Racemization and stereoselective alcoholysis of temazepam

✍ Scribed by Shen K. Yang

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 192 KB
• Volume: 11
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/(sici)1520-636x(1999)11:3<179::aid-chir2>3.0.co;2-g

✦ Synopsis

Enantiomers of temazepam (TMZ), an anxiolytic drug in clinical use, were resolved and stabilized by the use of aprotic solvents in chiral stationary phase high-performance liquid chromatography (CSP-HPLC). The enantiomers were used to study racemization and heteronucleophilic substitution (alcoholysis) reactions in anhydrous acidic methanol and ethanol. Kinetics of spontaneous racemization and stereoselective conversions to 3-O-methyltemazepam (MeTMZ) and 3-O-ethyltemazepam (EtTMZ) were determined by circular dichroism (CD) spectropolarimetry and CSP-HPLC. The rates of conversion of rac-TMZ to rac-MeTMZ (or rac-EtTMZ) were determined by ultraviolet-visible spectrophotometry. The results indicated that, for example, both N4-protonated and unprotonated forms of (S)-TMZ underwent spontaneous racemization and its 3S-hydroxyl group was highly stereoselectively substituted at C3 position by the ethoxy group of ethanol to form EtTMZ enriched in (S)-EtTMZ. Similar stereoselective reactions occurred for TMZ enantiomers in acidic methanol.