CN110105272B - 一种酰胺缩醛类化合物及其制备方法与应用 - Google Patents
一种酰胺缩醛类化合物及其制备方法与应用 Download PDFInfo
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- A61P31/04—Antibacterial agents
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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
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- C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
技术领域
本发明涉及有机合成技术领域,具体涉及一种酰胺缩醛类化合物及其制备方法与应用。
背景技术
醛类化合物(包括醛及其衍生物)是一种具有较高反应活性的化合物,其能参与众多反应;醛基上带有极性,氧原子是碳氧键中的负极,将碳原子的电子拉向氧原子。由于醛的结构特点,在羰基中的π键极化,使得氧原子上带部分负电荷,而碳原子上带部分正电荷。在反应中,分子中的碳氧双键很容易被带有负电荷的试剂,即亲核试剂进攻,并发生反应。此外,受羰基的影响,与羰基直接相连的碳原子上的氢原子很活泼,能发生一系列反应。因此,羰基的亲核加成和相邻氢原子的活泼性是醛的主要反应。
酰胺类化合物(包括酰胺及其衍生物)从构造上,可以看作是羧酸分子中羧基上的羟基被氨基或烃氨基(-NHR或-NR2)取代而成的化合物;也可以看作是氨或胺分子中氮原子上的氢被酰基取代而成的化合物。
按照常规席夫碱的液相合成方法,将邻香草醛和吡啶2,6-二甲酰胺分别溶于溶剂(N,N-二甲基甲酰胺(N,N-Dimethylformamide,DMF)和二甲基亚砜(Dimethyl sulfoxide,DMSO))中,然后混合加热后反应,未能得到席夫碱产物,即未能发生反应。
这可能是由于酰胺的氨基氮是sp2杂化,剩下的p轨道孤对电子已经与羰基形成了p-π共轭,电子密度减小,失去了亲和进攻的能力,比较难以进攻醛基,酰胺的氨基与醛基不能发生“缩合脱水”反应生成席夫碱。同理地,其他酰胺类化合物与醛基反应时,也将难以制得席夫碱化合物。
目前,关于酰氨基与醛基之间的反应机理研究相对较少,尤其是尚未有关于酰氨基与醛基发生“缩合脱氧反应”生成亚氨基C-NH-的报道,更没有邻香醛与吡啶2,6-二甲酰胺发生“缩合脱氧反应”的报道。
发明内容
本发明所要解决的第一个技术问题是:提供一种含有亚氨基C-NH-的酰胺缩醛类化合物。
本发明所要解决的第二个技术问题是:提供一种含有亚氨基C-NH-的酰胺缩醛类化合物的制备方法。
本发明所要解决的第三个技术问题是:提供一种上述化合物在配合物制备的应用。
本发明所要解决的第四个技术问题是:提供一种上述配合物在抗癌或抑菌制剂的制备的应用。
为了解决上述第一个技术问题,本发明采用的技术方案为:一种酰胺缩醛类化合物,所述化合物中含有如下式(I)所示的结构:
其中,R1或R2各自独立代表H或任意取代基。
优选地,所述式(I)中的取代基选自:烃基或烃基衍生物。
更优选地,所述烃基为脂肪烃基、芳香烃基或杂环烃基,所述烃基衍生物为脂肪烃基衍生物、芳香烃基衍生物或杂环烃基衍生物。
进一步地,所述化合物中含有如下式(II)所示的结构:
