类SGLT2抑制剂的合成及基于异腈的多组分选择性合成吡咯[1，2-f]菲啶衍生物的反应研究
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摘要
SGLT2抑制剂是一种新型的降糖药物,它通过增加肾脏葡萄糖的清除率降低血糖,可减弱肾脏对葡萄糖的重吸收,使多余的葡萄糖从尿液排出,从而降低血糖,为糖尿病的治疗提供了新的途径。本论文将葡萄糖基片段引入到三唑类杂环化合物中,有效改善和提高了杂环化合物的生物活性,并改善其水溶性差的缺点。
菲啶并吡咯类杂环化合物是一类具有抗肿瘤作用的药物分子,某些分子还可以作为分子机器,是一类重要的含氮杂环类化合物。异腈类化合物具有独特的官能团,它可以和某些亲电试剂形成两可性离子来构筑杂环以及碳环化合物。本文基于该特征,利用取代异腈与亲电试剂形成的两可性离子与菲啶发生1,3-偶极环加成反应,采用新型多组分有机反应合成方法,构筑和发展新型菲啶并吡咯类杂环体系的合成方法。
论文首先综述了酰肼,酰胺基硫脲,1,2,4-三唑类杂环化合物,全乙酰化溴代糖,钠依赖性葡萄糖转运体2(SGLT2)抑制剂的合成和应用;对异腈,基于异腈的多组分反应,多杂环菲啶衍生物进行了概述。
其次以羟基苯甲酸乙酯与水合肼制得酰肼,由酰肼分别与三种不同取代基的异硫氰酸苯酯反应得到氨基硫脲,在碱性条件下合环后与卤代烷发生烷基化,得到1,2,4-均三唑衍生物。三唑与全乙酰化溴代糖发生亲核取代反应,进一步经水解脱去乙酰基得到类SGLT2抑制剂类目标化合物。在三唑类化合物的合成中,放弃了固相合成方法,使用更为简便并且易于跟踪反应进程的普通方法。在烷基化过程中,控制反应物的用量,无需进行羟基的保护。三唑与糖类化合物的反应,使用相转移催化剂使反应速度加快,产率明显提高,反应条件温和。合成了三个目标化合物1b,2b和3b。
最后研究了以取代异腈,取代2-亚芳基丙二腈和菲啶三组分的反应,构建了新型菲啶并吡咯类杂环化合物。研究了溶剂以及取代基等条件对反应的影响。对于三组分反应,乙醚为最佳溶剂溶剂,在室温条件下便可以得到较高产率的目标产物。异腈类化合物取代基的空间位阻以及2-亚芳基丙二腈取代基的供/吸电子作用,都对反应产率有影响。得到产物通过乙醚洗涤便可得到纯品,无需进一步分离。该反应条件温和,操作简便,无需使用催化剂或者是活化剂。重要的是,所有目标产物有两个手性中心,却只有一种对映异构体,合成方法具有高度区域及立体选择性。合成了25个目标化合物4a-4k, 5a-5f, 6a-6h,这种方法合成吡咯并菲啶类化合物迄今未见文献报道。
所有新化合物的结构均经IR,~1H NMR,~(13)C NMR, HRMS等手段进行了鉴定,并对反应提出了可能的反应机理。
Sodium glucose co-transporter 2 (SGLT2) inhibitors are a kind of new glucose-lowering drugs. They can reduce the renal reabsorption of glucose by increasing the clearance of renal glucose and make the extra glucose exclude through urine thus can lower blood sugar. Therefore, SGLT2 inhibitors provided a new method for the treatment of diabetes. In this paper, analogous SGLT2 inhibitors--thiazole derivatives containing glycosyl were synthesized to improve the bioactivity and poor water-solubility of triazoles.
Pyrrolophenanthridine derivatives displayed high antitumor and antileukemic activity. Some of them could be used as molecular scale devices. Therefore, they play an important role in nitrogen-containing heterocycles. Isocyanides with its unique functional groups could form zwitterions with some electrophiles to construst novel protocols for the synthesis of heterocycles and carbocycles. Here, we developed the reaction of the zwitterions generated in situ from isocyanides and electrophiles with phenanthridine via 1,3-dipolar cycloaddition.
