在地西泮和阿托品的连续流合成中使E因子最小化。

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

作者信息

Bédard Anne-Catherine, Longstreet Ashley R, Britton Joshua, Wang Yuran, Moriguchi Hideki, Hicklin Robert W, Green William H, Jamison Timothy F

机构信息

Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.

出版信息

Bioorg Med Chem. 2017 Dec 1;25(23):6233-6241. doi: 10.1016/j.bmc.2017.02.002. Epub 2017 Feb 4.

DOI:10.1016/j.bmc.2017.02.002

PMID:28284869

Abstract

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

摘要

从经济和环境角度来看，尽量减少与活性药物成分（API）和商品化学品合成相关的废物流在化学工业中备受关注。在探索该领域的解决方案时，我们在此报告了两种被世界卫生组织确定为基本药物的API（即地西泮和阿托品）的高度优化且具有环境意识的连续流合成方法。值得注意的是，通过连续流化学技术、计算计算和溶剂最小化的结合，这些方法显著降低了先前发表路线的E因子。与阿托品合成相关的E因子从2245降至24，降低了94倍（约两个数量级），而地西泮合成的E因子从36降至9，降低了4倍。