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利伐沙班中间体的合成 被引量：3

Synthesis of Intermediate of Rivaroxaban
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摘要 4-(3-氧代-4-吗啉基)苯胺与氯甲酸苄酯发生取代反应制得N-[4-(3-氧代-4-吗啉基)苯基]氨基甲酸苄酯,后者与(S)-N-[(2-乙酰氧基-3-氯)丙基]乙酰胺经缩合制得(S)-3-[4-(3-氧代-4-吗啉基)苯基]-5-乙酰胺甲基-1,3-噁唑烷-2-酮,再经酸性水解即可制得合成利伐沙班的重要中间体(S)-3-[4-(3-氧代-4-吗啉基)苯基]-5-氨甲基-1,3-噁唑烷-2-酮,总收率约35%。 4-（3-Oxomorpholin-4-yl）aniline was reacted with benzyl chloroformate to afford benzyl AT-[4-（3- oxomorpholin-4-yl） phenyl] carbamate. The latter was then condensed with （S）-N-（2-acetoxy-3-chloro）propylacetamide to afford （S）-3-[4-（3-oxomorpholin-4-yl）phenyl]-5-acetaminomethyl-1,3-oxazolidin-2-one, which was hydrolyzed under acidic condition to afford （S）-3-[4-（3-oxomorpholin-4-yl）phenyl]-5-aminomethyl-1,3-oxazolidin-2-one, the key intermediate for rivaroxaban. The total yield was about 35 %.
作者 蒋婧章 温颖玲 孙辉 张顺利 周伟澄
机构地区 中国医药工业研究总院上海医药工业研究院创新药物与制药工艺国家重点实验室上海市抗感染药物重点实验室
出处 《中国医药工业杂志》 CAS CSCD 北大核心 2013年第5期431-433,共3页 Chinese Journal of Pharmaceuticals
基金 国家973项目(2012CB724501)
关键词 利伐沙班 中间体 噁唑烷酮 合成 rivaroxaban intermediate oxazolidinone synthesis
分类号 O626.2 [理学—有机化学]
  • 相关文献

参考文献6

  • 1Becker R, Berkowitz SD, Breithardt G, et al. Rivaroxaban- once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study [J]. Am Heart J, 2010, 159 (3) : 340-347.
  • 2高扬,梁斌,倪国伟,王环,张福利.利伐沙班合成路线图解[J].中国新药杂志,2012,21(4):371-374. 被引量：8
  • 3Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-( { (5S)-2-oxo- 3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5- yl}methyl) thiophene-2-carboxamide (BAY 59-7939) : an oral, direct factor Xa inhibitor [Jl. J Med Chem, 2005, 48: 5900-5908.
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二级参考文献21

  • 1GULSETH MP, MICHAUD J, NUTESCU EA. Rivaroxaban: an oral direct inhibitor of factor Xa[J]. Am J Health Pharm, 2008, 65(16) : 1520 -1529.
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  • 5C 托马斯,M 贝尔韦,A 施特劳布.制备4-(4-氨基苯基)-3-吗啉酮的方法:中国,200480026537.X[P].2006-10-25.
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  • 9MASSE CE. Substituted oxazolidione derivatives: WO, 2009023233 [P]. 2009 -02 - 19.
  • 10THOMAS C, BERWE M, STRAUB A. Method for the production of 4-(4-amlnophenyl)-3-morpholinone: WO, 2005026135 [P]. 2005-03-24.

共引文献7

同被引文献19

  • 1Piccini JP, Patelm R, Mahaffey KW, et al. Rivaroxaban, an oral direct factor Xa inhibitor [J]. Expert Opin Investig Drugs, 2008, 17 (6) : 925-937.
  • 2Laux V, Perzborn E. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xa inhibitor [J]. Semin ThrombHemost, 2007, 33 (5): 515-523.
  • 3Eseolar G, Villalta J, Casals F, et al. Rivaroxaban: factor Xa inhibitor anticoagulant [J]. Drugs of the future, 2006, 31 (6) : 484-493.
  • 4Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-[ E (5S)-2-oxo- 3- [ 4- ( 3 -oxo-morpholin-4-yl) phenyl] - 1,3 -oxazolidin-5- yl] methyl] thiophene-2-carboxamide (BAY 59-7939) : an oral, direct factor Xa inhibitor[J]. J Med Chem, 2005, 48 (19) : 5900-5908.
  • 5Masse CE. Substituted oxazolidinone derivatives: WO, 2009023233 [P]. 2009-02-19.
  • 6Prabhudas B, Gamini W. Processes for the preparation of rivaroxaban and intermediates thereof: WO, 2010124385 [P]. 2010-11-04.
  • 7Sipos E, Kovanyine LG, Havasi B, et al. Process for preparation ofrivaroxaban: WO, 2012153155 [P]. 2012-11-15.
  • 8Pace V, Cabrera AC, Fernandez M, et al. First general route to substituted α-arylamino-α-chloropropan-2-ones by oxidation of N-protected aminohalohydrins: the importance of disrupting hydrogen bond networks [J]. Synthesis, 2010, (20) : 3545-3555.
  • 9Sturm H, Knepper K. Method for preparation of oxazo- lidinone derivatives via coupling of 4-chloromethyl-[ 1,3,2] dioxathiolane 2,2-dioxide and 4-(4- aminophenyl)- morpholin-3-one: WO, 2012140061 [P]. 2012-10-18.
  • 10Thomas CR. Procedure for the production of 5-chloro- N- [ E (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) - phenyl] -1,3-oxazolidin-5-yl] -methyl] -2-thiophenecarbox- amide: WO, 2004060887 [P]. 2004-07-22.

引证文献3

二级引证文献5

中国医药工业杂志
2013年 第5期

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