CN111013194B - 一种能拆分多种不同类型外消旋化合物的手性poc分离柱 - Google Patents
一种能拆分多种不同类型外消旋化合物的手性poc分离柱 Download PDFInfo
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Abstract
本发明公开了一种能拆分多种不同类型外消旋化合物的手性POC分离柱。该手性柱是以2‑羟基‑1,3,5‑均苯三甲醛和(1R,2R)‑1,2‑环己二胺通过席夫碱一步缩合反应合成的手性多孔有机分子笼材料作为固定相，采用静态制柱法制得。本发明的色谱柱对许多不同类型的外消旋体化合物表现出优秀的手性拆分效果，相比市售的β‑DEX 120色谱柱表现出明显的分离优势。另外，本发明色谱柱用于气相色谱拆分外消旋化合物具有热稳定性好、拆分能力强、适用范围广等特点，而且合成该手性多孔有机分子笼材料固定相的方法简单、原料廉价，有利于大规模推广应用。
Description
技术领域
本发明属于气相色谱手性分离技术领域，涉及一种气相色谱毛细管分离柱，特别是涉及一种能拆分多种不同类型外消旋化合物的手性POC分离柱。
背景技术
在许多领域中，手性拆分变得越来越重要，例如药物、化学工业、农业和临床分析。手性化合物的对映体由于其空间结构存在差异，对于同一物质的对映异构体，在手性环境中可能会表现出不同的化学性质；特别是其两个对映体在生命体环境中通常具有不同的生物活性，因此表现出手性择优的现象；人们把具有生命体环境需要的药理活性的对映体称为“优构体”，把无活性或者具有毒副作用的对映体称为“劣构体”。“优构体”与药物靶点作用后有药物活性，“劣构体”与药物靶点作用后无药物活性，或者有相反的作用，甚至产生毒副作用。如R-构型的酞胺哌啶酮对映体对妊娠早期的孕妇具有止吐镇静的作用，S-构型的酞胺哌啶酮对映体具有强烈的致畸性；R构型的西替利嗪是抗过敏的活性异构体，而S构型不具有抗过敏作用。因此，对手性化合物进行拆分获得单一构型的“优构体”有着极其重要的研究意义。
目前，环糊精衍生物是应用最广泛且手性识别性能较好的一类气相色谱手性固定相，但是环糊精衍生物作为手性固定相也存在一些不足，如分析时间长，一些手性化合物仍然得不到拆分。除此之外，环糊精衍生物的合成比较繁琐，因而很多环糊精衍生物型的商品气相色谱柱的价格昂贵。因此，研究开发合成简单、价格低廉、手性选择性优越的气相色谱固定相具有重要的意义。近年来，随着超分子化学的发展，多孔材料在手性识别、手性分离和手性催化等领域有着广泛的应用前景。多孔有机分子笼(POC)是近年来发展起来的一种新型的多孔材料，它是由具有三维空间结构的分立的笼状分子通过弱的分子间作用力自组装而形成的一类多孔分子固体。多孔有机笼拥有可调控的孔洞尺寸和孔通道，与客体分子显示出很强的亲和力和匹配性，并且多孔有机笼的合成方法简单，可通过动态共价化学的方法一步合成，因此具有作气相色谱固定相的潜在应用价值。
发明内容
本发明的目的在于针对现有技术的不足，提供一种能拆分多种不同类型外消旋化合物的手性POC毛细管气相色谱分离柱。该分离柱能拆分许多不同类型的外消旋体化合物，与市售的环糊精衍生物型β-DEX 120手性毛细管商品柱相比，表现出更好的手性拆分性能，有推广应用的前景。
本发明的目的通过以下技术方案予以实现的：利用希夫碱环缩合反应制备一种[4+6]亚胺型手性多孔有机分子笼(POC)材料，将其作为固定相，采用静态制柱法，制备毛细管气相色谱手性柱，并应用于气相色谱实现许多不同类型的外消旋体化合物的拆分。
本发明包括如下具体步骤：
(1)制备手性多孔有机分子笼(POC)材料：基于希夫碱环缩合反应，用2-羟基-1,3,5-均苯三甲醛和(1R,2R)-1,2-环己二胺(摩尔比为2:3)，三氯甲烷和二甲亚砜(V/V＝4:3)为反应溶剂，三氟乙酸作催化剂，通过缩合反应制备[4+6]亚胺型手性多孔有机分子笼(POC)材料；
