Pyrido[2,3-b]pyrazine 유도체의 합성과 토토머화 현상 = Synthesis and tautomerism of novel pyrido[2,3-b]pyrazines

다국어 초록 (Multilingual Abstract)

The known heterocyclic compounds have an enormous diversity of structure and a wide range of applications. Many pharmaceuticals have heterocyclic structures and have a fundamental importance to living systems. Our current research work is concerned with methods of synthesis and properties of deri-vatives of the heterocyclic compounds pyrido[2,3-b]pyrazine.
Pyrido[2,3-b]pyrazine derivatives are used as antibacterial, antimalarial, anti-inflammatory and as anticancer agents amongst other things. The syntheses of pyrido[2,3-b]pyrazine derivatives, 3-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-3-yl) propanoic acid(18), begins with reaction of 2,3-diaminopyridine (9) and 2-ketoglutaric acid. The two nucleophilic centers can both be hetero atoms.
The reaction of compound 18 with methanol gave methyl 3-(2-oxo-1,2-dihydro-pyrido[2,3-b]pyrazin-3-yl)propanoate (19). Compound 19 reacts with hydrazine hydrate to give 3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl) propanohydrazide(20). There are very many ways of achieving the synthesis of pyrido[2,3-b]pyrazine derivatives; the following reactions describe the main general methods. The reaction of compound 20 with substituted benzaldehydes, heteroaryl aldehydes, substituted benzoyl chlorides, heteroacyl chlorides, substituted phenylacetyl chlorides, benzyl chloroformate, and sulfonyl chlorides afforded 3-substituted pyrido[2,3-b]pyrazines (21-29), respectively. The reaction of compound 20 reacts with methyl isothiocyanate afforded 2-[3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)propanoyl]-N-methylhydrazinecarbothioamide (30). Diazotization of compound 20 reacts with sodium nitrite gave 3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)pro-pionyl azide (32). Compound 32 reacts with p-substituted anilines, resulting in the Curtius rearrangement to give N-[2-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)-ethyl]-N'-(substituted phenyl)ureas (33). The reaction of compound 20 with alkyl(ethoxymethylene)cyanoacetates, ethoxymethylenemalononitrile, and acetyl-acetone resulted in the intramolecular cyclization to give pyrazolyl-pyrido[2,3-b]-pyrazines (34-36).
The pyrido[2,3-b]pyrazines have been shown to exist in the two tautomeric forms, lactam (A) and lactim (B), in dimethyl sulfoxide solution.
Pyrido[2,3-b]pyrazine derivatives will be submitted to preliminary pharma-cological screening, and will be tested differentially for biological activities as new antihypertensive, antiinflammatory, and antibiotics agents. If any of the compounds show promise as therepeutic agents, this will provide motivation for further research on this class of compounds.

목차 (Table of Contents)

• Ⅰ.서론 = 1
• Ⅱ.실험 = 7
• 1.시약 및 기기 = 7
• 2.화합물의 합성 = 7
• 2-1.3-(2-Oxo-1,2-dihydropyrido[2,3-b]pyrazin-3-yl)propanoic acid 18)의 합성 = 7
• 2-2.Methyl 3-(2-Oxo-1,2-dihydropyrido[2,3-b]pyrazin-3-yl)propanoate (19)의 합성 = 8
• 2-3.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)propanohydrazide (20)의 합성 = 9
• 2-4.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-N'-[(substituted phenyl)methylidene]propanohydrazide류 (21)의 합성 = 9
• 2-5.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-N'-[(pyridin-4-yl)methylidene]propanohydrazide (22)의 합성 = 12
• 2-6.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-N-[(3-methylthien-2-yl)methylidene]propanohydrazide (23)의 합성 = 13
• 2-7.N'-[(2-Heteroaryl)methylidene]-3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)propanohydrazide류 (24)의 합성 = 13
• 2-8. N'-Substituted benzoyl-3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)propanohydrazide류 (25)의 합성 = 15
• 2-9.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-N'-(2-thenoyl)propanohydrazide (26)의 합성 = 18
• 2-10.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-N'-(substituted acetyl)propanohydrazide류 (27)의 합성 = 19
• 2-11.N'-[3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)-propanoyl]methanesulfonohydrazide (28)의 합성 = 20
• 2-12.N'-[3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)propanoyl]substituted benzenesulfonohydrazide류 (29)의 합성 = 21
• 2-13.2-[3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)propanoyl]-N-methylhydrazinecarbothioamide (30)의 합성 = 23
• 2-14.3-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)propionyl azide (32)의 합성 = 23
• 2-15.N-[2-(2-Hydroxypyrido[2,3-b]pyrazin-3-yl)ethyl]-N'-(substituted phenyl)urea류 (33)의 합성 = 24
• 2-16.Alkyl 5-Amino-1-[3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)propanoyl]-1H-pyrazole-4-carboxylate류 (34)의 합성 = 26
• 2-17.5-Amino-1-[3-(2-hydroxypyrido[2,3-b]pyrazin-3-yl)propanoyl]-1H-pyrazole-4-carbonitrile (35)의 합성 = 30
• 2-18.3-[3-(3,5-Dimethyl-1H-pyrazole-1-yl)-3-oxopropyl]pyrido[2,3-b]pyrazin-2(1H)-one (36)의 합성 = 31
• Ⅲ.결과 및 고찰 = 32
• 1.3-Substituted-pyrido[2,3-b]pyrazine류의 합성 = 32
• 2.3-Pyrazolylpyrido[2,3-b]pyrazine류의 합성 = 60
• Ⅳ.결론 = 68
• 참고문헌 = 70
• Spectra = 73