Transposition of a triphosgene-based process for pharmaceutical development: from mg·h-1 to kg·h-1 of an unsymmetrical urea

Abstract

A two reaction synthesis of a urea, using triphosgene, was studied. The objective was to transpose the process from laboratory scale to pre-industrial plant. The whole study was performed in a continuous process, adapting the characteristic dimensions and length of the reactor. In this paper, the development of the process is presented, and the choices about safety and operating conditions constraints are discussed. The final operation allows a 70% global yield in a 7 week study. Furthermore, the use of microreactors not only permits an exhaustive study of the process operating parameters, but also provides feedback on the developed chemistry itself. The results obtained are a demonstration of the use of continuous processes in small scale reactors for complex molecule development. The mg · h -1 to kg · h -1 is a key transposition in the pharmaceutical industries project development, as it can help to accelerate the first lot production used in toxicological or pre-clinic stages.

Flow Photo-On-Demand Phosgenation Reactions with Chloroform

“…Flow phosgenation reactions have been reported with bis­(trichloromethyl)­carbonate (BTC) capable of generating three molecules of COCl 2 upon mixing with an organic base (Scheme a). − Phosgene (COCl 2 ) is a useful C1 building block with high reactivity in organic syntheses but has extremely high toxicity. , The flow reaction system allows continuous chemical on-demand generation of COCl 2 from BTC and its in situ reaction with the substrate. This reduces potential risks of COCl 2 .…”

Real time monitoring of the quiescent suspension copolymerization of vinyl chloride with methyl methacrylate in microreactors – Part 3. A kinetic study by raman spectroscopy and evolution of droplet size

“…It is important to emphasize that microreactors may exhibit characteristic dimensions of the order of millimeters and sub-millimeter (Pattekar and Kothare, 2004;Richard et al, 2013). Microreactors find potential use in many applications, including biocatalysis (Fernandes, 2010), biodiesel production (Sun et al, 2008;Richard et al, 2013), heterogeneous catalysis (Kiwi-Minsker and Renken, 2005), drug synthesis (Kang et al, 2008;Leroyer et al, 2013), hydrogen production (Pattekar and Kothare, 2004), photocatalysis (Gorges et al, 2004) and polymerization processes (Bodoc et al, 2012;Bally et al, 2010;Castor et al, 2015Castor et al, , 2016Mahadevan et al, 2016). Following the general principles of the Green Chemistry, microreactors can be used to synthesize and purify organometallic compounds by atomic layer deposition (ALD) and chemical vapor deposition (CVD), allowing for safe operations and production of chemicals with higher degree of purity (Lipiecki et al, 2008(Lipiecki et al, , 2009.…”