7-氮杂吲哚及其衍生物5-溴-7-氮杂吲哚的合成
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摘要
7-氮杂吲哚是一种重要的杂环化合物,是合成维罗非尼、ABT-199等抗肿瘤药物的重要中间体,具有较高的生物医药价值。优化了合成7-氮杂吲哚的方法,以廉价易得的2-氨基-3-甲基吡啶为起始原料,经过两步反应,以48%的总收率得到7-氮杂吲哚。并在此合成方法的基础上进一步合成了5-溴-7-氮杂吲哚,经过三步反应,总收率达到43%。该合成方法具有原料易得、操作简便、路线简短、收率较高等优点。产物的结构经过核磁共振和高分辨质谱得到确认。
7-Azaindole compounds are important heterocyclic compounds,used for the synthesis of vemurafenib and ABT-199.It has high value of biological medicine.New methods for the synthesis of 7-azaindole is reported herein.7-Azaindole is synthesized from 2-amino-3-methylpyridine via a two-step synthetic route in an overall yield of 48%.5-Bromo-7-azaindole is synthesized from 2-amino-3-methylpyridine via a three-step synthetic route in an overall yield of 43%.The product is characterized by NMR and HRMS.The advantages of synthsis are simplified operational procedure,short reaction steps,good yields and the raw materials easy to get.
7-Azaindole compounds are important heterocyclic compounds,used for the synthesis of vemurafenib and ABT-199.It has high value of biological medicine.New methods for the synthesis of 7-azaindole is reported herein.7-Azaindole is synthesized from 2-amino-3-methylpyridine via a two-step synthetic route in an overall yield of 48%.5-Bromo-7-azaindole is synthesized from 2-amino-3-methylpyridine via a three-step synthetic route in an overall yield of 43%.The product is characterized by NMR and HRMS.The advantages of synthsis are simplified operational procedure,short reaction steps,good yields and the raw materials easy to get.
引文
[1]徐敏.浅谈7-氮杂吲哚是生物碱的重要骨架及其药理作用[J].江西化工,2009,(1):19-20.
[2]王淑月.生物电子等排原理在新药设计中的应用[J].河北工业科技,2003,20(3):50-53.
[3]FLAHERTY K T,UMA Y,PETER K.Vemurafenib[J].Nat.Rev.Drug Discov.,2011,10(11):811-812.
[4]SOUERS A J,LEVERSON J D,BOGHAERT E R,et al.ABT-199,a potent and selective BCL-2 inhibitor,achieves antitumor activity while sparing platelets[J].Nat.Med.,2013,19(2):202-208.
[5]LORENZ R R,TULLAR B F,KOELSCH C F,et al.A new indole synthesis[J].J.Org.Chem.,1965,30(8):2 531-2 533.
[6]HUDSON R,BIZIER N P,ESDALE K N,et al.Synthesis of indoles,benzofurans,and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO[J].Org.Biomol.Chem.,2015,13(7):2 273-2 284.
[7]SCHIROK H,PAULSEN H,KROH W,et al.Improved synthesis of the selective rho-kinase inhibitor 6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl} pyrimidin-2,4-diamine[J].Org.Process Res.Dev.,2010,14(1):168-173.
[8]夏青青,吴明剑,张路路.一种5-溴-7-氮杂吲哚的合成工艺:CN 2 016 120 068.5[P].2016-01-13.
[9]WU P W,HSIEH W T,CHENG Y M,et al.Synthesis of 7-azaserotonin:Its photophysical properties associated with excited state proton transfer reaction[J].J.Am.Chem.Soc.,2006,128(45):14 426-14 427.
[10]KISELEV E,AGAMA K,POMMIER Y,et al.Azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents:a systematic study of structure-activity relationships[J].J.Med.Chem.,2012,55(4):1 682-1 697.
[11]PILLARD C,BASSENE C E,SUZENET F,et al.Synthesis of 4-,5- and 6-benzoylated 7-azaindoles[J].Synthesis,2008,(13):2 049-2 054.
[12]BRAHMACHARI G,LASKAR S.A very simple and highly efficient procedure for N-formylation of primary and secondary amines at room temperature under solvent-free conditions[J].Tetrahedron Lett.,2010,51(17):2 319-2 322.
[2]王淑月.生物电子等排原理在新药设计中的应用[J].河北工业科技,2003,20(3):50-53.
[3]FLAHERTY K T,UMA Y,PETER K.Vemurafenib[J].Nat.Rev.Drug Discov.,2011,10(11):811-812.
[4]SOUERS A J,LEVERSON J D,BOGHAERT E R,et al.ABT-199,a potent and selective BCL-2 inhibitor,achieves antitumor activity while sparing platelets[J].Nat.Med.,2013,19(2):202-208.
[5]LORENZ R R,TULLAR B F,KOELSCH C F,et al.A new indole synthesis[J].J.Org.Chem.,1965,30(8):2 531-2 533.
[6]HUDSON R,BIZIER N P,ESDALE K N,et al.Synthesis of indoles,benzofurans,and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO[J].Org.Biomol.Chem.,2015,13(7):2 273-2 284.
[7]SCHIROK H,PAULSEN H,KROH W,et al.Improved synthesis of the selective rho-kinase inhibitor 6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl} pyrimidin-2,4-diamine[J].Org.Process Res.Dev.,2010,14(1):168-173.
[8]夏青青,吴明剑,张路路.一种5-溴-7-氮杂吲哚的合成工艺:CN 2 016 120 068.5[P].2016-01-13.
[9]WU P W,HSIEH W T,CHENG Y M,et al.Synthesis of 7-azaserotonin:Its photophysical properties associated with excited state proton transfer reaction[J].J.Am.Chem.Soc.,2006,128(45):14 426-14 427.
[10]KISELEV E,AGAMA K,POMMIER Y,et al.Azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents:a systematic study of structure-activity relationships[J].J.Med.Chem.,2012,55(4):1 682-1 697.
[11]PILLARD C,BASSENE C E,SUZENET F,et al.Synthesis of 4-,5- and 6-benzoylated 7-azaindoles[J].Synthesis,2008,(13):2 049-2 054.
[12]BRAHMACHARI G,LASKAR S.A very simple and highly efficient procedure for N-formylation of primary and secondary amines at room temperature under solvent-free conditions[J].Tetrahedron Lett.,2010,51(17):2 319-2 322.