卡培他滨杂质的合成

Synthesis of Capecitabine Impurity

以卡培他滨中间体(2R,3R,4R,5R)-2-(4-氨基-5-氟-2-氧嘧啶-(2H)-基)-5-甲基四氢呋喃-3,4-二乙酸酯(1)为起始原料制备出卡培他滨杂质(A、B、C、D)。卡培他滨杂质A是由1在碱性条件下水解制备;卡培他滨杂质B是由杂质A在酸催化下脱氨制备;卡培他滨杂质C是由1先发生胺酰化和水解反应合成卡培他滨后再与三光气成环制备;卡培他滨杂质D是由1与三光气、3-甲基丁醇通过酰化反应与水解反应制备。杂质纯度均大于99.5%,杂质结构经^(1)H NMR、^(13)C NMR以及MS确证。

Capecitabine impurities(A,B,C,D)were prepared from capecitabine intermediate(2R,3R,4R,5R)-2-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-5-methyltetrahydrofuran-3,4-diyl diacetate(1).Capecitabine impurity A was prepared by hydrolysis of 1 under alkaline conditions;Capecitabine impurity B was prepared by deamination of impurity A under acidic catalysis;Capecitabine impurity C was synthesized by amination and hydrolysis of 1,and then cyclized with triphosgene;Capecitabine impurity D was prepared by acylation and hydrolysis of 1 with triphosgene and 3-methylbutanol.The purity of all prepared impurities was more than 99.5%.The structure of the impurities was confirmed by ^(1)H NMR,^(13)C NMR and MS.