新型抗乳腺癌药瑞博西尼的合成研究进展
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摘要
本文较全面地综述了瑞博西尼及其关键中间体的合成路线。通过合成工艺的比较和分析,瑞博西尼的合成主要包括2个关键步骤:构建6-位酰胺取代、7-位环戊基取代的吡咯并嘧啶环,以及2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺与4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的缩合。传统的合成路线存在诸多缺点,如反应步骤多、采用价格昂贵的金属钯以及有毒的氰化物、部分操作条件苛刻和总收率低等。新开发的路线通过选择恰当的原料和反应,或通过汇聚式合成方式来减少反应步骤,避免采用钯类化合物,从而构建反应步骤少、收率高、环境友好和具有工业化价值的合成路线。瑞博西尼的合成路线总体上向着原辅料廉价易得、反应路线短、试剂环保、操作简单、反应条件温和及总收率高的方向不断改进。就现有路线而言,以2,4-二氯嘧啶为起始原料的路线最具工业化前景。
In this paper, the synthetic routes of ribociclib and its key intermediates were reviewed. The comparison and analysis of these synthetic routes showed that, the synthesis of ribociclib had two key steps: constructing7 H-pyrrolo[2,3-d]pyrimidine with amide substituted in 6-position and cyclopentyl in 7-position, and condensation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7 H-pyrrolo[2,3-d]pyrimidin-6-carboxamide and tert-butyl 4-(6-aminopyridin-3-yl)piperazin-1-carboxylate. Traditional synthetic routes have many disadvantages, such as more reaction steps, using expensive metal palladium and toxic cyanide compounds, harsh operation conditions and low overall yield, etc.. The newly developed route reduces the reaction steps by choosing appropriate raw materials and reactions, or adopting aggregated synthetic methods, avoids the use of palladium compounds, thus achieving the effect of constructing synthetic routes with less reaction steps, high yield, environmental friendliness and industrial value. In general, the synthetic route of ribociclib has been improved in the direction of using cheap raw and auxiliary materials, short reaction route,environmentally reagents, simple operation, mild reaction conditions and getting high overall yield. As far as the existing route is concerned, the route with 2,4-dichloropyrimidine as the starting material has the most prospect for industrialization.
In this paper, the synthetic routes of ribociclib and its key intermediates were reviewed. The comparison and analysis of these synthetic routes showed that, the synthesis of ribociclib had two key steps: constructing7 H-pyrrolo[2,3-d]pyrimidine with amide substituted in 6-position and cyclopentyl in 7-position, and condensation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7 H-pyrrolo[2,3-d]pyrimidin-6-carboxamide and tert-butyl 4-(6-aminopyridin-3-yl)piperazin-1-carboxylate. Traditional synthetic routes have many disadvantages, such as more reaction steps, using expensive metal palladium and toxic cyanide compounds, harsh operation conditions and low overall yield, etc.. The newly developed route reduces the reaction steps by choosing appropriate raw materials and reactions, or adopting aggregated synthetic methods, avoids the use of palladium compounds, thus achieving the effect of constructing synthetic routes with less reaction steps, high yield, environmental friendliness and industrial value. In general, the synthetic route of ribociclib has been improved in the direction of using cheap raw and auxiliary materials, short reaction route,environmentally reagents, simple operation, mild reaction conditions and getting high overall yield. As far as the existing route is concerned, the route with 2,4-dichloropyrimidine as the starting material has the most prospect for industrialization.
引文
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[19]ANDREWS D,FINLAY M R,GREEN C,et al.(Imidazolo-5-yl)-2-anilo-pyrimidines as agents for the inhibition of cell proliferation:US,20090233928[P].2009-09-17.
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[21]宋磊.一种快速合成合成Ribociclib方法:中国,108623599[P].2018-10-09.
[2]WONG I O,SCHOOLING C M,COWLING B J,et al.Breast cancer incidence and mortality in a transitioning Chinese population:current and future trends[J].Br JCancer,2014,112(1):167-170.
[3]Novartis Kisqali?(ribociclib,LEE011)receives FDAapproval as first-line treatment for HR+/HER2-metastatic breast cancer in combination with any aromatase inhibitor[EB/OL].[2017-03-13].https://www.novartis.com/news/media-releases/novartis-kisqalir-ribociclib-lee011-receives-fda-approval-first-line-treatment.
[4]CALDON C E,DALY R J,SUTHERLAND R L,et al.Cell cycle control in breast cancer cells[J].J Cell Biochem,2006,97(2):261-274.
[5]陈本川.治疗晚期乳腺癌新药--瑞博西尼(ribociclib)[J].医药导报,2017,36(8):945-951.
[6]王艳梅,薛春苗,于晓维,等.立博昔利布:细胞周期蛋白依赖性激酶4/6抑制剂类抗癌新药[J].药物评价研究,2017,(10):1520-1524.
[7]BESONGG,BRAINCT,BROOKS CA,et al.Pyrrolopyrimidine compounds as CDK inhibitors:WO,2010020675[P].2010-02-05.
[8]ROBERTBM,BOOTHRJ,REPINEJT,et al.2-(Pydine-2-ylamino)pyrido[2,3-d]pyrimidin-7-ones:US,20050137214[P].2005-06-23.
[9]BRIAN P,IDE N D.Solid forms of a selective CDK4/6inhibitor:WO,2014128588[P].2014-08-28.
[10]CALIENNI J V,CHEN G P,GONG B Q,et al.Salt(s)of7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof:US,20120115878[P].2012-05-10.
[11]俞炜,蒋怀志.瑞博西尼中间体的新合成方法:中国,106478641[P].2018-07-24.
[12]俞炜,张一平.瑞博西尼新中间体及其制备瑞博西尼的合成方法:中国,108586356[P].2018-09-28.
[13]吴学平,邢继刚,储贻结,等.一种合成瑞博西尼的方法:中国,107936029[P].2018-04-20.
[14]陈令浩.一种治疗乳腺癌药物瑞博西尼中间体的制备方法:中国,107118215[P].2017-09-01.
[15]陈令浩.一种瑞博西尼的合成工艺:中国,106928236[P].2017-09-01.
[16]CHEN J,CUNICO R F.Synthesis ofα-ketoamides from a carbamoylsilane and acid chlorides[J].J Org Chem,2004,69(16):5509-5511.
[17]许学农.瑞博西尼中间体及其制备方法:中国,105037236[P].2017-07-28.
[18]ZHAO H,HU X,CAO K,et al.Synthesis and SAR of4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors[J].Eur J Med Chem,2018,(157):935-945.
[19]ANDREWS D,FINLAY M R,GREEN C,et al.(Imidazolo-5-yl)-2-anilo-pyrimidines as agents for the inhibition of cell proliferation:US,20090233928[P].2009-09-17.
[20]胡文浩,常欢,许海群.一种环戊基嘧啶并吡咯类化合物的合成方法:中国,106749259[P].2017-05-23.
[21]宋磊.一种快速合成合成Ribociclib方法:中国,108623599[P].2018-10-09.