Acid‐catalyzed stereoselective heteronucleophilic substitution and racemization of 3‐O‐methyloxazepam and 3‐O‐ethyloxazepam

Abstract

Enantiomers of 3-O-methyloxazepam (MeOX) and 3-O-ethyloxazepam (EtOX) were resolved by chiral stationary phase high-performance liquid chromatography (CSP-HPLC). Reaction kinetics and deuterium isotope effects of acid-catalyzed racemization of enantiomeric MeOX in ethanol and enantiomeric EtOX in methanol were studied by spectropolarimetry. The acid-catalyzed heteronucleophilic substitution reactions of racemic MeOX in ethanol and racemic EtOX in methanol were studied by reversed-phase HPLC. Thermodynamic parameters involved in the reactions were obtained by temperature-dependent reaction rates. The effects of solvent's dielectric constant on the heteronucleophilic substitution reactions were also determined. A nucleophilically solvated and transient C3 carbocation intermediate resulting from an N4-protonated enantiomer, derived from a 1,4-benzodiazepine either in M (minus) or P (plus) conformation, is proposed to be an intermediate and responsible for the acid-catalyzed stereoselective nucleophilic substitution and the resulting racemization.

Racemization and stereoselective alcoholysis of temazepam

“…This situation was similar to those stereoselective homonucleophilic and heteronucleophilic substitution reactions studied earlier. 2,[4][5][6][9][10][11] We therefore propose that the mechanism involved in the acid-catalyzed stereoselective alcoholysis of TMZ enantiomers was the same as those involved in the Scheme 2. Proposed mechanism responsible for the racemization and stereoselective heteronucleophilic substitution of (R)-TMZ in anhydrous acidic alcoholic solvents.…”

“…6 The K a values of rac-MeTMZ in MeOH and rac-EtTMZ in EtOH were 38 ± 3 (n = 3) and 110 ± 14 (n = 3) mM H 2 SO 4 , respectively. The K a values of rac-TMZ in MeOH and EtOH were 5.0 ± 0.5 and 15 ± 2 mM H 2 SO 4 , respectively.…”

Homochiral Drug Design and Development by Racemization

“…Furthermore, they also suggested that racemization reaction occurred due to keto-enol tautomerism between C2 carbon of -CO group and C3 carbon; catalysed by a base. Similarly, Yang [25] reported acid catalyzed racemization of 3-O-methyloxazepam and 3-O-ethyl oxazepam in ethanol and methanol, respectively. These authors described a C3 carbocation intermediate as one of the most important steps in the racemization.…”

“…The chiral inversion of certain antiinflammatory drugs was reported as unidirectional in rat [112], rabbit and humans [113]. The important factors affecting racemization of these drugs were temperature, pH [25,28,[114][115][116][117][118] and organic solvent [25,28,[114][115][116]. In drug racemization and epimerization, the important action of human serum albumin (HSA) was also reported [106].…”

“…A remarkable study was carried out by Yang et al [21][22][23][24][25][26][27][28][29] on the racemization of various homochiral drugs. The authors [27] reported that the conjugated benzylic C-H at the chiral center was responsible for the racemization reaction in oxazepam.…”