含D-Phenylglycine之Cefotaxime雙酯先驅藥的合成研究   全文下載

Methods in the Preparation of D-Phenylglycine-containing Cefotaxime Double Esters

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D-phenylglycine之羧基以亞乙基作為橋鍵形成雙酯先驅藥1a及1b，使該先驅藥透過D-phenylglycine與腸膜上雙胜?載體輸遞系統的親合力而穿透腸壁吸收。合成先驅藥1a及1b的方法係將1-iodoethyl2-N（Boc）-phenylglycine （3a及3b） 與cefotaxime sodium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Δ3→Δ2異構化反應，產生Δ2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埋想，其半表期分別為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。

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 theirΔ2 isomeric analogues 5a and 5b. The Δ3→Δ2 isomeric transformation from 4a and 4b to 5a and 5b during the synthesis was successfully eliminated by the addition of TBA+HS04- to the reaction media. Hydrolysis of the mixture of 4a and 4b followed by medium pressure 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 t1/2 of 1a and 1b in a mucosal suspension prepared 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. 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D-phenylglycine之羧基以亞乙基作為橋鍵形成雙酯先驅藥1a及1b，使該先驅藥透過D-phenylglycine與腸膜上雙胜肽載體輸遞系統的親合力而穿透腸壁吸收。合成先驅藥1a及1b的方法係將1-iodoethyl2-N（Boc）-phenylglycine （3a及3b） 與cefotaxime sodium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Δ3→Δ2異構化反應，產生Δ2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埋想，其半表期分別為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。