Scavenger assisted combinatorial process for preparing libraries of amides, carbamates and sulfonamides
申请人:ELI LILLY AND COMPANY
公开号:EP0825164A2
公开(公告)日:1998-02-25
This invention relates to a novel solution phase process for the preparation of amide, carbamate, and sulfonamide combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
that can make the ester bond hydrolysis ultrafast. A series of molecules comprising ultrasensitive esters that can be activated by H2O2 were synthesized, and it was found that those able to form an HBC structure showed complete esterhydrolysis within 5 h in both water and phosphate‐buffered saline solution, which was several times faster than other methods reported. Then, a series of amphiphilic poly(amidoamine)
酯键作为通用接头由于其在切割后通过静电排斥而有效释放基因,因此最近已在基因传递系统中得到应用。但是,酯键不稳定且难以在细胞中裂解。这项工作报告了一种方法,其中将仲胺引入酯键的β位以生成氢键环化(HBC)结构,该结构可使酯键水解超快。一系列包含可被H 2 O 2活化的超敏酯的分子合成后发现,能够形成HBC结构的化合物在水和磷酸盐缓冲盐溶液中均在5小时内完全酯水解,这比报道的其他方法快几倍。然后,构建了一系列两亲性聚(酰胺基胺)树枝状大分子,其中包括用于基因传递的超灵敏酯基;人们发现,他们可以有效地释放基因h的相当低的浓度下2 Ò 2(<200μ米在Hela细胞中具有高安全性)和传输它们到细胞核中在2小时内。他们的基因转染效率高于PEI 25k。结果表明,氢键诱导的超敏酯可以有效地用于构建基因传递系统。
Effective dephosphorylation catalyzed by fluoride ion: A novel synthesis of terminal f-alkylacetylenes from f-alkanoyl chlorides
1H-F-Alkene-1-phosphonates, easily accessible from F-alkanoyl chlorides, underwent dephosphorylation on treatment with a catalytic amount of fluoride ion at O°C to room temperature to give terminal F-alkylacetylenes in good yields.
Diethyl (Z)-1H-F-1-alkene-1-phosphonates were synthesized in good yields by the treatment of diethyl (Z)-1-[(diethoxyphosphinyl) oxy]-F-1-alkene-1-phosphonates, prepared from F- alkanoic acid chlorides and triethyl phosphite, with butylcopper (I) reagent in tetrahydrofuran-tetramethylethylenediamine at −78 °C.
Reaction of F-alkanoic acid chlorides with trialkyl phosphites leading to 1-(dialkoxyphosphinyl)oxy-f-1-alkenephosphonates or 1-(dialkoxyphosphinyl)oxy-1H-F-alkanephosphonates
F-Alkanoic acid chlorides exothermically reacted with 2 equivalents of trialkylphosphite without solvent at −20 °C to ambient temperature to give the corresponding dialkyl (Z)-1- (dialkoxyphosphinyl)oxy-F-1-alkenephosphonate in high yields. When the reaction was conducted at −78 °C in an ethereal solvent, dialkyl 1-(dialkoxyphosphinyl)oxy-1H-F-alkanephosphonate was obtained exclusively in place of