CN1042418C - 旋光异构体分离剂、其制法及用途 - Google Patents

旋光异构体分离剂、其制法及用途 Download PDF

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CN1042418C
CN1042418C CN94190414A CN94190414A CN1042418C CN 1042418 C CN1042418 C CN 1042418C CN 94190414 A CN94190414 A CN 94190414A CN 94190414 A CN94190414 A CN 94190414A CN 1042418 C CN1042418 C CN 1042418C
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村上达史
市田昭人
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Abstract

在硅胶等载体上，用多官能交联剂使多糖衍生物只在自身分子之间交联，从而使多糖衍生物固定在载体上。用这种方法制造的旋光异构体分离剂耐溶性性优异，最适合作为光学拆开分离剂。

Description

旋光异构体分离剂、其制法及用途
本发明涉及旋光异构体分离剂及其制备方法，更具体地说，涉及借助于使载体上的多糖衍生物只在自身分子之间交联得到的、可用作外消旋体光学拆开剂的分离剂及其制备方法。
在硅胶上载带了多糖衍生物的填充剂已知可用来作为外消旋旋光异构体的分离剂(Y.Okamoto,M.Kawashima和K.Hatada,J.Am.Chem.Soc.,106,P.5357,1984)。然而，这样的分离剂由于是只靠涂布而简单地把多糖衍生物载带在硅胶上，所以耐溶剂性差。因此，当用这种分离剂作为液体色谱法填充剂时，有一些洗脱液不能使用。
因而，需要一种在载体上载带了多糖衍生物且耐溶剂性良好的分离剂。
本发明者等人深入研究了既不损害多糖衍生物所具有的优异性能又克服了上述缺点的分离剂，从而实现了本发明。
本发明提供一种旋光异构体的色谱分离用的分离剂，它包括载体和多糖衍生物。该载体是表面已经失活的硅胶，其粒径为1μm-10mm，孔径为10-100μm。该多糖衍生物是每个葡萄糖单元有至少0.1个未反应羟基的纤维素或直接淀粉的酯或氨基甲酸酯衍生物。用二异氰酸酯衍生物的多官能交联剂，使多糖衍生物的分子在该载体上互相交联，借此使多糖衍生物固定于载体上。上述分离剂的制法包括用二异氰酸酯衍生物的多官能交联剂，使只有多糖衍生物的分子在载体上互相交联的步骤。此外，本发明分离剂可用作色谱柱的填料。
本发明中的多糖，只要是有光学活性，不管是合成多糖、天然多糖还是改性天然多糖，任何一种均可，但结合方式规整性高的多糖较好。多糖的实例包括：β-1,4-葡聚糖(纤维素)、α-1,4-葡聚糖(直链淀粉、支链淀粉)、α-1,6-葡聚糖(右旋糖酐)、β-1,6-葡聚糖(Bustulan)、β-1,3-葡聚糖(例如Curdlan,Schizophyllan等)、α-1,3-葡聚糖、β-1,2-葡聚糖(CrownGall多糖)、β-1,4-半乳聚糖、β-1,4-甘露聚糖、α-1,6-甘露聚糖、β-1,2-Fructan(旋复花粉)、β-2,6-Fructan(果聚糖)、β-1,4-木聚糖、β-1,3-木聚糖、β-1,4-聚氨基葡糖、β-1,4-N-乙酰聚氨基葡糖(壳多糖)、支链淀粉、琼脂糖、藻酸等。此外，含有直链淀粉的淀粉等也属于多糖类。其中，可容易地以高纯度状态得到的纤维素、直链淀粉、β-1,4-聚氨基葡糖、壳多糖、β-1,4-甘露聚糖、β-1,4-木聚糖、旋复花粉、Curdlan等较好，而纤维素、直链淀粉尤其好。
