目的 为保证瑞舒伐他汀钙质量,建立了一个标准质量控制体系,合成了3个有关物质。方法 以6-[(1E)-2-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰)氨基]-5-嘧啶]乙烯基]-2, 2-二甲基-1,3-二氧六环-4-乙酸叔丁酯(1a)为起始原料,经脱缩酮得1b、水解叔丁酯得1c、分子内脱水合成(2S, 4R)-N-[4-(4-氟苯基)-5-[2-(4-羟基-6-氧代四氢吡喃-2-基)乙烯基]-6-异丙基嘧啶-2-基]-N-甲基甲磺酰胺(杂质1),1b经DDQ氧化5位羟基再用四甲基三乙酰氧基硼氢化铵还原、接着水解叔丁酯、最后制备钙盐得(3R, 5R, 6E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基]-3,5-二羟基-6-庚烯酸(杂质2),1c经DDQ氧化5位羟基得(3R, 6E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]-5-嘧啶基]-3-羟基-5-氧代-6-庚烯酸(杂质3)。结果 3个杂质的结构经过核磁共振氢谱和质谱确证。结论 本实验所得3个目标化合物可以作为瑞舒伐他汀钙质量研究的有关物质对照品。

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.