3-羟基-5-甲氧基吡啶合成工艺
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摘要
3-羟基-5-甲氧基吡啶作为一种药物中间体,其合成工艺的研究具有一定价值。本文对比研究了以3,5-二溴吡啶和N-苄基甘氨酸乙酯为原料的4条3-羟基-5-甲氧基吡啶的合成路线。其中以3,5-二溴吡啶为原料经甲醚化、氮氧化、氨解、脱氮氧和重氮化水解的5步反应工艺较好地合成了3-羟基-5-甲氧基吡啶1,总收率达到66. 7%。目标化合物结构经1H NMR、IR、MS和X-ray单晶衍射确证。该工艺操作简单,收率理想,可为目标产品工业化生产提供参考。
3-hydroxyl-5-methoxyl pyridine is an important intermediate of drug. It is valuable to research the synthetic process. In this paper,four synthesis routes of 3-hydroxyl-5-methoxyl pyridine,which used 3,5-dibromopyridine and N-benzyl glycine ethyl ester as raw materials,were studied. Among them,the 3-hydroxyl-5-methoxyl pyridine was successfully synthesized by the five step reaction process of methyletherification,nitrogen oxidation,aminolysis,denitrification and nitrification and hydrolysis 3,5-dibromopyridine was used as raw material with a total yield of 66. 7%.The structure of aim compound was characterized by1 H NMR,IR,MS and X-ray single crystal. This synthesis method is simple with an ideal yield. It can provide reference for the industrial production of aim products.
3-hydroxyl-5-methoxyl pyridine is an important intermediate of drug. It is valuable to research the synthetic process. In this paper,four synthesis routes of 3-hydroxyl-5-methoxyl pyridine,which used 3,5-dibromopyridine and N-benzyl glycine ethyl ester as raw materials,were studied. Among them,the 3-hydroxyl-5-methoxyl pyridine was successfully synthesized by the five step reaction process of methyletherification,nitrogen oxidation,aminolysis,denitrification and nitrification and hydrolysis 3,5-dibromopyridine was used as raw material with a total yield of 66. 7%.The structure of aim compound was characterized by1 H NMR,IR,MS and X-ray single crystal. This synthesis method is simple with an ideal yield. It can provide reference for the industrial production of aim products.
引文
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[13]张园园,马梦林,杨维清.2-(3-苯基-4-氟代苄氧基苯胺基)亚甲基丙二酸二乙酯的合成[J].西华大学学学报(自然科学版),2014,33(4):55-57.
[14]OLOFSSON B,BOGAR K,FRANSSON A L.Divergent asymmetric synthesis of 3,5-disubstituted piperidines[J].Journal of Organic Chemistry,2006,71(21):8256-8260.
[2]SELVARAJ M R,SHASHIKANT M P,JEYAKANNU P.Recent synthetic scenario on imidazo[1,2-a]pyridines chemical intermediate[J].Research on Chemical Intermediates,2016,42(4):2749-2790.
[3]KOHN T J,DU X H,LAI S,et al.5-Alkyl-2-urea-substituted pyridines:identification of efficacious glucokinase activators with improved properties[J].ACS Medicinal Chemistry Letters,2016,7(7):666-670.
[4]SAITO N,NAKAMURA K,SHIBANO S,et al.Addition of cyclic ureas and 1-methyl-2-oxazolidone to pyridynes:A new approach to pyridodiazepines,pyridodiazocines,and pyridooxazepines[J].Organic Letter,2013 15(2):386-389.
[5]CHEN L C,YANG S C.Synthesis and 1,3-dipolar cycloaddition of 3-hydroxy-5-methoxy-pyridinium N-imine[J].Heterocycles,1986,24(12):3411-3415
[6]BANERJEE M,MIDDY S,SHRIVASTAVA R,et al.Inhibitors of the kynurenine pathway:WO2014/186035[P].2014-11-20.
[7]AYDON D,CZAPLEWSKI L G.Antibacterial compositions:WO,2009074810[P].2009-06-18.
[8]CHEUNG C,SURRY D S,BUCHWALD S L.Mild and highly selective palladium-catalyzed monoarylation of ammonia enabled by the use of bulky biarylphosphine ligands and palladacycle precatalysts[J].Organic Letters,2013,15(14):3734-3737.
[9]DULL G M,WAGNER J M,HADIMANI S,et al.Pharmaceutical compositions and methods for use:US,2001014691[P].2001-08-16.
[10]MORGENTIN R,JUNG,FREDERIC,et al.An efficient large-scale synthesis of alkyl 5-hydroxy-pyridin-and pyrimidin-2-yl acetate[J].Tetrahedron,2009,65(4):757-764
[11]TAMURA Y,FUJITA M,CHEN L C,et al.Studies on 3,5-dioxopiperidines:novel and facil synthetic routes to 3-amino-5-hydroxypyridine derivatives[J].Heterocycles,1981,15(2):871-874
[12]KANWAR A,EDUFUL B J,BARBETOL,et al.Synthesis and activity of a new series of antileishmanial agents[J].ACS Medicinal Chemistry Letters,2017,8(8):797-801
[13]张园园,马梦林,杨维清.2-(3-苯基-4-氟代苄氧基苯胺基)亚甲基丙二酸二乙酯的合成[J].西华大学学学报(自然科学版),2014,33(4):55-57.
[14]OLOFSSON B,BOGAR K,FRANSSON A L.Divergent asymmetric synthesis of 3,5-disubstituted piperidines[J].Journal of Organic Chemistry,2006,71(21):8256-8260.