多糖的数均聚合度(一分子中所含的吡喃糖或呋喃糖环的平均数)是5以上，较好是10以上。多糖的数均聚合度无具体上限，但就加工性能而言，500以下者较好。
作为本发明中使用的多糖衍生物的实例，可以列举使如上所述的多糖与具有能与此类多糖的羟基反应的官能团的化合物用众所周知的方法反应得到的，原料多糖的部分羟基已成为酯键或聚氨酯键的化合物。
其中，作为具有能与羟基反应的官能团的化合物的实例，包括异氰酸衍生物、羧酸、酯、酰卤、酰胺、卤化物、环氧化物、醛、醇及其它有离去基团的化合物，它们可以是脂族化合物、脂环族化合物、芳族化合物、杂芳族化合物中的任何一种。
本发明中，作为可供交联反应的多糖衍生物，尤其好的是纤维素或直链淀粉的酯或氨基甲酸酯衍生物，其中每个葡萄糖单元有0.1个以上未反应羟基，且在所引进的基团中每个葡萄糖单元有0.1个以上反应性官能团，从而使纤维素或直链淀粉能转变成其酯或氨基甲酸酯衍生物。其中，作为反应性官能团，可以列举诸如羟基、氨基、巯基、羧基、乙烯基。
作为本发明中所用的载体实例，可以列举对其表面进行了失活处理从而使之不与交联剂反应的多孔有机载体和多孔无机载体，较好是多孔无机载体。作为多孔有机载体，适用的有聚苯乙烯、聚丙烯酰胺、聚丙烯酸酯等高分子物质形成的载体，面作为多孔无机载体，适用的有硅胶、二氧化硅、氧化镍、氧化镁、玻璃、高岭土、二氧化钛、硅酸盐等。尤其好的载体是硅胶，其粒径是1μm～10mm，较好是1～1000μm，更好的是1～300μm，其平均孔径是10～100μm，较好是50～50000。硅胶表面的失活处理可以用众所周知的方法实施。
在本发明中，作为可用来使多糖衍生物只在其自身分子之间交联的多官能交联剂，可以列举诸如多官能异氰酸酯衍生物、二羧酸的酰氯衍生物、二环氧衍生物、二乙烯基衍生物。这些交联剂既可以是脂族类化合物，也可以是芳族类化合物。作为多官能交联剂，特别好的二异氰酸酯衍生物。
在本发明中，使纤维素或直链淀粉的6位羟基彼此发生选择性交联得到的交联多糖衍生物所组成的交联体尤其好。
多糖衍生物的交联率较好是1～20％。这里的交联率系指当多糖衍生物中未反应的羟基或反应性官能团与多官能交联剂的官能团按1∶1的比例反应时，相对于原料多糖所具有的全部羟基而言，参与交联反应的未反应羟基和/或反应性官能团的比例。
为了使多糖衍生物中的羟基彼此交联、反应性官能团彼此交联或羟基与反应性官能团交联，必须使多糖衍生物载带(固定)在事先对其表面进行了失活处理的载体上。作为固定方法的实例，可以列举多糖衍生物溶液对载体的涂布。此外，在载体上固定的多糖衍生物数量，以载体重量为基准，较好是1～100％(重量)，尤其好的是5～60％(重量)。
以下说明本发明分离剂制备方法的一个实例。
使纤维素与三苯甲基氯反应，得到6-O-三苯甲基纤维素。所得到的三苯甲基纤维素与具有能与羟基反应的官能团的化合物用众所周知的方法反应，使三苯甲基纤维素的羟基与具有能与羟基反应的官能团的化合物的那些官能团形成酯键或聚氨酯键。所得到的纤维素衍生物用盐酸等酸处理，以消除其三苯甲基，从而得到本发明所涉及的纤维素衍生物。所得到的，本发明所涉及的纤维素衍生物溶解在溶剂中，将所得到的溶液涂布到已使其表面失活的硅胶上，形成已涂布了纤维素衍生物的硅胶。在干燥的惰性溶剂中，使已涂布了纤维素衍生物的硅胶上的纤维素衍生物与多官能异氰酸酯衍生物反应，以使纤维素衍生物在自身分子之间发生交联。这样，便能得到在硅胶上固定了纤维素衍生物的本发明分离剂。
