CN106957270B - 一种硝基尿嘧啶药物超分子共晶及其制备方法 - Google Patents

一种硝基尿嘧啶药物超分子共晶及其制备方法 Download PDF

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CN106957270B
CN106957270B CN201710181534.2A CN201710181534A CN106957270B CN 106957270 B CN106957270 B CN 106957270B CN 201710181534 A CN201710181534 A CN 201710181534A CN 106957270 B CN106957270 B CN 106957270B
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李星
田园园
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Hebei Dahe Biological Technology Co ltd
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    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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Abstract

本发明公开了一种硝基尿嘧啶药物超分子共晶及其制备方法，该超分子共晶是一种具有确定空间结构的5‑硝基尿嘧啶和4,4’‑二联吡啶的超分子共晶化合物，其分子式为C18H14N8O8，结构单元为[(C10H8N2)(C4H3N3O4)2]，晶系为三斜晶系，空间群为P‑1，晶胞参数为α＝97.373°，β＝101.803°，γ＝105.339°。所述超分子共晶的制备方法为：将具有共轭大π键的4,4’‑二联吡啶、5‑硝基乳清酸钾与具有催化活性的钴离子按一定的比例混合进行化学反应，制得一种超分子共晶。该制备方法操作简单，成本低廉，适合规模化生产。本发明制备的超分子共晶化合物作为药物或药物中间体具有潜在的应用前景。

