CN114681952B - 基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱 - Google Patents
基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱 Download PDFInfo
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Abstract
本发明公开的基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱。通过多元醛和多元胺缩合反应合成了一种[3+3]型手性多胺大环化合物，将其键合于巯基硅胶表面作为高效液相色谱手性固定相，采用高压匀浆填充法制备了高效液相色谱手性分离柱。该手性分离柱在正相和反相模式下均具有优秀的手性拆分性能，可拆分包括手性醇、酮、醚、醛、酯、胺等在内的许多手性化合物及手性药物，并且该柱具有分离效率高、选择性好、制备简单、成本低、重现性和稳定性好等优点，在手性分离领域具有很好的应用前景。
Description
技术领域
本发明属于高效液相色谱手性柱技术领域，具体是涉及一种[3+3]型手性多胺大环化合物键合于巯基硅胶上形成的复合材料作为固定相制备的高效液相色谱手性分离柱及其手性拆分性能。
背景技术
手性在自然界中非常常见，它就像人的双手，虽然成镜像对称关系，但是并不能重合。许多有机化合物都具有手性，如乳酸分子、丙氨酸分子等。手性化合物通常具有两个或两个以上的对映体，不同的对映体在一些性质上有一定的不同，尤其是手性药物对映体在生物体内将会表现出截然不同的生物活性及药效作用。在很多手性药物中往往只是它的某一种对映体具有药效作用，而它的其它对映体没有药效，或者具有相反的药效，甚至还具有毒副作用。例如，抗生素药物氯霉素的左旋对映体具有杀菌作用，而右旋体对映体基本没有药效；巴比妥酸盐的S构型对映体具有抑制神经活动的作用，而其R构型对映体却具有使神经兴奋的作用；沙利度胺药物的R构型对映体对孕妇具有镇静止呕作用，而其S构型对映体则对胎儿有严重的致畸作用。此外，手性还涉及农药、食品添加剂、香精和香料等领域。因此，对手性化合物分离分析和获取其单一构型对映体就显得极为重要。
高效液相色谱法具有分离效率高、灵敏度高、分离范围广等特点，已被广泛用于手性化合物的分离分析研究，是一种重要的手性分离分析方法。高效液相色谱手性柱是其手性分离分析的核心部件，而手性柱里所填充的手性固定相在手性分离分析中起决定性作用。因此，研究选择性好、拆分物质范围广、制备简单、成本低的新型手性固定相一直以来都是该领域的研究热点。
大环化合物是指由许多原子连接而成的具有环状结构的有机化合物，其具有独特的空腔结构，可以通过多种非共价相互作用参与识别和组装过程，因而在催化、分离、医药、农业、国防等领域彰显广阔的应用前景。目前，已经有许多大环化合物，如冠醚、环糊精、杯芳烃、葫芦脲、柱芳烃等。其中冠醚、环糊精已被开发用作高效液相色谱手性固定相制备手性柱，但它们也存在一些不足，如合成手性冠醚过程较复杂，并且手性冠醚固定相只对氨基酸和伯胺类手性化合物具有较好的手性拆分效果；冠醚和环糊精手性固定相一般只能在反相色谱条件下才具有手性拆分效果。因此，研究开发适用范围广、选择性好、合成简单、成本低的新型高效液相色谱手性固定相也具有重要的意义。
发明内容
本发明针对现有技术的不足，提供一种基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱，该柱在正相和反相模式下均具有较好的手性拆分效果，可拆分包括醇、酮、醚、醛、酯、胺等在内的许多手性化合物及手性药物。
本发明的目的通过以下技术方案予以实现。
