3-硝基-4-氯苯甲酸(2)经甲胺化得3-硝基4-甲氨基苯甲酸(3),2-氨基吡啶与丙烯酸乙酯经迈克尔加成得3-[(吡啶-2-基)氨基]丙酸乙酯(5),化合物3与5经缩合、催化氢化得3-{[(3-氨基-4-甲胺基)苯甲酰基](吡啶-2-基)氨基}丙酸乙酯(7),化合物7再与N-(4-氰基苯基)甘氨酸(8)酰化、环合和Pinner反应,最后与氯甲酸正己酯反应得到达比加群酯(1),总收率约40％(以3-硝基-4-氯苯甲酸计),结构经IR、1H NMR和MS测试技术确证.
参考文献
| [1] | Blech S,Ebner T,Ludwing-Schwellinger E,et al.The Metabolism and Disposition of the Oral Direct Thrombin Inhibitor,Dabigatran,in Hunman[J].Drug Metab Dispos,2008,36(2):386-399. |
| [2] | XING Songsong,WANG Xiaolei,ZHOU Fugang,et al.Synthesis of Dabigatran Etexilate[J].Chinese J Pharm,2010,41 (5):321-325 (in Chinese).邢松松,王晓蕾,周付刚,等.达比加群酯的合成[J].中国医药工业杂志,2010,41 (5):321-325. |
| [3] | Jirman J,Richter J,Lustig P.A Method for the Preparation of Dabigatran,WO2009111997[P],2009-03-10. |
| [4] | LIN Guoqiang,MA Jingyi,XU Liang,et al.Process for Synthesizing Antithrombin Inhibitor of Non-asymmetric Non-peptide Kind:CN186596[P],2006-11-15 (CA2006,146:27828) (in Chinese).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,CN186596[P],2006-11-15(CA2006,146:27828). |
| [5] | Segade Rodriguez A,Pasto Aguila M.Process of Preparing A Thrombin Specific Inhibitor,WO2012004396[P],2011-07-08. |
| [6] | Lou X B,He L,Qian Y,et al.Highly Chemo-and Regioselective Transfer Reduction of Aromatic Nitro Compounds Using Ammonium Formate Catalyzed by Supported Gold Nanoparticles[J].Adv Synth Catal,2011,353 (2/3):281-286. |
| [7] | Kilburn J P,Andersen H S,Kampen G C,et al.Pharmaceutical Use of Substituted Amides:WO,2007051811[P],2007-05-10(CA2007,146:501049). |
| [8] | Simila S T M,Martin S F.Toward the Total Synthesis of FR901483:Concise Synthesis of the Azatricyclic Skeleton[J].J Org Chem,2007,72(14):5342-5349. |
| [9] | Hauel N H,Nar H,Priepke H,et al.Structure-based Design of Novel Potent Nonpeptide Thrombin Inhibitors[J].J Med Chem,2002,45 (9):1757-1766. |
| [10] | Lappin G R.Cyclization of 2-Aminopyridine Derivatives:Ⅲ.Reaction of Some 2-Aminopyridines with Alkyl Acrylates and Alkyl 3-Halopropionates[J].J Org Chem,1958,23 (9):1358-1360. |
| [11] | Kuzniewski N C,Gertsch J,Wartmann M,et al.Total Synthesis of Hypermodified Epothilone Analogs with Potent in Vitro Antitumor Activity[J].Org Lett,2008,10 (6):1183-1186. |
上一张
下一张
上一张
下一张
计量
- 下载量()
- 访问量()
文章评分
- 您的评分：
-
10%
-
20%
-
30%
-
40%
-
50%