【作者】 董冬吟；

【导师】 杨琍苹；

【作者基本信息】 华东师范大学 ， 有机化学， 2009， 硕士

【摘要】 本论文的内容分为两个部分:阿伐他汀钙侧链中间体的合成研究和β-氨基酸衍生物的高效液相色谱手性拆分。阿伐他汀钙是新一代羟甲戊二酞辅酶A（HMG一CoA）还原酶抑制剂（他汀类降血脂药）。它既能降低胆固醇,又能降低甘油二醋,作用远比其他他汀类药物强。其疗效显著、副作用少,在降血脂药物市场中占据了主导地位,发展速度也在他汀类药物的前列。他汀类药物的合成一般通过会聚式方法,即先单独合成母体环和具有手性双羟基的己酸酯,然后再缩合得到最终产物。关于侧链的合成,文献报道很多。我们研究（2R,4S）-4-氯甲基-6-碘甲基-2,2-二甲基-[1,3]-二氧六环的合成,由其可以方便的进一步转化成制备他汀类药物所需的中间体,经过对已有合成路线的研究,我们提出了一条创新路线:以廉价的（R）-环氧氯丙烷为起始原料,经乙烯基格氏试剂进攻环氧开环、（Boc）₂O保护后进行碘内酯化反应、再经过丙酮叉保护得目标产物。该方法经由手性源诱导产生另一个手性中心,相比其他方法,避免了重金属的污染而且可以很好地保持第一个手性中心的手性。另一部分是利用高效液相色谱手性拆分β-氨基酸衍生物。在过去二十多年里,利用高效液相色谱进行对映体光学拆分已取得了巨大的进展,成为测定光学纯度和获得光学纯药物的确实可行的方法。本论文利用直链淀粉三苯基酯类手性固定相先对4组β-氨基衍生物进行手性拆分条件的摸索,主要讨论流动相种类、酸碱改性剂和流速对保留和拆分的影响,最终得到的较优的手性拆分条件。利用该手性拆分条件可以在较短时间内,方便地检测出多种β-氨基酸衍生物。更多还原

【Abstract】 The paper was focused on the synthesis of key intermediate for atorvastatin calcium and chiral separation ofβ-amino-α-hydroxy acid derivatives by HPLC.Atorvastatin calcium is a new type of hypolipidemic drugs-statin drugs,which has extreme efficacy with little side-effect,and won a dominant position in the hypolipidemic drugs market,meanwhile has the highest growth rate leapt to the forefront in the entire cardiovascular drugs market.Generally,statin drugs are synthesized by the clustering approaches,that is, firstly the main skeleton and hexanoate with double chiral hydroxy group are synthesized separately,and then gain the final product.by condensation reaction. There are various approaches to synthesize the crucial intermediates.Therein,we take times on the synthesis of 4-chloromethyl-6-iodomethyl-2,2-dimethyl-[1,3]dioxane,by which other statins intermediates can prepare.By doing research on the literature reports,we are groping for a innovational route:use the low-cost(R)-epichlorohydrin as the starting material and gain the product by epoxy ring-opening,iodolactonization and hydroxyl protection.Compared with other ways,this method avoids the pollution of heavy metals and can be very good to maintain the first chiral center.Another part is the separation ofβ-amino acid derivatives enantiomers by high-performance of chromatography(HPLC) using chiral chroamtafraphy. Particularly in the past 20 years,optical resolution by HPLC has progressed rapidly, and has become a practical and useful method fordetermining optical purity.In this paper,we use the chiral IA column to explore the optimal conditions.The influence of the alcohol in mobile phase,pH modifier and flow of the mobile phase was studied. The ultimate condition can be used to separate variesβ-amino acid derivatives in relatively short period.更多还原