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达比加群酯的合成 被引量：7

Synthesis of Dabigatran Etexilate
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摘要 4-甲胺基-3-硝基苯甲酸与3-(吡啶-2-基氨基)丙酸乙酯在羰基二咪唑的作用下反应形成3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,经锌粉还原得到3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,随后与N-(4-氰基苯基)甘氨酸在羰基二咪唑以及醋酸作用下一锅制得3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯,再进行成脒化反应以及酰化反应后即可制得达比加群酯,总收率约48%。 In the presence of CDI, the reaction of 4-methylamino-3-nitrobenzoic acid with ethyl 3-（pyridin-2-ylamino）propanoate produced ethyl 3-[（4-methylamino-3-nitrobenzoyl）（pyridin-2-yl）amino]propanoate. It was reduced by zinc to afford ethyl 3-[（3-amino-4-methylaminobenzoyl）（pyridin-2-yl）amino]propanoate, which was reacted with [（4-cyanophenyl）amino] acetic acid to give ethyl 3-[[2-[（4-cyanophenylamino）methyl]-1-methyl-1H-benzimidazol-5-carbonyl]（pyridin-2-yl）amino]propanoate in the presence of CDI, followed by acetic acid in one-pot. Dabigatran etexilate was finally synthesized by amidination and acylation with an overall yield of about 48%.
作者 陈宇 竺伟 梁俊 陈欢生
机构地区 上海奥博生物医药技术有限公司
出处 《中国医药工业杂志》 CAS CSCD 北大核心 2013年第7期652-654,共3页 Chinese Journal of Pharmaceuticals
关键词 达比加群酯 凝血酶抑制剂 前药 抗凝血药 合成 dabigatran etexilate thrombin inhibitor prodrug anticoagulant synthesis
分类号 R973.2 [医药卫生—药品]
  • 相关文献

参考文献11

  • 1Hauel N, Ries U, Priepke H, et al. Disubstituted bicycleheterocycles, their production and use as medicaments: WO,9837075 [P].1998-02-16.
  • 2宫平,贾薇.新型口服抗凝血药物达比加群酯[J].世界临床药物,2008,29(9):544-547. 被引量：27
  • 3方干,郑永勇,张晓培,李建其.达比加群酯合成路线图解[J].中国医药工业杂志,2011,42(9):717-719. 被引量：8
  • 4邢松松,王晓蕾,周付刚,苏信杰,杜玉民.达比加群酯的合成[J].中国医药工业杂志,2010,41(5):321-325. 被引量：20
  • 5程青芳,王启发,陆微,黄芬芬,陈娜.达比加群酯的合成[J].中国医药工业杂志,2012,43(12):961-964. 被引量：7
  • 6Jirman J, Richter J, Lustig P. A method for the preparation ofdabigatran: WO, 2009111997 [P]. 2009-03-10.
  • 7Hauel NH, Nar H, Priepke H, et al. Structure-based designof novel potent nonpeptide thrombin inhibitors [J]. J MedChem,2002, 45 (9): 1757-1766.
  • 8林国强,马景毅,徐亮,等.一种合成非手性、非肽类的抗凝血酶抑制剂方法:中国,1861596 [P]. 2006-05-18.
  • 9Zerban G, Hausherr A, Schlarb K, et al. The method forproducing 4- (benzimidazolylmenthylamino) -benzamidines:WO, 2006000353 [P]. 2005-06-18.
  • 10Zerban G,Hausherr A, Hamm R, et al. Improved process forpreparation of the salts of 4- (benzimidazolylmenthylamino) .benzamidines: WO, 2007071743 [P]. 2006-12-20.

二级参考文献45

  • 1张竹霞,吕荣文,张珂珂,高昆玉.水合肼还原芳硝基物的研究[J].精细化工,2001,18(4):239-242. 被引量：54
  • 2郑淑玲,赵增国,张红艳.2-氯吡啶氮氧化物的合成方法研究[J].天津师范大学学报（自然科学版）,2006,26(1):9-11. 被引量：5
  • 3Blech S,Ebner T,Ludwing-Schwellinger E,et al.The metabolism and disposition of the oral direct thrombin inhibitor,dabigatran,in hunman[J].Drug Memb Dispos,2008,36(2):386-399.
  • 4Hauel NH,Nar H,Priepke H,et al.Structure-based design of novel potent nonpeptide thrombm inhibitors[J].J Med Chem,2002,45(9):1757-1766.
  • 5Katz LE,Dumas RH.Process for oxidizing halopyddines to halopyridine-N-oxides:US,4504667[P].1985-05-12.(CA 1985,102:220755).
  • 6Schiessl HW,Manke SA.Oxidation of pyridine and derivatives:WO,9736872[P].1997-10-09.(CA 1997,127:346303).
  • 7Boudaklan MM.Process for oxidizing halopyridines to haiopyridine-N-oxides:EP,0090177[P].1983-02-24.(CA 1983,100:51458).
  • 8Smith RL,Kumaravel G,Kuhla DE.Synthesis of substituted N-hctcroaromatic compounds by combinatorial chemistry:WO,9715557[P].1997-05-01.(CA 1997,127:5014).
  • 9ALI FE,Bondinell WE,Keenan RM,et al.Vitronectin receptor antagonists:WO.9724124[P].1997-07-10.(CA 1997,127:149073).
  • 10Marchais S,Nowicki B,Wikstr6m HV et al.Short and efficient syntheses of analogues of WAY-100635:new and potent 5-HTIA receptor antagonists[J].Bioorg Med Chem,2001,9(3):695-702.

共引文献39

同被引文献62

  • 1林国强,马景毅,徐亮,等.一种合成非手性,非肽类的抗凝血酶抑制剂的方法:中国,1861596[P].2006-11-15.(CA2006,146:27828).
  • 2Blech S,Ebner T,Ludwig-Schwellinger E,et al.The metabolism and disposition of the oral direct thrombin inhibitor,dabigatran,in humans[J].Drug Metab Dispos,2008,36 (2):386-399.
  • 3Serra ML,Duran LE,Rao LX.Dabigatran etexilate and related substances,processes and compositions,and use of the substances as reference standards and markers:WO,2012152855[P].2012-11-15.
  • 4Hauel NH,Nar H,Priepke H,et al.Structure-based design of novel potent nonpeptide thrombin inhibitors[J].J Med Chem,2002,45(9):1757-1766.
  • 5Yang XZ,Yang WH,Xu YG,et al.Synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing a cleavable moietywith anti-platelet activity[J].EurJMed Chem,2012,57:21-28.
  • 6Venkatraman J,Samir P,Samir M,et al.Novel reference markers of dabigatran etexilate:WO,2013024394[P].2013-02-12.
  • 7Hernandez GS,Marquillas OF,Pomares MP.Process for the preparation of intermediates for the synthesis of dabigatran etexilate,and crystalline forms of said intermediates:WO,2014012880[P].2014-01-23.
  • 8Georg Z,Arndt H,Rainer H,et al.Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof:WO,2007071742[P].2007-06-28.
  • 9Hans RM,Kurt W.Benzofuranyl-benzimidazoles:US,4360679[P].1982-11-23.
  • 10HUGHES B. First oral warfarin alternative approved in the US[J]. Nat. Rev. Drug. Discov. ,2010,9(12) :903- 906.

引证文献7

二级引证文献16

中国医药工业杂志
2013年 第7期

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