Organic Process Research & Development 2009, 13, 698–705
Facile, Fast and Safe Process Development of Nitration and Bromination Reactions Using Continuous Flow Reactors Jacques Pelleter* and Fabrice Renaud AstraZeneca, Centre de recherches, Z. I. La Pompelle, BP1050, 51689 Reims cedex 2, France
Abstract: Chemists working in a pilot plant often face safety issues during scale-up operations. With the help of emerging microfluidic applications and microdevices, running hazardous, highly exothermic or potentially unstable reactions can be easily transposed into a safe continuous flow mode. This paper describes how a potentially hazardous pyrazole nitration and the bromination of a variety of electron-rich heteroaromatic substrates were efficiently performed using a cheap and easily available system for bench chemists. Advantages of the continuous flow mode in organic synthetic chemistry will be exemplified by the large-scale production of raw materials under safe, green and reproducible conditions. Figure 1. Compounds scaled up and produced using a microfluidic continuous flow reactor.
1. Introduction Due to the fast-paced industrial environment, scale-up chemists need to solve quickly the safety, cost and environmental issues they face when optimising chemical processes. Through the implementation of emerging technologies like microfluidics, microreactors and continuous flow chemistry,1,2,13 synthetic chemists can develop fast, efficient and safe organic processes. In modern pharmaceutical research, there is a routine demand to scale-up processes to produce large quantities of key intermediates for further derivatisation. However, some reactions performed at the bench are often potentially more hazardous on larger scales due to, for example, high exotherms, unstable mixtures and/or toxic issues of the intermediates generated during the reaction itself. We faced such problems recently with a pyrazole nitration and the bromination of imidazo[1,2-a]pyridine. The implementation of a continuous flow reactor helped us to synthesise these key intermediates under safe conditions, without compromising reaction yield. After an initial period of reaction optimisation to find the best process in solution, we determined suitable operating parameters and * Corresponding author. Telephone: +33(0)3 26 61 69 68. Fax: +33(0)3 26 61 68 42. E-mail:
[email protected].
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Table 1. Parameter comparison of a tank reactor vs a microreactor1a tank reactor internal structure type of flow mixing times specific surface heat-transfer rate
few milliliters to thousands of liters turbulent ∼10 s ∼100 (m2/m3) ∼2000 (W/m2/K)
microfluidic system
