多沙唑嗪中间体的手性分离方法优化研究

Optimum Study of the Enantioseparation of Doxazosin Intermediate Enantiomers

多沙唑嗪是一种抗高血压手性药物，1-（1，4-苯并二噁烷-2-羰基）哌嗪（BCP）是合成该药物的重要手性中间体。手性多沙唑嗪的光学纯度可以通过BCP的光学纯度来控制。该文采用柱前衍生化-反相高效液相色谱法优化了BCP的手性分离方法，以便对其进行光学纯度检测。结果表明：以乙酰葡萄糖异硫氰酸酯（GITC）为柱前手性衍生化试剂，C18柱（4．6mm×250mm）为色谱柱，可以将BCP对映体分离，优化的其他色谱条件为：流动相组成V（CH3OH）：V[C（KH2PO4的水溶液）=0．02mol／L]=50：50，流速0．6mL／min，检测波长250nm。在选择的测定条件下，BCP与GITC形成的非对映异构体达到基线分离，分离度约等于1．5（R=1．5），在2～250μg·mL^-1内，非对映体的色谱峰面积与质量浓度之间线性相关系数大于0．998。

Doxazosin is a chiral antihypertensive drug. 1-（ 1,4-Benzodioxane-2-carbonyl）-piperazine （BCP） is an important chiral intermediate for the preparation of doxazosin. To control the optical purity of BCP is very important for the synthesis of chiral doxazosin. A high-performance liquid chromatographic method for the separation of enantiomers of BCP has been developed and optimized for the optical purity determination of BCP. The results showed that the enantiomers could be separated with 2,3,4,6-tetra-O-acetyl-fl-D-glucopyranosyl isothiocynate（ GITC ） as the derivatization reagent on the C18 column. Other chromatographic conditions are：mobile phase consisting of methanol and 0.02 mol/L aqueous potassium dihydrogen phosphate solution（50：50, V/V） at a flow rate 0.6 mL/min,and the wavelength for detection set at 250 nm. The results showed that two diastereoisomers were almost baseline separated under the optimum conditions （R = 1.5）. Over the concentration range of 20 - 250 μg · mL^-1, the linearity between the peak area and the mass concentration of the diasteroisomers is satisfactory （ regression coefficient 〉 0. 998 ）.