CN103154723A - 层析用分离剂 - Google Patents
层析用分离剂 Download PDFInfo
- Publication number
- CN103154723A CN103154723A CN2011800494186A CN201180049418A CN103154723A CN 103154723 A CN103154723 A CN 103154723A CN 2011800494186 A CN2011800494186 A CN 2011800494186A CN 201180049418 A CN201180049418 A CN 201180049418A CN 103154723 A CN103154723 A CN 103154723A
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- Prior art keywords
- dinaphthalene
- separating agent
- chromatography
- carrier
- derivatives
- Prior art date
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- Granted
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Abstract
提供一种层析用分离剂,其用于特定化合物的分离,例如用于氨基酸的光学解离。该分离剂具有较高产率,并含有具有类冠醚环状结构和光学活性的联萘。含有具有类冠醚环状结构和光学活性的联萘的该特定层析用分离剂通过以下提供:将载体连接基团引入特定的市售可得且在2、2'、3和3'位具有取代基的1,1'-联萘衍生物中,然后引入类冠醚环状结构,并随后通过使用载体连接基团将联萘衍生物和载体化学键合。
Description
技术领域
本发明涉及一种层析用分离剂并涉及一种含有类冠醚环状结构和有光学活性的联萘的层析用分离剂。
背景技术
已知具有各种特定结构以适应待分离化合物的各种分离剂作为层析用分离剂。例如以下为这些特定结构中已知的:类冠醚环状结构、联萘结构、苯基酯结构和苯基氨基甲酸酯结构。
在含有类冠醚环状结构(crown ether-like cyclic structure)和联萘结构的层析用分离剂的领域内,已知用于光学异构体的分离剂,其中具有类冠醚环状结构(其跨过联萘中单独的萘环而桥接)的联萘衍生物吸附在载体上(参考例如专利文献1)。用于光学异构体的该分离剂适合于具有氨基的化合物(例如氨基酸)的光学解离(optical resolution)。
此外,作为在其中前述联萘衍生物通过化学键合到载体而受支撑的层析用分离剂,其中具有下式(i)或(ii)的联萘衍生物的联萘结构或类冠醚结构通过例如化学键键合到载体表面的层析用分离剂是已知的(参考例如非专利文献1和2及专利文献2)。已知含有式(i)联萘衍生物的层析用分离剂具有对于氨基酸的光学解离能力(optical resolving power),同时已知含有式(ii)联萘衍生物的层析用分离剂缺乏对于氨基酸的光学解离能力。此外,对于含有式(i)联萘衍生物的层析用分离剂,还已知一种技术,其中用作载体的二氧化硅凝胶中的残余硅烷醇基团通过使用正辛基三乙氧基硅烷处理而受保护(例如非专利文献2),且已知对于α-氨基酸、胺和氨基醇的光学解离能力通过该处理得以提高。
[C1]
式(i)联萘衍生物有希望作为对氨基酸光学解离有效的分离剂,而且虽然可使用市售可得的产品作为起始材料将其合成,但是合成路线冗长,而从产率观点来说,留有研究的余地。
引用列表
[专利文献]
专利文献1 日本审查专利公开号H3-57816
专利文献2 韩国专利申请公开号20040080034
[非专利文献]
非专利文献1 J. Chromatogra. A, 910 (2001) 359
