CN1462263A - 由具有多环结构的多糖衍生物构成的分离剂 - Google Patents
由具有多环结构的多糖衍生物构成的分离剂 Download PDFInfo
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Abstract
本发明提供一种具有优良不对称识别能力的旋光异构体用分离剂。它由具有芳香环或脂肪族环或杂环的2环或以上构成的多糖衍生物作为有效成分的旋光异构体用分离剂。
Description
技术领域
本发明涉及具有含芳香环或脂肪环或杂环的2环或以上的结构(下面称作多环结构)的多糖衍生物作为有效成分的分离剂，本发明还涉及可用于各种化学物质的分离，特别是用于光学离析的旋光异构体用分离剂。
现有技术
多种有机化合物，其物理性质、化学性质，例如沸点、熔点、溶解度等物理性质完全相同，但存在生理活性不同的旋光异构体。这是由于构成生物的蛋白质及糖质本身大致相同时，一方面存在旋光异构体，对其他旋光异构体的作用方法产生差异，呈现生理活性的差别，特别是在药品领域，往往看到旋光异构体的药效、毒性方面有显著差别，因此，厚生省在药品制造指南中写道：“当该药物为外消旋体时，要求探讨各种异构体的吸收、分布、代谢、排泄动态”。
先前所述的旋光异构体的物理、化学性质，例如沸点、熔点、溶解度等物理性质由于完全相同，采用通常的分离办法不能进行分析，所以，要研究简便、精密的分析种类繁多的旋光异构体的分析技术。作为符合这种要求的分析方法，有高速液相色谱法(HPLC)的光学离析法、特别是HPLC所用的手性柱的光学离析方法已取得进展。这里的所谓手性柱是不对称识别剂本身，或者，使用使不对称识别剂负载在适当载体上的手性固定相。
例如，光学活性聚甲基丙烯酸三苯基甲酯(特开昭57-150432号)、纤维素、直链淀粉衍生物(Y.Okomoto，M.Kawashima and K.Hatada，J.Am.Chem.Soc.106，5337，1984)，蛋白质的卵类粘蛋白(特开昭63-307829号)等已被开发出来。在这几种HPLC手性固定相中，纤维素和直链淀粉衍生物负载在硅胶上的光学分离柱，对极广泛的化合物已知有很高的不对称识别能力。近几年来，使HPLC用手性固定相和模拟移动床法加以组合的工业规模光学活性体液体色谱法分离的探讨已得到进展(Phram Tech Japan12，43)，不仅将其简单地完全分离，而且，要使色谱分离的生产性提高，对目的化合物的分离更加有效，即要求具有更大的分离系数α值的手性固定相。
另外，最近伴随着向微量分析技术发展的企图，用毛细管电泳(CE)领域的旋光异构体分离、或采用HPLC更简便的分离操作而进行旋光异构体分离的旋光异构体分离用薄层色谱法(手性TLC)受到极大的关注，要求适用于这些领域的具有高的不对称识别能力的多糖衍生物。
发明的公开
本发明人为了解决上述课题，进行悉心研究的结果发现，具有立体的、体积大的多环结构的多糖衍生物具有优良的不对称识别能力，而完成本发明。
即，本发明提供一种以具有多环结构的多糖衍生物作为有效成分的旋光异构体分离剂。
本发明提供一种采用具有芳香环或脂肪环或杂环的2环或以上的结构(下面称作多环结构)的多糖衍生物作为旋光异构体用分离剂，以及，采用具有含芳香环或脂肪环或杂环的2环或以上的结构(下面称作多环结构)的多糖衍生物作为旋光异构体用分离剂的旋光异构体分离方法。
本发明的详细说明
下面对本发明的实施方案加以详细说明。