一种基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱，由以下方法制备得到：
(1)[3+3]型手性多胺大环化合物的合成：将(1R,2R)-1,2-二苯基乙二胺和2,6-二甲酰基-4-叔丁基苯酚以摩尔比1:1溶于乙腈中进行席夫碱缩合反应制备[3+3]型手性多胺大环化合物；
(2)[3+3]型手性多胺大环化合物的修饰烯基功能化：将合成的[3+3]型手性多胺大环化合物与5-溴-1-戊烯进行反应，修饰烯基功能基团；
(3)巯基化硅胶的制备：购买的商品球形硅胶首先用10％的盐酸溶液进行活化处理，然后与(3-巯基丙基)三甲氧基硅烷反应制备巯基化硅胶；
(4)[3+3]型手性多胺大环化合物手性固定相的制备：将巯基化硅胶与修饰烯基功能基团的[3+3]型手性多胺大环化合物在AIBN引发下反应制备手性固定相；
(5)手性柱的制备：将制备的手性固定相通过高压匀浆的方法制备高效液相色谱手性柱。
相对于现有技术，本发明具有以下优点：
(1)本发明的[3+3]型手性多胺大环化合物制备方法简单，制备的手性柱在正相和反相模式下均具有较好的手性拆分性能，可拆分许多不同种类的手性化合物；
(2)本发明的手性柱具有分离效率高、选择性好、制备简单、成本低、重现性和稳定性好等优点。
附图说明
图1为本发明[3+3]型手性多胺大环化合物的合成示意图；
图2为本发明手性固定相的制备过程示意；
图3为利用本发明制备的手性分离柱在正相模式(正己烷/异丙醇为流动相)下对部分手性化合物的拆分色谱图；
图4为利用本发明制备的手性分离柱在反相模式(甲醇/水为流动相)下对部分手性化合物的拆分色谱图；
图5为手性化合物在本发明手性分离柱上重现性和稳定性色谱图。
具体实施方式
以下结合附图和实施例对本发明作进一步的详细说明，但附图和实施例并不是对本发明技术方案的限定，所有基于本发明教导所做出的变化或等同替换，均属于本发明的保护范围。
实施例1
[3+3]型手性多胺大环化合物的合成：称取2.06g(10mmol)(1R,2R)-1,2-二苯基乙二胺溶解于50mL乙腈中，2.12g(10mmol)2,6-二甲酰基-4-叔丁基苯酚溶于30mL乙腈中，将二者混合后室温搅拌反应45分钟，溶液中有黄色固体析出。过滤黄色沉淀物，用20mL乙腈洗涤，然后放入鼓风干燥箱，在60℃下干燥2小时即得所需的[3+3]型手性多胺大环化合物。
实施例2
(1)[3+3]型手性多胺大环化合物的修饰烯基功能化：称取实施例1合成的[3+3]型手性多胺大环化合物0.7g溶解于10mL无水三氯甲烷中；再取50mL无水三氯甲烷到充满氮气的另一个100mL圆底烧瓶中，加入0.6g氢化钠，在0℃条件下搅拌20分钟，然后缓慢逐滴加入上述已经溶解的[3+3]型手性多胺大环化合物的三氯甲烷溶液。滴加完后继续搅拌30分钟，然后加入0.12mL 5-溴-1-戊烯，升温至60℃搅拌回流72小时。加入20mL蒸馏水，分液，有机相用去离子水洗涤3次，然后有机相用无水硫酸镁干燥以后进行抽滤，蒸发溶剂即得产物。
(2)巯基化硅胶的合成：取10g硅胶于250mL容量瓶中，加入100mL 10％的盐酸溶液，在氮气条件下反应24小时进行活化。过滤，用去离子水洗涤硅胶至中性，在180℃真空条件下干燥6小时即得活化的硅胶。将5.0g活化硅胶放入250mL圆底烧瓶中，加入80mL无水甲苯、4mL(3-巯基丙基)三甲氧基硅烷和2mL无水吡啶，在氮气条件下100℃反应72小时。减压抽滤，用甲苯和甲醇依次洗涤，然后在80℃条件下真空干燥6小时即得巯基化硅胶。
(3)[3+3]型手性多胺大环化合物手性固定相的制备：取(1)中产物0.67g、(2)中1.3g巯基化硅胶和0.06g AIBN加入到100mL圆底烧瓶中，加入70mL甲苯，在氮气条件下100℃反应3天。减压抽滤，滤渣用甲醇洗涤数次，干燥得到手性固定相。