其中,R3和R4各自独立的代表H或任意取代基。
优选地,所述式(II)中的取代基选自:烃基或烃基衍生物。
优选地,所述化合物的结构式如下:
本发明的有益效果在于:首次公开了一种含有亚氨基C-NH-的酰胺缩醛类化合物,该化合物含有孤对电子,可作为配体用于金属配合物的制备,具有良好的应用前景。
为了解决上述第二个技术问题,本发明采用的技术方案为:一种酰胺缩醛类化合物的制备方法,包括以下步骤:
将醛类化合物和酰胺类化合物混合后,在微波加热的条件下按如下方程式反应制得所述酰胺缩醛类化合物:
其中,R1或R2各自独立代表H或任意取代基;优选地,所述烃基为脂肪烃基、芳香烃基或杂环烃基,所述烃基衍生物为脂肪烃基衍生物、芳香烃基衍生物或杂环烃基衍生物。
进一步地,所述制备方法还包括提纯的操作,具体操作为:取微波加热反应后制得的产物,溶于N,N-二甲基甲酰胺或二甲亚砜,搅拌使其完全溶解后,再加入无水乙醇重结晶纯化。
进一步地,所述将醛类化合物和酰胺类化合物混合的操作为:先使醛类化合物或酰胺类化合物熔解得到熔液,再将酰胺类化合物或醛类化合物加入到所述熔液中。选择熔点低的组分进行加热使其熔解后,转换为液相,以便于更好地混合,若两种物质中有某种物质本身呈液态,而也可不进行此操作。
进一步地,所述微波炉的功率为400W~800W,加热时间为1~15min;优选地,功率为500W,加热时间为5min。
本发明方案的有益效果在于:本发明方案的化合物可采用固相微波法成功制备得到酰胺缩醛类化合物,反应体系简单且操作简便。
为了解决上述第三个技术问题,本发明采用的技术方案为:一种酰胺缩醛类化合物在酰胺缩醛类金属配合物的制备中的应用。
优选地,所述金属为主族金属或过渡金属或稀土金属;更优选地,所述主族金属为铋,所述过渡金属为铜、锌、银,所述稀土金属为镧、铈、钐、钕。
本发明的有益效果在于:本发明方案的化合物中具有多对孤对电子可以作为配体制备金属配合物。
为了解决上述第四个技术问题,本发明采用的技术方案为:一种上述酰胺缩醛类金属配合物在抗癌或抑菌制剂的制备中的应用。
优选地,所述制剂可以为药物制剂也可以是其他形式的制剂。
本发明的有益效果在于:将本发明方案的酰胺缩醛类化合物应用于金属配合物的制备中,制得的配合物在抗癌、抑菌等领域具有广泛的应用前景。
附图说明
图1为本发明实施例制得的配体化合物的质谱图;
图2为本发明实施例制得的铋配合物的质谱图;
图3为本发明实施例制得的配体化合物的结构式;
图4为本发明实施例制得的铋配化合物的结构式;
图5为本发明实施例制得的配体化合物的氢核磁共振谱图;
图6为本发明实施例制得的铋配化合物的氢核磁共振谱图;
图7为本发明实施例制得的配体化合物及铋配合物的红外光谱图;
图8为本发明实施例的配体化合物及铋配合物的紫外光谱图;
图9为本发明实施例的配体化合物及铋配合物的热重分析图。
具体实施方式
为详细说明本发明的技术内容、所实现目的及效果,以下结合实施方式并配合附图予以说明。
本发明的实施例为:一种酰胺缩醛类化合物,所述酰胺缩醛类化合物为邻香草醛缩吡啶2,6-二甲酰胺的结构式如下:
采用固相微波合成法,将邻香草醛与吡啶2,6-二甲酰胺进行固相微波合成反应,得到了产物邻香草醛缩吡啶2,6-二甲酰胺配体,其反应方程式为:
2C8H8O3+C7H7N3O2=C23H23N3O6+O2↑
具体制备过程可按以下步骤操作:
