尼达尼布的合成
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摘要
间硝基苯甲酸甲酯(1)与氯乙酸甲酯反应制得4-甲氧基羰基甲基-3-硝基苯甲酸甲酯(2);2依次经催化氢化、乙酰化及与原苯甲酸三乙酯反应制得关键中间体(E)-1-乙酰基-3-(乙氧基-苯基-甲烯基)-2-氧-2,3-二氢-1H-吲哚-6-羧甲酸甲酯(5);N-甲基对硝基苯胺依次经氯乙酰化、取代和催化氢化反应制得N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺(9);5和9经拼合合成了治疗特发性肺纤维化药尼达尼布,总收率22.0%,纯度99.4%,其结构经1H NMR和MS确证。
4-Methoxycarbonylmethyl-3-nitrobenzoic acid methyl ester( 2) was synthesized by reaction of 3-nitrobenzoic acid methyl ester with methyl chloroacetate. The key intermediate,( E)-1-acetyl-3-( ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester( 5),was synthesized by a three-step reaction of hydrogenation,acetylation and reaction with ortho-benzoic acid triethyl ester from 2. N-( 4-aminophenyl)-N-methyl-2-( 4-methylpiperazin-1-yl) acetamide( 9) was synthesized by a three-step reaction of acylchlorination,substitution and hydrogenation from N-methyl-4-nitro-benzenamine. Nintedanib with an overall yield of 22. 0% and purity of 99. 4% was synthesized by reaction of 5 with 9. The structure was confirmed by1 H NMR and MS.
4-Methoxycarbonylmethyl-3-nitrobenzoic acid methyl ester( 2) was synthesized by reaction of 3-nitrobenzoic acid methyl ester with methyl chloroacetate. The key intermediate,( E)-1-acetyl-3-( ethoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester( 5),was synthesized by a three-step reaction of hydrogenation,acetylation and reaction with ortho-benzoic acid triethyl ester from 2. N-( 4-aminophenyl)-N-methyl-2-( 4-methylpiperazin-1-yl) acetamide( 9) was synthesized by a three-step reaction of acylchlorination,substitution and hydrogenation from N-methyl-4-nitro-benzenamine. Nintedanib with an overall yield of 22. 0% and purity of 99. 4% was synthesized by reaction of 5 with 9. The structure was confirmed by1 H NMR and MS.
引文
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[2]Taniguchi H,Ebina M,Kondoh Y,et al.Pirfenidone in idiopathic pulmonary fibrosis[J].European Respiratory Journal,2010,35(4):821-829.
[3]Richeldi L,Costabel U,Selman M,et al.Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis[J].New England Journal of Medicine,2011,365(12):1079-1087.
[4]Richeldi L,du Bois RM,Raghu G,et al.Efficacy and safety of Nintedanib in idiopathic pulmonary fibrosis[J].New England Journal of Medicine,2014,370(22):2071-82.
[5]US FDA.FDA approves Ofev to treat idiopathic pulmonary fibrosis[EB/OL].[2014-10-15].http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm418994.htm.
[6]US FDA.Ofev(nintedanib):US prescribing information[EB/OL].[2014-10-28].http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205832s000lbl.pdf.
[7]European Medicines Agency.Summary of opinion:Vargatef(Nintedanib)[EB/OL].[2014-10-28].http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002569/WC500173607.pdf.
[8]Roth G J,Heckel A,Colbatzky F,et al.Design,synthesis,and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone(BIBF 1120)[J].Journal of medicinal chemistry,2009,52(14):4466-4480.
[9]Wolfgang,Dirk,Christian,et al.Intedanib salts and solid state forms thereof cross reference to related application[P].WO 2012/68441 A2.
[10]Miller K M,Huang W S,Jamison T F.Catalytic asymmetric reductive coupling of alkynes and aldehydes:Enantioselective synthesis of allylic alcohols andα-hydroxy ketones[J].Journal of the American Chemical Society,2003,125(12):3442-3443.
[11]Diehl K,Himbert G,Henn L.Cycloadditionen,7.Intramolekulare Diels-Alder-Reaktionen bei allencarboxaniliden;Variation der substituenten in p-position des anilinkerns[J].Chemische Berichte,1986,119(8):2430-2443.
[12]Joern M,Svenja R,Carsten R,et al.Indolinone derivatives and process for their manufacture[P].WO200 971 524 A2,2009.