非专利文献2 J. Chromatogra. A, 1138 (2007) 169。
发明摘要
技术问题
本发明提供一种含有类冠醚环状结构和有光学活性的联萘的层析用分离剂,其用于特定化合物的分离(例如,用于氨基酸的光学解离),且其提供较高产率。
问题解决方案
本发明人发现了含有类冠醚环状结构和有光学活性的联萘的层析用分离剂可通过以下更容易获得:将与载体结合的取代基团(其将与载体键合)引入到联萘衍生物中,然后将类冠醚环状结构引入联萘衍生物中,并将得到的联萘衍生物化学键合到载体。本发明基于该发现得以实现。
因此,本发明提供一种层析用分离剂,其具有载体和有光学活性的联萘化合物(其通过化学键键合到载体表面),其中联萘化合物由以下式(I)表示。
[C2]
在式(I)中,R1和R2各自表示氢、可能经取代的苯基、可能经取代的萘基、可能经取代的其中任何非相邻亚甲基可能为氧的C1-8烷基、或其中每个烷基中的碳数为1或2的三烷基甲硅烷基;A1和A2各自表示与载体表面键合且取代了联萘环上的氢的基团;且l表示4-6的整数,而m和n各自表示0-5的整数,其中m+n为1-10。
本发明还提供前述层析用分离剂,其中l为4;前述层析用分离剂,其中R1和R2为苯基;前述层析用分离剂,其中A1和A2各自含有由以下式(II)表示的取代了式(I)联萘中的氢的结构;前述层析用分离剂,其中m和n中的一个为1而另一个为0;以及前述层析用分离剂,其中载体表面呈现憎水性。
[C3]
在式(II)中,o表示1-30的整数。
本发明还提供生产层析用分离剂的方法,其包括:步骤B:将与载体结合的取代基团引入到由以下式(III)表示的联萘衍生物A的联萘环中,以获得联萘衍生物B;步骤C:使所述联萘衍生物B的2和2'位的甲氧基水解以获得联萘衍生物C,其中所述甲氧基已转化为羟基;步骤D:用聚乙二醇衍生物交联所述联萘衍生物C中的两个羟基,以获得具有类冠醚环状结构的联萘衍生物D;和步骤E:通过所述联萘衍生物D上所述与载体结合的取代基团将所述联萘衍生物D通过化学键键合到所述载体表面。
[C4]
在式(III)中,R1和R2分别与式(I)中的R1和R2相同。
本发明还提供前述生产方法,其还包括步骤A:用R1和R2分别取代3,3'-二溴-2,2'-二甲氧基-1,1'-联萘中的溴基,以获得所述联萘衍生物A。
本发明还提供前述生产方法,其中所述联萘衍生物B在步骤B中通过使所述联萘衍生物A与C4 - 33脂族二羧酸单甲酯单酰氯在氯化铁存在下反应而获得。
本发明还提供前述生产方法,其中所述联萘衍生物D在步骤D中通过具有5-7个重复氧乙烯基的聚氧乙烯二醇二甲苯磺酸酯在碱性条件下的反应来交联所述联萘衍生物C中的羟基而获得。
本发明还提供前述生产方法,其中在步骤E中,经表面处理的二氧化硅凝胶用于所述载体,且化学键在以下之间实现:所述联萘衍生物D中所述与载体结合的取代基团以及由所述二氧化硅凝胶的表面处理所提供的官能团。
本发明还提供前述生产方法,其还包括步骤F:使所述载体表面上的亲水基团憎水化。
发明的有利作用
因为本发明的层析用分离剂中的联萘衍生物所具有的结构允许首先将与载体结合的取代基团,然后将类冠醚环状结构按此顺序引入联萘衍生物(其在联萘环的2和2'位具有甲氧基)中,所以可提供含有类冠醚环状结构和有光学活性的联萘的层析用分离剂,其用于例如氨基酸的光学解离,且其提供较高产率。
附图简述
图1为显示使用本发明的柱4光学解离丙氨酸的色谱的图;
图2为显示使用本发明的柱4光学解离蛋氨酸的色谱的图;
图3为显示使用本发明的柱4光学解离谷氨酸的色谱的图;且
图4为显示使用本发明的柱4光学解离苯基甘氨酸的色谱的图。
实施方案描述
本发明的层析用分离剂包含载体和有光学活性的联萘化合物(其通过化学键键合到载体表面)。该联萘化合物通过以下式(I)给出。该联萘化合物为S-异构体或R-异构体,但也可能是S-异构体和R-异构体的混合物(在呈现光学解离能力的范围内)。该联萘化合物通常为单一物种,但也包括具有不同的m和/或n值的两个或更多个物种。
[C5]