S1、准确称取邻香草醛(可以稍过量),置入带磨口塞的锥形瓶中,将盛有邻香草醛的锥形瓶置于60℃的恒温水浴中,使邻香草醛熔化,变为亮黄色熔液。然后,将准确称取吡啶-2,6-二甲酰胺,邻香草醛与吡啶-2,6-二甲酰胺的物质的量之比为2:1,加入到熔化的邻香草醛中,并用玻璃棒搅拌均匀,混合物为黄色粘稠状。熔解操作是为使两种化合物更好地混合,也可省去此操作,直接将两种物质的固体物质混合后在微波加热下反应,或者对于一些熔点低的物质,本身就呈液态,则可直接更好地混合。
S2、将装有混合物的锥形瓶磨口塞塞好,放入微波炉中500W(中高档火),加热5min,得到黑褐色固体即为所述酰胺缩醛类化合物。
对上述操作制得的化合物进行结构表征,具体操作如下:
取出制得的黑褐色固体冷却后,用玛瑙研钵将黑褐色固体研磨成粉末。
将粉末放入烧杯中,加入少量的N,N-二甲基甲酰胺,搅拌使其完全溶解,溶液呈棕褐色。
将溶液加入适量的无水乙醇,溶液变为亮黄色溶液,有浅黄色的固体析出,静置3h后,抽滤,将其滤饼干燥、研磨后,用少量无水乙醇洗涤数次,抽滤,产物在50℃干燥箱中干燥24h后,得邻香草醛缩吡啶2,6-二甲酰胺纯净物。采用该方案进行提纯操作,提纯效果好。
将制得的邻香草醛缩吡啶2,6-二甲酰胺与三氯化铋反应,制得邻香草醛缩吡啶2,6-二甲酰胺铋配合物,其反应方式程式和结构式依次如下所示:
C23H23N3O6+BiCl3=C23H21N3O6BiCl+2HCl
取上述操作制得的邻香草醛缩吡啶2,6-二甲酰胺及邻香草醛缩吡啶2,6-二甲酰胺铋配合物,通过元素分析、化学分析、质谱、核磁分析、红外光谱、紫外光谱和热重差热等多种手段对其组成和结构进行表征:
1)元素分析和化学分析
配体及铋配合物中的C、H和N用Perkin-Elmer 2400元素分析仪测定;配合物中金属铋离子的含量用EDTA标准溶液滴定;氯离子含量用莫尔法测定。元素分析和化学分析结果如下表1所示:
表1本发明实施例制得的配体及铋配合物的元素分析和化学分析
由上表1可以看出配体及铋配合物中的C、H和N元素含量,以及铋和氯元素的化学分析的结果都与其分子组成吻合,表明配体及铋配合物的组成分别为C23H23N3O6和C23H21N3O6BiCl。
2)质谱分析
取1mg配体化合物溶解于10mL DMSO中,再用甲醇稀释10倍,浓度约为10ppm。取铋配合物1mg溶解于10mL甲醇中,再用甲醇稀释10倍,浓度约为10ppm。在ThermoFisher公司LCQ Fleet离子阱质谱仪上,采用电喷雾(ESI)正离子模式采集,测定邻香草醛缩吡啶2,6-二甲酰胺(即配体)和邻香草醛缩吡啶2,6-二甲酰胺铋配合物(即配合物)的质谱图,结果如图1和图2所示。由图1和图2可以看出,配体化合物和配位化合物质谱图中的分子离子峰,EI-MS,m/z:437.22(M+)和679.38(M+),与邻香草醛缩吡啶2,6-二甲酰胺和邻香草醛缩吡啶2,6-二甲酰胺铋配合物的理论分子量M=436.2和M=678.38,基本吻合。更进一步证实了合成的化合物分别为邻香草醛缩吡啶2,6-二甲酰胺和邻香草醛缩吡啶2,6-二甲酰胺铋配合物。其结构式分别如图3和4所示。
3)核磁共振分析
以氘代DMSO为溶剂,四甲基硅烷(Tetramethylsilane,TMS)为内标,在瑞士Bruker公司生产400MHZ核磁共振仪上分别测定了邻香草醛缩吡啶2,6-二甲酰胺(即配体)和邻香草醛缩吡啶2,6-二甲酰胺铋配合物(即配合物)的核磁共振H谱图,如图5和6所示,具体数据如下表2所示:
表2本发明实施例制得的配体和铋配合物的H核磁图谱数据
注:表2中,峰值归属中C原子的序号与图3中的序号对应。
从上表2可以看出,本发明实施例制得的配体化合物和铋配位化合物的核磁表征结果与邻香草醛缩吡啶2,6-二甲酰胺和邻香草醛缩吡啶2,6-二甲酰胺铋配合物的核磁共振H谱类似,只有δ10.30ppm的两个-OH质子峰消失了,这证明铋配合物中的配体两个羟基参与了配位。
4)红外光谱分析
通过傅立叶变换红外光谱仪(Avatar360,USA)采用溴化钾压片法,分别测定了邻香草醛缩吡啶2,6-二甲酰胺和邻香草醛缩吡啶2,6-二甲酰胺铋配合物的红外光谱图,具体如图7所示,对应红外特征吸收峰变化情况如下表3所示:
表3配体和铋配合物的主要红外光谱数据
由表3可以看出,配体形成配合物后配体的尖锐酚羟基νAr-OH的伸缩振动峰3405cm-1消失;νC-N-H的伸缩振动峰向高波数移动了75cm-1,同时νC-N的伸缩振动峰也弱有位移,说明氨基中的氮原子参加了配位,佐证了氢核磁共振谱的结论,即铋配合物中配体上的两个羟基参与了配位。
5)紫外光谱分析
将上述操作制得的配体和铋配合物分别配成0.0010mol/L DMSO溶液,测定其紫外光谱,结果如图8所示,图中的主要紫外特征吸收峰数据如下表4所示:
表4配体和铋配合物的主要紫外光谱数据
由表4可以看出,在343nm处的吸收带为配体C-N基团中氮原子的p轨道上的孤对电子与苯杂环大π键的p-π共轭的n→π*吸收带;在283nm处的吸收峰,主要是由于苯环酚羟基的氧原子上的孤对电子与苯环大π键的p-π共轭的n→π*吸收带;在260nm处的吸收峰,这是由于苯环上双键共轭的π→π*跃迁的吸收光光谱。形成配合物后2个n→π*吸收带合并成了一个吸收带,这说明苯环酚羟基的氧原子和苯杂环C=N双键上的氮原子可能与金属Bi3+离子发生了配位形成了一个更大的共轭体系。此外,还可能是由于参与配位的Bi3+离子还结合着1个氯离子,由于氯离子的诱导效应使苯环酚羟基和苯杂环C=N双键上电子云密度减少,n→π*跃迁所需能量增大,故发生蓝移至299nm。
6)热重差热分析
在空气气氛中,以10℃/min的升温速率在25~1450℃温度范围对铋配合物进行了热重-差热(TG--DSC)分析,结果如图9所示。从图9中可以看出,TG-DSC曲线显示在230~516℃之间有一个放热强峰,显示失重百分数75.4%,对应的是C23H23N3O6和Cl的脱去,与理论值74.0%很相近。最终残留物为三氧化二铋(或BiO1.5),残余百分含量与理论值基本吻合。进一步证明了铋配合物的组成为C23H21N3O6BiCl。
综上所述,结合元素分析、化学分析、质谱、核磁共振、红外光谱、紫外光谱和热重差热等多种分析方法的结果间的相互佐证,可以推断出本发明实施例方案制得的配体及铋配合物的组成分别为:C23H23N3O6和C23H21N3O6BiCl,且结构式如图3和4所示。
邻香草醛缩吡啶2,6-二甲酰胺与三氯化铋反应,合成了邻香草醛缩吡啶2,6-二甲酰胺铋配合物,其反应方程式如下:
C23H23N3O6+BiCl3=C23H21N3O6BiCl+2HCl。
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书及附图内容所作的等同变换,或直接或间接运用在相关的技术领域,均同理包括在本发明的专利保护范围内。
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