在本发明中，作为使载体上的多糖衍生物只在自身分子之间交联从而使多糖衍生物固定在载体上的方法，包括利用多糖衍生物的原料多糖中原有的羟基部分进行交联的方法，和利用在使多糖形成其衍生物时引进的基团所具有的反应性官能团部分进行交联的方法，但在前一种方法中还包含以下反应式所示的方法。
在利用在使多糖形成其衍生物时引进的基团所具有的反应性官能团部分进行交联的情况下，在上述反应式所示的各种方法中，也可以增加引进具有反应性官能团的取代基的步骤。这就是说，在交联前使多糖转化成衍生物时，也可以使除了能与多糖的羟基反应的官能团外还具有其它反应性官能团的化合物与多糖或已对特定羟基进行了保护的多糖衍生物反应。
用这种方法得到的本发明分离剂，由于把载体包含在用多官能交联剂使多糖衍生物自身分子之间彼此交联而得到的交联多糖衍生物内，因而形成了载体不会与交联多糖衍生物脱离的结构。
本发明的光学异构体分离剂一般可用于气相色谱法、液体色谱法、薄层色谱法等色谱法，但尤其好的是适用于液体色谱法。这就是说，本发明的光学异构体分离剂可在各种色谱法中用作填充剂。
若使用本发明的光学异构体分离剂，则可使光学异构体混合物彼此分离。
本发明的分离剂耐溶剂性优异，因而最适合用作光学拆开分离剂。
实施例
以下参照实施例详细说明本发明，但本发明不只限于这些实施例。
实施例1
(1)硅胶表面的失活处理
多孔硅胶(Daiso SP-1000)用众所周知的方法进行氨基丙基硅烷处理(APS处理)。在1000ml二氯甲烷中，在室温下，使200g所得到的APS-硅胶与15ml异氰酸3,5-二甲苯酯反应1.5小时。所得到的生成物用玻璃过滤器过滤，用二氯甲烷/甲醇(2/1)混合物、二氯甲烷、乙醇、丙酮、正己烷依次洗涤、干燥，得到已对其表面进行了失活处理的硅胶。
(2)纤维素衍生物[纤维素的6-羟基-2,3-二(氨基甲酸3,5-二甲基苯酯)衍生物]的合成
在氮气氛下，使4.0g具有每个葡萄糖单元约0.9～1个三苯甲基的三苯甲基纤维素溶于无水吡啶中，在所得到的溶液中添加10ml异氰酸3,5-二甲基苯酯。在氮气氛下，所得到的混合物在100℃加热搅拌25小时，向所得到的反应混合物中注入700ml甲醇。用玻璃过滤器滤出所析出的固体，用乙醇、正己烷依次洗涤、干燥。然后，将其固体放进加入了浓盐酸的甲醇中，搅拌所得到的混合物，使反应生成物中的三苯甲基消除。用玻璃过滤器滤出固体，用乙醇、正己烷依次洗涤、干燥，得到纤维素的6-羟基-2,3-二(氨基甲酸3,5-二甲基苯酯)衍生物。
(3)载带了纤维素衍生物的硅胶的制备
把1.5g上述(2)得到的纤维素衍生物溶解在四氢呋喃中。所得到的溶液与5.7g上述(1)得到的硅胶一起摇荡均匀，蒸出溶剂，使纤维素衍生物载带在硅胶上。所得到的生成物用甲醇、乙醇、正己烷依次洗涤、干燥，得到载带了纤维素衍生物的硅胶。
(4)纤维素衍生物依靠仅在自身分子之间的交联反应固定到硅胶上
在6.7g上述(3)得到的载带了纤维素衍生物的硅胶中添加35ml用金属钠干燥的甲苯(以下称无水甲苯)，再添加110mg二苯甲烷二异氰酸酯。所得到的混合物在110℃加热搅拌6小时。反应结束后，生成物用玻璃过滤器过滤，用四氢呋喃、甲醇、乙醇、正己烷依次洗涤后干燥，得到在硅胶上固定了纤维素衍生物的分离剂。
(5)固定在硅胶上的纤维素衍生物中未反应羟基的改性
在上述(4)得到的分离剂中添加25ml无水甲苯、15ml无水吡啶，再添加0.5ml异氰酸3,5-二甲基苯酯。所得到的混合物在110℃加热搅拌15小时。反应结束后，生成物用玻璃过滤器滤出，用四氢呋喃、甲醇、乙醇、正己烷依次洗涤、干燥，从而使固定在硅胶上的纤维素衍生物的未反应羟基发生氨基甲酰化。
