抗憂鬱症藥百憂解之前驅物鹽化光學分割及分割原理探究

Abstract

本研究嘗試鹽化非鏡相光學分割方法，製備光學活性之抗憂鬱症藥物分子氟西汀，實驗設計以胺醇化合物為前驅物，進行光學分割，最終合成具光學活性的氟西汀，並鑑定分割產物分子手性為(R)-氟西汀並有81%鏡像超越值與14.57°[α]D值。透過理論計算與XRD方法，推測光學分割源自(R)-胺醇化合物與(S)-扁桃酸所形成的規律堆積結構(R, S)-95，與強氫鍵網路促使的結構穩定。同時，我們也透過理論計算驗證，(S)-胺醇化合物與(S)-扁桃酸形成的鹽類結構，較難產生規律堆積的結果(S, S)-95。鹽化非鏡相光學分割方法，可應用在手性化合物的分割，根據實驗結果，我們得到泥狀固體沉澱與固體結晶兩種鹽類固體的形式，透過類似條件，但不同的操作方法獲得，而固體結晶所得之鏡像超越值較高。We attempted to preparing high chiral purity enantiomer by applying the diastereomeric salt resolution method on the amino alcohol 78 as the precursor. We achieved the result by indentyfying fluoxetine (R)-79, besides, gaining 81% ee and +5.7° [α]D value in final. By the computational method and the result of XRD, we purposed that the resolution may probably intrigued by the proper packing way of (R)-aminoalcohol．(S)-mandelic acid salt 95 with the strong assistive hydrogen-bonding system. Furthermore, the computational (S)-aminoalcohol．(S)-mandelic acid salt 95, the unfavour energy will prevent this salt crystal being formed.The diastereomeric salt resolution method can be applied for various chiral compounds preparation. As the result, We got both the slurry solid and the crystal by same condition but operation in a little difference. According to the result, we prove that the crystal salt could provide better% ee value.