新型环糊精手性固定相的制备及其对氟西汀对映体的拆分
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摘要
手性药物的对映体在人体内的药理活性、代谢过程以及毒性上均存在显著差异,往往只有某种对映体对疾病有效,而其它对映体则疗效低或无效,甚至有明显的毒副作用。手性药物单一对映体的开发已显得非常迫切。光学纯物质的制备方法有多种:手性源合成法、不对称合成法、结晶拆分法、化学衍生拆分法、酶或微生物法、膜拆分法和手性色谱拆分法等。手性色谱拆分法是发展较快的一种手性分离方法,但目前研究侧重于手性药物的分析与手性识别机理研究,大规模制备的应用研究还很少。本文以广泛用于临床的抗抑郁药物——氟西汀作为研究对象。综合比较其各种拆分方法,选用全苯异氰酸酯基-β-环糊精键合手性固定相色谱法拆分外消旋氟西汀,并对手性色谱分离过程进行了研究。
本文主要分为四大部分:(1)全苯异氰酸酯基-β-环糊精手性柱的制备;(2)自制手性固定相(CSP)的静态吸附性能研究;(3)自制环糊精手性柱对氟西汀的拆分;(4)氟西汀手性色谱分离过程分析。
首先,采用分步法制备了全苯异氰酸酯基-β-环糊精键合硅胶手性固定相,并装填得手性柱。①在氢氧化钠水溶液中合成了六位单取代对甲苯磺酰-β-环糊精,得到了最佳的工艺条件,即反应温度为10℃,反应时间为3h,加入对甲苯磺酰氯的量为5g,加入时间为10min。在此最佳条件下,得到单取代物的收率为4.62%。采用树脂HZ-841吸附纯化法,对磺酰化反应得到的混合产物进行了分离,得到了六位单取代物纯品。②以丙烯胺为反应物和溶剂,回流合成了六位单取代丙烯胺基-β-环糊精,产物的收率为92.5%。采用结晶法对丙烯胺基环糊精粗品进行了精制,其收率约为91%,纯度达到了98%以上。③丙烯胺环糊精与过量的异氰酸苯酯,在吡啶中合成了苯异氰酸酯基-β-环糊精衍生物粗品。采用硅胶柱层析法分离酯化反应的混合产物。确定了小柱分离的最佳工艺条件为:填料为200-300目硅胶,床层高度为32cm,流动相为正己烷—乙酸乙酯(2/1,v/v),流速为0.6 mL/min,柱温为30℃,最大上样量为0.02 g。在此实验条件下,可得纯品0.01 g。纯化过程加以放大,确定了半制备硅胶柱层析的最佳工艺条件为:在规格为Φ3.7cm×70cm的带夹套玻璃柱中,填料和流动相组成不
The production of individual enantiomers has become more and more important as the increased knowledge of the different medicine effect of enantiomers. There are several approaches to obtain enantiomerically pure chemicals. They are asymmetric synthesis, chemical derivation, crystallization, biotransformation, inclusion, membrane separation and chiral chromatography. The chiral chromatography is more attractive and has been developed rapidly in recent years. However, research was concentrated on the chiral analysis and chiral recognition mechanism, and the study on the preparative separation is not excessive. This work chooses the chiral widely used antidepressant drug — fluoxetine as the object to study the common technique of chiral chromatographic separation. After comparing the chiral resolution methods of fluoxetine, we intend to separate the enantiomers of fluoxetine by the perphenylcarbamoylated B-cyclodextrin bonded CSP chromatography.The experimentation of dissertation is consisted of four parts: the preparation of perphenylcarbamoylated B-cyclodextrin bonded chiral column, the static adsorptive capacity of CSP, the chromatographic separation of fluoxetine enantiomers on self-made column and the analysis of the chromatographic process.In the first part, the perphenylcarbamoylated B-cyclodextrin CSP was prepared step by step. In the project, mono-6-p-toluenesulfonyl-B-cyclodextrin, mono-6-N-allylamino-β-cyclodextrin and mono-6-N-allylamino-perphenylcarbamoylated-β-cyclodextrin were synthesized and purified;and then, the last was bonded to the y-aminopropyl silica gel. The slurry method was applied to prepare the HPLC column with methanol as the packing solvent. After suspended in CCl_4-dioxane (2/1, V/V) and sonicated for 10 min, slurry of CSPs were packed into a stainless steel column at a pressure of 28 MPa. At 0.5 mL/min of flow rate, the theoretical plate numbers of two columns were 6222 and 5630, respectively.Secondly, separation of fluoxetine enantiomers on five chiral stationary phases (Chiralcel OD-H, Chiralcel OJ-H, Chiralpak AD-H, Cyclobond I 2000 DM and Kromasil CHI-TBB) was investigated. Baseline separation was obtained on OD-H, AD-H, and Cyclobond I 2000 DM while the best was obtained on the last one. After
