丙酸氟替卡松中试放大制备工艺及质量研究

【作者】 殷莉梅；

【导师】 韩静；

【作者基本信息】 沈阳药科大学 ， 生物化工， 2009， 硕士

【摘要】 丙酸氟替卡松为一种新型糖皮质激素药物,临床应用于治疗哮喘、过敏性鼻炎、慢性梗塞性肺炎、特应性皮炎等。该药物具有很强的疗效和较弱的不良反应,国内无上市,有很好的研究价值。本文的主要工作是寻找一条成熟、稳定、适合于工业生产的技术工艺路线并对放大后的产品进行质量研究。包括：合成新工艺的实验室研究、中试放大、三废处理、质量研究四个阶段。首次采用醋酸地塞米松为原料,经乙酰化、氟化、水解三步反应制得双氟米松,再经氧化、巯基化、酯化、氟甲基化反应得目标化合物,经过单因素优化试验,六步反应总收率为52.84%；产物通过薄层色谱比移值和高效液相保留时间进行鉴别,通过红外吸收光谱、核磁共振谱、质谱对丙酸氟替卡松进行结构鉴定。在酰化反应后处理,一锅法等方面表现出独创性。氟米松的制备需通过两次柱层析法进行纯化,收率较低,约为61.6%,工艺不够成熟,不适合放大生产。但是从氟米松到丙酸氟替卡松的制备,总收率约为85.75%,经无水乙醇重结晶一次,纯度大于98%,小试工艺稳定可行。我们对该段反应开展中试放大研究,通过工艺数据的积累、中间体的质量控制、工艺的优化与中试、三废的处理,进一步考核小试提供的工艺路线,逐一解决在中试放大后出现的诸多问题。总收率以氟米松计为85.19%。经重复性试验论证,中试放大工艺稳定可行。最后对丙酸氟替卡松进行了系统的质量研究。按中国药典2005版二部,通过外观、溶解度、吸收系数、比旋度和熔点,考察了丙酸氟替卡松的性状和物理常数。参照欧洲药典采用高效液相色谱法对丙酸氟替卡松进行有关物质、含量、稳定性的测定。并对分析方法的效能指标进行了实验验证,包括线性与范围、回收率、精密度、稳定性等,结果证明含量测定方法可行。三批样品含量测定结果均大于98%。更多还原

【Abstract】 Fluticasone propionate is a new type of glucocorticoid drugs, clinical application of the treatment of asthma, allergic rhinitis, chronic infarct pneumonia, such as atopic dermatitis. The drug has strong efficacy and less adverse reactions, and it is free in the domestic market. So it is valuable to research.The main task was to find a mature, stable and suitable technology line for industrial production and to study the quality of the products after pilot amplification. It included four parts:new method for synthesis of laboratory research, pilot amplification, waste disposal and the quality of research.Fluoride Betamethasone was prepared from Dexamethasone Acetate by acetylation, fluoride, hydrolysis of a three-step reaction. and the target product was prepared by oxidation, sulfhydryl, esterification, and fluorine methylation. After single-factor optimization experiments, the total yield of six-step reaction was 52.84%; The product was identificated by Rf value of TLC and retention time of HPLC. The chemical structure of Fluticasone Propionate was confirmed by infrared absorption spectroscopy, MS and NMR. It is originative to the one-pot reaction and the post-processing in the acylation.Betamethasone fluoride was purificated through column chromatography for two times and the yield was relatively low, nearly 61.6%. So the technology was not mature enough to enlarge the production. However, the small test process that fluticasone propionate prepared from fluoride betamethasone was stable and feasible. Response to the above, we carried out pilot studies through the accumulation of process data, quality control of intermediates, process optimization of the pilot. And we solved the problems after the amplification.The total yield of amplification was 85.19%. It was demonstrated that the amplification process was stable and feasible by repeatability test.Finally, we studied the quality of Fluticasone Propionate systematicly. The characters and physical constants were studied by appearance, solubility, absorption coefficient, melting point, solubility and rotatio according to Chinese Pharmacopoeia 2005 EditionⅡ. The related substance, the content, and the stability was detected by HPLC according European Pharmacopoeia.The performance of analytical methods and experimental validation of indicators, including the linear and the scope of the recovery, precision and stability. The results showed that the method was feasible. The purify of three batches of samples was greater than 98%.更多还原