硅胶上的纤维素衍生物载带量是大约19％(纤维素的葡萄糖单元所具有的羟基3个中有2.5个被氨基甲酰化，以此来计算在硅胶上的载带量)。
比较例1
(依靠多糖衍生物自身分子之间交联和多糖衍生物与硅胶之间交联使多糖衍生物固定在硅胶上的分离剂的制备)
把1.8g具有每个葡萄糖单元约0.9～1个三苯甲基的三苯甲基纤维素溶解在四氢呋喃中。所得到的溶液与6.0g进行了氨基丙基硅烷处理的硅胶(Daiso公司制)一起摇匀，蒸出溶剂，使三苯甲基纤维素载带在硅胶上。向这种硅胶中注入75ml甲醇、0.75ml浓盐酸，所得到的混合物在室温静置过夜，除去纤维素中的三苯甲基。过滤生成物，用甲醇洗涤。向其中添加75ml甲醇、0.75ml三乙胺，所得到的混合物搅拌5分钟。过滤生成物，用甲醇洗涤、干燥。
在氮气氛下，向3.4g如上所述得到的吸附了纤维素的硅胶中添加在6.5ml无水甲苯中溶解了49.3mg 4,4′-二苯甲烷二异氰酸酯的溶液，再添加2.5ml无水吡啶。所得到的混合物在60℃加热搅拌。5小时后，向其中加入20ml无水吡啶和0.75ml异氰酸3,5-二甲基苯酯，此后在110℃加热。18小时后，所得到的反应混合物用玻璃过滤器过滤，滤出物用四氢呋喃洗涤，在其干燥前用甲醇、乙醇、正己烷依次洗涤、干燥，得到了依靠多糖衍生物自身分子之间交联和多糖衍生物与硅胶交联两种方式把多糖衍生物固定在硅胶上的分离剂。
硅胶上的纤维素衍生物载带量是大约18％(纤维素的葡萄单元所具有的羟基3个中有2.5个被氨基甲酰化，以此来计算硅胶上的载带量)。
比较例2
(在硅胶上涂布了纤维素三(氨基甲酸3,5-二甲基苯酯)的分离剂的制备)
在氮气氛下，把3.5kg纤维素(聚合度约300)加进56升吡啶中在100℃向其中添加相对于纤维素大大过量的异氰酸3,5-二甲基苯酯(23.1kg)。所得到的混合物在105℃搅拌、反应12小时。然后，将此反应液冷却，向其中加入3升甲醇。把所得到的混合物投入160升甲醇中。生成的沉淀物通过过滤回收后干燥，得到11.8kg纤维素三(氨基甲酸3,5-二甲基苯酯)(收率88％)。
720g所得到的纤维素三(氨基甲酸3,5-二甲基苯酯)溶于4.7升丙酮中，所得到的溶液边搅拌边滴加到2,880g用3-氨基丙基硅烷处理的硅胶(Daiso SP-1000)中。所得到的混合物完全混合后，蒸出溶剂，得到3,580g分离剂。
应用例1
用实施例1制备的，由固定在硅胶上的多糖衍生物组成的分离剂作为填充剂，用淤浆填充法装填到长25cm、内径0.46cm的不锈钢色谱柱中，制作成光学拆开柱。
这种柱就这样使用，或用各种有机溶剂洗涤后使用，进行表1所示各种外消旋体的光学拆开。高效液体色谱法(HPLC)使用的是日本分光公司制造的JASCO 875-UV型色谱仪。在洗脱液流速为1.0ml/分钟、温度为25℃的条件下进行实验。
结果表示在表1中。
此外，表中所示用语的定义如下。
Figure C9419041400131
Figure C9419041400132
Figure C9419041400133
应用例2
用比较例1制备的分离剂作为填充剂，用淤浆填充法装填到长10cm、内径0.46cm的不锈钢色谱柱中，制作成分离柱。
所得到的分离柱用各种有机溶剂洗涤后，用来进行表1中所示各种外消旋体的光学拆开。高效液体色谱法(HPLC)使用的是日本分光公司制造的JASCO 875-UV型色谱仪。在洗脱液流速为0.4ml/分钟、温度为25℃的条件下进行实验。
结果表示在表1中。
表1
Figure C9419041400141
