新型N-苯基哌嗪喹啉類衍生物的設計與合成
發(fā)布時間：2018-09-09 18:39
【摘要】：雜環(huán)類化合物是一類非常重要的化合物，它在有機藥物合成中有著十分重要實用地位，這主要取決于它們的二環(huán)和三環(huán)的衍生物在醫(yī)藥和農藥方面具有可應用的生理活性。在這其中，1,5-苯并硫氮雜及其衍生物是一類比較重要的七元雜環(huán)化合物，它同時含有N元素和S元素。1,5-苯并硫氮雜及其衍生物之所以應用廣泛，主要是因為他們具有廣闊的生物活性，例如它們具有抗高血壓、抗驚厥、抗癌、抗HIV、抗?jié)�、抗菌等作用，另外，它們也可以作為鈣離子拮抗劑，是許多止痛劑等重要藥物的主要成分。例如，在人類目前廣泛使用的一類臨床藥物—鹽酸地爾硫中，就含有雜環(huán)結構。目前，1,5-苯并硫氮雜及其衍生物的合成及研究已經(jīng)成為了許多藥物化學家們的重要研究熱點。 在醫(yī)藥工業(yè)中，許多喹啉化合物都是重要的藥物中間體。近年來，許多含喹啉環(huán)的新型藥物不斷的被人們開發(fā)出來。喹啉最初是從抗瘧藥物—奎寧中經(jīng)過蒸餾而得到的，喹啉主要應用于合成抗瘧藥物，如磷酸氯喹、磷酸伯胺喹和胺酚喹啉等；也可以合成重要的局部麻醉藥物，如鹽酸地布卡因；還可以合成解熱鎮(zhèn)痛藥物辛可芬，抗菌素藥物克菌定；還有抗阿米巴病藥喹碘仿、氯碘喹啉、雙碘喹啉等等。同時由喹啉環(huán)及其他雜環(huán)化合物還可以合成撲蟯靈和克瀉痢寧。通過前人的研究，我們發(fā)現(xiàn)通過1,3-偶極環(huán)加成反應可以成功的構建四元、五元雜環(huán)，考慮到藥物設計的拼接原理，在研究過程中，，我們把1,5-苯并硫氮雜引入到喹啉環(huán)母核中，借以期望獲得有潛在生物學活性的化合物，為有機藥物的篩選提供合成方法及先導化合物。 我們的主要工作是將N-苯基哌嗪作為取代基引入到喹啉雜環(huán)分子中，并通過1,3-偶極環(huán)加成反應合成了一系列結構新穎且具有潛在生物學活性的衍生物，成功的合成了一系列含N-苯基哌嗪的喹啉類衍生物。 本論文分為以下兩部分： 第一部分為文獻綜述部分： 該部分對喹啉、1,5-苯并硫氮雜和1,2,4-VA二唑的重要合成方法以及生理、藥理活性等在國內外的研究狀況作了比較系統(tǒng)的闡述；同時還簡要介紹了1,3-偶極環(huán)加成反應等對1,5-苯并硫氮雜衍生物及含喹啉基1,2,4-VA二唑啉類衍生物進行結構修飾的環(huán)合反應。 第二部分為實驗部分，主要工作如下： 1、新型含苯基哌嗪取代的喹啉基1,5-苯并硫氮雜及其衍生物的合成與表征 利用新合成的1,5-苯并硫氮雜衍生物與簡單對位取代的氯代肟通過1,3-偶極環(huán)加成反應得到一系列1,2,4-VA二唑并1,5-苯并二氮雜類衍生物。 2、新型含苯基哌嗪取代的喹啉基1,2,4-VA二唑啉類衍生物的合成與表征 2-（4-苯基哌嗪-1-基）-3-喹啉甲醛與對位取代的苯胺反應得到不同的亞胺，接著亞胺和簡單對位取代的氯代肟通過1,3-偶極環(huán)加成反應得到一系列含喹啉基1,2,4-VA二唑啉類衍生物。 3、新型含苯基哌嗪取代的喹啉基1,3,4-VA二唑啉類衍生物的合成與表征 2-（4-苯基哌嗪-1-基）-3-喹啉甲醛與不同取代苯甲酰肼反應得到一系列新型的酰腙類化合物，然后在乙酸酐中氧化關環(huán)得到了一系列新型含喹啉基1,3,4-VA二唑啉類衍生物。 產(chǎn)物結構經(jīng)過元素分析、MS、IR、1H NMR和13C NMR得到確認，并對其波譜性質進行了分析和討論。
[Abstract]:Heterocyclic compounds are a very important class of compounds, which play a very important role in the synthesis of organic drugs, mainly depending on their dicyclic and tricyclic derivatives have applied physiological activities in medicine and pesticides. Cyclic compounds, which contain both N and S elements. 1,5-benzothiaza and their derivatives are widely used because they have broad biological activities, such as anti-hypertension, anticonvulsant, anticancer, anti-HIV, anti-ulcer, antibacterial and so on. In addition, they can also be used as calcium ion antagonists and are many analgesics. For example, Diltiazem hydrochloride, a widely used clinical drug, contains heterocyclic structure. At present, the synthesis and research of 1,5-benzothiazole and its derivatives have become an important research hotspot of many pharmaceutical chemists.
