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

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。

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.