Capmatinib is a is a kinase inhibitor which is a treatment for metastatic non-small cell lung cancer. In the synthetic route towards the final API described by Hughes in 2021 [1] an early step in the synthesis is the electrophilic aromatic bromination of 3-amino-1,2,4-triazine. The development of a flow chemistry process for the synthesis of 6-bromo-3-amino-1,2,4-triazine and the subsequent integrated continuous work-up is presented. Hughes’ report in July of 2021 described a 17% yield of the brominated triazine on a 33 Kg scale, other reports on a research scale (50-500mg) vary from 34% (patent), 68% [2] and 80%[3] yield respectively. It was envisaged that the issue of scale-up could be solved by investigating the chemistry optimisation and subsequent quench in flow and from there translating the reaction and work-up to continuous unit operations in series. The bromination of 3-amino-1,2,4-triazine using N-bromosuccinimide (NBS) was optimised in flow to 94.5% yield by HPLC with the aid of computational fluid dynamics (CFD) to characterise and deliver an improved mixing performance. A continuous work-up protocol was developed using two mixer settler units in series to produce 6-bromo-3-amino 1,2,4-triazine with 99% purity and with an isolated yield of 75% on a 46 g/day scale. To understand the potential application of this process workflow a proposed scale-up approach with the potential for a kg/day production output is presented.
Patent = https://patents.google.com/patent/US11091462B2/en
[1] D. L. Hughes, Org. Process Res. Dev. 2021, 25, 2192–2204.
[2] D. N. Kamber, Y. Liang, R. J. Blizzard, F. Liu, R. A. Mehl, K. N. Houk, J. A. Prescher, J. Am. Chem. Soc. 2015, 137, 8388–8391.
[3] M. M. Littleson, A. D. Campbell, A. Clarke, M. Dow, G. Ensor, M. C. Evans, A. Herring, B. A. Jackson, L. V. Jackson, S. Karlsson, D. J. Klauber, D. H. Legg, K. W. Leslie, Š. Moravčík, C. D. Parsons, T. O. Ronson, R. E. Meadows, Org. Process Res. Dev. 2019, 23, 1407–1419.
Keywords: Continuous Processing, Bromination, Process Development, Work-Up, CFD