Quinoline compounds are important pharmaceutical intermediates in the pharmaceutical industry. In recent years, many new drugs containing quinoline rings have been developed. Quinoline was originally obtained by distillation from quinine, an antimalarial drug. Quinoline is mainly used in the synthesis of antimalarial drugs, such as chloroquine phosphate, primary aminoquine phosphate and aminophenol quinoline. It can also be used to synthesize important local anesthetics, such as dibucaine hydrochloride, antipyretic and analgesic drugs, such as cinchofen and clotridine, as well as quinolidoform, chloroiodoquinoline, bisiodoquinoline, etc. Quinoline rings and other heterocyclic compounds can also be used to synthesize chlorphenamine and clotridine. Previous studies have shown that tetrad and quintuple heterocycles can be successfully constructed by 1,3-dipolar cycloaddition reaction. Considering the splicing principle of drug design, we introduced 1,5-benzothiazide into quinoline nucleus in order to obtain compounds with potential biological activity and provide a basis for the screening of organic drugs. Synthesis methods and lead compounds.
Our main work is to introduce N-phenylpiperazine as a substituent into quinoline heterocyclic molecules and synthesize a series of novel derivatives with potential biological activities by 1,3-dipolar cycloaddition reaction. A series of quinoline derivatives containing N-phenylpiperazine were successfully synthesized.
This thesis is divided into two parts:
The first part is the literature review.
In this part, the important synthetic methods, physiological and pharmacological activities of quinoline, 1,5-benzothiazole and 1,2,4-VA diazole are systematically reviewed, and the 1,5-benzothiazole derivatives and quinoline-containing 1,2,4-VA diazoline derivatives are also briefly introduced. Structural modification of cyclization.
The second part is the experimental part. The main tasks are as follows:
1, the synthesis and characterization of novel quinoline 1,5- benzoxazide substituted phenoxy piperazine derivatives
A series of 1,2,4-VA diazo 1,5-benzodiazo derivatives were synthesized by 1,3-dipolar cycloaddition of 1,5-benzothiazole derivatives with simple para-substituted chlorooximes.
2, synthesis and characterization of a new quinoline 1,2,4-VA two azoline derivative containing phenyl piperazine.
2-(4-phenylpiperazine-1-yl) -3-quinoline formaldehyde reacts with para-substituted aniline to obtain different imines. Then imines and simple para-substituted oximes react with 1,3-dipolar cycloaddition to obtain a series of quinoline-containing 1,2,4-VA diazoline derivatives.
3, synthesis and characterization of a new quinoline 1,3,4-VA two azoline derivative containing phenyl piperazine.
A series of new acylhydrazones were synthesized by the reaction of 2-(4-phenylpiperazine-1-yl) -3-quinoline formaldehyde with different substituted benzoylhydrazines. Then a series of new quinolino-containing 1,3,4-VA diazoline derivatives were obtained by oxidative ring-closure in acetic anhydride.
