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Evidence of Rate Limiting Proton Transfer in an S N Ar Aminolysis in Acetonitrile under Synthetically Relevant Conditions

An early synthetic step in the synthesis of adavosertib, AZD1775, is the SNAr 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 pKa's (acetonitrile) of the amine nucleophile.

Related Products

Cat.No. Product Name Information
S1525 Adavosertib (MK-1775) Adavosertib (MK-1775, AZD1775) is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM in a cell-free assay; hinders G2 DNA damage checkpoint. Phase 2.

Related Targets

Wee1