the analytical method was determined, the static adsorptive capacity of CSP was tested. Experimental results demonstrated that the chiral selector has selectivity, that is, the adsorption of S-fluoxetine on perphenylcarbamoylated B-cyclodextrin is easily.The enantiomers of fluoxetine were separated on perphenylcarbamoylated B-cyclodextrin bonded CSP with the mobile phase of methanol/TEAA. After determining of the chromatographic model, the composition, ionic strength and pH of mobile phase were investigated, as well as the flow rate and column temperature. The first eluate by self-made column is the R-enantiomer. Besides, paroxetine, naproxen, propranolol and alprenolol were baseline separated on the column;the preparation of CSPs and packing of columns are repeatable.At the end of the dissertation, the chromatography separation process of fluoxetine enantiomers was studied. The effects of the composition and flow rate of mobile phase on the throughput and energy of solvent evaporation were studied. It was found that the throughput increases with the increase of the content of methanol and the flow rate of the mobile phase. The energy of solvent evaporation increases with the increase of the flow rate of mobile phase, but decreases with the increase of the content of methanol in mobile phase. Taking into account of the resolution, throughput and energy of solvent evaporation, the compromise composition of mobile phase may be methanol/TEAA=40/60 (V/V- The elution curve was analyzed with moment analysis. The equilibrium constant of solute between the mobile and stationary phases can be calculated from the first absolute moment, the total mass transport resistance can be calculated from the second central moment. A linear driving force model was set up to simulate the experimental elution curve. Based on the model, effects of loading and flow rate of mobile phase on separation process were studied. The results could be used to scale up of preparative chromatography.In this paper, a new CSP ~ perphenylcarbamoylated 6-cyclodextrin bonded chiral stationary phase was prepared. And it was the foundation of preparation of some enantiomerically pure chemicals, such as fluoxetine enantiomers etc.
本文主要分为四大部分:(1)全苯异氰酸酯基-β-环糊精手性柱的制备;(2)自制手性固定相(CSP)的静态吸附性能研究;(3)自制环糊精手性柱对氟西汀的拆分;(4)氟西汀手性色谱分离过程分析。
首先,采用分步法制备了全苯异氰酸酯基-β-环糊精键合硅胶手性固定相,并装填得手性柱。①在氢氧化钠水溶液中合成了六位单取代对甲苯磺酰-β-环糊精,得到了最佳的工艺条件,即反应温度为10℃,反应时间为3h,加入对甲苯磺酰氯的量为5g,加入时间为10min。在此最佳条件下,得到单取代物的收率为4.62%。采用树脂HZ-841吸附纯化法,对磺酰化反应得到的混合产物进行了分离,得到了六位单取代物纯品。②以丙烯胺为反应物和溶剂,回流合成了六位单取代丙烯胺基-β-环糊精,产物的收率为92.5%。采用结晶法对丙烯胺基环糊精粗品进行了精制,其收率约为91%,纯度达到了98%以上。③丙烯胺环糊精与过量的异氰酸苯酯,在吡啶中合成了苯异氰酸酯基-β-环糊精衍生物粗品。采用硅胶柱层析法分离酯化反应的混合产物。确定了小柱分离的最佳工艺条件为:填料为200-300目硅胶,床层高度为32cm,流动相为正己烷—乙酸乙酯(2/1,v/v),流速为0.6 mL/min,柱温为30℃,最大上样量为0.02 g。在此实验条件下,可得纯品0.01 g。纯化过程加以放大,确定了半制备硅胶柱层析的最佳工艺条件为:在规格为Φ3.7cm×70cm的带夹套玻璃柱中,填料和流动相组成不
The production of individual enantiomers has become more and more important as the increased knowledge of the different medicine effect of enantiomers. There are several approaches to obtain enantiomerically pure chemicals. They are asymmetric synthesis, chemical derivation, crystallization, biotransformation, inclusion, membrane separation and chiral chromatography. The chiral chromatography is more attractive and has been developed rapidly in recent years. However, research was concentrated on the chiral analysis and chiral recognition mechanism, and the study on the preparative separation is not excessive. This work chooses the chiral widely used antidepressant drug — fluoxetine as the object to study the common technique of chiral chromatographic separation. After comparing the chiral resolution methods of fluoxetine, we intend to separate the enantiomers of fluoxetine by the perphenylcarbamoylated B-cyclodextrin bonded CSP chromatography.The experimentation of dissertation