The Preperation And Analysis Of Doxazosin Enantiomers

Cardiovascular disease is one of the principal diseases jeopardizing human's health with the aging and the living standards elevating. Hypertension is the most common one among cardiovascular diseases. So to develop safe and well therapeutic antihypertensive drugs is imminent. The project that will study a chiral antihypertensive drug, doxazosin is of much importance and extensive prospect.Doxazosin is a selective alphal-adrenoceptor antagonist that can efficiently control the symptom of hypertension. Doxazosin has a high degree of selectivity for post-synaptic alphal-adrenoceptor. It does not influence stimulant activity of noradrenaline either at pre-synaptic or at post-synaptic alpha2-adrenoceptors. The principalad vantages of doxazosin are: 1. Ameliorate the microcirculation. The widespread vasodilatation induced by doxazosin relieves both cardiac preload and afterload, consequently, reduces left ventricular wall stress and myocardial oxygen consumption, that is, it can induce both resistance vessel and capacitance vessel vasodilatation,reflectively holdback or retard syncopexia; 2. Ameliorate plasma lipid metabolism. It can reduce the plasma concentrations of triglycerides and total cholesterol. So it can reduce the risk and liability of coronary artery disease. But in the recent ALLHAT reports, doxazosin in the alphal-adrenoceptor antagonist group led higher probability of cardiovascular incidents, and then this group had to terminate the test in 2000. Such results severely prevent its clinical application and decrease its saleroom. However, why are there so many incidents in doxazosin group?Doxazosin is a chiral drug with two enantiomers because of one asymmetric carbon atom in its molecule. The racemic doxazosin is used in clinic. So this project is about the preperation and chiral analysis of the two enantiomers of doxazosin.The work developed in this dissertation is as follows1.Develop a chemical chiral separation method for the preparation of BCP single enantiomers. L-camphor sulphonic acid was selected as a chiral selector. A reaction of (±)-BCP with an equimolar amount of L-camphor sulphonic acid gave a mixture of diastereomeric salts. Twice recrystallization of the mixture salts in a mixture of methanol-acetone2: 1 gave the salt of (+)-BCP, the yield of which was 25%. The optical purity of this salt was nearly 100% and specific rotation was +107.6. While (-)-BCP whose optical purity is 66% is still in the study.2.To determine the structure of (+)-doxazosin, it was synthesized in this paper by methylation of (+)-BCP with ACQ.Its single crystal prepared from methanol containing a small amount of acetone is determined by X-ray diffraction analysis.The crystal is of monoclinic, space group P2(1) with a = 12.454(2) A, b = 9.5772(16) A, c = 19.608(3) A,α=90°,β=106.453(3)°,γ=90°,V=2243.0(7) A3, Z=4, F(000)=1024, Dc=1.445 mg.m-3,μ=0.217 mm-1. The absolute configuration of (+)-doxazosin was proved to be S enantiomer.3.A capillary electrophoretic method for enantiomeric separation of doxazosin and its intermediate was described. Several tetraalkylammonium reagents were examined for controlling the electroosmotic flow in order to improve resolution of the enantiomers. Tetramethylammonium hydroxide (TMB) was found more suitable than tetrabutylammoniumhydroxide (TAB) and hexadecyltrimethylammonium bromide (CTAB) for the enantiomer separation. In addition, the effects of the PH value, the voltage on the chiral separation and the concentration of the sodiumdihydrogen phosphate were investigated. An uncoated fused-silica capillary (40cm×50μm i.d., effective length 30cm) was used. The voltage was 20kV and the temperature was 25℃.The detective wavelength was set at 205nm. Samples were injected into the capillary under 5kPa pressure for 5s. A background electrolyte of 60mmol/L sodiumdihydrogen phosphate (PH 2.4), 30mmol/L TMB and 12mmol/Lβ-CD resulted in the baseline separation of the doxazosin enantiomers and its intermediate. It showed that the presence of TMB was essential in some chiral separations that were previously not achieved by only using theβ-CD.