The structure of the product was confirmed by elemental analysis, MS, IR, 1H NMR and 13C NMR, and its spectral properties were analyzed and discussed.
【學位授予單位】：新疆大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：O626
[Abstract]:Heterocyclic compounds are a very important class of compounds, which play a very important role in the synthesis of organic drugs, mainly depending on their dicyclic and tricyclic derivatives have applied physiological activities in medicine and pesticides. Cyclic compounds, which contain both N and S elements. 1,5-benzothiaza and their derivatives are widely used because they have broad biological activities, such as anti-hypertension, anticonvulsant, anticancer, anti-HIV, anti-ulcer, antibacterial and so on. In addition, they can also be used as calcium ion antagonists and are many analgesics. For example, Diltiazem hydrochloride, a widely used clinical drug, contains heterocyclic structure. At present, the synthesis and research of 1,5-benzothiazole and its derivatives have become an important research hotspot of many pharmaceutical chemists.
Quinoline compounds are important pharmaceutical intermediates in the pharmaceutical industry. In recent years, many new drugs containing quinoline rings have been developed. Quinoline was originally obtained by distillation from quinine, an antimalarial drug. Quinoline is mainly used in the synthesis of antimalarial drugs, such as chloroquine phosphate, primary aminoquine phosphate and aminophenol quinoline. It can also be used to synthesize important local anesthetics, such as dibucaine hydrochloride, antipyretic and analgesic drugs, such as cinchofen and clotridine, as well as quinolidoform, chloroiodoquinoline, bisiodoquinoline, etc. Quinoline rings and other heterocyclic compounds can also be used to synthesize chlorphenamine and clotridine. Previous studies have shown that tetrad and quintuple heterocycles can be successfully constructed by 1,3-dipolar cycloaddition reaction. Considering the splicing principle of drug design, we introduced 1,5-benzothiazide into quinoline nucleus in order to obtain compounds with potential biological activity and provide a basis for the screening of organic drugs. Synthesis methods and lead compounds.
Our main work is to introduce N-phenylpiperazine as a substituent into quinoline heterocyclic molecules and synthesize a series of novel derivatives with potential biological activities by 1,3-dipolar cycloaddition reaction. A series of quinoline derivatives containing N-phenylpiperazine were successfully synthesized.
This thesis is divided into two parts:
The first part is the literature review.
In this part, the important synthetic methods, physiological and pharmacological activities of quinoline, 1,5-benzothiazole and 1,2,4-VA diazole are systematically reviewed, and the 1,5-benzothiazole derivatives and quinoline-containing 1,2,4-VA diazoline derivatives are also briefly introduced. Structural modification of cyclization.
The second part is the experimental part. The main tasks are as follows:
1, the synthesis and characterization of novel quinoline 1,5- benzoxazide substituted phenoxy piperazine derivatives
A series of 1,2,4-VA diazo 1,5-benzodiazo derivatives were synthesized by 1,3-dipolar cycloaddition of 1,5-benzothiazole derivatives with simple para-substituted chlorooximes.
2, synthesis and characterization of a new quinoline 1,2,4-VA two azoline derivative containing phenyl piperazine.
2-(4-phenylpiperazine-1-yl) -3-quinoline formaldehyde reacts with para-substituted aniline to obtain different imines. Then imines and simple para-substituted oximes react with 1,3-dipolar cycloaddition to obtain a series of quinoline-containing 1,2,4-VA diazoline derivatives.
3, synthesis and characterization of a new quinoline 1,3,4-VA two azoline derivative containing phenyl piperazine.
A series of new acylhydrazones were synthesized by the reaction of 2-(4-phenylpiperazine-1-yl) -3-quinoline formaldehyde with different substituted benzoylhydrazines. Then a series of new quinolino-containing 1,3,4-VA diazoline derivatives were obtained by oxidative ring-closure in acetic anhydride.
The structure of the product was confirmed by elemental analysis, MS, IR, 1H NMR and 13C NMR, and its spectral properties were analyzed and discussed.
【學位授予單位】：新疆大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：O626
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