【作者】 秦光成；

【导师】 李逐波；

【作者基本信息】 西南大学 ， 基础兽医学， 2009， 硕士

【摘要】 本课题在上届同学研究的基础上,选用新型、高效催化剂DMAP以及溶剂丙酮合成得到氟苯尼考琥珀酸酯,并在此基础上通过单因素考察以及正交设计实验对合成工艺进行了优化。同时还对氟苯尼考琥珀酸钠的体内抗菌活性、局部毒性以及在大鼠体内的药代动力学及组织分布做了相应的研究。在使用催化剂DMAP和丙酮做溶剂的条件下,合成得到的产品,通过熔点仪、薄层色谱、高效液相色谱分析表明,该化合物具有较高的纯度,并且在相同条件下其Rf值和保留时间与氟苯尼考琥珀酸酯的标准品一致;熔点测定结果与杨鹏等测定的结果相当;红外光谱测定表明产品与标准品图谱高度吻合。因此结合以上方法综合分析可以得出,合成得到的产品为氟苯尼考琥珀酸酯。优化后的合成工艺与传统合成工艺对比分析表明,优化后的合成工艺反应温度由原来的80℃降低到60℃,反应条件温和,使得合成的选择性提高,副反应减少,为后期的分离纯化方法的优化奠定了基础;反应时间缩短由原来的15h以上缩短到4h;产率提高由原来的70%左右上升到88.1%;传统的分离纯化方法用稀酸和去离子水反复洗涤后,用有机溶剂多次重结晶后才可以得到纯品,新的分离纯化方法,在减少了繁琐洗涤过程的同时,用溶剂水代替有机溶剂作为结晶溶液结晶一次可以得到相同纯度的产品,其纯度可达97%以上。合成过程中使用的有机溶剂回收率大于80%。合成原料成本降低。后期的合成放大实验表明,该工艺下得到的产品质量、产率稳定,工艺条件简便、易操作、可控;同时经初步成本核算表明,该工艺条件下合成得到的氟苯尼考琥珀酸酯有较大的利润空间,因此该工艺进行工业化的进一步研究具有良好的经济价值和广阔的应用前景。用微生物法通过对氟苯尼考(母药)及其氟苯尼考琥珀酸钠(前药)对大肠杆菌、金葡球菌、枯草杆菌、变形杆菌的体内抑菌实验的对比研究表明,前药与母药从给药后0～3h这段时间内其抑菌圈直径基本一致,统计学分析表明也无显著差异(P＜0.05),就是说前药和母药对四种菌都有良好的抗菌活性,且效果相当。通过肌肉注射30mg/kg(按氟苯尼考计算)氟苯尼考琥珀酸钠后,在大鼠体内氟苯尼考琥珀酸钠能迅速转化为氟苯尼考,并主要以FF、Fs-Na、FFa三种形式存在,它们在大鼠体内的药时数据符合一级吸收一室模型。转化后的FF的Tmax为1 h,最大血药浓度Cmax为6.28μg/mL,Vd、AUC、CL/F(s)分别为0.77 mg/L、37.03μg/mL和0.258 L/h,表明FF在体内各组织中分布广泛,消除缓慢,维持有效血药浓度的时间较长。停药后FF主要集中在肺脏、肝脏和肾脏组织中,但经过统计学分析表明差异不显著。但FF与FFa在大鼠的肝脏和肾脏组织中残留总量最高,提示肝脏和肾脏是FF的主要靶器官。这一系列动力学参数和组织分布规律为其临床给药的进一步研究提供了相应的理论基础。局部毒性实验中的皮肤刺激性试验和给药部位刺激性试验表明氟苯尼考琥珀酸钠在其临床的给药剂量和范围内是无刺激或者是低刺激性的。溶血性试验表明,在试验剂量内不同浓度的氟苯尼考琥珀酸钠在其观察期内没有发现有溶血现象发生,并按部标法检测溶血率,均远远小于规定的5%,说明该受试药物可以静脉注射使用。因此局部毒性实验表明在临床给药剂量内该化合物是低毒,安全的。更多还原