在式(I)中,R1和R2各自表示氢、可能经取代的苯基、可能经取代的萘基、可能经取代的其中任何非相邻亚甲基可能为氧的C1-8烷基、或其中每个烷基中的碳数为1或2的三烷基甲硅烷基。可能在R1和R2中的苯基等上存在的取代基是不与类冠醚环状结构中的氧原子相互作用的基团,而这种取代基可以是例如甲基和氯基。从提高分离性能的观点来看,R1和R2优选两者都为苯基。
式(I)中的A1和A2各自表示与载体表面键合且取代联萘环上的氢的基团。A1和A2的大小不特别受限;然而,从易于合成和提高分离性能的观点来看,每一个的分子量优选为100-600。A1和A2可由多种基团构造,例如C1-30亚烷基、C6-30亚芳基、醚基、羰基、亚氨基、酰胺基等。
从便于合成上述联萘化合物的观点来看,A1和A2优选各自含有由以下式(II)表示的结构,其替代式(I)联萘中的氢。
[C6]
在式(II)中,o表示1-30的整数。从便于合成和提高分离性能的观点考虑,o优选为4-10。
在式(I)中,l表示4-6的整数。出于包含铵离子的观点,该l更优选为4。
在式(I)中,m和n各自表示0-5的整数。然而,m+n为1-10。出于便于合成联萘化合物的观点,m和n优选两者都至少为1,同时更优选地,m和n中的一个为1而另一个为0。当m或n为0时,这表示与载体没有键合。
可通过化学键使联萘化合物固定的载体可用作考虑范围内的载体。该载体可以是无机载体或有机载体。无机载体可以是例如二氧化硅、氧化铝、氧化镁、玻璃、高岭土、氧化钛、硅酸盐和羟磷灰石。有机载体可以是例如聚苯乙烯、聚丙烯酰胺和聚丙烯酸酯。
载体可按适于特定类型层析的形式使用。载体形式可以是例如颗粒和以液密方式容纳于圆柱形管中的多孔圆柱。
从提高分离性能的观点来看,载体优选为多孔的,且更优选具有100-600m2/g的BET比表面积。对于多孔载体的孔径,从提高分离性能的观点来看,按汞孔率法测量的孔径优选为60-300埃。
例如,考虑到上文提及的性质,二氧化硅凝胶为特别优选的载体。
从便于合成联萘化合物的观点来看,优选用表面处理试剂使载体经受表面处理,以在载体表面上形成官能团(其将组成式(I)中A1和/或A2的一部分)。可适当选择该表面处理试剂,以与载体类型相适应。
例如当载体为二氧化硅凝胶时,硅烷偶联剂可用作表面处理试剂。该硅烷偶联剂可以是例如3-氨基丙基三乙氧基硅烷,和3-(2-氨基乙基氨基丙基)三甲氧基硅烷。
从提高分离性能的观点来看,载体表面优选呈现憎水性。这种载体可以是例如其表面已用憎水基团处理的载体。
本发明的层析用分离剂经适当处理以适应层析类型而使用。例如,在用于柱层析的情况下,本发明的层析用分离剂被填充或容纳在圆柱形管中。在用于薄层层析的情况下,当用作例如颗粒分离剂时,使用本发明的层析用分离剂以在基底(例如玻璃板或塑料板)的表面上形成为薄层。该处理可通过普通方法进行。
不考虑联萘化合物的光学性质,本发明的层析用分离剂可用于分离不同于光学异构体的特定化合物,但所述特定化合物与联萘化合物的结构相互作用。当用于不同于光学异构体的化合物的这种分离时,联萘化合物可以甚至是S-异构体和R-异构体的混合物,其程度为不呈现光学解离能力(例如其可以为外消旋体)。
本发明的层析用分离剂可由包含以下的方法生产:步骤B:将与载体结合的取代基团引入到由以下式(III)表示的联萘衍生物A的联萘环中,以获得联萘衍生物B;步骤C:使所述联萘衍生物B的2和2'位的甲氧基水解以获得联萘衍生物C,其中这些甲氧基已转化为羟基;步骤D:用聚乙二醇衍生物交联所述联萘衍生物C中的两个羟基,以获得具有类冠醚环状结构的联萘衍生物D;和步骤E:通过所述联萘衍生物D上所述与载体结合的取代基团将所述联萘衍生物D通过化学键键合到所述载体表面。
[C7]
式(III)中的R1和R2与式(I)中的R1和R2相同。联萘衍生物A可作为市售可得的产品而获得。这种市售可得的产品可以是例如2,2'-二甲氧基-1,1'-联萘和3,3'-二溴-2,2'-二甲氧基-1,1'-联萘(两者为Tokyo Chemical Industry Co., Ltd.的产品)。出于便于合成联萘化合物的观点,这种市售可得的产品的使用是优选的。
