臺灣博碩士論文加值系統

Canagliflozin及Ipragliflozin是兩種第二型糖尿病治療藥SGLT2抑制劑，兩者皆為醣苷類化合物。本篇論文第一部分以2-氯-溴噻吩及苯並噻吩為起始物分別經由三步驟及兩步驟得到兩種噻吩結構。接著再進行c-醣基化並去除所有保護基後得醣苷形態。最後對甲氧基進行還原得到產物。在論文第二部分中，為了尋找神經再生活性更佳的神經節苷脂Hp-s1以及DSG-A而合成出不同的衍生物，本篇將Hp-s1及DSG-A的中央醣體和脂肪酸間的醣鏈結由氧更動為硫的結構獲得新的Hp-s1及DSG-A衍生物，期盼能帶來更好的神經再生活性。

Canagliflozin, Ipragliflozi and Dapagliflozin are SGLT2 inhibitors that have potential use in the treatment of type II diabetes. All of them are C−Glycoside structure. Starting with 2-clorothiophene, Benzothiophene and 2- ethoxybenzene furnishes two thiophene structures and one benzene structure. After C-glycosylation reactions afford three C−Glycoside structures, reduction a methoxy, Canagliflozin, Ipragliflozi and Dapagliflozin were obtained.
In second part of thesis, synthesis of analogues of ganglioside Hp-s1 and DSG-A is presented. In order to optimize the neuritogenic activity, we change the oxygen atom between central glucosyl moiety and phytosphingosine part with sulfur atom of ganglioside Hp-s1 and DSG-A to syntheisized new analogues 67 and 70.

謝誌…………………………………………………………………...……i
縮寫表........................................................................................................... ii
摘要............................................................................................................... v
Abstract ........................................................................................................ vi
目次............................................................................................................. vii
表目次.......................................................................................................... xi
圖目次......................................................................................................... xii
流程目次………………………………………………………………...xiii
第一部分: ...……………………………………………………………….1
合成SGLT2抑制劑Canagliflozin及Ipragliflozin………………….1
Synthesis of SGLT2 inhibitors Canagliflozin and Ipragliflozin.........1
一、 緒論................................................................................................... 2
(一) 前言.................................................................................................. 2
(二) 第二型糖尿病(Type 2 diabetes mellitus, T2DM)........................... 3 (三) 鈉-葡萄糖共同運輸蛋白(sodium-glucose co-transporter, SGLTs)4
(四) SGLT2抑制劑(SGLT2 inhibitors)及其合成歷史........................... 5
(五) C−Glycoside合成機制介紹............................................................. 6
(六) 研究動機.......................................................................................... 8
viii
二、 結果與討論...................................................................................... 9
(一) Canagliflozin 1之逆合成分析.......................................................... 9
(二) Canagliflozin 1之製備...................................................................... 9 1. 醯氯化合物8 之製備 ................................................................. 10 2. 噻吩化合物9 之製備 ................................................................. 10 3. 三甲基矽基保護葡萄糖內酯6 之製備 ..................................... 11 4. 噻吩化合物5 之製備 ................................................................. 11
5. Canagliflozin 1 之合成…………………………………………..12 (三) Ipragliflozin 2 之逆合成分析................................................ 14 (四) Ipragliflozin 2 之製備............................................................... 15 1. 羥基化合物 16 之製備............................................................... 15 2. 噻吩化合物15 之製備.............................................................. 16 3. Ipragliflozin 2 之合成.............................................................. 16
(五) Dapagliflozin 3 之逆合成分析...................................................... 18
(六) Dapagliflozin 3 之製備.................................................................. 19 1. 醯氯化合物22 之製備 ............................................................... 19 2. 甲酮類化合物21 之製備 ........................................................... 19 3. 苯類化合物20 之製備 ............................................................... 20
4. Dapagliflozin 3 之合成…………………………………….……20 三、結論................................................................................................... 22
第二部分: ………………………………………………………………..23
利用s-醣苷化反應合成出Hp-s1及DSGA的衍生物…………………23
Synthesis of Ganglioside Hp-s1 and DSGA Analogues with
ix
S-Glycosylation……………………………………………………….…23
四、緒論…………………………………………………………………24
(一) 前言................................................................................................ 24
(二) 阿茲海默症(Alzheimer’s disease, AD)......................................... 24
(三) 神經生長因子(nerve growth factor, NGF) ................................... 26
(四) 醣苷神經鞘胺脂質(glycosphingolipids, GSLs) ........................... 26
(五) 神經節苷脂Hp-s1......................................................................... 28
(六) 神經節苷脂Hp-s1衍生物合成之文獻介紹................................. 29
(七) 神經節苷脂Hp-s1之合成方法回顧............................................. 32
(八) 後續Hp-s1相關衍生物結構介紹................................................. 34
(九) 神經節苷脂DSG-A之全合成方法回顧..................................... 35
(十) 硫醣苷於藥物上之應用................................................................ 37
(十一) 硫鍵結醣苷(S-linked glycosylation)之機制介紹..................... 40
(十二) 研究目的.................................................................................... 41
五、結果與討論…………………………………………………………43
(一) 神經節苷脂Hp-s1及DSG-A衍生物67、70之逆合成分析...... 43
(二) 醣鏈結片段之製備........................................................................ 44 1. 唾液酸醣予體78之製備............................................................... 44
2. 植物神經鞘胺醇衍生物81之製備............................................... 44
3. 葡萄醣衍生物80之製備............................................................... 45
4. 唾液酸醣予體79之製備............................................................... 46
5. 脂肪酸衍生物76之製備............................................................... 46
x
(三) Hp-s1衍生物67及DSG-A衍生物70之合成................................. 47
1. 硫-醣鏈結反應製備醣脂質及保護基之選擇.............................. 47
(1) 醣脂質96之製備…………………………………….…….... 47
(2) 乙醯基保護醣脂質99之合成路徑…………………………. 48
(3) 苄保護醣受體101之合成路徑…………………..….…….... 50
2. Hp-s1衍生物67之合成................................................................... 50
3. DSG-A衍生物70之合成............................................................... 53
六、結論…………………………………………………………………56 七、實驗部分............................................................................................ 57
(一) 一般實驗敘述................................................................................ 57
(二)實驗步驟與物理數據...................................................................... 58
八、參考文獻............................................................................................. 98
九、化合物核磁共振光譜圖.................................................................. 104

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