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.
作者
翁智兵
田苗
WENG Zhibing;TIAN Miao(Changzhou Institute of Engineering Technology, Changzhou 213164)
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2019年第6期596-603,共8页
Chinese Journal of Pharmaceuticals
关键词
瑞博西尼
抗乳腺癌
合成
ribociclib
anti-breast cancer
synthesis
