库潘尼西合成研究进展
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摘要
库潘尼西是一种新型口服磷脂酰肌醇3-激酶(PI3K)抑制剂。临床用于已接受至少2种系统性疗法治疗后病情复发的或难治性滤泡性淋巴瘤成人患者的治疗。本文综述了库潘尼西的合成路线,根据原料及中间体的不同,报道了7条合成路线,其中,以2-氨基-3-甲氧基-4-[3-(4-吗啉基)丙氧基]苯甲腈为原料的2条合成路线原料易得、成本低、反应步骤少、总收率高,适合工业化生产。
Copanlisib is a novel oral phosphoinositide 3-kinase(PI3 K) inhibitor, and it has been used for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least two prior systemic therapies. Based on different materials and intermediates, seven synthetic routes have been reported. The two synthetic routes, which uses 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzonitrile as the original material to synthesize copanlisib, are suitable for industrial production due to the advantages such as simple operation, low cost and high total yield.
Copanlisib is a novel oral phosphoinositide 3-kinase(PI3 K) inhibitor, and it has been used for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least two prior systemic therapies. Based on different materials and intermediates, seven synthetic routes have been reported. The two synthetic routes, which uses 2-amino-3-methoxy-4-(3-morpholinopropoxy)benzonitrile as the original material to synthesize copanlisib, are suitable for industrial production due to the advantages such as simple operation, low cost and high total yield.
引文
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[13]SCHWARZ T,LIU N S,POLITZ O,et al.2-Amino-N-[7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-pyrimidine-5-carboxamides:WO,2017153220A1[P].2017-09-14.
[14]PETERS J G,STIEHL J,LOVIS K.Synthesis of copanlisib and its dihydrochloride salt:WO,2016071426 A1[P].2016-05-12.
[15]PETERS J G,RUBENBAUER P,GOETZ D,et al.Synthesis of copanlisib and its dihy-drochloride salt:WO,2016071435 A2[P].2016-05-12.
[16]彼得斯·J D,施蒂尔·J,洛维斯·K.Copanlisib及其二盐酸盐的合成:中国,201580059995.1[P].2017-08-18.
[17]许学农.库潘尼西的制备方法:WO,2017049983 A1[P].2017-03-30.
[18]许学农.一种库潘尼西的制备方法:中国,105130997 A[P].2015-12-09.
[2]李春杏,刘桦,孙桂凤,等.复发性滤泡性淋巴瘤治疗新药copanlisib的药理作用与临床评价[J].临床药物治疗杂志,2018,16(1):27-31.
[3]MENSAH F,BLAIZE J P,BRYAN L.Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma:evidence to date[J].Onco Targets Ther,2018,11:4817-4827.
[4]MARKHAM A.Copanlisib:first global approval[J].Drugs,2017,77(18):2057-2062.
[5]U.S.Food and Drug Administratrion.FDA grants accelerated approval to copanlisib for relapsed follicular lymphoma[EB/OL].[2017-09-14].https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm576098.htm.
[6]王金,胡晓,王文玲,等.芳香腈类化合物的合成方法:中国,107382771 A[P].2017-11-24.
[7]MOHAMMADPOOR-BALORK I,ABDOLLAHI-ALIBEIK M.Microwave-assisted facile and convenient synthesis of imidazolines[J].Bull Korean Chem Soc,2003,24(9):1354-1356.
[8]SCOTT W J,HENTEMANN M F,ROWLEY R B,et al.Discovery and SAR of novel 2,3-dihydroimidazo[1,2-c]-quinazoline PI3K inhibitors:identification of copanlisib(BAY 80-6946)[J].ChemMedChem,2016,11(14):1517-1530.
[9]WU Y,DAI W,CHEN X,et al.Design,synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-c]-quinazoline derivatives as novel phosphatidylinositol3-kinase and histone deacetylase dual inhibitors[J].RSCAdv,2017,7(82):52180-52186.
[10]SHIMADA M,MURATA T,FUCHIKAMI K,et al.Fused azole-pyrimidine derivatives:WO,2004029055[P].2004-04-08.
[11]HENTEMANN M,WOOD J,SCOTT W J,et al.Substituted2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorder associated with angiogenesis:WO,200807150 A1[P].2008-06-12.
[12]SCOTT W,LIU N S,MOEWES M.Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis:WO,2012062748 A1[P].2012-05-18.
[13]SCHWARZ T,LIU N S,POLITZ O,et al.2-Amino-N-[7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-pyrimidine-5-carboxamides:WO,2017153220A1[P].2017-09-14.
[14]PETERS J G,STIEHL J,LOVIS K.Synthesis of copanlisib and its dihydrochloride salt:WO,2016071426 A1[P].2016-05-12.
[15]PETERS J G,RUBENBAUER P,GOETZ D,et al.Synthesis of copanlisib and its dihy-drochloride salt:WO,2016071435 A2[P].2016-05-12.
[16]彼得斯·J D,施蒂尔·J,洛维斯·K.Copanlisib及其二盐酸盐的合成:中国,201580059995.1[P].2017-08-18.
[17]许学农.库潘尼西的制备方法:WO,2017049983 A1[P].2017-03-30.
[18]许学农.一种库潘尼西的制备方法:中国,105130997 A[P].2015-12-09.