【作者】 屈海涛；

【导师】 张密林；

【作者基本信息】 哈尔滨工程大学 ， 材料学， 2010， 博士

【摘要】 众所周知,手性化合物中单一光学纯对映体表现出不同毒性、药理以及生物活性等特性,所以分离和纯化对映体在中间体、天然产品、农用化学品、制药行业等很多科学领域得到越来越多的重视。最近几十年里,用于分离对映体的色谱技术得到广泛发展,其中高效液相色谱法(HPLC)在手性药物的研发过程中表现出了很大的优势,该法对于分析对映体的光学纯度以及大规模的制备对映体方面,具有非常重要的地位。在众多的手性固定相中(CSPs),多糖衍生物,如纤维素和淀粉苯基氨基甲酸酯类,对大多数的手性化合物表现出了广泛的适应性和优异的拆分能力。目前,为了能够更好的、更多的分离手性化合物,对新型手性固定相的探求已经引起了学者们的极大关注。本文合成了三种新型纤维素苯基氨基甲酸酯类衍生物：纤维素-[2,3-二苯基-6-(3,5-二氯苯基)]氨基甲酸酯(CSP-1),纤维素-[2,3-二(4-甲基苯基)-6-(3,5-二氯苯基)]氨基甲酸酯(CSP-2)及纤维素[2,3-二(4-氯苯基)-6-(3,5-二氯苯基)]氨基甲酸酯(CSP-3),并将其涂敷在氨丙基硅胶的表面制备HPLC手性固定相。利用三苯基氯甲烷能够与纤维素上6-位羟基优先反应的特性,实现了纤维素糖单元上6-位羟基的保护和去保护。在以正己烷/异丙醇(90/10,v/v)作为流动相的条件下,考察了对10种手性化合物的手性识别能力,并与以手性识别能力高而著称的、含有单一取代基的纤维素衍生物(CDMPC, CDCPC, CPC, CMPC和CCPC)进行比较,结果表明该类新型手性固定相对于绝大多数对映体显示出更优的手性拆分能力,尤其值得一提的是在CDMPC上难以拆分的7号对映体,在三种新型固定相上均能获得更好的分离；在CTPC上难于拆分的3号对映体,在CSP-1上获得基线分离(分离因子α值为1.38)；2号对映体在CSP-3上的拆分能力(a值为1.95)远高于CDMPC与CDCPC;4号对映体在CSP-1和CSP-3上的α值分别达到了2.06和1.81,所呈现的立体选择性远超过CDMPC与CDCPC。进一步说明了苯基氨基甲酸酯类衍生物的手性识别能力,受到糖单元2-位、3-位以及6-位苯环上的对位吸电子的甲基基团或者推电子的卤素基团的影响。为了克服涂敷型手性固定相在一些有机溶剂中能够溶解或者溶胀的缺点,本文合成了新型键合型手性固定相：分别含有1.2%(CSP-4),1.7%(CSP-5)和3.0%(CSP-6)的3-(三乙氧基硅基)丙基基团的纤维素-三(3,5-二氯苯基氨基甲酸酯)衍生物,并通过三乙氧基硅基基团之间的分子内缩聚反应键合在硅胶表面,得到新的键合型手性固定相；通过高效液相色谱法,用含有极性溶剂(四氢呋喃或氯仿)的混合溶液作为流动相,考察该手性固定相的手性识别能力,并与CDCPC进行比较。结果表明该新的键合型手性固定相在用极性溶剂做流动相时,可以极大的提高手性识别能力,绝大多数手性化合物的分离因子(a)值得到很大程度的提高,甚至3号对映体使用传统流动相H/I(90/10)时在CSP-5上不能拆分,而在H/T(70/30)和H/T/I(90/10/1)的极性流动相中均能得到很好的分离(α值分别为1.43和1.15)；扩大了流动相的选择范围；色谱柱的使用寿命得到延长。本文还提出利用纤维素氨基甲酸酯衍生物与异氰酸酯进行交换反应制备新纤维素衍生物的方法,并应用该方法合成出两种同时含有3,5-二氯苯基氨基甲酸酯(CSP-7中含量为17.3%, CSP-8中含量为26.8%)和3,5-二甲基苯基氨基甲酸酯基团的混合型纤维素衍生物,考察了其作为HPLC手性固定相的手性拆分性能；通过实验证实了纤维素衍生物的稳定性、反应时间和反应体系对于交换反应的终点和进程具有很大的影响。由于CDMPC更加稳定,在DMAc/LiCl/Pyridine体系中,用纤维素-三(3,5-二氯苯基氨基甲酸酯)(CDCPC)与3,5-二甲基苯基异氰酸酯(DMPI)进行了交换反应时CDCPC几乎完全被CDMPC取代,13小时即达到反应终点；同时因该交换反应优先发生在6-位,所以可以通过控制反应时间来控制纤维素衍生物2-位、3-位或者6-位上苯基氨基甲酸酯基团的含量；而该反应在Pyridine溶剂中只有3.0%的氨基甲酸酯基团发生了交换反应；以DMSO溶剂时,CDCPC与DMPI交换反应能力居中,需要44小时方能反应结束。所以利用交换反应合成纤维素衍生物,操作方法简单便捷,克服了传统的浪费异氰酸酯和使用昂贵的保护剂的缺点；通过改变反应时间和反应体系,很容易实现在纤维素三个位置上合成含有不同氨基甲酸酯基团的衍生物；并且本文新合成的纤维素衍生物展示出了很好的手性识别能力。更多还原

