Under continuous processing conditions, C-N bond formation via SN2 and SNAr substitutions by amines can be an effective preparative method, especially when volatile amines are used under high pressure and temperature. We have demonstrated SN2 substitution of a 2° mesylate with ammonia and opening of an epoxide with benzylamine, and SNAr substitution of a heteroaryl chloride with aqueous ammonia on multi-kg scales. The homogeneous continuous processes offered better process control, higher efficiency, and comparable or superior reaction profiles and yields to batch conditions.
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The solvent miscibility may change under high temperature, although we have not experienced any issues of carrier solvent miscibility with the spacer solvent
The carrier solvent system and inert spacer may have different volumetric expansion coefficients with the temperature. However, it is not expected to affect the segmented flow provided they are immiscible
We thank the support of Mr. Remzi Duzguner and Robert A. Giusto for carrying out DSC and TSu process safety testing.
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Li, B., Bader, S., Guinness, S.M. et al. Continuous flow aminolysis under high temperature and pressure. J Flow Chem 10, 145–156 (2020). https://doi.org/10.1007/s41981-019-00049-6
- Continuous flow
- Nucleophilic substitution
- High temperature