【Abstract】 This topic selecting DMAP as a new catalyst and solvent acetone synthesized florfenicol succinic based on others’ resarech,at the same time,optimize the synthetic process through the single factor experiment and orthogonal design experiment.Also studies on antibacterial activity,local toxicity, pharmacokinetic and organization distribution in rats of florfenicol succinic.Under the condition of useing DMAP as catalyst and acetone as solvent,synthesis florfenicol succinic.Through melting point,TLC and HPLC analysis shows that the compounds with high purity. Under the same conditions for its Rf and retention time are at equal with the standard of florfenicol succinic.The result of melting point is the same with Yangpeng’s rearech,Infrared spectrometry showes products and standard atlas of florfenicol succinic is identical.Therefore it can be obtained by those methods of comprehensive analysis that synthesis of products are florfenicol succinic.The optimized synthesis process and the traditional comparative analysis shows that reaction temperature by original 80℃decrease to 60℃,mild reaction conditions making the selective raise and the side reaction reduce,so that the work of purification become very easy.Reaction time is shortened by the original 15h above to 4h,Yield increase by 70%up to 88.1%.The traditional method of separation and purification by dilute acids and deionized water repeated washing,after repeated crystallization with organic solvent can be highly purified products;a new method of separation and purification,reduced the process trival,wash with water instead of organic solvents as solvent solution can be a crystallization of crystallization of the product,the same purity purity 97%above. Using organic solvents have been recoved than 80%in the synthetic process.Synthetic raw material cost have been reducted too.Later the synthetic amplification experiments showed that the process of product quality and yield stable,process conditions simple,easy to operate and controllable,While the preliminary evaluation process conditions of synthesis florfenicol succinic’s profit will be so large,so that the process of industrialization of further research has good economic value and broad application prospect.We have reseach antibacterial effect of florfenicol and florfenicol sodium succinic on escherichia coli,staphylococcus aureus,bacillus subtilis and Bacillus proteus by using the microorganism method.Contrast research shows that,with the produrg and florfenicol administration after from 0～3h inside this paragraph of time the bacteriostatic circle diameter are the same,and the statistical analysis shows that,also had no significant difference(P＜0.05),and that produrg and florfenicol of four kinds of bacteria have good antibacterial activity,and the result is quite.Through i.m 30mg/kg(by florfenicol) florfenicol sodium succinic,in rats florfenicol sodium succinic can quickly into florfenicol,and which exist in rats mainly with three forms FF,Fs,FFa. The pharmacokintie characcteriatis was conformed to one-coparment open model with first-absorption tare.The primary parameters were as following;FF Tmax was 1 h,Cmax was 6.28u g/mL,Vd,AUC,CL/F(s) respectively was 0.77 mg/L,37.03μg/mL and 0.258 L/h,show in vivo FF,eliminate distributed widely in slow,maintain effective blood concentrations of for a long time.After discontinuation FF mainly concentrated in the lung,liver and kidney,but through statistical analysis showed no significant differences.The highest total residual of FF and FFa in the liver and kidneys organization,and we can know that liver and kidneys are the main target organs in rats of FE This series of dynamic parameters and organization for the distribution of clinical medicine of further research provides corresponding theoretical basis.Local toxicity test of skin irritation test and dosing parts excitant experiments show that fiorfenicol sodium succinic is no stimulation or low excitant in its clinical dosing and range.In the test,hemolytic test shows that the concentration of different doses florfenicol sodium succinic in its observation period of time were found to show no hemolysis phenomenon,and according to the standard method of Health Department,are far smaller than the rate of hemolysis of 5%,so it can be use intravenous injection administration.Therefore local toxicity in clinical drug experiments showed that the compound was toxicity and safe within the dose.更多还原