Synthesis of the Related Substances of Rosuvastatin
LI Xia-jun1,2, CAI Zheng-yan2, PAN Jing2, HAO Qun2, ZHOU Wei-cheng2*
1. Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China; 2. Shanghai Key Laboratory of Anti-infectives, State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China
Abstract：OBJECTIVE To synthesize three related substances of rosuvastatin and establish its standard quality control system. METHODS t-Butyl-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropanyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]ethenyl]-2,2-dimethyl-1,3-dioxane-4-acetate (1a) was converted into the de-ketal compound 1b, then the latter underwent hydrolysis to get 1c. Finally, N-[4-(4-fluorophenyl)-6-isopropanyl-5-[(1E)-2-[(2S, 4R)-4-hydroxyl-6-oxo-2H-pyran-2-ethenyl]-2-pyrimidinyl]-N-methyl methane sulfonamide (impurity 1) was obtained through intramolecular dehydration. Meanwhile, (3R, 5S, 6E)-7-[4-(4-fluoropheny-1)-6-isopropanyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid (impurity 2) was prepared from compound 1b via oxidation with DDQ, reduction with tetramethylammonium triacetoxyborohydride, followed by hydrolysis. (3R, 6E)-7-[4-(4-fluorophenyl)-6-isopropanyl-2-[methyl(methylsulfonyl) amino]-5-pyrimidinyl]-3-hydroxy-5-oxo-6-heptenoic acid (impurity 3) was synthesized through oxidation of compound 1c with DDQ. RESULTS The structures of three impurities were confirmed by 1H-NMR and MS. CONCLUSION The synthesized three target compounds can be used as references for the quality control of rosuvastatin calcium.
李侠骏, 蔡正艳, 潘竞, 郝群, 周伟澄. 瑞舒伐他汀钙有关物质的合成[J]. 中国药学杂志, 2020, 55(12): 985-989.
LI Xia-jun, CAI Zheng-yan, PAN Jing, HAO Qun, ZHOU Wei-cheng. Synthesis of the Related Substances of Rosuvastatin. Chinese Pharmaceutical Journal, 2020, 55(12): 985-989.
HU J Q, ZANG H C. Research progress of rosuvastatin[J]. Food Drug(食品与药品), 2018,20(4): 87-90.
[2]
LI Y X, JIANG S. Research progress of rosuvastatin[J]. Adv Cardiovasc Dis(心血管病学进展), 2010, 31(4):585-588.
[3]
ZHOU J, ZHANG H, BIAN Z J, et al. Analysis of the current status of patent protection of rosuvastatin[J]. China Invent Pat(中国发明与专利), 2011,94(10): 50-52.
[4]
HAO J, ZHANG Z F, BI X P, et al. Analysis of research and control of impurities in API[J]. Chin J Mod Appl Pharm(中国现代应用药学), 2015, 32(6): 757-763.
[5]
The European Pharmacopoeia Commission. The European Pharmacopoeia(2017)(9th Ed) [S]. 2017: 3511-3513.
[6]
ZHANG Y R, SHI Y, LI W, et al. Synthesis of related substances of rosuvastatin calcium[J]. Chem Reag(化学试剂), 2014, 36(12):1143-1146.
2020, Vol. 55 