(2)毛细管粗糙化预处理：为使手性有机分子笼材料更均匀的涂敷在毛细管柱内壁，对石英毛细管内壁采用NaOH溶液进行粗糙化处理；
(3)手性POC分离柱的制备：取步骤(1)制备得到的手性多孔有机分子笼材料和聚硅氧烷OV-1701配制成一定浓度的溶液，将其充入到步骤(2)粗糙化处理过的毛细管柱中，采用静态制柱的方法制得所需的能拆分多种不同类型外消旋化合物的手性POC分离柱。
(4)用于外消旋化合物的拆分：将(3)制备的手性POC分离柱接入气相色谱仪，老化待基线平稳后(老化升温程序：先在常温条件下保持2min，再以5℃/min的升温速率将温度升到260℃，并在260℃下保持2小时)，优化实验条件实现对一元醇、二元醇、酯、内酯、卤代烃、醚、环氧化合物、酮、亚砜等在内的许多不同类型外消旋化合物的拆分。
本发明具有以下优点：
1、本发明应用于气相色谱分析，可拆分许多外消旋体化合物。本发明的手性POC分离柱的手性拆分能力强，能拆分许多不同类型的外消旋体化合物；
2、与商品环糊精衍生物β-DEX 120手性柱相比，本发明手性POC分离柱能拆分许多β-DEX 120手性柱不能拆分的外消旋体化合物，具有显著的手性拆分优势；
3、本发明的手性POC分离柱具有拆分重现性好、稳定性好、使用寿命长等特点，并且所用的固定相材料的合成方法简单、合成原料价格低廉易得，有利于推广应用。
附图说明
图1-1为本发明所使用的手性多孔有机分子笼材料的分子结构示意图；
图1-2为本发明所使用的手性多孔有机分子笼材料的热重分析图；
图2为利用本发明色谱柱对部分外消旋体的拆分色谱图；
图3为利用本发明色谱柱和商品环糊精衍生物β-DEX 120(30m×0.25mm i.d.×0.25μm film,Supelco Inc.,USA)手性毛细管色谱分离柱，对部分外消旋体化合物进行拆分的效果对比图。
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修改，等同变换，改进均属于本发明的保护范围。
实施例1
(1)制备手性多孔有机分子笼(POC)材料：取0.171g(1.5mmol)(1R,2R)-1,2-环己二胺加入到圆底烧瓶，在不搅拌的情况下分别缓慢加入40mL三氯甲烷和30mL二甲基亚砜，然后将0.178g(1mmol)2-羟基-1,3,5-均苯三甲醛缓慢加入到其中，再加入10μL三氟乙酸作催化剂并一直搅拌，在室温下反应半个月，最后抽滤混合液，得到的固体用乙醚/氯仿(1/1，V/V)少量多次洗涤，重结晶制得[4+6]亚胺型手性多孔有机分子笼(POC)材料；
(2)毛细管粗糙化预处理：为使手性有机分子笼材料更均匀的涂敷在毛细管柱内壁，对石英毛细管内壁采用NaOH溶液进行粗糙化处理，具体步骤如下：取长30m、内径为0.25mm的石英毛细管柱，在氮气压力下，向毛细管内部连续充入0.1mol/L的氢氧化钠溶液并保持3小时，分别用超纯水、0.1mol/L的盐酸溶液和超纯水冲洗至毛细管排除液体的pH＝7，再在120℃条件下通干燥的氮气2h后备用；
(3)取步骤(1)制备得到的手性多孔有机分子笼(POC)材料和聚硅氧烷OV-1701分别溶于有机溶剂二氯甲烷中，将其配制成浓度分别为3.0mg/mL、4.5mg/mL的溶液，再将这两种溶液等体积混合，超声脱去气泡。将混合液抽入到步骤(2)粗糙化处理过的石英毛细管柱中，采用静态制柱的方法，待混合液充满整个毛细管柱后，毛细管一端除去气泡后封口，另一端接在恒压真空装置上在36℃温度下使管内溶剂挥发。当溶剂完全挥干后，手性多孔有机分子笼(POC)材料将均匀地沉积在毛细管柱内壁，最后进行老化。老化升温程序：先在常温条件下保持2分钟，再以5℃/min的升温速率将温度升到260℃并保持2小时，即制得所需的能拆分多种不同类别外消旋化合物的手性POC分离柱。
