N-(2,6-二氯-4-氰基苯基)-2-甲氧基烟酰胺合成研究
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摘要
以2-氟烟酸为原料,通过酯化、氨解反应、 S_NAr反应, 3步合成N-(2,6-二氯-4-氰基苯基)-2-甲氧基烟酰胺,总收率52.5%。其中间体及目标化合物结构经~1H NMR、~(13)C NMR和ESI-MS确证。并对合成目标化合物的反应条件进行研究,优化反应条件为:物料比n (2-氟烟酸甲酯)∶n (4-氨基-3,5-二氯苯腈)=1.0∶1.1, n(2-氟烟酸甲酯)∶n(六甲基二硅基氨基锂化合物)=1.0∶1.4;回流反应14 h,在优化条件下目标化合物收率为56.8%。
N-(2,6-Dichloro-4-cyanophenyl)-2-methoxynicotinamide was synthesized from 2-fluoronicotinic acid through a 3-step reaction in a total yield of 52.5%, involving esterification, ammonolysis, S_NAr reaction.The structure of intermediates and the product were confirmed by~(1)H NMR,~(13) C NMR and ESI-MS. The optimal reaction conditions of key step(the synthesis of target compound) were also investigated. The reaction of compound 3 and 4 with the mole ratio of n(3) ∶n(4) =1.0 ∶1.1, n(3) ∶n(LiHMDS) =1.0 ∶1.4, target compoundwas obtained in a yield of 56.8% with reflux for 14 h.
N-(2,6-Dichloro-4-cyanophenyl)-2-methoxynicotinamide was synthesized from 2-fluoronicotinic acid through a 3-step reaction in a total yield of 52.5%, involving esterification, ammonolysis, S_NAr reaction.The structure of intermediates and the product were confirmed by~(1)H NMR,~(13) C NMR and ESI-MS. The optimal reaction conditions of key step(the synthesis of target compound) were also investigated. The reaction of compound 3 and 4 with the mole ratio of n(3) ∶n(4) =1.0 ∶1.1, n(3) ∶n(LiHMDS) =1.0 ∶1.4, target compoundwas obtained in a yield of 56.8% with reflux for 14 h.
引文
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[3]靳培英.烟酰胺在皮肤病中的应用[J].国际皮肤性病学杂志,1997,35(3):139-141.
[4]宋红萍,陈冠容,徐隽,等.烟酰胺应用于治疗寻常痤疮的有效性和安全性[J].中国医院药学杂志,2008,28(16):1 383-1 385.
[5]Pennington L D,Sham K K,Pickrell A J,et al.4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide:apotent and selective agonist of S1P1.[J].ACS Medicinal Chemistry Letters,2011,2(10):752-757.
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[7]Huang L,Brinen L S,Ellman J A.Crystal structures of reversible ketone-Based inhibitors of the cysteine protease cruzain[J].Bioorganic&Medicinal Chemistry,2003,11(1):21-29.
[8]张慧丽,张文,康永利,等.新型烟酰胺类杀菌剂啶酰菌胺的合成[J].农药,2016,59(7):491-492.
[9]De S C,Cox R J,Warner D J,et al.Efficacious inhaled PDE4inhibitors with low emetic potential and long duration of action for the treatment of COPD[J].Journal of Medicinal Chemistry,2014,57(11):4 661-4 676.
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