作为构成本发明所用的具有多环结构的多糖衍生物的多糖，有合成多糖、天然多糖以及天然物质变成的多糖的任何一种只要有光学活性的均可以使用，但是，优选的是希望结合状态规则性高的。例如，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(石脐素)、β-1，3-葡聚糖(例如力ド一ラン，シゾフイラン等)、α-1，3-葡聚糖、β-1，2-葡聚糖(五棓子多糖)、β-1，4-半乳聚糖、β-1，4-甘露聚糖、α-1，6-甘露聚糖、β-1，2-果聚糖(フラクタン)(菊糖)、β-2，6-果聚糖(左聚糖)、β-1，4-木聚糖、β-1，3-木聚糖，β-1，4-脱乙酰壳多糖、α-1，4-N-乙酰脱乙酰壳多糖(吉廷)、支链淀粉、琼脂糖、藻酸等，还包括含直链淀粉的淀粉。其中，易于得到高纯度多糖的纤维素、直链淀粉、β-1，4-木聚糖、β-1，4-脱乙酰壳多糖、吉廷苷、β-1，4-甘露聚糖、菊糖、力一ドラン等是优选的，特别优选的是纤维素、直链淀粉。
这些多糖的数均聚合度(1个分子中所含的吡喃糖或呋喃糖环的平均数)在5以上，优选10以上，无特别的上限，但从易于处理考虑，100以下是优选的。
所谓本发明的多糖衍生物，具有与上述多糖的羟基的一部分或全部反应而得到的官能基的化合物和通过酯键、氨基甲酸酯键、或醚键等结合的化合物，氨基甲酸酯衍生物或酯衍生物是优选的。作为本发明所用的多糖衍生物，特别优选的是1个葡萄糖单元具有0.1个以上酯键或氨基甲酸酯键的多糖酯衍生物或氨基甲酸酯衍生物，氨基甲酸酯衍生物是更加优选的。
本发明中的所谓多环结构，是指含有芳香环或脂肪环或杂环的2环或以上的结构，含芳香环的结构是优选的。对结合的环数未作特别限定，但2环或以上是优选的。作为具有多环结构的基团具体例子，可以举出芴基、茚满基、蒽基、芘基、菲基、喹啉基、并环戊基、茚基、萘基、奥基、庚基等。
本发明所用的具有多环结构的多糖衍生物，是多糖和具有多环结构、并且具有能和多糖的羟基反应的官能基的化合物通过反应，形成酯键、氨基甲酸酯键、或醚键等而得到的多糖衍生物。作为具有多环结构并且能与多糖的羟基反应的官能基的化合物，是具有能与上述羟基反应的官能基的化合物，而且具有上述多环结构的化合物，例如，9H-芴基异氰酸酯、5-茚满基异氰酸酯等。
本发明的具有多环结构的多糖衍生物，作为功能材料是极有用的物质，可用作旋光异构体分离剂，特别是作为色谱用手性固定相是有用的。本发明的多糖衍生物作为分离剂，在用于分离化合物及旋光异构体时，一般用于气相色谱法、液相色谱法、薄层色谱法、超临界色谱法、毛细管电泳法、连续液体色谱分离法等色谱法，但是，负载在其他膜上进行膜分离也可。
作为采用本发明的多糖衍生物的色谱用手性固定相，优选的是往液相色谱法用固定相、薄层色谱法用固定相、胶束导电色谱法为代表的毛细管电泳的泳动液中添加不对称识别剂、模拟移动床式为代表的连续液体色谱分离用固定相等。
在把本发明的分离剂用于液相色谱法时，采用作为粉末填充柱的方法、在毛细管柱上涂布的方法、由该分离剂形成毛细管柱、利用其内壁进行分离的方法，但一般使用粉体。在把该分离剂制成粉体时，优选的是将其粉碎或制成珠状。粒子的大小因所用柱子的大小而异，但是，优选的是1μm-10mm的粒径，1μm-300μm是更优选的。另外，粒子最好是多孔性的。
另外，为了提高分离剂的耐压能力，防止因溶剂置换引起的膨润、收缩，提高理论塔板数，把该分离剂保持在载体上是优选的。载体的大小，因所使用的柱及板的大小而异，但是，一般为1μm-10mm，优选1μm-300μm，载体为多孔性的是优选的，平均孔径10-100μm是优选的，50-50000是更优选的。该分离剂的保持量，对载体达到1-100重量％是优选的，5-50重量％是更优选的。
作为多糖衍生物在载体上负载的方法，既可用化学法也可用物理法。作为化学法，是在使多糖进行衍生物化时，保护一部分羟基，在衍生物化后，脱保护，使其和硅胶进行化学结合的方法(Y.Okamoto等人，J.Liq.Chromatogr.，10(89)，1616，1987)。作为物理法，是使多糖衍生物溶于可溶性的溶剂中，与载体充分混合，在减压、加温下或在气流下蒸出溶剂的方法等。