Description

一种硝基尿嘧啶药物超分子共晶及其制备方法
技术领域
本发明属于超分子化学领域，具体涉及一种硝基尿嘧啶药物超分子共晶及其制备方法。
背景技术
超分子化学的诞生使化学的发展进入了革命性的新时代，其发展十分迅猛，因为超分子具有与其组成分子不同的物理、化学和生物性质，一般都具有特殊的用途，如用作导体、光学材料、纳米材料、传感器等。超分子化学涉及到的领域十分广泛，它不仅涉及无机化学、有机化学、配位化学、高分子化学和药物化学，而且涉及材料科学、环境科学、信息科学和生命科学。超分子化学的发展标志着化学走进了一个崭新的研究领域。
随着超分子化学研究的深入，超分子化学在药物研发领域的延伸成为化学发展的一个重要分支。药物超分子逐渐成为国内外学者共同关注的一个研究热点。药物超分子具有许多优点，如低的药物毒性、良好的稳定性、较高的安全性。药物超分子化学是一个新兴交叉学科并逐渐成为一个独立的研究领域。到目前为止，已经有许多药物超分子作为化学药物在临床上使用，事实表明其疗效非常好，还有许多作为候选药物的超分子化合物正在进行临床的实验和研究开发。
目前，嘧啶环系化合物在医药方面的应用受到生物界、化学界和医学界的关注，如5-甲基嘧啶是遗传物质的重要组成部分，是合成抗艾滋病药物AZT、DDT及相关药物的关键中间体，也是合成抗肿瘤、抗病毒药物β-胸苷的起始原料；5-氟脲嘧啶是一种阻止肿瘤细胞嘧啶类核苷酸形成的抗代谢药物。
然而，人们研究发现一些嘧啶类药物具有半衰期短、选择性差、稳定性差、生物利用度低、药溶性差、副作用大等弱点，限制了其广泛应用。因此，人们试图对嘧啶化合物进行各种化学修饰，力求找到一种低毒、利用高效的嘧啶类化合物，并以此作为抗癌药物的先导化合物。
近年来研究发现药物超分子共晶能够提高药物的利用度、改善药物的溶解度或药物活性。因此，对药物超分子共晶的研究引起了人们的极大兴趣。
本发明以水合醋酸钴、联吡啶和硝基乳清酸为原料，通过简单的水热反应，制备了一种硝基尿嘧啶和联吡啶的超分子共晶化合物，该化合物具有确定的空间结构和准确的分子式，分子中存在多种非典型的氢键(C—H···O： )和π-π作用这些结构信息对本发明获得的硝基尿嘧啶药物超分子共晶化合物的性能研究和应用具有重要的意义。
发明内容
本发明所要解决的技术问题是针对现有技术，提供一种硝基尿嘧啶药物超分子共晶及其制备方法。
本发明为解决上述技术问题所采取的技术方案为：一种硝基尿嘧啶药物超分子共晶，该超分子共晶是一种5-硝基尿嘧啶和4,4’-二联吡啶的超分子共晶化合物，该化合物具有确定的空间结构，结构单元为[(C10H8N2)(C4H3N3O4)2]，其分子式为C18H14N8O8，晶系为三斜晶系，空间群为P-1，晶胞参数为 α＝97.373°，β＝101.803°，γ＝105.339°。
一种上述硝基尿嘧啶药物超分子共晶的制备方法，包括以下步骤：
(1)向25mL聚四氟乙烯内衬中加入适量的5-硝基乳清酸钾单水合物、4,4’-二联吡啶和水合氯化钴，然后加入蒸馏水5～10mL和体积分数95％的乙醇5～8mL，搅拌，得反应混合物；
(2)将上述聚四氟乙烯内衬密封，放入不锈钢反应釜中，将不锈钢反应釜放入烘箱中，120～150℃加热反应48～72h，然后自然冷却至室温，打开反应釜得浅黄色块状晶体；
(3)将浅黄色块状晶体取出，自然风干，即得所述的超分子共晶。
优选的，所述参加反应的物质均为化学纯，所述水合氯化钴为六水氯化钴。
较佳地，所述5-硝基乳清酸钾单水合物、4,4’-二联吡啶和水合氯化钴的摩尔比为2∶1∶1～2。
与现有技术相比，本发明的特点在于：
将具有共轭π键的4,4’-二联吡啶、5-硝基乳清酸钾与具有化学催化活性的钴离子进行化学反应，在化学反应中5-硝基乳清酸脱去羧基成为5-硝基尿嘧啶，并与4,4’-二联吡啶进行自组装，制得一种联吡啶与硝基尿嘧啶的超分子共晶化合物，该化合物具有准确的空间结构(图1)和准确的分子式，分子中存在多种非典型的氢键(C—H···O：)和π-π作用所制备的超分子共晶化合物作为药物或药物中间体具有潜在的应用前景。
附图说明
图1为本发明的超分子共晶化合物结构单元图。
具体实施方式
以下结合实施例对本发明作进一步详细描述。
实施例1：
向25mL聚四氟乙烯内衬中加入5-硝基乳清酸钾单水合物(1.0mmol，0.257g)，4,4’-二联吡啶(0.5mmol，0.0781g)，和CoCl2·6H2O(0.5mmol，0.119g)，并加蒸馏水10mL和体积分数95％的乙醇5mL，搅拌，得反应混合物；将聚四氟乙烯内衬密封，放入不锈钢反应釜中，将不锈钢反应釜放入烘箱中，150℃加热反应48h，然后自然冷却至室温，打开反应釜得浅黄色块状晶体；取出浅黄色块状晶体，自然风干，即得所述的超分子共晶化合物。
实施例2：
向25mL聚四氟乙烯内衬中加入5-硝基乳清酸钾单水合物(0.2mmol，0.0514g)，4,4’-二联吡啶(0.1mmol，0.0156g)，和CoCl2·6H2O(0.2mmol，0.0476g)，并加蒸馏水5mL和体积分数95％的乙醇8mL，搅拌，得反应混合物；将聚四氟乙烯内衬密封，放入不锈钢反应釜中，将不锈钢反应釜放入烘箱中，120℃加热反应72h，然后自然冷却至室温，打开反应釜得浅黄色块状晶体；取出浅黄色块状晶体，自然风干，即得所述的超分子共晶化合物。
实施例3：
向25mL聚四氟乙烯内衬中加入5-硝基乳清酸钾单水合物(0.2mmol，0.0514g)，4,4’-二联吡啶(0.1mmol，0.0156g)，和CoCl2·6H2O(0.15mmol，0.0357g)，并加蒸馏水7mL和体积分数95％的乙醇7mL，搅拌，得反应混合物；将聚四氟乙烯内衬密封，放入不锈钢反应釜中，将不锈钢反应釜放入烘箱中，130℃加热反应60h，然后自然冷却至室温，打开反应釜得浅黄色块状晶体；取出浅黄色块状晶体，自然风干，即得所述的超分子共晶化合物。
将实施例1-3制得的浅黄色块状晶体用单晶X射线进行结构测试，结果表明该浅黄色块状晶体为5-硝基尿嘧啶和4,4’-二联吡啶的超分子共晶化合物，其结构单元如图1所示，其分子式为C18H14N8O8，结构单元为[(C10H8N2)(C4H3N3O4)2]，晶系为三斜晶系，空间群为P-1，晶胞参数为 α＝97.373°，β＝101.803°，γ＝105.339°。

Claims (1)

1.一种硝基尿嘧啶药物超分子共晶的制备方法，其特征在于，包括以下步骤：
(1)向25mL聚四氟乙烯内衬中加入适量的5-硝基乳清酸钾单水合物、4,4’-二联吡啶和水合氯化钴，然后加入蒸馏水5～10mL和体积分数95％的乙醇5～8mL，搅拌，得反应混合物；
(2)将上述聚四氟乙烯内衬密封，放入不锈钢反应釜中，将不锈钢反应釜放入烘箱中，120～150℃加热反应48～72h，然后自然冷却至室温，打开反应釜得浅黄色块状晶体；
(3)将浅黄色块状晶体取出，自然风干，即得所述的超分子共晶；
所述超分子共晶是由5-硝基尿嘧啶和4,4’-二联吡啶组成的一种超分子共晶化合物，具有确定空间结构，其分子式为C18H14N8O8，结构单元为[(C10H8N2)(C4H3N3O4)2]，晶系为三斜晶系，空间群为P-1，晶胞参数为α＝97.373°，β＝101.803°，γ＝105.339°；
所述5-硝基乳清酸钾单水合物、4,4’-二联吡啶和水合氯化钴的摩尔比为2∶1∶1～2；
所述参加反应的物质均为化学纯，所述水合氯化钴为六水氯化钴。
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