Micellar Catalysis of Organic Reactions. XXX. A Study of the Mechanism of Hydrolysis of Oxazepam and 2'-Methyldiazepam in the Presence of Micelles and in Water

Abstract

Acidic hydrolysis of oxazepam in water involved initial azomethine cleavage at low acid concentrations (0.1-0.2 M) with initial amide hydrolysis occurring concurrently at higher acid concentrations (0.3-0.6 M). In the presence of micelles of sodium dodecyl sufate the percentage of initial amide cleavage increased. For the basic hydrolysis of oxazepam in water the rate was dependent on [ NaOH ] indicating at least some initial amide hydrolysis. At higher base concentrations the rate became independent of [ NaOH ], because of the ionization of the NH group of oxazepam, producing an unreactive nitranion. In the presence of cetyltrimethylammonium bromide, the rate of basic hydrolysis was slower than in water, due to the increased amount of ionization in the presence of micelles. Acidic hydrolysis of 2′-methyldiazepam in water was independent of [ HCl ] in the range 0.1-0.3 M, indicating initial azomethine hydrolysis. The rate was slower than for diazepam itself, indicating the existence of steric hindrance by the 2′-methyl group to water attack at C5. In basic solution, a biphasic reation was observed. The rate of the first phase was dependent on [ NaOH ], indicating the presence of initial amide hydrolysis for 2′-methyldiazepam, cf. initial azomethine hydrolysis for diazepam. At high base concentrations, a greater than first-order dependence on base concentration was observed. This was attributed to the formation of dianionic intermediates, as previously reported for the hydrolysis of similar anilides at high base concentrations.

Effect of Detergents and Other Amphiphiles on the Stability of Pharmaceutical Drugs

“…SDS micelles favour the amide hydrolysis route, presumably by concentrating H + at the micellar surface. In alkali, the route for oxazepam hydrolysis is also dependent on the OH-ion concentration and the effect of HTAB is dependent on the relative OH-concentration (Broxton & Wright 1991). Addition of a 2-methyl group (2'-methyl diazepam) produces a mechanistic effect similar to that observed for the alkaline hydrolysis of diazepam with HTAB micelles (Broxton et al 1984).…”

“…1,4-Benzodiazepinones, exhibiting anxiolytic, anticonvulsant and muscle-relaxing properties have been widely used, especially as these drugs are hydrophobic and display t l "" interesting decomposition routes (Scheme 7) Han et a1 1977;Broxton & Wright 1991). The hydrolysis of 1,4-benzodiazepinones can be initiated by nucleophilic attack at C-5, yielding intermediate 2 or, alternatively, at C-2 with amide hydrolysis producing inter-SCHEME 8 mediate 3.…”

“…Recently, Broxton & Wright (1991) have reinvestigated the mechanism of hydrolysis of oxazepam and 2'-methyldiazepam in water and in the presence of micelles (Scheme 7). In dilute acid ( < 0.2 M) the reaction pathway is mostly azomethine cleavage.…”

Synthesis of Alkylphenyl Ethers in Aqueous Surfactant Solutions by Micellar Phase-Transfer Catalysis. 2. Two-Phase Systems

“…The reaction investigated in this work is the preparation of unsymmetrical phenolic ethers via alkylation with alkyl halides (the Williamson reaction). The specific reaction of interest is the synthesis of butyl phenyl ether in aqueous sodium hydroxide solution. The objective was to compare reaction rates and conversions observed under three catalytic schemes in emulsion systems: (1) phase-transfer catalysis (PTC); − (2) micellar catalysis (MC); − (3) micellar phase-transfer catalysis (MPTC), , which is an integration of conventional micellar catalysis and phase-transfer catalysis.…”