Firstly, the synthesis and applications of hydrazide, thiosemicarbazide, triazoles, peracetylglucopyranosyl bromide, and SGLT2 inhibitors were reviewed in brief. Then isocyanide, isocyanide-based multicomponet reactions (IMCRs) and fused heterocyclic phenanthridine were introduced.
Secondly, hydrazide compound was derived from the reaction of hydroxybenzoate with hydrazine hydrate. Thiosemicarbazide derivatives were synthesized through hydrazide and phenylisothiocyanate containing different subtituents. Thiosemicarbazide derivatives cyclized at alkaline conditions and then reacted with alkyl halide to obtain 1,2,4-triazole derivatives. Under phase transfer conditions, triazole derivatives proceeded with 2,3,4,6-tetra-O-acetyl-α- D-glucopyranosyl bromide to give the peracetylated sugar derivatives which underwent hydrolysis to give analogous SGLT2 inbitors. The synthesis of 1,2,4-triazole derivatives proceeded with the common method without using solid phase synthesis to make this reaction convenient and easy to trace. Adjusting the reactant amount could avoid the protection of hydroxyl group during the alkylation reaction. Using phase transfer catalyst could increase the reaction rate and improve the yield effectively under mild conditions. Three target compounds 1b, 2b and 3b were synthesized.
Finally, Novel pyrrolophenanthridine derivatives were constructed through three-component reaction of isocyanides, 2-arylidenemalononitriles with phenanthridine as well as four-component reaction of isocyanides, malononitrile, aromatic aldehyde with phenanthridine. The reaction conditions including solvent and substituents were also investigated. Using diethyl ether as the solvent resulted in higher yields and shorter reaction time at room temperature in three-component reaction. The steric hinerance of substituents of isocyanides and different electronically substituents of arylidenemalononitriles also had some influence on the yields. All the isolated products only need washing with diethyl ether twice rather than column chromatography or recrystallization. These reactions proceeded in mild conditions and are rapid to execute without using any catalyst or activation. All the target compounds owned two chiral centers but only one corresponding stereoisomers was achieved. This indicated that this transformation provided a highly regio- and stereoselective method for the preparation of pyrrolophenanthridine derivatives. Twenty-five target compounds 4a-4k, 5a-5f, 6a-6h were synthesized
Structures of all the target compounds were confirmed by IR, ~1H NMR, ~(13)C NMR, and HRMS, and the possible mechanism was also proposed. The unambiguous molecular structure of 4a, 5f and 6d were determined by X-ray diffraction analysis.
菲啶并吡咯类杂环化合物是一类具有抗肿瘤作用的药物分子,某些分子还可以作为分子机器,是一类重要的含氮杂环类化合物。异腈类化合物具有独特的官能团,它可以和某些亲电试剂形成两可性离子来构筑杂环以及碳环化合物。本文基于该特征,利用取代异腈与亲电试剂形成的两可性离子与菲啶发生1,3-偶极环加成反应,采用新型多组分有机反应合成方法,构筑和发展新型菲啶并吡咯类杂环体系的合成方法。
论文首先综述了酰肼,酰胺基硫脲,1,2,4-三唑类杂环化合物,全乙酰化溴代糖,钠依赖性葡萄糖转运体2(SGLT2)抑制剂的合成和应用;对异腈,基于异腈的多组分反应,多杂环菲啶衍生物进行了概述。
其次以羟基苯甲酸乙酯与水合肼制得酰肼,由酰肼分别与三种不同取代基的异硫氰酸苯酯反应得到氨基硫脲,在碱性条件下合环后与卤代烷发生烷基化,得到1,2,4-均三唑衍生物。三唑与全乙酰化溴代糖发生亲核取代反应,进一步经水解脱去乙酰基得到类SGLT2抑制剂类目标化合物。在三唑类化合物的合成中,放弃了固相合成方法,使用更为简便并且易于跟踪反应进程的普通方法。在烷基化过程中,控制反应物的用量,无需进行羟基的保护。三唑与糖类化合物的反应,使用相转移催化剂使反应速度加快,产率明显提高,反应条件温和。合成了三个目标化合物1b,2b和3b。
最后研究了以取代异腈,取代2-亚芳基丙二腈和菲啶三组分的反应,构建了新型菲啶并吡咯类杂环化合物。研究了溶剂以及取代基等条件对反应的影响。对于三组分反应,乙醚为最佳溶剂溶剂,在室温条件下便可以得到较高产率的目标产物。异腈类化合物取代基的空间位阻以及2-亚芳基丙二腈取代基的供/吸电子作用,都对反应产率有影响。得到产物通过乙醚洗涤便可得到纯品,无需进一步分离。该反应条件温和,操作简便,无需使用催化剂或者是活化剂。重要的是,所有目标产物有两个手性中心,却只有一种对映异构体,合成方法具有高度区域及立体选择性。合成了25个目标化合物4a-4k, 5a-5f, 6a-6h,这种方法合成吡咯并菲啶类化合物迄今未见文献报道。
所有新化合物的结构均经IR,~1H NMR,~(13)C NMR, HRMS等手段进行了鉴定,并对反应提出了可能的反应机理。
