合成Cefuroxime雙酯先驅藥中四級銨鹽對Δ3→Δ2 異構化反應之影響   全文下載

Study on the Δ3→Δ2 Isomerization During Preparation of Cefuroxime Double Ester Prodrugs

在合成Cefuroxime雙酯先驅藥的過程中，我們不斷觀察到產物有Δ3→Δ2 異構化之現象，此現象在文獻上亦多所記載。根據報導，此異構化反應多在鹼性條件下發生，因此如何避免反應溶液被鹼催化為合成該類化合物之必要條件。本研究考慮使用四級銨鹽作為酯化反應形成雙酯先驅藥之催化劑。為研究該類催化劑之抗衡離子（counter ion）的酸鹼性對異構化之影響，我們選取TBA+HSO4-及TBA+I-作為催化劑，觀察催化劑含量對Δ3及Δ2 產物（化合物1a及1b）比例之影響。結果顯示酸類催化劑TBA+ HSO4-確實可影響異構化程度及Δ3／Δ2產物之比例。當TBA+HSO4-／cefuroxime sodium之莫耳數比例超過0.35時，所欲之Δ3化合物1a幾為唯一之產物。而中性TBA+I-催化劑則使Δ2產物1b成為反應之主產物。

Δ3→Δ2 Isomerization during preparation of cephalosporin ester prodrugs has been frequently reported. Methods to eliminate the isomerization must be established. In the course of preparing cefuroxime double ester prodrugs, quarternary ammonium salts with different counter ions were usedas catalysts for alkylations and their effects on the isomerization were compared. The structures of Δ3 and Δ2 isomeric esters 1a and 1b were identified with 1H-1H COSY 2D NMR and DEPT 135 NMR. The degree of isomerization during alkylation was monitored with HPLC. It was demonstrated that tetrabutyl ammonium hydrogen sulfate (TBA+HSO4-) was a better catalyst than TBA+I-in regard to preventing any isomerization. The desired cefuroxime double ester la was obtained as a sole product in this reaction when the molar ratio of TBA+HSO4- to cefuroxime sodium was beyond 0.35 We have successfully eliminated the Δ3→Δ2 isomerization commonly reported for preparation of cephalosporin esters.