中文摘要
2-(3,4-雙氯苯基)-氮-甲基-氮-[2-(1-咯啶基)-1-苯基-乙基]-乙醯(ICI199,441)對Kappa阿片受器有很強的親合力及選擇性。本研究主要目的是合成ICI199,441的類似物(R)-5-{1-[(3,4-雙氯苯基)-氮-甲基乙醯基]-2-(1-咯啶基)乙基}-二氫-3-亞甲基-2(3H)-喃酮 (1), 將其苯基取代改成-亞甲基-γ-丁內酯的嗜電子基, 期望此化合物對Kappa阿片受器有好的親和力及選擇性, 並可藉與受器上之嗜核基形成共價鍵而產生不可逆的結合。
首先以 (R)-(+)-glycidol (3) 為起始物來合成目標化合物1, 將化合物3 之基保護後行開環反應, 得到(S)-2-基-4-(氮-苯甲基-氮甲基基)三級丁基二甲基矽醚 (5), 之後將化合物5的基轉換成離去基, 再與咯啶進行置換, 並以氫化條件切除苯甲基, 得到含有氮甲基基與咯啶基的雙基化合物8。化合物8 與3,4-雙氯苯基乙酸反應成, 接著去基保護後得到中間體(R)-氮-[1-基-3(1-咯啶基)丙-2-基]-氮-甲基-3,4-二氯苯基乙醯(10); 但以各種反應條件皆無法將化合物10的基氧化成醛基以得到化合物11,乃放棄此合成路徑。
接著嘗試合成相對應的甲基酯2, 再將之還原以得到化合物11。當以N-Boc-D-serine methyl ester為起始物, 將基以TBDMS保護後, 欲進行氮上甲基化反應, 卻遭遇到β-elimination的問題; 改 以D-serine 為起始物, 經Boc及苯甲基保護後, 進行氮上甲基化反應順利得到化合物15。化合物15在濃硫酸和甲醇作用下得到去Boc保護的甲基酯化合物16, 化合物16與3,4-雙氯苯基乙酸形成, 以氫化去苯甲基後導入咯啶基得到甲基酯化合物2。但對化合物2進行還原反應亦無法得到醛類化合物11,推測是因為醛類化合物11的不穩定性造成的。
接著嘗試將化合物2轉化為甲基酮化合物2a, 期望經Reformatsky反應得到另一目標化合物1a亦即化合物1的甲基衍生物, 但實驗結果只得到微量的化合物2a, 推測是因為化合物2的其他部份反應性高, 造成實驗中分解。
最後我們由經Boc和TBDMS保護的D-serine (26)成功的合成其甲基酮衍生物27, 並順利進行Reformatsky反應得到具有 -亞甲基-γ-丁內酯基團的化合物28, 目前正以化合物27為中間體, 在導入3,4-雙氯苯基乙醯基及咯啶基部份後, 將以Reformatsky反應來完成目標化合物1a的合成。

英文摘要
2-(3,4-dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-phenyl-ethyl]-acetamide (ICI199,441) was among a recently reported series of potent  selective opioids. The objective of this study is the synthesis of (R)-5-{1-[(3,4-dichlorophenyl)-N-methylacetamido]-2-(1-pyrrolidinyl)-ethyl}-dihydro-3-methylene-2(3H)-furanone(1) as an irreversible  opioid ligand. Compound 1 differs from ICI199,441 in that the phenyl ring is replaced by an -methylene-γ-butyrolactone moiety. Compound 1 is expected to retain the high affinity and selectivity towards the  opioid receptor, which the -methylene-γ-butyrolactone moiety may form a covalent bond with the receptor.
The synthetic route starting from (R)-(+)-glycidol (3) was first attempted. Compound 3 was first converted to its silyl ether 4, which underwent epoxide opening with N-benzylmethylamine to give 5. Compound 5 was subjected to mesylate formation, followed by displacement with pyrrolidine to give diamine 7. Compound 7 then underwent debenzylation via hydrogenolysis, amide formation with 3,4-dichlorophenyl acetic acid, and desilylation to give (R)-N-[1-hydroxy-3-(1-pyrrolidinyl)prop-2-yl]-N-methyl-3,4-dichlorophenylacetamide(10). However, under a variety of oxidation conditions, compound 10 failed to give the desired aldehyde intermediate 11.
We then tried to obtain 11 via reduction of the corresponding ester 2. Thus, N-(t-Boc)-D-serine methyl ester was first protected by treatment with TBDMSCl to give compound 20, which underwent the undesirable - elimination during attempts of N-methylation. With the free acid N-Boc-O-benzyl-D-serine (14), the N-methylation was successfully executed to give compound 15. Compound 15 was then successfully converted to ester 2. However, the reduction of 2 with DIBAL-H has failed to give cleanly the corresponding aldehyde 11, probably due to its instability.
With a shift of our target compound from 1 to its methyl analog 1a, ester 2 was converted to the less-reactive methyl ketone 2a, albeit in very low yields. Finally, the less reactive intermediate N-Boc-O-TBDMS-D-serine (26) was converted to the corresponding methyl ketone 27 in satisfactory yields. Compound 27 was also subjected to Reformatsky reaction with ethyl -(bromomethyl)acrylate to give -methylene-γ-butyrolactone derivative 28. In progress is the attemp to convert intermediate 27 to target compound 1a.

中文摘要 1
英文摘要 3
一、背景 5
阿片受器的種類與作用 5
具選擇性及不可回復性的阿片受器結合劑 7
二、動機與目的 12
三、化學合成與討論 13
四、結論 30
五、實驗部分 31
溶劑與藥品來源 31
一般儀器與方法 32
合成步驟 33
六、參考文獻 49
附圖 53

六、參考文獻
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