Study on the ∆^3→∆^2 Isomerization during Preparation of Cefuroxime Double Ester Prodrugs

合成Cefuroxime雙酯先驅藥中四級銨鹽對△^3→△^2異構化反應之影響

王惠珀(Hui-Po Wang) ； 李嘉帥(Jia-Shuai Lee)

《藥物食品分析》 1卷2期 (1993/05) Pp. 145-153

摘要

在合成cefuroxime雙酯先驅藥的過程中，我們不斷觀察到產物有∆^3→∆^2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(上標 +)HSO4(上標 -)及TBA(上標 +)I(上標 -)作為催化劑，觀察催化劑含量對△^3及△^2產物(化合物1a及1b)比例之影響。結果顯示酸類催化劑TBA(上標 +)HSO4(上標 -)確實可影響異構化程度及△^3/△^2產物之比例。當TBA(上標 +)HSO4(上標 -)／cefuroxime sodium之莫耳數比例超過0.35時，所欲之△^3化合物1a幾為唯一之產物。而中性TBA(上標 +)I(上標 -)催化劑則使△2產物1b成為反應之主產物。

並列摘要

∆^3→∆^2 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 ∆^3 and∆^2 isomeric esters la and lb were identified with1H-1H COSY 2D NMR and DEPT 135 NMR. The degree of isomerization during alkylation was monitored with HPLC. It was demonstrated that tetrabuty1 ammonium hydrogen sulfate (TBA(superscript +) HSO4(superscript -))was a better catalyst than TBA(superscript +) I(superscript -) in regard to preventing any isomerization. The desired cefuroxime double ester 1a was obtained as a sole product in this reaction when the molar ratio of TBA(superscript +) HSO4(superscript -) to cefuroxime sodium was beyond 0.35 We have successfully eliminated the ∆^3→∆^2 isomerization commonly reported for preparation of cephalosporin esters.

並列關鍵字

∆^3→∆^2 isomerization ； Cefuroxime prodrug ； Quarternary ammonium salts