【Abstract】 It is well know that a pair of optically pure enantiomers have exhibited quite different toxicological and pharmacological behaviors, bioactivities, etc. The separation or resolution of enantiomers have beome very import in many fields of sicence, for example intermediates, natural products, agrochemicals and drugs. In recent decades, the chromatographic techniques for the separation of enantiomers are developed extensively. The high-performance liquid chromatography (HPLC) method has become most advantageous for the research and development of chiral drugs, which is essential for analysizing the optical purity of enantiomers and preparing separation for a large scale. Among many chiral stationary phases (CSPs), the polysaccharide derivatives, such as the phenylcarbamayes of cellulose and amylose exhibit broad applicability to a wide range of compounds. In order to resolve the chiral compound better, more new CSPs have been attracting much attention.In order to widen the chiral recognition range of chiral compounds, three new cellulose phenylcarbamate derivatives, [6-(3,5-dichlorophenyl)-2,3-bisphenyl]carbamates (CSP-1), [6-(3,5-dichlorophenyl)-2,3-bis(4-methylphenyl)] carbamates (CSP-2) and [6-(3,5-dichlorophenyl)-2,3-bis(4-chlorophenyl)] carbamates (CSP-3) were synthesized and used as the chiral stationary phase for high-performance liquid chromatography (HPLC) after coating on aminopropyl silica gel. The synthesis involved the protection and deprotection of 6-position using triphenylmethyl chloride, which can predominantly react with 6-OH of cellulose. The chiral recognition ability of obtained derivatives was evaluated using 10 racemates and a hexane/2-propanol (90:10, v/v) mixture as the eluent. The result showed that most of racemates were better resolved on the new derivatives than on the typical homogeneously substituted phenylcarbamate derivatives, tris(3,5-dimethylphenylcarbamates), tris(3,5-dichlorophenylcarbamates), tris(phenylcarbamates), tris(4-methylphenylcarbamates) and tris(4- chlorophenylcarbamates), some of which are well known due to their high ability. Especially compound 7 not resolved on CDMPC could be seperated better on CSP-1, CSP-2 and CSP-3, and compound 3 not resolved on CTPC is able to obtain baseline separation (separation factorαis 1.38), andαvalue (1.95) of compound 2 on CSP-3 andαvalues of compound 4 on CSP-1 (2.06) and CSP-3 (1.81) are much higher than those on CDMPC and CDCPC. It indicates that the chiral recognition on the phenylcarbamate derivates is influenced by the electron-donating methyl group or electron-withdrawing halogen at r-position of the phenyl ring introduced at 2-,3-and 6-site.Because the coated CSPs can be sissolved or swelled by some organic solvents, such as THF, chloform, toluene, ethyl acetate, and acetone, which is sometimes essential for efficient analytical and preparative resolution of enantiomers, several immobilized polysaccharide-based CSPs have been prepared. In this study, the tri-(3,5-dichlorophenylcarbamates) of cellulose (CDCPC) bearing a small amount of 3-(triethoxysilyl) propyl residues (1.2%,1.7% and 3.0%) were synthesized by a simple process (one-pot method) and efficiently immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups. The obtained chiral packing materials (CPMs) were evaluated by high-performance liquid chromatography with the polar solvents (THF and chloform) in the mobile phase, and compared with CDCPC. The results indicate that the new immobilized CSPs enhance the chiral separations, separation factor (chiral recognitions) for most of the racemates were immproved to different degrees. Even compound 3 can be resolved well on CSP-5 when using H/T (70/30) and H/T/I (90/10/1) as eluents, which couldn’t be chiral recognized when the traditional mobile phase H/I (90/10) is used. The immobilized columns expand the kind of solvents which can be used as the eluent and have long life. We expect that the immobilized CSPs will become more popular and will replace the coated-type CSPs.In this study, we discovered a new method, exchange reaction, for obtaining the phenylcarbamates derivatives with different phenylcarbamate groups. Using the exchange reaction method, new phenylcarbamate derivatives containing 3,5-dichloropnenyl carbamate and 3,5-dimethylphenyl carbamate were synthesized, and their chiral recognition ability were studied used as CSPs. It is proved that the stability of cellulose derivatives, reaction time and reaction solvents can affect the reaction end and exchange degree of the exchange reaction. Because CDMPC has more stability than CDCPC, CDCPC is almost completely replaced by CDMPC when CDCPC reacts with DMPI, and the reaction end reaches at 13 h. Since the exchange reaction occurrs on the 6- site of cellulose first, the contents of two carbamate groups at 2-,3- and 6-positions can be controlled by changing reaction time. But only 3.0% CDCPC is changed by CDMPC when pyridine is used as solvent, and 24.6% CDCPC is substitute when DMSO is used as solvent and the reaction end occurrs at 44h. The result showed that the operation of exchange reaction is simple and convenient, and overcomeing the shortcomings of the waste of isocyanate and expensive the protection agents, various new derivatives with different carbamate groups at the three positions can be easily synthesized by changing the reaction conditions, and the cellulose derivatives obtained by exchange reaction can provide new chiral packing materials with interesting chiral recognition abilities.更多还原