论文标题:聚乙二醇支载的氮杂环化合物的液相合成
PEG-Supported Liquid-Phase Synthesis of Nitrogen-Containing Heterocycles
论文作者 林旭锋
论文导师 王彦广,论文学位 博士,论文专业 化学生物学
论文单位 浙江大学,点击次数 364,论文页数 149页File Size4636k
2004-08-01论文网 http://www.lw23.com/lunwen_399912/ 聚乙二醇;组合化学;杂环化合物;液相合成;噁二唑啉;吡唑啉;吡唑;呋喃并喹啉;吡喃并喹啉;吲哚
poly (ethylene glycol); combinatorial chemistry; Heterocycle; liquid-phase synthesis; 1,2,4-oxadiazolines; pyrazolines; pyrazoles; furoquinolines; pyranoquinolines; indoles
杂环化合物是一大类具有重要生理功能和药理活性的有机分子化合物,因此,杂环化合物库的组合合成已经成为当前组合化学研究的前沿和热点领域之一。随着组合化学的迅速发展,兼容固相合成和溶液相合成优点的可溶性聚合物支载的液相合成方法已成为实现组合化学的一条重要途径,受到了化学家们的重视。本论文综述了聚乙二醇(PEG)支载的小分子化合物库的液相合成研究进展,发展了一系列以可溶性聚合物聚乙二醇(平均分子量4000)为支载体,液相合成多取代1,2,4—噁二唑啉、吡唑啉和吡唑、呋喃并四氢喹啉和吡喃并四氢喹啉、呋喃并喹啉和吡喃并喹啉以及吲哚等含氮杂环化合物库的新方法。这些方法操作简便,反应条件温和,产率良好,产物纯度高,符合组合化学的基本要求。主要研究内容和结果如下: 1.发展了聚乙二醇支载的1,2,4—噁二唑啉的一锅法平行液相合成方法。PEG与对羧基苯甲醛酯化得到的PEG支载的苯甲醛,与羟胺缩合得到PEG支载的苯甲醛肟。后者以平行一锅法的方法相继用N—氯代丁二酰亚胺氧化氯代、三辛胺脱氯化氢原位生成PEG支载的苯基腈氧化物,与各种由胺和醛或酮直接制备的粗亚胺发生[3+2]环加成反应,得到PEG支载的1,2,4—噁二唑啉。最后用甲醇钠/甲醇处理发生酯交换反应解离PEG,得到三取代1,2,4—噁二唑啉。用此合成方法获得了一个含有13种1,2,4—噁二唑啉衍生物的化合物库。产率为79～93%,纯度达到89～98%。作为比较,发展了Merrifield树脂支载的1,2,4—噁二唑啉库的一锅法平行固相合成方法。树脂支载的苯甲醛肟用过量的N—氯代丁二酰亚胺处理得到树脂支载的苯甲醛氯代肟,不经过分离纯化,继续用过量的三乙胺和粗亚胺处理,原位生成的树脂支载的苯基腈氧化物捕获亲偶极子亚胺得到树脂支载的1,2,4—噁二唑啉。然后用酯交换反应和酯胺解反应从树脂解离出1,2,4—噁二唑啉衍生物。利用上述方法,得到了含有20种1,2,4—噁二唑啉衍生物的化合物库。产率为64～96%,纯度达到77～97%。 2.发展了聚乙二醇支载的吡唑啉和吡唑的平行液相合成方法。从醛和肼直接制备的粗腙,以平行一锅法的方法相继用N—溴代丁二酰亚胺氧化溴代、三辛胺脱溴化氢原位生成腈亚胺,跟PEG支载的丙烯酸酯和丙炔酸酯发生[3+2]偶极环加成
Heterocycles are a class of organic molecule with important physiological function and potent pharmacological activity. The polymer-supported synthesis of heterocyclic molecules has been a subject of intense research activity. With the development of combinatorial chemistry, liquid-phase synthesis which profits from both the advantageous features of homogeneous solution chemistry and of solid-phase synthesis has presented an important approach to realize combinatorial chemistry. In this thesis, soluble polymer poly (ethylene glycol)(PEG) supported synthesis of small organic molecule libraries are reviewed and PEG-supported parallel liquid-phase synthesis of some nitrogen-containing heterocycles, incuding 1,2,4-oxadiazolines, pyrazolines, pyrazoles, furoquinolines, pyranoquinolines as well as indoles, are described. The research results are summarized below:1. The parallel liquid-phase one pot synthesis of oxadiazolines via 1,3-dipolar cycloaddition reaction on poly(ethylene glycol) support is developed. 1, 3-Dipolar cycloadditions of nitrile oxide generated in situ on soluble polymer with a variety of imines provided a 13-member library of 1, 2, 4-oxadiazolines with yields 79～93% and purity 89~98%. The solid phase synthesis of 1,2,4-oxadiazolines via 1,3-dipolar cycloaddition of nitrile oxide generated in situ on solid support with a variety of imines is also studied. The synthetic sequences performed in parallel one-pot fashion on Merrifield resin. Cleavage from the resin under two different mild conditions afforded a 20-member library of 1, 2, 4-oxadiazolines which exploited four sites of chemical diversity in good yields (64-96%) and purity (77-97%).2. Rapid parallel liquid-phase synthesis of pyrazoles and pyrazolines is developed. The 1,3-dipolar cycloaddition between nitrilimines generated in situ and soluble polymer-supported alkynyl or alkenyl dipolarophiles in parallel one-pot fashion gave the corresponding PEG-supported regioisomeric pyrazoles or regiospecific pyrazolines as indicated by NMR. Cleavage from the support under mild conditions afforded a 5-member library of regioisomeric pyrazoles with yields 70～93% and purity 93～99%, and a 9-member library of regiospecific 5-substituted pyrazolineswith yields 86~94% and purity 85~97%. The PEG-supported regiospecific pyrazolines was assuredly oxidated by DDQ to PEG-supported regiospecific pyrazoles. Cleavage from the support with transesterification afforded a 9-member library of regiospecific 5-substituted pyrazoles with yields 81 —93% and purity 92 ~3. A parallel liquid-phase protocol for the synthesis of furoquinolines and pyranoquinolines is developed. The one-pot three-component aza-Diels-Alder reaction of PEG-supported benzaldehyde, primary aryl amines and 2,3-dihydrofuran or dihydropyran under 2%TFA/CH3CN gave PEG-supported tetrahydroquinolines. Cleavage from the support with transesterification reaction afforded a 10-member library of cis and trans isomers tetrahydroquinolines with yields 69~90%, purity 78~90% and diastereoselectivity 81~93%. PEG-supported tetrahydroquinolines was assuredly oxidated by DDQ and then cleaved from the support to afford the novel heterocycles furoquinolines and pyranoquinolines. Using this method, a 10-member library of quinolines was prepared in yields 53~78 % and purity 69~94%.4. A parallel liquid-phase synthesis of indoles via palladium-mediated heteroannulation is developed. PEG-supported o-iodoaniline was afforded through nucleophilic substitution reaction between 4-amino-3-iodobenzoic acid and PEG-supported methyl sulfonate. The former was actived by methanesulfonyl chloride, then was treated with excessive terminal alkyne in the presence of 5% PdCl2(PPh3)2 and 10%CuI in DMF and Et3N at 80 °C for 16 h to afford PEG-supported indole through Sonogashira coupling and undergoes an intramolecular cyclization procedure. Under the same conditions, if the amino group of PEG-supported o-iodoaniline was not mesylated prior to coupling with a terminal
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