Degradation kinetics of (±)‐4′‐ethyl‐2‐methyl‐3‐(1‐pyrrolidinyl)propiophenone hydrochloride (HY‐770) and structure–stability relationship among its analogues in aqueous solution

The kinetics and pathways for degradation of (±)‐4′‐ethyl‐2‐methyl‐3‐(1‐pyrrolidinyl)propiophenone hydrochloride (HY‐770; 1), a newly developed muscle‐relaxing agent, and its analogues were studied in aqueous solution at 50°C, ionic strength 0.5 M, and pH 8.0–12.0. Compound 1 and its four analogues followed pseudo‐first‐order degradation kinetics at constant pH and temperature. From the analysis of the pH degradation–rate profiles, it is evident that specific hydroxide ion‐catalyzed degradations of ionized and un‐ionized species occur for 1 and its structural analogue, 3′‐fluoro‐2‐methyl‐3‐(1‐pyrrolidinyl)propiophenone hydrochloride (HN‐961;5). The hydroxide ion‐catalyzed degradation of the ionized species was found to be 100 times faster than that of the un‐ionized species and to be the major process at pH < 9.0. On the contrary, 1 was extremely stable in 0.5 M HCl at 50°C, suggesting that the hydronium ion‐catalyzed degradation and the spontaneous degradation of the ionized species is negligible. The Arrhenius plot for the degradation of 1 at 35–50°C and pH 9.0 showed that the apparent energy of activation was 22.0 kcal/mol. The degradation rates of the five structural analogues were significantly dependent on the electron withdrawing effect of the benzene substituents of the molecule.