还可通过合成获得联萘衍生物A。例如,联萘衍生物A可通过从3,3'-二溴-2,2'-二甲氧基-1,1'-联萘合成而获得。从产生联萘化合物中R1和R2多样性的方面来看,本发明的这种方法还优选包含步骤A:用R1和R2分别取代3,3'-二溴-2,2'-二甲氧基-1,1'-联萘中的溴基,以获得所述联萘衍生物A。
步骤B提及的与载体结合的取代基团可以是与载体表面上的官能团键合的基团,或可以是直接与载体表面键合的基团。与载体结合的取代基团可以是单个物种或两个或更多个物种。可存在至少一个与载体结合的取代基团,或可存在两个或更多个。当有两个或更多个与载体结合的取代基团时,与载体结合的取代基团可以与联萘中两个萘环中的仅一个键合,或可以与两个都键合。从便于联萘衍生物D和载体之间键合的观点来看,与载体结合的取代基团优选为与通过载体的表面处理所提供的官能团键合的基团。
优选的步骤B的实例为以下步骤:其中联萘衍生物B通过使联萘衍生物A与C4 - 33脂族二羧酸单甲酯单酰氯在氯化铁存在下反应而获得。
倘若联萘的2和2'位也在联萘衍生物B中具有高的反应性,步骤C可通过中等温度条件下的反应进行。这些反应条件可以是例如在室温下或在冰浴上的以三溴化硼为媒介的脱烷基反应。在这些条件下执行步骤C是优选的,因为这抑制对联萘衍生物B中其它结构的影响,并以更好的收率提供联萘衍生物C。
可使用诱导聚氧乙烯跨过联萘衍生物C的2和2'位的羟基而交联的条件来进行步骤D。可利用水解来进行这种交联:例如,其可通过在碱性条件下具有5-7个重复氧乙烯基的聚氧乙烯二醇二甲苯磺酸酯的反应而进行。
可使用和与载体结合的取代基团的类型以及载体的类型相适应的已知技术类型来适当进行步骤E。例如,当经表面处理的二氧化硅凝胶用作载体时,步骤E可通过以下进行:使联萘衍生物D中与载体结合的取代基团与产生于二氧化硅凝胶的表面处理的官能团之间产生化学键。该化学键可通过使用偶联剂进行反应而实现,比如,所述偶联剂为例如1-乙基-3-(3-二甲基氨基丙基)碳二酰亚胺盐酸盐(WSC)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、1H-苯并三唑-1-基氧基三吡咯烷六氟磷酸盐(PyBop)或4-(4,6-二甲氧基-1,3,5-三吖嗪-2-基)-4-甲基吗啉氯化物·nH2O(DMT-MM)。
在每个特定步骤获得的联萘衍生物可经纯化,或产物可用作例如随后步骤的起始材料。
本发明还可包含步骤F:使载体表面上的亲水基团憎水化。步骤F优选在步骤E后进行。步骤F可通过具有憎水有机基团或憎水剂(其与载体表面上的亲水基团反应以形成憎水基团)的表面处理试剂对载体或步骤E的产物的作用而进行。载体表面上的亲水基团可以是,例如,存在于载体(例如二氧化硅凝胶)表面上和/或在上述表面处理之后存在于载体表面上的羟基和/或氨基。
具有憎水有机基团的表面处理试剂可以是例如六甲基二硅氮烷、正十八烷基三乙氧基硅烷和正十八烷基三甲氧基硅烷。上文提及的憎水剂可作适当选择以与亲水基团类型相适应,而对于氨基的情况,所述憎水剂可以是例如醋酸酐、癸酸和硬脂酸。在载体表面上通过步骤F形成的憎水基团优选以和上述(A1)m和(A2)n相同或类似的结构构造,并处于相同的尺度。
根据本发明的方法,每个单独步骤中的反应为一阶段反应,而且,除步骤F以外,本发明的层析用分离剂在不包括联萘衍生物A的合成时可分四阶段反应而获得,在包括合成联萘衍生物A的步骤A时分五阶段反应而获得。
实施例
手性冠醚(1)的合成
在氮气流下操作,将0.946g (S)-3,3’-二溴-2,2’-二甲氧基-1,1’-联萘、0.736 g苯基硼酸和24.8 mg四(三苯基膦)钯(Pd(PPh3)4)溶于20mL甲苯。向此添加7mL碳酸钾饱和水溶液并在100℃下进行加热4小时。此后,用饱和的含水氯化钠洗涤反应溶液并用醋酸乙酯萃取。获得的有机相经无水MgSO4干燥并浓缩以获得粗产物,其通过二氧化硅凝胶柱层析纯化以获得由以下结构式给出的二甲基醚(1-1)。
