臺灣博碩士論文加值系統

一種新型的離子液體的支持下，合成的協議已經發展走向合成四氫-β-&;#21652;氧和硫乙內&;#37232;&;#33074;類似物，二氫&;#21945;唑&;#21833;和四氫&;#21945;唑&;#21833;類似物的使用重點微波照射高純度和優良的產量。對於我們第一次開發出合成四氫-β-&;#21652;氧和硫乙內&;#37232;&;#33074;類似物在環境良性媒體對離子液體的支持。

A novel ionic liquid supported, synthetic protocol has been developed toward the
synthesis of tetrahydro-β-carboline oxo and thio hydantoin analogs, dihydro-quinazolines
and tetrahydro-quinazolines analogue by the use of focused microwave irradiation with
high purity and excellent yields. For the first time we have developed the synthesis of
tetrahydro-β-carboline oxo and thio hydantoin analogs in environmentally benign media
on ionic liquid support. We have also developed the synthesis of dihydro-quinazolines
and tetrahydro-quinazolines analogue on ionic liquid support under mild condition with
minimum synthetic step.
In a study aimed at developing a novel concise approach to the benzimidazole-pyrrolo[1,2-a]quinoxaline and benzimidazole-pyrrolo[1,2-a]quinoxalinone core of
medicinal interest, a SNAr/Pictet-Spengler reaction and partial nitro group reduction/SN2
reaction has been identified that gives the direct access to the target compound on soluble
polymer support under focused microwave irradiation. For the first time we have
introduced pyrrole and pyrrole carboxylate moiety into the aromatic system by SNAr
reaction. Further subsequent pictet-spengler cyclisation, partial nitro group reduction and
SN2 reaction has been developed for the medicinally important core of benzimidazole-pyrrolo[1,2-a]quinoxaline and benzimidazole-pyrrolo[1,2-a]quinoxalinone analogs.

