A Practical Approach of Continuous Processing to High Energetic Nitration Reactions in Microreactors

Abstract

Continuous processing in microreactors represents a novel way for the safe and expedient conduct of high energetic reactions and potentially hazardous chemistry. Apart from handling benefits (such as minimised problems in the scale-up process), reactions in microreactors proceed under precisely controlled conditions providing improved yields and product quality compared to the batch procedure. In this paper, the potential of this technology is exemplarily determined in the crucial nitration of the pharmaceutically relevant intermediate 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid (1). Further fundamental nitration examples demonstrate the unproblematic handling of hazardous H₂SO₄/HNO₃ mixtures for the nitration of 2-methylindole (4) and pyridine-N-oxide (6) or even the explosive acetyl nitrate Ac₂O/HNO₃ (nitration of toluene, 8) in the continuous reaction mode.

Key words

continuous chemistry - pyrazoles - nitration reactions - microreaction technology - heterocycles

References

• 1 Olah GA. Squire DR. Chemistry of Energetic Materials   Academic Press; New York: 1991. 
• 2 Schwalbe T. Autze V. Wille G. Chimia  2002,  56:  636 
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• 4 Schwalbe T, Golbig K, Hohmann M, Georg P, Oberbeck A, Dittmann B, Stasna J, and Oberbeck S. inventors; (Cellular Process Chemistry Inc., USA) Eur. Pat. Appl. EP 1 123  734. All experiments described in this report were carried out in the CYTOS® microreaction system developed by CPC - Cellular Process Chemistry Systems GmbH; ; Chem. Abstr. 2001, 135, 154468; The effective reaction volume of the CYTOS^® microreactor is 1.2 mL, however, along with the feed lines inside the cell the total volume results in 2.0 mL. Although the standard CYTOS^® microreactor is made from stainless steel, the application of undiluted acids was found compatible with this material, probably due to surface inactivation. For further information please visit our website at www.cpc-net.com. CYTOS^® is registered by CPC-Systems GmbH
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8

In the meantime the yield was increased up to 96% by intensive development efforts, see Lit. [6]

12

The nitration reagent was prepared by adding HNO₃ (7.27 g, 5.19 mL, 75 mmol) to ice cold H₂SO₄ (11.43 g, 6.21 mL, 113 mmol). This reagent was dropped into neat toluene (4.61 g, 50 mmol) over 20 min so that the inner temperature did not exceed 10 °C. The solution was stirred for additional 2 h at r.t. (monitored by internal thermometer and adjusted by external cooling if needed). The mixture was poured into ice-water for quenching and the aqueous layer was extracted with CH₂Cl₂ (3 × 100 mL).