第一部分 : Miglustat的製程研究 第二部分 : (+)-Alpha-Dihydrotetrabenazine 之不對稱全合成

Abstract

第一部分： 高雪氏症是一種無法正常提供 glucocerebrosidase而引起醣酯類儲積症的體染色體隱性遺傳疾病。目前 Zavesca® (miglustat) 已經被美國以及歐盟核准用來治療第一型高雪氏症疾病，它是以抑制醣脂合成酶來治療高雪氏症的藥物。然而此藥不易取得，且一名病人的藥品費一年約需四百萬台幣。因此我們探討以較經濟的成本合成原料藥 miglustat 的可行性。在此我們成功的利用1,2-O-isopropylidene-alpha-D-glucofuranose 為起始物經由氧化、水解以及環化等三步反應合成出原料藥 miglustat (總產率為 40%), 同時我們也利用高效能液相層析儀搭配蒸發式光散射偵檢器建立 miglustat 的定量分析方法。我們相信此製程是具有量產 miglustat 的潛力。

第二部分： Tetrabenazine (TBZ) 為一種FDA核准用於治療杭亭頓病之舞蹈症的藥物，此外 (+)-TBZ和 (+)-alpha-DTBZ 是具有高度潛力應用在正子斷層掃描之分子影像試劑。本研究主要探討以不對稱合成製備單一鏡像的 (+)-TBZ。我們使用了丙二酸二甲酯為起始物，經由烷化、還原、選擇性的保護和氧化反應成醛類化合物後，與利用異喹啉衍生物所製備出的 Grignard 試劑進行親核性加成反應。由於加成反應所得到之化合物穩定度不佳，我們探討了一些解決辦法後，模擬出兩個較佳的合成路徑，最後都成功的經由分子內環化得到消旋之 TBZ，且此分子內環化具有良好 diastereomeric selectivity。接著使用 Noyori 催化劑進行不對稱之還原反應，第一種路徑可以成功合成出具有光學活性之 (+)-TBZ。但是另外一種路徑所合成出的中間體因為有較強的共振系統和立體障礙的關係，無法使用此催化劑進行不對稱之還原。同時也利用 chiral-HPLC 偵測反應過程所產生的中間體之光學活性，發現只有在環化的過程中會有消旋現象的產生。本研究成功的開闢以不對稱全合成製備單一鏡像的 (+)-TBZ之方法，未來我們期望進一步的改良此路徑使得可合成出具有更高光學活性之 (+)-TBZ。

Part I: Gaucher’s disease is an autosomal recessive genetic disorde and is caused by abnormal glucocerebrosidase in the patient. Miglustst is a potent glycolipid synthase inhibitor and has been approved in US and EU for the treatment of Type I Gaucher’s disease. However, this drug is not easy to obtain and the expense of the drug cost each patient 4 million NT dollars per year. Therefore, the potentiality of synthesis of the miglustat by economic cost is awaited. In this research, we have succeed in using 1,2-O-isopropylidene-alpha-D-glucofuranose as the start material to synthesize miglustat in three steps such as oxidation, hydrolysis and cyclization (40% overall yield). we also have used high-performance liquid chromatography with evaporative light-scattering detector to establish the quantitative analysis of miglustat. We believed that this process has the potential for the scale up production of miglustat. Part II: TBZ is approved by FDA for the treatment of chorea associated with Huntington’s disease. In addition, positron-emitter labeled (+)-TBZ and (+)-alpha-DTBZ as potent PET imaging agents. This research is to explore the asymmetric total synthesis of (+)-TBZ. First, we used dimethyl malonate as the start material to do alkylation, reduction, selective protection and oxidation to afford the aldehyde compound. Then we used the aldehyde compound to do nucleophilic addition reaction with the Grignard reagent which is prepared by isoquinoline derivative. Unfortunately, the addition compound was not stable. We explored two better methods to solve this problem. Finally, these two methods were succeeded in affording racemate TBZ through intramolecular cyclization and this intramolecular cyclization had good diastereomeric selectivity. Then to use Noyori catalyst to do asymmetric reductive reaction. The results showed that the first of the study can succeed in synthesis of the (+)-TBZ containing optical activity (48% and 62% e.e). The another study cannot do asymmetric reduction by using this catalyst because the intermediate from this study had a stronger resonance system and the relationship of the steric effect. Moreover, to use the chiral-HPLC to detect the optical activity of intermediate in the previous study. The phenomenon of racemization was only detected in cyclization process. To sum up, in this research was succeed developing the method of asymmetric total synthesis of (+)-TBZ. In the future, we will expect to further improve this study to afford the high optical activity of (+)-TBZ.