[C8]
将537mg甲基己二酰氯溶于6mL二氯甲烷,然后添加411mg氯化铁(III)并在室温下进行搅拌1小时。将该溶液逐滴添加到溶于15mL二氯甲烷的466mg(1-1),然后在室温下进行搅拌24小时。此后,添加饱和的重碳酸钠水溶液和醋酸乙酯并在室温下搅拌然后分离。用饱和含水氯化钠洗涤获得的有机相,经无水MgSO4干燥,并浓缩以获得粗产物,其通过二氧化硅凝胶柱层析纯化以获得由以下结构式给出的酰化产物(1-2)。
[C9]
将599mg(1-2)溶于25mL二氯甲烷;在冰浴上逐滴添加BBr3的12mL 1M二氯甲烷溶液;并在室温下进行搅拌1小时。此后,逐滴添加10mL甲醇;在减压下将溶液浓缩;用醋酸乙酯进行萃取;用饱和的含水氯化钠洗涤获得的有机相,经无水MgSO4干燥,并浓缩以提供粗产物;且粗产物通过二氧化硅凝胶柱层析纯化以获得由以下结构式给出的联萘(1-3)。
[C10]
将53.2mg氢氧化钾添加到100mg(1-3),然后添加溶于10mL四氢呋喃的111mg五亚乙基二醇二甲苯磺酸酯并在80℃下搅拌4小时。此后,于室温添加2mL的10%氢氧化钠水溶液和10mL甲醇;在室温下进行搅拌30分钟;然后用2N盐酸进行中和;在减压下浓缩溶液并用醋酸乙酯萃取;获得的有机相经无水MgSO4干燥并浓缩,且获得的粗产物通过二氧化硅凝胶柱层析纯化以获得由以下结构式表示的手性冠醚(1)。
[C11]
固相(1)的合成
将508mg合成的手性冠醚(1)、156mg 1-乙基-3-(3-二甲基氨基丙基)碳二酰亚胺盐酸盐(WSC)、123mg 1-羟基-1H-苯并三唑一水合物(HOBt)和3.31g 3-氨基丙基二氧化硅凝胶(平均粒径=5μm,平均孔径=120埃,表面积=330m2/g)溶于66mL N,N'-二甲基甲酰胺(DMF)并在室温下进行搅拌24小时。然后,将通过过滤获得的固体相继用DMF、稀盐酸/甲醇溶液和甲醇每种20mL洗涤三次并干燥。将2.00g获得的固体和61.3mg 4-二甲基氨基吡啶溶于10mL二氯甲烷;从中添加溶于10mL二氯甲烷的567mg醋酸酐;并在室温下进行搅拌5小时。然后将通过过滤获得的固体相继用二氯甲烷和甲醇每种20mL洗涤两次,并干燥以获得根据本发明的固相(1)。由元素分析结果计算得到,每1g固相键合有约0.083mmol手性冠醚(1)。
固相(2)的合成
将1.29g 3-氨基丙基二氧化硅凝胶(平均粒径=5μm,平均孔径=120埃,表面积=330m2/g)溶于10mL DMF,并添加溶于15mL DMF的462mg合成手性冠醚(1)、342mg O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)和99.5mg N-甲基吗啉,并在室温下进行搅拌24小时。然后,将通过过滤获得的固体相继用DMF、稀盐酸/甲醇溶液和甲醇每种25mL洗涤三次,然后用25mL DMF另外洗涤三次(70℃,1小时),然后用25mL甲醇洗涤三次(50℃,1小时),并干燥以获得固相(2)。由元素分析结果计算得到,每1g固相键合有约0.30mmol手性冠醚(1)。
固相(3)的合成
将602mg固相(2)溶于24mL干燥的甲苯;添加1.0mL 1,1,1,3,3,3-六甲基二硅氮烷;并在136℃下进行搅拌6小时。然后将通过过滤获得的固体相继用甲苯、醋酸乙酯和甲醇每种15mL洗涤三次,并干燥以获得固相(3)。
固相(4)的合成
将593mg固相(2)溶于5mL DMF;添加溶于5mL DMF的55.1mg醋酸、245mg HATU和68.4mg N-甲基吗啉;在室温下进行搅拌24小时。然后,将通过过滤获得的固体相继用DMF、稀盐酸/甲醇溶液和甲醇每种15mL洗涤三次,然后用15mL DMF另外洗涤三次(70℃,1小时),然后用15mL甲醇洗涤三次(50℃,1小时),并干燥以获得固相(4)。
固相(5)的合成