(4)手性柱的制备：称取1.2g(3)中制备的手性固定相置于烧杯中，加入23mL体积比9:1的正己烷/异丙醇溶液形成匀浆悬浮液，然后迅速将悬浮液倒入匀浆罐中，再以体积比9:1的正己烷/异丙醇溶液为顶替液，在40MPa氮气压力下装柱5分钟，然后将氮气压力降到25MPa再装柱30分钟，得到本发明的手性分离柱。
实施例3
将实施例2制备好的手性分离柱在正相模式下，以正己烷/异丙醇为流动相，流速为0.1mL/min，紫外检测器波长为254nm，柱温为25℃的色谱条件下，对所配制的手性样品进行了拆分实验，部分手性化合物的拆分色谱图如附图3所示，拆分的色谱数据列在下表1中。
表1在正相模式(正己烷/异丙醇为流动相)下部分手性化合物在本发明手性分离柱上的拆分结果
实施例4
将实施例2制备好的手性分离柱在反相模式下，以甲醇/水为流动相，流速为0.1mL/min，紫外检测器波长为254nm，柱温为25℃的色谱条件下，对所配制的手性样品进行了拆分实验，部分手性化合物的拆分色谱图如附图4所示，拆分的色谱数据列在下表2中。
表2在反相模式(甲醇/水为流动相)下部分手性化合物在本发明手性分离柱上的拆分结果
实施例5
为了考察制备的手性分离柱的重现性和稳定性，在柱经过100次、200次、300次和500次进样使用之后分别对1-苯基乙醇进行了分离对比，其对比色谱图如附图5所示。图中色谱图(1)-(5)分别表示柱在使用之初、100次、200次、300次和500次进样使用之后对1-苯基乙醇的拆分色谱图。由图可知，在经历不同进样次数使用后，柱对1-苯基乙醇的拆分效果基本没有发生变化，表明该柱具有较好的重现性和稳定性。
Claims (1)
1.基于[3+3]型手性多胺大环化合物的高效液相色谱手性分离柱，其特征在于：该分离柱是以（1R,2R）-1,2-二苯基乙二胺和2,6-二甲酰基-4-叔丁基苯酚以摩尔比1:1通过席夫碱缩合反应所合成的[3+3]型手性多胺大环化合物键合于巯基硅胶上作为手性固定相；具体制备方法为：
（1）[3+3]型手性多胺大环化合物的合成：称取2.06 g（1R, 2R）-1,2-二苯基乙二胺溶解于50 mL乙腈中，2.12 g2,6-二甲酰基-4-叔丁基苯酚溶于30 mL乙腈中，将二者混合后室温搅拌反应45分钟，溶液中有黄色固体析出，过滤黄色沉淀物，用20 mL乙腈洗涤，然后放入鼓风干燥箱，在60 ℃下干燥2小时即得所需的[3+3]型手性多胺大环化合物；
（2）[3+3]型手性多胺大环化合物的修饰烯基功能化：取步骤（1）中合成的[3+3]型手性多胺大环化合物0.7 g溶解于10 mL无水三氯甲烷中；再取50 mL无水三氯甲烷到充满氮气的另一个100 mL圆底瓶中，加入0.6 g氢化钠，在0 ℃条件下搅拌20分钟，然后缓慢逐滴加入上述已经溶解的[3+3]型手性多胺大环化合物的三氯甲烷溶液，滴加完后继续搅拌30分钟，然后加入0.12 mL 5-溴-1-戊烯，升温至60 ℃搅拌回流72小时，加入20 mL蒸馏水，分液，有机相用去离子水洗涤3次，然后有机相用无水硫酸镁干燥后进行抽滤，蒸发溶剂即得产物；
（3）[3+3]型手性多胺大环化合物手性固定相的制备：取步骤（2）中产物0.67 g、1.3 g巯基化硅胶和0.06 g AIBN加入到100 mL圆底烧瓶中，加入70 mL甲苯，在氮气条件下100℃反应3天，减压抽滤，滤渣用甲醇洗涤数次，干燥得到手性固定相；
（4）手性柱的制备：将步骤（3）中合成物作为手性固定相，采用高压匀浆法进行柱的装填，制得[3+3]型手性多胺大环化合物高效液相色谱手性分离柱。
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