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題 名 | Methods in the Preparation of D-Phenylglycine-Containing Cefotaxime Double Esters=含D-Phenylglycine之Cefotaxime雙酯先驅藥的合成研究 |
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作 者 | 宋啟華; 王惠珀; | 書刊名 | 藥物食品分析 |
卷 期 | 6:2 1998.06[民87.06] |
頁 次 | 頁477-484 |
分類號 | 418.41 |
關鍵詞 | Cefotaxime雙酯先驅藥; 合成; 安定性; Cefotaxime prodrugs; Tetrabutylammonium hydrogen sulfate; D-phenylglycine; |
語 文 | 英文(English) |
中文摘要 | 本研究以研發cefotaxime的口服先驅藥為目標。我們將cefotaxime第四位置之羧基 與Dphenylglycine之羧基以亞乙基作為橋鍵形成雙酯先驅藥1a及1b,期使該先驅藥透過D- phenylglycine與腸膜上雙胜 載體輸遞系統的親和力而穿透腸壁吸收。合成先驅藥1a及1b 的方法係將1-iodoethy12-N(Boc)-phenylglycine(3a及3b)與cefotaxime soduim縮合形成中 間體4a及4b,再去除Boc保護基形成目標產物 1a及1b。縮合反應中出現cepham環Δ → Δ 異構化反應,產生Δ 異構物5a及5b。我們使用具有酸性抗衡離子之四級胺鹽 tetrabutylammonium hydrogen sulfate作為縮合反應催化劑,可成功防止異構化現象之發生。 先驅藥1a及1b在pH2.09及pH5.47之磷酸緩衝溶液中安定性甚佳,然而在pH7.39緩衝溶 液中則快速分解,其中1a之半衰期為8分鐘,1b為13分鐘。這二個先驅藥在離體老鼠小 腸黏膜培養液中的安定性亦不理想,其半衰期分別為11分鐘及1分鐘。分解速率過速,致 化合物1a及1b無法成為理想之cefotaxime先驅藥。 |
英文摘要 | Alkylation of cefotaxime sodium with 1-iodoethyl 2-N(Boc)-D-phenylglycine (3a and 3b) led to double esters 4a, 4b where the carboxyl group of D-phenylglycine was linked to the 4- carboxyl group of cefotaxime via an ethyledine moiety, and their Δ isomeric analogues 5a and 5b. TheΔ →Δ isomeric transformation from 4a and 4b to 5a and 5b during the synthesis was successfully eliminated by the addition of TBA+HSO to the reaction media. Hydrolysis of the mixture of 4a and 4b followed by medium liquid chromatographic separation afforded the D- phenylglycine-containing double ester prodrugs of cefotaxime (1a and 1b). Compounds 1a and 1b were stable in acidic phosphate buffer solution, but were degraded fairly rapidly in a pH 7.39 phosphate buffer solution. The t of 1a and 1b in a mucosal suspension from rat intestine were 11 minutes and 1 minute respectively. These two compounds failed to demonstrate satisfactory stability for formulation as oral prodrugs of cefotaxime. odrugs of cefotaxime. |
本系統中英文摘要資訊取自各篇刊載內容。