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A study was conducted to examine the kinetics of the HCl-catalyzed deprotection of the Boc-protected amine, thioester to liberate AZD3409 in a mixture of toluene and propan-2-ol. A general acid-catalyzed separation of a reversibly formed ion-molecule pair arising from the fragmentation of the protonated tert-butyl carbamate rationalized the reaction rate which was found to exhibit a second-order dependence upon the HCl concentration.

We observed that the product of a Buchwald-Hartwig coupling reaction extracted from the organic phase easily, relative to the starting aryl bromide as the pH was lowered. This was surprising given the similarity of their pKa's. The product's extraction curve was also significantly steeper than expected. A consideration of the relevant equilibria, including all three of the product's pKa's, led to a general model for the liquid-liquid extraction behavior of ionizable molecules. This model predicts the observed, useful extraction behavior. [ABSTRACT FROM AUTHOR]

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.

The final synthetic step in the synthesis of cediranib, AZD2171, 1, is the alkylation of a phenol with an alkyl halide to generate an ether. Our need to understand and control the formation of synthetic impurities generated in this step of the synthesis led us to investigate the kinetics and mechanism of the alkylation of indolphenol, 2, 4-[(4-fluoro-2-methyl-1 H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol, by chloropyrrolidine, 3, 1-(3-chloropropyl)pyrrolidine. Studies in 1-methyl-2-pyrrolidinone (NMP) established that the active alkylating agent is the azetidinium ion, 4, 4-azoniaspiro[3.4]octane, formed via a slow intramolecular cyclization reaction of chloropyrrolidine, 3. The azetidinium ion was isolated as its tetraphenylborate salt from water by heating 3 in the presence of aqueous potassium tetraphenyl borate, and its competence as an intermediate was demonstrated by its fast reaction with 2 to yield cediranib, 1.