Synthesis of Diazepam (Valium)
by Psycho Chemist

2-Methylamino-5-chloro-benzophenone Dissolve 400 g sodium hydroxide in 4 L ethanol and in a seperate flask, 1.5 moles (175.5 g) benzyl cyanide (see elsewhere on this site for its synthesis) and 1 mole 1-chloro-4-nitrobenzene and the min. amoount benzene or toluene or THF to obtain a solid-free solution. Add dropwise this organic mixture to the NaOH in alcohol at 17-22°C (control by cooling), and leave the mix for 4 days. Pour on 3 kg ice and 12 L water (This mix now contains cyanide and must not be contaminated with acid!!!). Vacuum-filter (in portions) the resinous mass or decant off the water layer. Dissolve the water-washed resin in 1 L (or more, but loss) boiling isopropanol and let cool down to 10°C, after 1 day, filter the intermediate, 0.9 moles or about 200 g 5-chloro-3-phenyl-benzo(2,1)-isoxazole. A mix of 200 g benzisoxazole and 500 ml dimethyl sulfate (caution) is stirred 12 h at 80°C (4 L flask), and through the condenser thereafter, 100 mL water and 2 L ethanol is added , then, direct to the flask, 100 g iron fillings. The flask content is mechanically stirred and over 90 min., 600 mL conc. hydrochloric acid is added. Then the mix is refluxed 90 min and filtered over Celite hot. The cake is washed with 1 L hot ethanol and the filtrate concentrated in vacuo to 500 mL. It is poured in 4 L water and 1 L dichloromethane is added until most is dissolved. The dichloromethane layer is seperated and reextracted with 1 L more dichloromethane. The combined dichloromethane extracts are filtered and evaporated to dryness to leave the 2-methylamino-5-chloro-benzophenone, cryst. From petrol ether, mp 95-98°C. Yield 180 g. Diazepam (personal experience) Dissolve 180 g 2-methylamino-5-chlorobenzophenone in 1 l dry dichloromethane, add 100 g chloroacetyl chloride over 1 h and reflux 10 h. Rotovap off the dichloromethane (dryness in the flask, end (60 °C, 20 torr). Dissolve 400 g hexamethylene tetramine (urotropine) in 3 l ethanol, and add to the chloroacetylated residue. Reflux and stirr 24 h (all organic material is dissolved) and then evapotate to dryness. Add 100 mL toluene, and 1 g toluenesulphonic acid, and reflux with a Dean-Stark water-trap until no more water separates. Add 1 L water, heat to 70°C and let cool down to 15°C. Filter off your diazepam, and wash with 50 mL ice-cold toluene. Dry in vacuo. Almost pure 150 g Diazepam will result. References: [1] Chem Abstr. 123-339841 p [2] Russ. J. Org. Chem., Vol. 30, p 1481-1484 (1994) (english) [3] Coll. Czechoslovak Chem. Commun., Vol. 50, p 1064-1069 (1985)