is consisted of four parts: the preparation of perphenylcarbamoylated B-cyclodextrin bonded chiral column, the static adsorptive capacity of CSP, the chromatographic separation of fluoxetine enantiomers on self-made column and the analysis of the chromatographic process.In the first part, the perphenylcarbamoylated B-cyclodextrin CSP was prepared step by step. In the project, mono-6-p-toluenesulfonyl-B-cyclodextrin, mono-6-N-allylamino-β-cyclodextrin and mono-6-N-allylamino-perphenylcarbamoylated-β-cyclodextrin were synthesized and purified;and then, the last was bonded to the y-aminopropyl silica gel. The slurry method was applied to prepare the HPLC column with methanol as the packing solvent. After suspended in CCl_4-dioxane (2/1, V/V) and sonicated for 10 min, slurry of CSPs were packed into a stainless steel column at a pressure of 28 MPa. At 0.5 mL/min of flow rate, the theoretical plate numbers of two columns were 6222 and 5630, respectively.Secondly, separation of fluoxetine enantiomers on five chiral stationary phases (Chiralcel OD-H, Chiralcel OJ-H, Chiralpak AD-H, Cyclobond I 2000 DM and Kromasil CHI-TBB) was investigated. Baseline separation was obtained on OD-H, AD-H, and Cyclobond I 2000 DM while the best was obtained on the last one. After
the analytical method was determined, the static adsorptive capacity of CSP was tested. Experimental results demonstrated that the chiral selector has selectivity, that is, the adsorption of S-fluoxetine on perphenylcarbamoylated B-cyclodextrin is easily.The enantiomers of fluoxetine were separated on perphenylcarbamoylated B-cyclodextrin bonded CSP with the mobile phase of methanol/TEAA. After determining of the chromatographic model, the composition, ionic strength and pH of mobile phase were investigated, as well as the flow rate and column temperature. The first eluate by self-made column is the R-enantiomer. Besides, paroxetine, naproxen, propranolol and alprenolol were baseline separated on the column;the preparation of CSPs and packing of columns are repeatable.At the end of the dissertation, the chromatography separation process of fluoxetine enantiomers was studied. The effects of the composition and flow rate of mobile phase on the throughput and energy of solvent evaporation were studied. It was found that the throughput increases with the increase of the content of methanol and the flow rate of the mobile phase. The energy of solvent evaporation increases with the increase of the flow rate of mobile phase, but decreases with the increase of the content of methanol in mobile phase. Taking into account of the resolution, throughput and energy of solvent evaporation, the compromise composition of mobile phase may be methanol/TEAA=40/60 (V/V- The elution curve was analyzed with moment analysis. The equilibrium constant of solute between the mobile and stationary phases can be calculated from the first absolute moment, the total mass transport resistance can be calculated from the second central moment. A linear driving force model was set up to simulate the experimental elution curve. Based on the model, effects of loading and flow rate of mobile phase on separation process were studied. The results could be used to scale up of preparative chromatography.In this paper, a new CSP ~ perphenylcarbamoylated 6-cyclodextrin bonded chiral stationary phase was prepared. And it was the foundation of preparation of some enantiomerically pure chemicals, such as fluoxetine enantiomers etc.
引文
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