实施例2
用实施例1所得的手性POC分离柱对部分外消旋体进行拆分，其拆分的色谱图见图2。图2中拆分的外消旋体顺序和色谱条件依次为：(a)2-己醇，柱温180℃，氮气线速度13.7cm s-1；(b)1,2-丁二醇，柱温170℃，氮气线速度14.0cm s-1；(c)3-丁烯-2-醇，柱温140℃，氮气线速度15.0cm s-1；(d)3-羟基丁酸甲酯，柱温175℃，氮气线速度14.0cm s-1；(e)丙二醇单甲醚醋酸酯，柱温155℃，氮气线速度13.8cm s-1；(f)γ-戊内酯，柱温180℃，氮气线速度14.0cm s-1；(g)1,2-二氯丁烷，柱温160℃，氮气线速度14.0cm s-1；(h)仲丁基甲醚，柱温120℃，氮气线速度11.1cm s-1；(i)1,2-二甲氧基丙烷，柱温155℃，氮气线速度12.9cm s-1；(j)环氧氯丙烷，柱温155℃，氮气线速度12.9cm s-1；(k)2-甲基四氢呋喃-3-酮，柱温150℃，氮气线速度13.2cm s-1；(l)苯甲亚砜，柱温220℃，氮气线速度15.0cm s-1。
由图2可知：本发明色谱柱使一元醇、二元醇、酯、内酯、卤代烃、醚、环氧化合物、酮、亚砜等在内的许多不同类型的外消旋体化合物获得了拆分效果，表现出很高的手性选择性和分离能力，分析结果如表1所示。
表1本发明色谱柱对部分外消旋体化合物的拆分数据结果
色谱参数：高纯N2为载气，分流比50：1，进样口和检测器的温度分别为300℃和300℃，柱规格：30m×0.25mm i.d.。
实施例3
用实施例1所得的手性POC分离柱以及现有的商品β-DEX 120毛细管气相色谱柱，对部分外消旋体(如2-庚醇、2-辛醇、2-甲基戊酸甲酯、3-羟基丁酸甲酯、δ-己内酯、仲丁基甲醚、环氧溴丙烷及苯甲亚砜)在合适的色谱条件下进行拆分实验。将本发明柱与目前广泛应用的β-DEX 120商品手性柱相比，其对比的拆分效果色谱图见附图3，对比色谱数据列举在表2中。
表2本发明色谱柱和β-DEX 120商品手性柱对比分析数据
-表示没有被拆分开
色谱参数：高纯N2为载气，分流比50：1，进样口和检测器的温度分别为300℃和300℃，柱规格：30m×0.25mm i.d.。
由表2和图3可知：2-庚醇、2-辛醇、2-甲基戊酸甲酯、3-羟基丁酸甲酯、δ-己内酯、仲丁基甲醚、环氧溴丙烷及苯甲亚砜在现有的商品β-DEX 120毛细管柱上均没有得到拆分，而本发明色谱柱上却能很好的拆分这些外消旋体化合物，显示了本发明色谱柱明显优于商品β-DEX 120毛细管柱的手性拆分优势。
Claims (1)
1.一种能拆分多种不同类型外消旋化合物的手性POC分离柱，其特征在于：在手性分离柱内壁涂敷了一种手性多孔有机分子笼材料(POC)，应用于气相色谱拆分外消旋化合物；
该手性分离柱的制备方法为：
(1)制备手性多孔有机分子笼(POC)材料：基于希夫碱环缩合反应，用2-羟基-1,3,5-均苯三甲醛和(1R,2R)-1,2-环己二胺在摩尔比为2:3，三氯甲烷/二甲亚砜体积比4:3为反应溶剂，三氟乙酸作催化剂，在室温下反应半个月，最后抽滤混合液，得到的固体用乙醚/氯仿体积比1:1的混合液洗涤3次，重结晶制得[4+6]亚胺型手性多孔有机分子笼(POC)材料；
(2)手性POC分离柱的制备：取步骤(1)制备得到的手性多孔有机分子笼材料(POC)溶于二氯甲烷配成浓度为3.0mg/mL的溶液，再将其与含4.5mg/mL的聚硅氧烷OV-1701二氯甲烷溶液等体积混合，超声除去气泡后充入到内壁粗糙化处理过的毛细管柱中，采用静态制柱的方法制得手性POC分离柱。
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