| Autor: |
Ashworth IW; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, SK10 2NA, U.K., Frodsham L; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, SK10 2NA, U.K., Moore P; Early Chemical Development, Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Macclesfield, SK10 2NA, U.K., Ronson TO; Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, SK10 2NA, U.K. |
| Abstrakt: |
An early synthetic step in the synthesis of adavosertib, AZD1775, is the S N Ar reaction between 4-fluoronitrobenzene and 1-methylpiperazine in acetonitrile. A simple kinetics-based design of four reaction profiling experiments was used to investigate the kinetics of the reaction for the purpose of building a kinetic model. Fitting of the reaction profile data from two experiments conducted at 70 °C with a different excess of 1-methylpiperazine showed the reaction to follow a third-order rate law with a second-order dependence upon 1-methylpiperazine. This was rationalized in terms of the reaction following a rate-limiting proton transfer mechanism (base catalyzed) in which the progress to product is driven by a proton transfer involving a second molecule of 1-methylpiperazine. The experimentally determined entropy of activation of -180 J K -1 is consistent with this mechanism. The formation of a low level impurity was found to be due to the presence of traces of piperazine in the 1-methylpiperazine, which was shown to react approximately 15 times faster than 1-methylpiperazine at 70 °C. The rate constants for the 1-methylpiperazine catalyzed reaction of piperazine, 1-methylpiperazine, and the piperazine derived impurity were found to correlate in a Brønsted type analysis with the p K a 's (acetonitrile) of the amine nucleophile. |
