Preparation of Nordiazepam 2-(chloroacetamido)-5-chlorobenzophenone In a 500 mL-round bottom flask, dissolve 46 gr. 2-amino-5-chlorobenzophenone (Aldrich) in 200 mL dry (!) chloroform. Add with stirring 20 mL chloroacetyl chloride within 10 min. dropwise, and stir 1 hr. more. The solution gets warm, HCL gas is evolved. After the hour, evaporate to complete dryness at the rotary evaporator. Add 100 mL fresh, dry chloroform to the yellow-orange residue and evaporate again. 7-chloro-1,3-dihydro-5-phenyl-benzo-1,4-diazepin-2-one (Nordiazepam) Drip 400 mL 25% aqueous ammonia solution on 250 g sodium hydroxide during 2 hrs, the evolved ammonia gas is bubbled into 1000ml of ice-cooled 95% ethanol. (Use a safety gas washing bottle between bubbling and generating unit!). Scrape off all the 2-(chloroacetamido)-5-chlorobenzophenone from the 500 mL flask, add this, the ammonia-saturated ethanol, 58g hexamethylenetetramine (hexamine), and 150 mL THF to a 2L round-bottomed flask with reflux condenser (double surface). Stir the suspension and heat on an oil-bath to reflux. After 6 hrs. of refluxing (all should be dissolved now), distill off any volatiles in vacuum. Add a few crystals (200 mg) para-toluenesulfonic acid and 250 mL toluene, and reflux with stirring (Dean-Stark-adapter, double-surface condenser) with azeotropic removal of water for 2 hrs. After re-cooling of the mixture to 70°C, add 150 mL hot (75°C) water with stirring. Let cool down, the next morning, the flask is shaken vigorously to break lumps. Vacuum-filter the crude product, wash twice with 100 mL water (20°C) and with 25 mL ice cold (0°C, important) toluene. The product is then dried on a glass dish for 1 day, and bottled. Yield 50 gr. An IR spectrum of the described product nordiazepam is equivalent to literature. 1H-NMR shows a) the identity of the product, and b) it contains 90% nordiazepam, and 10% unremoved urotropine (hexamethylenetetramine) and water traces. No other impurities could be detected. Pharmaceutical description Similar activity like diazepam, half-life in body 30-90 hrs, danger of cumulation! Dose: 5 mg nordiazepam = 5 mg diazepam, metabolite: oxazepam. Strong tranquillizer, higher doses induce sleep. Warning! Abuse leeds to habituation/addiction! |
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