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 degrees 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 less than 9.0. On the contrary, 1 was extremely stable in 0.5 M HCl at 50 degrees 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 degrees 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.
Nagata
O
O
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Terasaki
T
T
Yada
E
E
Sato
H
H
Tamai
I
I
Tsuji
A
A
D001888:Boric Acids; D002021:Buffers; D002384:Catalysis; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011427:Propiophenones / Q000032:analysis*; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013696:Temperature
D001888:Boric Acids; D002021:Buffers; D011427:Propiophenones; D012996:Solutions; C052425:inaperisone