Synthesis and application of a new isothiocyanate as a chiral derivatizing agent for the indirect resolution of chiral amino alcohols and amines
Synthesis and application of a new isothiocyanate as a chiral derivatizing agent for the indirect resolution of chiral amino alcohols and amines
复制标题
新型异硫氰酸酯的合成及手性衍生剂在手性氨基醇和胺间接拆分中的应用
DOI：
10.1016/0021-9673(95)01348-2
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发表时间：
1996
影响因子：
4.1
通讯作者：
W. Lindner
中科院分区：
文献类型：
--
作者：
O. P. Kleidernigg;K. Posch;W. Lindner
光学纯反式-1,2-二氨基环己烷（DACH）基n -3,5-二硝基苯甲酰DACH-异硫氰酸酯（ditc）的合成方法简单，该化合物有R、R和S、S构型，可作为高选择性、稳定的光学纯手性衍生剂（CDA）用于间接拆分手性伯胺和仲胺，特别是氨基醇。描述了获得ddditc的合成路线，并介绍了以ddditc衍生的ß-阻断剂等多种重要的药用氨基醇的RP-HPLC分离。用反相高效液相色谱法将后一种非对映体与已建立的gtc衍生化合物进行了比较。ddditc衍生物的分离因子（α）在1.05 ~ 2.00之间，峰分辨率(R)在0.67 ~ 6.67之间，且通常高于GITC衍生物。然而，在氨基官能团上含有叔丁基的仲胺（例如噻莫洛尔）的衍生化使用ddditc是不可能的，使用GITC作为CDA时没有观察到这一限制。与其他手性异硫氰酸酯相比，ddditc的优点是具有更高的色谱选择性和较高的检测灵敏度，包括由于硝基的氧化还原电位（- 0.62 V）而可以选择电化学检测。紫外检测DDITC衍生的氨基化合物表现出优异的灵敏度，因为从硝基发色剂推断出较高的摩尔吸收率（ε）（例如，苯丙胺的DDITC衍生物，ϵ242= 26000）。ddditc衍生物的化学稳定性比GITC衍生物高得多，因为没有易水解的酯基，这被认为是另一个优势。
The synthesis of the optical pure trans-1,2-diaminocyclohexane (DACH)-based N-3,5-dinitrobenzoyl-DACH-isothiocyanate (DDITC) is straightforward and the compounds, available in R,R and S,S configurations, can serve as highly selective, stable and optically pure chiral derivatizing agents (CDA) for the indirect resolution of chiral primary and secondary amines and in particular of amino alcohols. The synthetic route to obtain DDITC is described and RP-HPLC separations of a number of pharmaceutically important amino alcohols including ß-blockers derivatized with DDITC are presented. The latter diastereomers were compared with the well established GITC-derivatized compounds by RP-HPLC. The separation factor (α) of the diastereomeric thioureas ranged between 1.05 and 2.00 and the peak resolution (R) ranged from 0.67 to 6.67 for the DDITC derivatives, and were usually higher than the values for the GITC derivatives. However, derivatization of secondary amines containing a tertiary butyl group at the amino function (e.g., timolol) is impossible using DDITC, a limitation not observed using GITC as CDA. The advantage of DDITC over other chiral isothiocyanates is the higher chromatographic selectivity and the high detection sensitivity, including the option of electrochemical detection due to the redox potential (−0.62 V) of the nitro group. UV detection of the DDITC-derivatized amino compounds shows excellent sensitivity because of the higher molar absorptivity (ε) deduced from the nitroaryl chromophor (e.g., DDITC derivative of metamphetamine, ϵ242= 26 000). The chemical stability of the DDITC derivatives is much higher than that of GITC derivatives owing to the absence of easily hydrolysable ester groups, which is considered a further advantage.