35308-02-2Relevant academic research and scientific papers
Isolation and structure elucidation of novel products of the acidic degradation of diazepam
Nudelman,De Waisbaum
, p. 208 - 211 (1995)
The acidic degradation of diazepam in methanolic aqueous solution has been investigated. Apart from the known degradation products, 2-(N-methylamino)- 5-chlorobenzophenone and glycine, produced by the hydrolytic cleavage of the benzodiazepinone ring, five novel products were isolated and fully characterized by their spectroscopic features and independent synthesis. Substituted 2-amino-3,5-dichlorobenzophenones and 2,4-dichloroacridinones were found, the formation of which in the reaction media is mechanistically intriguing. The rule of these unexpected products in accelerated studies of diazepam stability is discussed.
Kinetic and mechanistic studies on the hydrolysis and photodegradation of diazepam and alprazolam
Cabrera, C. Gallardo,Goldberg De Waisbaum,Nudelman, N. Sbarbati
, p. 156 - 161 (2007/10/03)
The corresponding o-aminobenzophenones are usually reported as the main degradation products in the hydrolysis of 1,4-benzodiazepinones. Nevertheless, in previous studies of diazepam (DZ) in acidic aqueous medium we isolated and characterized seven unexpected degradation products. Kinetic measurements under several reaction conditions shed some light on the mechanisms of the complex reactions that are taking place, and photochemical studies give hints on the mechanisms of chlorination and annelation processes. Alprazolam (AL) seems to exhibit an unusually high stability against hydrolysis under several conditions; nevertheless, the structure is sensitive to photolytic cleavage. The photodegradation of AL was studied in aqueous and methanolic solutions. Characterization of the isolated products by 1H and 13C NMR and mass spectrometry revealed that electron transfer, oxidation and rearrangement reactions take place. The influence of several variables such as pH, solvent composition and light irradiation were examined and mechanisms for the formation of three photoproducts are proposed. A specific method for the determination of AL in the presence of photoproducts was developed, which allowed kinetic determinations of the photostability of AL. The photosensitivity observed in some patients treated with AL seems to be due to one of the characterized photoproducts. Copyright
Kinetic Study of the Reactions of 2-Amino-5-chlorobenzophenone with HCl in MeOH-H2O
Nudelman, N. Sbarbati,Waisbaum, R. G. de
, p. 97 - 106 (2007/10/03)
The reaction of 2-amino-5-chlorobenzophenone (1) with 0.5-2 M HCl was studied in 1:1 (v/v) MeOH-H2O at 60 and 80 deg C.Products that were isolated were characterized as 2-(N-methylamino)-5-chlorobenzophenone (2), 2-amino-3,5-dichlorobenzophenone (3), 2-N-methylamino-3,5-dichlorobenzophenone (4), 2-(N,N-dimethylamino)-5-chlorobenzophenone (5), 2,4-dichloro-10-methyl-9,10-acridinone (6) and 2,4-dichloro-9,10-acridinone (7).The rates of reaction of 1 and the rates of formation of 2-5 were measured at several HCl concentrations.The methyl transfers, the chlorination and the cyclization reactions that give rise to 2-7 were unexpected under the present reaction conditions.A set of differential equations was proposed in order to calculate the rate constants for each step of this complex reaction.The proposed reaction scheme also takes into account the reaction 21 and permits the calculation of the rate constants for this reversible reaction.The experimental values of the rate constants for reaction of 1 were compared with those for 2 under the same reaction conditions, in order to evaluate the importance of the methyl group on the methyl transfer reactions; it was found that the methyl group is not required for the unexpected reaction to occur. - Keywords: 2-amino-5-chlorobenzophenone; hydrochloric acid; kinetics
Acid hydrolysis of diazepam. Kinetic study of the reactions of 2-(N- methylamino)-5-chlorobenzophenone, with HCl in MeOH-H2O
Nudelman,De Waisbaum
, p. 998 - 1004 (2007/10/03)
In the acid hydrolysis of diazepam (1), several unusual products, apart from 2-(N-methylamino)-5-chlorobenzophenone (2) and glycine, were isolated. On the assumption that some of those products could arise from further degradation of 2, the reaction of this compound with 0.5-2 M HCl was studied, in 1:1 MeOH-H2O, at 60 and 80 °C. Several unexpected products were isolated from the reaction of 2 with HCl, namely, 2-amino-5-chlorobenzophenone (3), 2- (N,N-dimethylamino)-5-chlorobenzophenone (4), 2-(N-methylamino)-3,5- dichlorobenzophenone (5), 2-amino-3,5-dichlorobenzophenone (6), 2,4-dichloro- 10-methyl-9,10-acridinone (7), and 2,4-dichioro-9,10-acridinone (8). The methyl transfers, the chlorination, and the cyclization reactions that give rise to products 3-8 are unexpected under the present reaction conditions. The rate of reaction of 2, as well as the rate of formation of compounds 3- 6, was measured at several HCl concentrations.
