他克林类似物的合成与表征
摘要
他克林(THA),是第一个在美国FDA获批准用于治疗老年痴呆症的药物脂溶性高、易透过血脑屏障,是一个临床有效的胆碱酯酶抑制剂(ChEI)。但他克林的肝毒副作用大、生物利用度低等缺点制约了该药的广泛使用。
为了降低他克林的毒副作用,筛选出治疗AD效果更好的药物,本实验设计合成了一系列他克林的酰胺类衍生物。以芳香醛、丙二睛和萘酚为原料合成出3-氨基-2-氰基-1-芳基-1H-苯并[f]吡喃和2-氨基-3-氰基-4-芳基-4H-苯并[h]吡喃,然后分别与5-取代-1,3-环己二酮发生缩合、关环反应,合成出一系列国内外未见报道的他克林酰胺衍生物。
本论文用了两种不同的合成方法同时得到了目标产物,第一种方法是按照传统的合成路线,在甲苯作溶剂、对甲苯磺酸作催化剂的条件下,连有氰基和氨基的萘并吡喃衍生物和5-取代-1,3-环己二酮发生反应。处理后的产物在四氢呋喃中用碳酸钾、氯化亚铜作催化剂的条件下环化得到目标产物。这种方法操作繁琐、反应时间较长,并且对环境污染较大。为了改进合成方法,在第二种方法中,我们用水代替甲苯作溶剂,用稀盐酸代替对甲苯磺酸作催化剂,连有氰基和氨基的萘并吡喃衍生物和5-取代-1,3-环己二酮发生反应后,不需要处理直接进行下一步反应。改进后的方法较之前的方法不仅简化了操作步骤,缩短了反应时间,更重要的是降低了反应的成本、减少了反应对环境的污染。
本文共合成出新杂环类衍生物28个,其中他克林衍生物11个,所合成的化合物结构经IR、1H NMR、MS和元素分析予以证实,并且对两个化合物通过X-Ray单晶衍射进一步确定了化合物的空间构型。另外,本文对反应的可能机理进行了研究和探讨,并探究了新的合成方法的最佳条件,为以后进一步筛选出更好的AD治疗药物打下了坚实的基础。
Tacrine(THA) was the first cholinesterase inhibitor approved in USA for symptomatic treatment of AD. It is a centrally acting reversible cholinesterase inhibitor. However, it exhibits hepatotoxicity by markedly elevating serum alanine aminotransferase levels, and thus has a limited clinical application.
Considerable amount of THA derivatives and its analogues were synthesized in this paper in order to find compounds with reduced side effects. The intermediate product 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitrile and 2-amino-4-aryl-4H- benzo[h]chromene-3-carbonitrile were prepared by the reaction of malononitrile and naphthol with corresponding aromatic aldehydes in ethanol. Then, 5-substituted-1,3- cyclohexanedione reacted with the intermediate product respectively by condensation reaction and dieckman to afford a series of novel Tacrine derivatives.
We have utilized two methods for the synthesis of target compounds, in the first traditional the method that benzo[f/h]chromenes reacted with 5-substituted-1, 3-cyclohexanedione using pTSA (P-Toluene sulphonic acid) as catalyst in toluene, and then the title compounds were obtained in THF using K2CO3/Cu2Cl2 as catalysts. the method suffered from certain drawbacks such as long reaction time, unsatisfactory yields, using of hazardous solvents, complex process, low selectivity, co-occurrence of several side reactions and needing of chromatography for purification of adducts. In the second method, we improved the method, we used methanol instead of toluene using dilute hydrochloric acid as catalyst. Compared to other methods, the new methods offered many advantages such as simple operation, short reaction time and low toxic.
Twenty-eight new heterocyclic compounds were synthesized in this paper, including 11 tacrine analogues, the structures of all the synthesized compounds were characterized by IR、1H NMR、MS spectrum and elemental analysis. We also trained two single crystals to characterize the space configuration by using X-Ray diffraction. In addition, we discussed the Plausible Formation Mechanism and the optimum condition for reaction.
为了降低他克林的毒副作用,筛选出治疗AD效果更好的药物,本实验设计合成了一系列他克林的酰胺类衍生物。以芳香醛、丙二睛和萘酚为原料合成出3-氨基-2-氰基-1-芳基-1H-苯并[f]吡喃和2-氨基-3-氰基-4-芳基-4H-苯并[h]吡喃,然后分别与5-取代-1,3-环己二酮发生缩合、关环反应,合成出一系列国内外未见报道的他克林酰胺衍生物。
本论文用了两种不同的合成方法同时得到了目标产物,第一种方法是按照传统的合成路线,在甲苯作溶剂、对甲苯磺酸作催化剂的条件下,连有氰基和氨基的萘并吡喃衍生物和5-取代-1,3-环己二酮发生反应。处理后的产物在四氢呋喃中用碳酸钾、氯化亚铜作催化剂的条件下环化得到目标产物。这种方法操作繁琐、反应时间较长,并且对环境污染较大。为了改进合成方法,在第二种方法中,我们用水代替甲苯作溶剂,用稀盐酸代替对甲苯磺酸作催化剂,连有氰基和氨基的萘并吡喃衍生物和5-取代-1,3-环己二酮发生反应后,不需要处理直接进行下一步反应。改进后的方法较之前的方法不仅简化了操作步骤,缩短了反应时间,更重要的是降低了反应的成本、减少了反应对环境的污染。
本文共合成出新杂环类衍生物28个,其中他克林衍生物11个,所合成的化合物结构经IR、1H NMR、MS和元素分析予以证实,并且对两个化合物通过X-Ray单晶衍射进一步确定了化合物的空间构型。另外,本文对反应的可能机理进行了研究和探讨,并探究了新的合成方法的最佳条件,为以后进一步筛选出更好的AD治疗药物打下了坚实的基础。
Tacrine(THA) was the first cholinesterase inhibitor approved in USA for symptomatic treatment of AD. It is a centrally acting reversible cholinesterase inhibitor. However, it exhibits hepatotoxicity by markedly elevating serum alanine aminotransferase levels, and thus has a limited clinical application.
Considerable amount of THA derivatives and its analogues were synthesized in this paper in order to find compounds with reduced side effects. The intermediate product 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitrile and 2-amino-4-aryl-4H- benzo[h]chromene-3-carbonitrile were prepared by the reaction of malononitrile and naphthol with corresponding aromatic aldehydes in ethanol. Then, 5-substituted-1,3- cyclohexanedione reacted with the intermediate product respectively by condensation reaction and dieckman to afford a series of novel Tacrine derivatives.
We have utilized two methods for the synthesis of target compounds, in the first traditional the method that benzo[f/h]chromenes reacted with 5-substituted-1, 3-cyclohexanedione using pTSA (P-Toluene sulphonic acid) as catalyst in toluene, and then the title compounds were obtained in THF using K2CO3/Cu2Cl2 as catalysts. the method suffered from certain drawbacks such as long reaction time, unsatisfactory yields, using of hazardous solvents, complex process, low selectivity, co-occurrence of several side reactions and needing of chromatography for purification of adducts. In the second method, we improved the method, we used methanol instead of toluene using dilute hydrochloric acid as catalyst. Compared to other methods, the new methods offered many advantages such as simple operation, short reaction time and low toxic.
Twenty-eight new heterocyclic compounds were synthesized in this paper, including 11 tacrine analogues, the structures of all the synthesized compounds were characterized by IR、1H NMR、MS spectrum and elemental analysis. We also trained two single crystals to characterize the space configuration by using X-Ray diffraction. In addition, we discussed the Plausible Formation Mechanism and the optimum condition for reaction.
引文
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