将552mg固相(2)溶于5mL DMF;添加溶于5mL DMF的69.0mg癸酸、228mg HATU和62.2mg N-甲基吗啉;并在室温下进行搅拌24小时。然后,将通过过滤获得的固体相继用DMF、稀盐酸/甲醇溶液和甲醇每种15mL洗涤三次,并干燥以获得固相(5)。
固相(6)的合成
将553mg固相(2)溶于5mL DMF;添加溶于5mL DMF的114mg硬脂酸、228mg HATU和69.2mg N-甲基吗啉;并在室温下进行搅拌24小时。然后,将通过过滤获得的固体相继用DMF、稀盐酸/甲醇溶液和甲醇每种15mL洗涤三次,并干燥以获得固相(6)。
柱(1)-(6)的生产
使用浆料填充(slurry packing)方法,通过将固相(1)-(6)填充在具有2.1mm内径和15cm长度的圆柱形管中而获得。
评价
将样品溶解在用于测量的每一个流动相中,以提供样品浓度为约1mg/1mL的溶液,并在下文说明的条件下通过HPLC分析,并测定保留因子、分离因子和分离度。结果在表1-表6中给出。
条件
A—1: 高氯酸水溶液 (pH 1.5), 25℃
A—2: 高氯酸水溶液 (pH 1.5), 0℃
B—1: 高氯酸水溶液 (pH 1.5)/甲醇 = 80/20 (v/v), 25℃
B—2: 高氯酸水溶液 (pH 1.5)/甲醇 = 70/30 (v/v), 25℃
B—3: 高氯酸水溶液 (pH 1.5)/甲醇 = 60/40 (v/v), 25℃
B—4: 高氯酸水溶液 (pH 1.5)/甲醇 = 50/50 (v/v), 25℃
B—5: 高氯酸水溶液 (pH 1.5)/甲醇 = 80/20 (v/v), 0℃
C—1: 高氯酸水溶液 (pH 1.5)/乙腈 = 95/5 (v/v), 25℃
C—2: 高氯酸水溶液 (pH 1.5)/乙腈 = 90/10 (v/v), 25℃
C—3: 高氯酸水溶液 (pH 1.5)/乙腈 = 80/20 (v/v), 25℃
C—4: 高氯酸水溶液 (pH 1.5)/乙腈 = 70/30 (v/v), 25℃
C—5: 高氯酸水溶液 (pH 1.5)/乙腈 = 90/10 (v/v), 0℃
C—6: 高氯酸水溶液 (pH 1.5)/乙腈 = 80/20 (v/v), 0℃
D: 己烷/乙醇/三氟乙酸/水 = 50/50/0.5/0.5 (v/v), 25℃。
以下表格中的保留因子、分离因子和分离度各自定义如下。
[算式1]
保留因子={(对映体的保留时间)-(死时间)}/死时间
用于表1-表5的死时间使用草酸钠测量,而用于表6的死时间使用1,3,5-三叔丁基苯(ttb)测量。
[算式2]
分离因子 = 较强吸收的对映体的保留因子/较弱吸收的对映体的保留因子。
[算式3]
分离度 = 2×(较强吸收的对映体和较弱吸收的对映体的两个峰之间的距离)/两个峰的带宽之和。
表1
表2
表3
表4
用柱4光学解离
(高氯酸水溶液/甲醇流动相)
表5
用柱4光学解离
(高氯酸水溶液/乙腈流动相)
表6
用柱2光学解离
(己烷/乙醇流动相)
工业适用性
层析用分离剂,其含有联萘衍生物和类冠醚环状结构,使之可能通过像例如引入联萘中的取代基的类型和类冠醚环状结构的大小这些因素来调节分离特征。因为本发明能更容易合成(使用如现有技术中约一半的步骤)具有联萘衍生物和类冠醚环状结构的层析用分离剂,所以强烈预期本发明将允许和支持该分离剂的分离特征的进一步说明以及呈现新颖分离能力的分离剂的开发。
Claims (12)
1. 一种层析用分离剂,其具有载体和有光学活性的联萘化合物,所述联萘化合物通过化学键键合到所述载体表面,其中所述联萘化合物由以下式(I)表示:
[C1]
在式(I)中,R1和R2各自表示氢、可能经取代的苯基、可能经取代的萘基、可能经取代的其中任何非相邻亚甲基可能为氧的C1-8烷基、或其中每个烷基中的碳数为1或2的三烷基甲硅烷基;
A1和A2各自表示与所述载体表面键合且取代了联萘环上的氢的基团;且
l表示4-6的整数,而m和n各自表示0-5的整数,其中m+n为1-10。
2. 权利要求1的层析用分离剂,其中l为4。
