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含吡唑環的噁唑環酮類殺菌劑的設計與合成

時間:2019-05-03 08:30來源:畢業論文
以利奈唑胺為母體,對其進行結構修飾。以吡唑環取代原結構中的嗎啉環,保持其他的基團不變,設計并合成得到了一個結構新穎的含吡唑環的噁唑烷酮類似物。合成主要反應為(S)-環氧

摘要:本論文從對噁唑烷酮類抗菌化合物的抗菌機制,構效關系等方面的總結,主要設計合成了一種新的含氟吡唑環噁唑烷酮類化合物,以簡單的烯醚,環氧氯丙烷以及含氟酸酐為原料,通過多步反應合成了一種噁唑烷酮雜環化合物,并對其進行了結構表征,利奈唑胺是它的代表性藥物。35096
本文以利奈唑胺為母體,對其進行結構修飾。以吡唑環取代原結構中的嗎啉環,保持其他的基團不變,設計并合成得到了一個結構新穎的含吡唑環的噁唑烷酮類似物。合成主要反應為(S)-環氧氯丙烷和苯甲醛在氨水中反應,后加入鹽酸生成胺的鹽酸鹽,再經Boc保護生成中間體(S)-叔丁基(3-氯-2-羥基丙基)氨基甲酸酯。烯醚與三氟甲基基團取代的乙酸酐在吡啶作用下生成中間體(E)-4-乙氧基-1,1,1-三氟丁-3-烯-2-酮并與取代的對硝基苯肼經乙醇回流,三氟乙酸(TFA)脫羥基生成中間體1-(4-硝基苯基)-5-9三氟甲基-1H-吡唑。再經過Pd/C催化氫化得到中間體產物4-(5-三氟甲基-1H-吡唑-1-基)苯胺。在高溫條件下反應生成中間體并經羰基二咪唑(CDI)環合得到噁唑烷酮化合物,再經TFA脫Boc保護,與乙酸酐在三乙胺作用下,最終得到目標化合物。
目標產物經核磁以及高分辨質譜驗證。
畢業論文關鍵詞:利奈唑胺;噁唑烷酮類;吡唑環;抗菌性
Design and Synthesis of Novel Pyrazolyl-Containing Oxazolidinone Analog
Abstract:  Oxazolidinones are a new class of synthetic antibacterial agents that have high activity against a broad range of Gram-positive bacteria. Linezolid was developed by Pharmacia and Upjohn Company and approved in 2000 for the treatment of serious infections caused by the above-mentioned strains. However, bacterial resistance to linezolid has been found recently in Gram-positive bacteria Staphylococcus aureus and Enterococcus faecium.Herein, we use Linezolid as lead compound, designed and synthesized a novel oxazolidinone derivatives bearing pyrazole as the C-ring structure. Below is the detail synthesis reaction: (S)-epichlorohydrin and benzaldehyde in aqueous ammonia was reacted to form the intermediate after the addition of hydrochloride acid. Then the intermediate was transfomred to  (S)-tert-butyl (3-chloro-2-hydroxypropyl) carbamate via the Boc-protection. Enol ethers reacted with trifluoromethyl substituted acetic anhydride to form the intermediate (E)-4-ethoxy-1,1,1-trifluoro-pyridin-3-en-2-one, and then the intermediate reacted with p-nitrophenylhydrazone in the refluxing ethanol to generate 1-(4-nitrophenyl)-5- (trifluoromethyl) -1H- pyrazole after the dehydroxylation by trifluoroacetic acid (TFA). Then the Pd/C catalytic hydrogenation gave the intermediate 4-(5-(trifluoromethyl) -1H- pyrazol-1-yl) aniline. The intermediate was reacted under high temperature to afford the further intermediate, which was finally transformed to the target compound via the sequence carbonyldiimidazole (CDI) cyclization and deprotection of Boc group by TFA. 源¥自%六:維;論-文'網=www.aftnzs.live
The target product was verified by NMR and high resolution mass spectrometry.
Key words:  Linezolid, Oxazolidinone, Pyrazole, Antibacterial activity
目錄
1引言    1
1.1  抗菌藥概況    1
1.2  抗菌藥物作用機制    2
1.3  細菌的耐藥性現狀    2
1.4  噁唑烷酮類化合物的概況    3
1.5  噁唑烷酮類藥物的意義    4
1.6  噁唑烷酮類化合物的作用機制    4
1.7  利奈唑胺的介紹    5
1.8  利奈唑胺的作用機制    6
2文獻綜述與方案論證    7
2.1  文獻綜述    7
2.1.1  路線一    7
2.1.2  路線二    7 含吡唑環的噁唑環酮類殺菌劑的設計與合成:http://www.aftnzs.live/yixue/20190503/32891.html
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