Abstract……………………………………………………………...i
Acknowledgements.......................................iii
Declaration....................................iv
Table of contents .................................................v
List of Figures…………………………………………………………………xi
List of Schemes………………………………………………………………xiii
List of Tables…………………………………………………………xx
1.0. Introduction...............................................................................................................1
1.1. Green Chemistry for Sustainable Development........................................................2
1.2. Different definition of Green Chemistry………………………………………... ...3
1.3. The Twelve Principles of Green Chemistry……………………………………......4
1.4. Montreal Protocol………………………………………………………………….7
1.5. Solvent-free synthesis………………………………………………………….......8
1.6. Water, the Unique Reaction Medium………………………………………….......8
1.6.1. Introduction………………………………………………………………......8
1.6.2. Is water the green solvent?...............................................................................9
vi
1.6.3. Microwaves chemistry in aqueous medium?............................................ ….10
1.6.4. How does aqueous microwave chemistry expedite organic synthesis?.... ….11
1.6.5. Microwave assisted coupling reactions in water medium…………………..11
1.7. The use of aqueous microwave chemistry for drug discovery……………….......15
1.8. Introduction on ionic liquid………………………………………………………19
1.8.1. History of Ionic Liquid…………………………………………………. ….21
1.8.2. Designer green solvents……………………………………………………..21
1.8.3. Ionic Liquid for the synthesis of heterocyclic Organic
compound……………………………………………………………………22
1.8.4. The use of Ionic-Liquid as catalyst………………………………………....24
1.8.4.1. Cross coupling Reaction…………………………………………….......24
1.8.4.2. Knoevenagel Condensation/Robinson Annulations………………… ....25
1.8.4.3. Diels-Alder Reaction………………………………………………. …..26
1.8.4.4. Olefin Epoxidation………………………………………………….......26
1.8.4.5. Friedlander Synthesis…………………………………………………....27
1.8.4.6. Ring Closing Metathesis………………………………………………...27
1.8.4.7. Diol/Carbonyl Protection…………………………………………..........28
1.8.4.8. Swern Oxidation………………………………………………………...28
1.8.5. The use of Ionic-Liquid as Supported Catalysis……………………….. …...29
1.8.6. The use of Ionic-Liquid as Supported Reagents………………………… ….30
1.8.7. Ionic-Liquid-Supported Synthesis of Small Molecules and
Combinatorial Synthesis………………………………………………. ……31
1.9. Pictet-Spengler reaction………………………………………………………….39
1.9.1. Reaction mechanism…………………………………………………………40
1.10. Tetrahydro-β-carbolines and its hydantoin derivatives, importance
and synthesis……………………………………………………………………..42
1.11. Chemical methods for synthesizing Hydantoin Analogs Tethered
with Tetrahydro-β-Carbolines……………………………………………. …....44
1.12. Results and Discussions………………………………………………….. …....49
1.13. Dihydro and Tetrahydroquinazoline derivatives and its importance and
synthesis…………………………………………………………….. ………....58
1.14. Chemical methods for synthesizing Dihydro and Tetrahydroquinazoline
Derivatives…………………………. ………………………………………......59
1.15. Results and Discussion………………………………………………………......62
1.16 Conclusion……………………………………………………………………......70
1.17. General Methods………………………………………………………................71
1.18. Experimental Section……………………………………………………. ….......72
1.19. References……………………………………………………………….. ….......97
Chapter Two Novel Approach Toward Synthesis of Skeletally Diverse
Benzimidazole-pyrrolo[1,2-a]quinoxaline by SNAr/Pictet-Spengler
Reaction and Benzimidazole-(alkyloxy)-4-oxo-4,5-dihydropyrrolo[1,2-
a]quinoxalin by Partial Nitro Group Reduction Reaction.
2.0. Introduction……………………………………………………………………...107
2.1. Different Causes Cancer………………………………………………………....108
2.1.1. Different forms of cancer……………………………………………...108
2.1.2.Genetic factor leads to cancer………………………………………….108
2.2. Metastatic Cancer ………………………………………………………………109
2.3. What is tumor angiogenesis……………………………………………..............109
2.4. The angiogenesis signaling cascade…………………………………………….110
2.5. The VEGF ligand is the predominant regulator of tumor angiogenesis………...111
2.6. VEGF……………………………………………………………………...........112
2.7. VEGF receptors………………………………………………………. ……….113
2.8. The strategies for inhibiting the VEGF pathway……………………………….114
2.8.1. Extra cellular targeting of the VEGF ligand…………………………….114
2.8.2. Intra cellular targeting of the VEGF receptor…………………………...115
2.9. Lymphangiogenesis……………………………………………………..............115
2.10. How cancer can be treated…………………………………………………….116
2.11. Small molecules as Cancer Inhibitor…………………………..........................117
2.11.1 Gefitinib………………………………………………………………….117
2.11.2. Erlotinib hydrochloride ………………………………………………...117
2.11.3. Sunitinib ……………………………………………………..................118
2.11.4. Sorafenib………………………………………………………………...118
2.11.5. lapatinib…………………………………………………………….........119
2.12 .Protein Lysine Methyltransferase G9a Inhibitors ………………….................119
2.13. Soluble Polymer Supported Organic Synthesis…………………………….....121
2.13.1. Application and recent development of polyethylene glycol as
Soluble support in organic synthesis……………………………………………122
2.13.2. PEG for Small molecule Synthesis ………………………………………123
2.14. Pyrrolo[1,2-a]quinoxalines its importance and synthesis …………………….127
2.15. Various method of preparation of Pyrrolo[1,2-a]quinoxalines
derivatives ……………………………………………………………………..........128
2.16 Results and Discussions…………………………………………… ………….134
2.17. Pyrrolo[1,2-a]quinoxalinones its importance and synthesis…………………..132
2.18 Result and Discussion …………………………………………………………156
2.19 Conclusion……………………………………………………………………..163
2.20. General remarks..……………………………………………….......................164
2.21. Experimental Section …………………………………………………………165
2.22 References………………………………………………………………...........206
3.0. Multicomponent Reactions……………………………………………...............215
3.1. History and Types Multicomponent Reactions…………………………………216
3.2. Nature of multicomponent reaction ………………………………………….....217
3.3. Strecker amino acid synthesis…………………………………………….....217
3.3.1. Reaction Mechanism ………………………………………......................218
3.4. Biginelli Reaction…………………………………………...........................218
3.5. Passerini reation …………………………………………………………....219
3.6. Ugi Reaction ………………………………………………………..............221
3.6.1. Mechanism of the Ugi Reaction…………………………………….....221
3.6.1. Ugi-Diels-Alder reaction …………………………………………………222
3.6.2. Ugi-Smiles reaction ………………………………………………………223
3.6.3. Ugi-Buchwald-Hartwig reaction……………………………………............224
3.6.4. Ugi-Heck reaction …………………………………………..........................224
3.7. Solvent-free synthesis……………………………………………………………225
3.8. Benzimidazole-Imidazo[1,2-a]pyridine, importance and synthesis…………......228
3.9. Chemical methods for synthesizing imidazo[ 1,2-a]pyridines………………......230
3.10. Result and Discussion ………………………………………………………....235
3.11 Conclusion………………………………………………………………………243
3.12 Experimental section……………………………………………………………245
3.13 References………………………………………………………………………269
its importance and synthesis ………………………………………………………..274
4.1. Medicinal use ………………………………………………..............................274
4.2. Anti-inflammatory……………………………………………………………...275
4.3. Anti-cancer………………………………………………….. ………………...275
4.4. Anti-diabetic agents…………………………………………………………....276
4.5. Antiviral ……………………………………………………………….............276
4.6. Result and discussion…………………………………………………………..277
xi
4.7. Application of andrographolide and its analogs for potential
targets ………………………………………………………………………………281
4.8. Conclusion……………………………………………………………….
4.9. Experimental Section …………………………………………………………289
4.10 References………………………………………………………………….....287
APPENDIX...........................................................................................................A-V

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