3. 权利要求1或2的层析用分离剂,其中R1和R2为苯基。
5. 权利要求1-4中任一项的层析用分离剂,其中m和n中的一个为1而另一个为0。
6. 权利要求1-5中任一项的层析用分离剂,其中所述载体表面呈现憎水性。
7. 一种生产层析用分离剂的方法,其包含:
步骤B:将与载体结合的取代基团引入到由以下式(III)表示的联萘衍生物A的联萘环中,以获得联萘衍生物B;
步骤C:使所述联萘衍生物B的2和2'位的甲氧基水解以获得联萘衍生物C,其中所述甲氧基已转化为羟基;
步骤D:用聚乙二醇衍生物交联所述联萘衍生物C中的两个羟基,以获得具有类冠醚环状结构的联萘衍生物D;和
步骤E:通过所述联萘衍生物D上的所述与载体结合的取代基团将所述联萘衍生物D通过化学键键合到所述载体表面,
[C3]
在式(III)中,R1和R2各自表示氢、可能经取代的苯基、可能经取代的萘基、可能经取代的其中任何非相邻亚甲基可能为氧的C1-8烷基、或其中每个烷基中的碳数为1或2的三烷基甲硅烷基。
8. 权利要求7的生产层析用分离剂的方法,其还包含:
步骤A:用R1和R2分别取代3,3'-二溴-2,2'-二甲氧基-1,1'-联萘中的溴基,以获得所述联萘衍生物A。
9. 权利要求7或8的生产层析用分离剂的方法,其中所述联萘衍生物B在步骤B中通过使所述联萘衍生物A与C4 - 33脂族二羧酸单甲酯单酰氯在氯化铁存在下反应而获得。
10. 权利要求7-9中任一项的生产层析用分离剂的方法,其中所述联萘衍生物D在步骤D中通过具有5-7个重复氧乙烯基的聚氧乙烯二醇二甲苯磺酸酯在碱性条件下的反应来交联所述联萘衍生物C中的羟基而获得。
11. 权利要求7-10中任一项的生产层析用分离剂的方法,其中在步骤E中,经表面处理的二氧化硅凝胶用于所述载体,且化学键在以下之间实现:所述联萘衍生物D中所述与载体结合的取代基团以及由所述二氧化硅凝胶的表面处理所提供的官能团。
12. 权利要求7-11中任一项的生产层析用分离剂的方法,其还包含:
步骤F:使所述载体表面上的亲水基团憎水化。
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KR100364255B1 (ko) | 2000-09-08 | 2002-12-12 | 현명호 | 생리활성 라세미 일차 아미노 화합물의 광학분할을 위한lc용 크라운 에테르 키랄고정상 및 이들로 충진된키랄칼럼 |
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US7557064B2 (en) | 2007-08-13 | 2009-07-07 | Headwaters Technology Innovation, Llc | Methods for making immobilized aryl-containing ligands |
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EP2629091A1 (en) | 2013-08-21 |
US20130204014A1 (en) | 2013-08-08 |
KR101930097B1 (ko) | 2018-12-17 |
KR20130111563A (ko) | 2013-10-10 |
JP5940979B2 (ja) | 2016-06-29 |
JPWO2012050124A1 (ja) | 2014-02-24 |
CN103154723B (zh) | 2015-11-25 |
EP2629091B1 (en) | 2019-03-20 |
US9145430B2 (en) | 2015-09-29 |
WO2012050124A1 (ja) | 2012-04-19 |
EP2629091A4 (en) | 2014-04-02 |
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