(+)-双-[(3R,5R,6E)-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-6-烯庚酸]单钙盐(1)。5与2,2-二甲氧基丙烷形成缩酮得化合物(3R,5R,6E)-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基-6-庚烯酸叔丁酯(4)。结果与结论:合成了匹伐他汀钙及其中间体的C-5位差向异构体,并经核磁共振氢谱、碳谱、质谱和比旋光度等确证结构,3个目标化合物5、1和4的总收率分别为70%、68%和56%(以2计),纯度经HPLC检测均在97.5%以上,可以作为匹伐他汀钙原料药质量控制的对照品。
英文摘要:
      Objective: To control the quality, pitavastatin calcium and its C-5-epimeric intermediates were synthesized. Methods: Tert-butyl(3R, 5R, 6E)-7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3, 5-dihydroxyhept-6-enoate(5) was synthesized by de-ketal, oxidation and anti stereoselective reduction started from tert-butyl 2-((4R, 6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2, 2-dimethyl-1, 3-dioxan-4-yl)acetate(2). (+)-Monocalcium bis((3R, 5R, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxyhept-6-enoate) (1) was prepared from compound 5 via hydrolysis and salinization. Tert-butyl 2-((4R, 6R)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl)vinyl)-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate(4) was synthesized through ketalization of compound 5 with 2, 2-dimethoxypropane. Results and Conclusion: Pitavastatin calcium and its C-5-epimeric intermediates were synthesized and their chemical structures were confirmed by 1H-NMR, 13C-NMR, MS and specific rotation. The total yields of the three target compounds 5, 1 and 4 were 70%, 68% and 56%(based on 2), respectively. Their purities were over 97.5% by HPLC detection, and they can be used as reference substances in the quality control of pitavastatin calcium.
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