Sodium glucose co-transporter 2 (SGLT2) inhibitors are a kind of new glucose-lowering drugs. They can reduce the renal reabsorption of glucose by increasing the clearance of renal glucose and make the extra glucose exclude through urine thus can lower blood sugar. Therefore, SGLT2 inhibitors provided a new method for the treatment of diabetes. In this paper, analogous SGLT2 inhibitors--thiazole derivatives containing glycosyl were synthesized to improve the bioactivity and poor water-solubility of triazoles.
Pyrrolophenanthridine derivatives displayed high antitumor and antileukemic activity. Some of them could be used as molecular scale devices. Therefore, they play an important role in nitrogen-containing heterocycles. Isocyanides with its unique functional groups could form zwitterions with some electrophiles to construst novel protocols for the synthesis of heterocycles and carbocycles. Here, we developed the reaction of the zwitterions generated in situ from isocyanides and electrophiles with phenanthridine via 1,3-dipolar cycloaddition.
Firstly, the synthesis and applications of hydrazide, thiosemicarbazide, triazoles, peracetylglucopyranosyl bromide, and SGLT2 inhibitors were reviewed in brief. Then isocyanide, isocyanide-based multicomponet reactions (IMCRs) and fused heterocyclic phenanthridine were introduced.
Secondly, hydrazide compound was derived from the reaction of hydroxybenzoate with hydrazine hydrate. Thiosemicarbazide derivatives were synthesized through hydrazide and phenylisothiocyanate containing different subtituents. Thiosemicarbazide derivatives cyclized at alkaline conditions and then reacted with alkyl halide to obtain 1,2,4-triazole derivatives. Under phase transfer conditions, triazole derivatives proceeded with 2,3,4,6-tetra-O-acetyl-α- D-glucopyranosyl bromide to give the peracetylated sugar derivatives which underwent hydrolysis to give analogous SGLT2 inbitors. The synthesis of 1,2,4-triazole derivatives proceeded with the common method without using solid phase synthesis to make this reaction convenient and easy to trace. Adjusting the reactant amount could avoid the protection of hydroxyl group during the alkylation reaction. Using phase transfer catalyst could increase the reaction rate and improve the yield effectively under mild conditions. Three target compounds 1b, 2b and 3b were synthesized.
Finally, Novel pyrrolophenanthridine derivatives were constructed through three-component reaction of isocyanides, 2-arylidenemalononitriles with phenanthridine as well as four-component reaction of isocyanides, malononitrile, aromatic aldehyde with phenanthridine. The reaction conditions including solvent and substituents were also investigated. Using diethyl ether as the solvent resulted in higher yields and shorter reaction time at room temperature in three-component reaction. The steric hinerance of substituents of isocyanides and different electronically substituents of arylidenemalononitriles also had some influence on the yields. All the isolated products only need washing with diethyl ether twice rather than column chromatography or recrystallization. These reactions proceeded in mild conditions and are rapid to execute without using any catalyst or activation. All the target compounds owned two chiral centers but only one corresponding stereoisomers was achieved. This indicated that this transformation provided a highly regio- and stereoselective method for the preparation of pyrrolophenanthridine derivatives. Twenty-five target compounds 4a-4k, 5a-5f, 6a-6h were synthesized
Structures of all the target compounds were confirmed by IR, ~1H NMR, ~(13)C NMR, and HRMS, and the possible mechanism was also proposed. The unambiguous molecular structure of 4a, 5f and 6d were determined by X-ray diffraction analysis.
引文
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