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1、ISPE China Annual Spring Conference 2015 Beijing, China Greening the Process Chemistry by Telescoping 叠缩方法绿色化工艺化学叠缩方法绿色化工艺化学 Dr. Ji Zhang (张霁博士张霁博士) HEC Pharma (东阳光药业东阳光药业) Process of Midazolam by Telescoping 合成工艺实例合成工艺实例 叠缩工艺 Telescoping process (Telescoped or telescopic process) A BI1Ix + P 是直接将未经
2、纯化后处理的粗产物投入下一步反应，经 过数步免除纯化过程（用符号 表示）后才经分离纯 化而获取高纯度的产物。 The crude product was directly treated into the next reaction without purification, a process that eliminating purification steps (indicated by symbol represents) and finally isolation and purification to obtain a high purity product. 叠缩工艺叠缩工艺 (
3、Telescoping process ) 数步反应的简化; 避开一些中间体的分离 纯化; 工艺过程的简捷和快速途 径 simplifythenumberof steps Avoid separations of some intermediates Simple and fast way for process 一锅法反应一锅法反应 （One-pot reaction） 强调反应的简单性， 即把多步反应按顺序或 者一次性投料在一个反应器 里得到所需的产物，而不牵 涉到后处理纯化过程 Emphasizes simplicity Themulti-stepreaction sequence or
4、 a one-pot in a reactor,withoutinvolving post-treatmentpurification process VS 叠缩工艺和一锅法反应 (Telescoping and one-pot reaction 理想的工艺路线设计应使所有中间体无需 经过柱层析纯化 Ideal process should be designed so that all intermediate without purification by column chromatography 经过溶解、过滤、打浆和重结晶等经典操 作就能达到纯化目的 By dissolution,
5、filtration, and re-crystallization operations achieve the purpose of purification 放大生产时也多采用打浆、盐等方式以获 取最好产率和纯度 use re-slurry, salt formation and other ways to get the best yield and purity 叠缩工艺就是将多步工艺过程免叠缩工艺就是将多步工艺过程免 除柱层析纯化的理想状态除柱层析纯化的理想状态 Ideally telescoped process is to remove the multi-step purif
6、ied by column chromatography 1 2 3 叠缩工艺和一锅法反应 (Telescoping and One-pot reaction) 叠缩工艺的实例分析叠缩工艺的实例分析 (Case study 1)(Case study 1) 7 最后工艺特点最后工艺特点: : 用氢溴酸取代盐酸用于重氮盐和肼的制备，没有分离肼的氢溴酸盐，直接用于哒嗪 酮的制备，直接从水中析出高纯度高产率水溶性差的产品 Zhang, J. Morton, H. E.; Ji, J. Tetrahedron Lett. 2006, 47, 8733-8735 Org. Proc. Res. Dev.
7、 2006, 10, 512-517 叠缩工艺的实例分析叠缩工艺的实例分析 (Case study 1)(Case study 1) 1 产品质量及工艺的稳定性 Quality of product and process stability 2 3 4 5 叠缩工艺和工艺的绿色化叠缩工艺和工艺的绿色化 Telescoping and greening processTelescoping and greening process 增加产率、减少损失、减少劳动时间 Increase yields, reduce losses, reducing labor time 显著降低运作成本 Sign
8、ificantly reduce operating costs 提高工艺操作人员的安全保护 Improve the safety for operators 提高运行和环境安全 Improve the environment Zhang, J.; Cue, B. W. Green Techniques for Organic Synthesis and Medicinal Chemistry John Wiley Barnes, D.; Zhang, J.; J. Am. Chem. Soc. 1999, 121, 10215 Ji. J.; Barnes, D.; Zhang, J.; J
9、. Am. Chem. Soc. 2002, 124, 13097 O O OMe EtO2C O O OMe N H HO2C O O OMe N H EtO2C NO2 O O OEt O O O OMe NO2 + t-BuONa 1) Ra-Ni/H2 2) NaBH(OAC)3 D-tartaric acid 20% (40% of theory) * 1/2 D-tartaric acid rac- rac ABT-546 7 8 9 10 11 Ji. J.; Barnes, D.; Zhang, J.; J. Am. Chem. Soc. 1999, 121, 10215 Ji
10、. J.; Barnes, D.; Zhang, J.; J. Am. Chem. Soc. 2002, 124, 13097 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 2)(Case studies 2) 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 3)(Case studies 3) Zhang, J.; Blazecka, P. G.et al.; J. Org. Chem. 2009, 74, 1411 Zhang, J.; Blazecka, P. G.et al.; J. Org. Chem. 2009, 74, 1411 Conclu
11、sion: Lactam is more stable than lactone 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 3)(Case studies 3) Zhang, J.; Blazecka, P. G.et al.; J. Org. Chem. 2009, 74, 1411 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 3)(Case studies 3) 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 4)(Case studies 4) Zhang, J.; Blazecka, P. G. et al.; Tetra
12、hedron Lett. 2009, 50, 1167 Top 12 best-selling drugs 2014 的销售额高达51.68亿美元 Zhang, J.; Blazecka, P. G.et al.; Tetrahedron Lett. 2009, 50, 1167 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 4)(Case studies 4) Zhang, J.; Blazecka, P. G.et al.; Tetrahedron Lett. 2009, 50, 1167 手性醛手性醛 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies
13、4)(Case studies 4) 相应手性相应手性酸酸 Zhang, J.; Blazecka, P. G.et al.; Tetrahedron Lett. 2009, 50, 1167 CO2Et O CO2Et NOMeNH2OMe HCl (1.1 eq), NaOAc (1.0 eq) MeOH, rt, 24h Ra-Ni MeOH, H2 98% 97% oil 3638 叠缩工艺的实例分析叠缩工艺的实例分析 (Case studies 4)(Case studies 4) 反应进行得干净彻底，产物的产率及纯度很高，无需进一步分离纯化反应进行得干净彻底，产物的产率及纯度很高，
14、无需进一步分离纯化 The reaction was carried out a thorough clean, high yield and purity of the product, without further separation and purification 中间体为液体，纯化分离不易，且杂质副产物也多为液体中间体为液体，纯化分离不易，且杂质副产物也多为液体 Intermediates are liquid, purification and separation is not easy, and the impurities are liquid 中间体不稳定，如怕光、怕热
15、、怕氧等，或容易降解中间体不稳定，如怕光、怕热、怕氧等，或容易降解 Unstable intermediates, such as photophobia, heat intolerance, oxygen sensitive, or easily degradable 1 2 3 产物为固体，易纯化分离，且杂质副产物多为液体产物为固体，易纯化分离，且杂质副产物多为液体 The product is a solid, easy separation and purification, and the impurities are liquid 4 叠缩工艺的一些规律和特点叠缩工艺的一些规律和特
16、点 ( (Rules) ) 反应的产物或杂质是有机胺或有机羧酸，可通过成盐而避免不必要的分离纯反应的产物或杂质是有机胺或有机羧酸，可通过成盐而避免不必要的分离纯 化化 products or impurities is an organic amine or an organic carboxylic acid, salt formation can avoid unnecessary separation and purification 8 中间体对酸或碱以及水的后处理极为敏感，容易分解中间体对酸或碱以及水的后处理极为敏感，容易分解 Intermediate is extremely sensitive, readily decomposed in basic, acidic or in water 7 产物或副产物物理化学性质尤其是溶解度差别很大，一般的过滤或吸附能将产物或副产物物理化学性质尤其是溶解度差别很大，一般的过滤或吸附能将 其一迅速分离出来其一迅速分离出来 Physical chemica
