文档介绍：硕士学位论文 II 摘要地尔硫卓是一种治疗心绞痛、高血压等疾病的苯并硫氮卓类钙拮抗剂,分子结构中含有两个手性中心,只有( 2S, 3S )-构型能有效扩张冠状动脉,临床仅用此单一异构体。相对于拆分外消旋体的传统合成法,不对称催化合成法由于使用少量手性催化剂即能高产率地获得手性产品而受到广泛关注。本文通过两种不对称催化法即不对称二羟化与不对称环氧化分别合成了两种不同的地尔硫卓手性中间体。 用改进的方法合成了金鸡纳生物碱衍生物配体 1,4-双(9- O-奎宁)-2,3-二氮杂萘 [(QN) 2 PHAL] :使用氢氧化钾做缚酸剂, 于甲苯中反应,有效缩短了反应时间,粗产物通过乙酸乙酯重结晶即可提纯,简化了后处理,产率达 81% , 明显降低了合成成本; 同样, 此方法也可扩大至其它几种双生物碱配体的合成上, 都取得了较为理想的效果。采用(QN) 2PHAL 与四氧化锇原位配合,在 K 3 ) 6 -K 2 CO 3 /H 2O-‘BuOH 体系中催化反式对甲氧基肉桂酸乙酯的不对称二羟化反应,制备手性邻二醇( 2R,3S )-2,3-二羟基-3-(4-甲氧基苯基)丙酸乙酯,产率达 87% , ee 值大于 99% ,手性邻二醇再与氯化亚砜转化为地尔硫卓手性中间体( 4S,5R) -4-(4-甲氧基苯基)-5-乙氧羰基-1,3-二氧杂-2-氧化硫杂环戊烷。参考有关文献,以果糖为起始原料, 通过缩合、氧化两步得到手性酮 1,2:4,5- 二- O - 异亚丙基-3- 酮- 吡喃型果糖,后者与过氧硫酸氢钾( oxone )作用原位生成手性二氧杂环丙烷,氧化反式对甲氧基肉桂酸乙酯的不对称环氧化反应,得到另一种地尔硫卓手性中间体( 2R,3S ) -3-(4- 甲氧基苯基) -2,3- 环氧丙酸乙酯,产率 48% , 82% ee ,并考察了相转移催化剂、 pH 值、温度及氧化剂等一系列因素的影响, 该手性酮在反式对甲氧基肉桂酸乙酯的不对称环氧化反应中表现出了较高的立体选择性,加之原料价廉易得,反应条件温和,且避免了引入有毒的金属元素,具有一定的应用前景。关键词: 地尔硫卓;不对称二羟化;不对称环氧化;金鸡纳生物碱;手性配体; 手性酮 地尔硫卓手性中间体的合成 III Abstract Diltiazem is one of the most potent calcium antagonists and used as a remedy for angina and hypertension. Diltiazem has two asymmetric carbons in its chemical struture, among the four possi ble stereoisomers, only the ( 2S, 3S )-isomer exhibits potent coronary vasodilating activity. Diltiazem has been de veloped and marketed as a single isomer. Compared to resolution methods, asymme tric synthesis with high catalytic activity and excellent enantioselectiv ity have been noticed in recent years. In this thesis, two different kinds of ke y chiral intermediates for diltiazem were obtained by asymmetric dihydroxylation and asy mmetric epoxidation. The synthesis method of 1,4-bis(9- O-quininyl)- phthalazine[(QN) 2PHAL] was improved by using KOH as acid-binding agen t in refluxing toluene in 81% yield. The crude product was purified by recrystalli zation from ethyl acetate. The reaction time and cost were reduced and the e xperimental operation was simplified. This method was used to synthesize other cincho na alkaloi