注：1)实施例1制作的分离柱；
洗脱液∶己烷/异丙醇=9/1(体积比)。
2)实施例1制作的分离柱，用四氢呋喃、丙酮、甲醇以
1.0ml/分钟的流速各洗涤30分钟；
洗脱液∶己烷/异丙醇=9/1(体积比)。
3)比较例1制作的分离柱，用四氢呋喃、丙酮以1.0ml/
/分钟的流速各洗涤30分钟；
洗脱液∶己烷/异丙醇=9/1(体积比)。
应用例3
用比较例2制备的分离剂作为填充剂，用淤浆填充法装填到长25cm、内径0.46cm的两根不锈钢色谱柱中，制成两根光学拆开柱。
一根柱按原样用于进行表2所示各种外消旋体的光学拆开实验，得到表2的结果。在洗脱液为己烷/异丙醇(9/1，体积比)混合物，洗脱液流速为1.0ml/分钟、温度为25℃的条件下进行实验。
另一根柱依次用己烷/异丙醇/四氢呋喃的4种混合物(体积混合比=9/1/1、9/1/2、9/1/4、9/1/8)和甲醇各洗涤30分钟，然后用于进行表2所示各种外消旋体的光学拆开实验，得到表2的结果。实验条件是：洗脱液为己烷/异丙醇(9/1,体积比)混合物，洗脱液流速为1.0ml/分钟、温度为25℃。
表2
Figure C9419041400161

Claims (6)

1．一种旋光异构体的色谱分离用的分离剂，它包括载体和多糖衍生物，所述载体是一种表面已经失活的硅胶，该硅胶的粒径为1μm-10mm，孔径为10-100μm，所述多糖衍生物是每个葡萄糖单元有至少0.1个未反应羟基的纤维素或直链淀粉的酯或氨基甲酸酯衍生物，所述多糖衍生物是用二异氰酸酯衍生物的多官能交联剂，使多糖衍生物的分子在该载体上相互进行交联，借此使所述多糖衍生物固定在载体上。
2．根据权利要求1所述的分离剂，其中，交联前的多糖衍生物是纤维素或直链淀粉的酯或氨基甲酸酯衍生物，且在引入该酯或氨基甲酸酯衍生物的基团中，每个葡萄糖单元有至少0.1个反应性官能团，从而使其转化为其酯或其氨基甲酸酯的衍生物。
3．一种权利要求1所述分离剂的制备方法，它包括以下的步骤，
用二异氰酸酯衍生物的多官能交联剂，使多糖衍生物的分子只与多糖衍生物的分子在载体上进行相互交联。
4．根据权利要求3所述的制备方法，其中，所述多糖衍生物在进行交联之前，是纤维素或直链淀粉的酯或氨基甲酸酯，所述酯或氨基甲酸酯在引入纤维素或直链淀粉的基团中，具有每个葡萄糖单元至少一个反应性官能基，以使其转化为其酯或其氨基甲酸酯。
5．根据权利要求3所述的制备方法，其中，使纤维素或直链淀粉的6位羟基彼此发生选择性交联。
6．权利要求1所述分离剂作为色谱柱填料的应用。
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US5587467A (en) 1996-12-24
CN1111057A (zh) 1995-11-01
JP3190206B2 (ja) 2001-07-23
WO1995000463A1 (fr) 1995-01-05
DE69412973T2 (de) 1999-01-14
EP0656333A1 (en) 1995-06-07
EP0656333A4 (en) 1996-08-21
EP0656333B1 (en) 1998-09-02
KR0184294B1 (ko) 1999-05-15
KR950702949A (ko) 1995-08-23
DE69412973D1 (de) 1998-10-08
JPH0859702A (ja) 1996-03-05

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