作为载体，有多孔性有机载体或多孔性无机载体，优选多孔性无机载体。作为合适的多孔性有机载体，可以举出聚苯乙烯、聚丙烯酰胺、聚丙烯酸酯等高分子物质。作为合适的多孔性无机载体，可以举出硅石、氧化铝、氧化镁、氧化钛、玻璃、硅酸盐、高岭土等合成的或天然的物质，为了使之与多糖衍生物的亲和性好，也可进行表面处理。作为表面处理的方法，有采用有机硅烷化合物的硅烷处理以及采用等离子聚合的表面处理法等。
本发明的效果
本发明提供一种具有优良的不对称识别能力的旋光异构体用分离剂。
实施例
通过实施例更详细地说明本发明，但本发明又不受这些实施例的局限。
实施例1
①纤维素三(9H-芴基氨基甲酸酯)(1a)的合成
使纤维素(商品名アビセル，メルク社制)0.30g和氯化锂0.21g干燥3小时后，添加二甲基乙酰胺(DMA)2.0ml，于90℃～100℃膨润过夜。然后，添加吡啶6.0ml，添加9H-芴基异氰酸酯1.3当量，使反应6小时。采用再沉淀法以从反应液析出氨基甲酸酯衍生物。用玻璃过滤器过滤后，进行真空干燥，得到以式(1a)表示的纤维素三(9H-芴基氨基甲酸酯)1.16g。所得到的(1a)元素分析值示于表1。
②硅胶上载有(1a)的填充剂制造
把①中得到的氨基甲酸酯衍生物(1a)0.75g溶于10ml四氢呋喃(THF)中，将其在3g硅胶(ダイソ一(株)制，粒径7μm，孔径1000)中均匀振荡后，蒸出溶剂，制成载有纤维素三(9H-芴基氨基甲酸酯)(1a)的填充剂。
③硅胶上载有(1a)的填充剂的填充柱的制造
把②中制成的负载型填充剂2.5g，采用淤浆填充法，在φ0.46cm×L25cm的不锈钢柱中加压填充，制成光学异构体分离柱。
实施例2
①纤维素(5-茚满基氨基甲酸酯)(1b)的合成
使纤维素(商品名アビセル，メルク社制)0.20g和氯化锂0.15g干燥3小时后，添加DMA1.5ml，于90℃～100℃膨润过夜。然后，添加吡啶5.0ml，添加5-茚满基异氰酸酯1.5当量，使反应6小时。采用再沉淀法，以从反应液析出氨基甲酸酯衍生物，用玻璃过滤器进行过滤后，进行真空干燥，得到以式(1b)表示的纤维素三(5-茚满基氨基甲酸酯)0.53g。所得到的(1b)元素分析值示于表1。
②在硅胶上载有(1b)的填充剂制造
把①中得到的氨基甲酸酯衍生物(1b)，与实施例1中的②同样操作，制成载有纤维素三(5-茚满基氨基甲酸酯(1b)的填充剂。
③在硅胶上载有(lb)填充剂的填充柱的制造
把②中制成的负载型填充剂，在φ0.20cm×L25cm的不锈钢柱中用与实施例1中的③同样的方法进行填充，制成光学异构体分离柱。
实施例3
①直链淀粉三(5-茚满基氨基甲酸酯)(2b)的合成
把直链淀粉(商品名AS-50，(株)アジノキ制)0.20g和氯化锂0.15g干燥3小时后，添加DMA1.5ml，于90℃～100℃膨润过夜。然后，添加吡啶6.0ml，添加5-茚满基异氰酸酯1.6当量使反应6小时。采用再沉淀使之从反应液析出氨基甲酸酯衍生物，用玻璃过滤器过滤后，真空干燥，得到以式(2b)表示的直链淀粉三(5-茚满基氨基甲酸酯)0.69g。所得到的(2b)元素分析值示于表1。
②硅胶上载有(2b)的填充剂的制造
采用①中得到的氨基甲酸酯衍生物(2b)，与实施例1中的②同样操作，制成载有直链淀粉三(5-茚满基氨基甲酸酯(2b)的填充剂。
⑧硅胶上载有(2b)填充剂的填充柱的制造
用②中制成的负载型填充剂，在φ0.20cm×L25cm的不锈钢柱中采用与实施例1中的③同样的方法进行填充，制成光学异构体分离柱。
表1
比较例1
| 元素分析结果 | ||||
| C％ | H％ | N％ | ||
| (1a) | 计算值 | 73.55 | 4.76 | 5.36 |
| 分析值 | 71.95 | 4.98 | 5.13 | |
