Diketopiperazine Formation, Hydrolysis, and Epimerization of the New Dipeptide Angiotensin-Converting Enzyme Inhibitor RS-10085

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Abstract
The degradation kinetics, products, and mechanisms of RS-10085(1), 2-[2-(l-ethoxycarbonyl)-3-phenylpropyl]amino-l-oxopropyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid(S,S,S), in aqueous solution were investigated at 40, 60, and 80°C from pH 1 to pH 13. Pseudo-first-order kinetics were observed throughout the pH range studied and the log(rate)−pH profiles reflected four kinetic processes (ko, k′o, k″o, and kOH) as well as the two pKa's of 1. Excellent (>98%) mass balance was obtained through products 2–5. At pH 4 or below, intramolecular cyclization leading to diketopiperazine 5 accounted for greater than 93% of the observed neutral- or water-catalyzed processes (ko and k′o). At pH levels greater than 5, hydrolysis giving 2 predominated and was responsible for the observed neutral- or water-catalyzed (k″o) and specific base-catalyzed (kOH) kinetic processes. Some epimerization leading to the S,S,R drug isomer (4) was also observed at pH levels greater than 7. The relative acidity of the protons at the three chiral centers of 1 was qualitatively compared and was used to explain the observed specificity in epimerization.