Aporphines. 50. Kinetics of solvolysis of N-(2-chloroethyl)norapomorphine, an irreversible dopamine receptor antagonist

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Abstract
The rates and mechanism of solvolysis of (-)-N-(2-chloroethyl)norapomorphine (NCA, 1c) in aqueous solution were examined by reversed-phase liquid chromatography (HPLC) to follow the levels of starting material and products. The 1st-order rate constants for aziridinium ion formation at 25 and 37.degree. C at pH 7.0 are 0.024 and 0.096/min, respectively. Determination of the 1st-order rate constant for the disappearance of NCA as a function of pH allowed the calculation of an approximate pKa, of 6.3 for the tertiary amine, while the influence of reaction conditions (e.g., pH, buffer salt and concentration, and added nucleophiles) on product distribution support the view that NCA solvolysis proceeds through an intermediate aziridinium ion. Application of the HPLC procedure allowed simultaneous observation of the loss of NCA and the appearance of an intermediate and multiple products at trace levels; it also permitted the facile isolation and subsequent identification of small amounts of hydrolysis products. At pH 7, maximum aziridinium concentration was reached only after 10 min at 37.degree. C and at 25.degree. C after 1 h. Increased temperatures and pH facilitated the rate of aziridinium ion formation, as well as of non-dopamine antagonist solvolysis products. The significance of these findings, including the ease with which buffer ions add to the intermediate ion, are discussed in relation to the use of NCA and its tritiated isomer, [3H]NCA, in dopamine receptor studies.