| (1b) | 计算值 | 67.59 | 5.83 | 6.57 |
| 分析值 | 65.49 | 5.75 | 6.26 | |
| (2b) | 计算值 | 67.59 | 5.83 | 6.57 |
| 分析值 | 66.19 | 5.76 | 6.44 | |
采用纤维素三苯基氨基甲酸酯作为分离剂，通过特开昭60-108751号公报的实施例1同样的方法，制作旋光异构体分离柱。应用例1
采用实施例1～3及比较例1中制成的柱，对下列外消旋体(a)～(g)，采用下列条件的液体色谱法进行光学分离。结果示于表2。
外消旋体(a) 外消旋体(b) 外消旋体(c) 外消旋体(d)Co(acac)3
外消旋体(e) 外消旋体(f) 外消旋体(g)分析条件
移动相：己烷/异丙醇＝90/10(v/v)
流速：实施例1及比较例1的柱为0.5ml/min，实施例2及3的柱为0.1ml/min。
温度：25℃
检测：254nm
还有，表中的分离系数(α)由下式定义：
α＝K2’/K1’
这里的K1’为较弱保持旋光异构体的保持系数，K2’为较强保持的旋光异构体的保持系数。
表2
| 分离对象外消旋体 | 分离系数(α) | |||
| 实施例1 | 实施例2 | 实施例3 | 比较例1 | |
| (a) | 1.56 | 1.41 | 1.46 | 1.19 |
| (b) | ～1 | 1.25 | 1.49 | 1.0 |
| (c) | 1.26 | 1.78 | 1.30 | 1.47 |
| (d) | ～1 | 1.21 | 1.41 | ～1 |
| (e) | ～1 | 1.5 | ～1 | 1.0 |
| (f) | 1.14 | 1.67 | ～1 | 1.52 |
| (g) | ～1 | 1.57 | 1.21 | ～1 |
Claims (9)
1.一种旋光异构体用分离剂，其中，含有具有芳香环或脂肪族环或杂环的2环或以上结构(下面称作多环结构)的多糖衍生物作为有效成分。
2.权利要求1中所述的分离剂，其特征是，具有多环结构的多糖衍生物是纤维素衍生物或直链淀粉衍生物。
3.权利要求1或2中所述的分离剂，其特征是，具有多环结构的多糖衍生物含有芳香环。
4.权利要求1～3中任何1项所述的分离剂，其特征是，具有多环结构的多糖衍生物是酯衍生物或氨基甲酸酯衍生物。
5.权利要求1～4中任何1项所述的分离剂，其特征是，可用于色谱用手性固定相。
6.权利要求5中所述的分离剂，其特征是，色谱用手性固定相是液相色谱用固定相。
7.权利要求5中所述的分离剂，其特征是，色谱用手性固定相为薄层色谱用固定相。
8.权利要求5中所述的分离剂，其特征是，色谱用手性固定相是在毛细管电泳的泳动液中添加的不对称识别剂。
9.权利要求5中所述的分离剂，其特征是，色谱用手性固定相是连续式液体分离用固定相。
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| US20040065608A1 (en) | 2004-04-08 |
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| JPWO2002088048A1 (ja) | 2004-08-12 |
| EP1389606A1 (en) | 2004-02-18 |
| CN1211322C (zh) | 2005-07-20 |
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| EP1389606A4 (en) | 2007-04-18 |
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