Barbital, marketed under the brand namesVeronal for the pure acid and Medinal for the sodium salt, was the first commercially available barbiturate. It was used as a sleeping aid from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid; hence, the sodium salt is known also as sodium diethylbarbiturate.
Synthesis
Barbital, then called "Veronal", was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering, who published their discovery in 1903. Barbital was prepared by condensing diethylmalonic ester with urea in the presence of sodium ethoxide, or by adding at least two molar equivalents of ethyl iodide to the silver salt of malonylurea or possibly to a basic solution of the acid. The result was an odorless, slightly bitter, white crystalline powder. Its introduction followed the investigations of Fischer and von Mering on the pharmacological properties of certain open and closed Acylureas. Led by the impression that hypnotic action appears to be largely dependent on the presence of ethyl groups, they prepared diethylacetyl urea, diethylmalonyl urea, and dipropylmalonyl urea. All three were found to be hypnotics: the first was about equal in power to the already-known sulphonal, whilst the third was four times as powerful, but its use was attended by prolonged after-effects. Veronal was found to be midway. Barbital can also be synthesized in a condensation reaction from urea and diethyl-2,2-diethylmalonate, a diethyl malonate derivative:
Marketing
Barbital was marketed in 1904 by the Bayer company as “Veronal”. A soluble salt of barbital was marketed by the Schering company as “Medinal.” It was dispensed for “insomnia induced by nervous excitability”. It was provided in either crystal form or in cachets. The therapeutic dose was ten to fifteen grains. 3.5 to 4.4 grams is the deadly dose but sleep has also been prolonged up to ten days with recovery.
Pharmacology
Barbital was considered to be a great improvement over the existing hypnotics. Its taste was slightly bitter, but better than the strong, unpleasant taste of the commonly used bromides. It had few side effects, and its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. "I'm literally saturated with it," the Russian tsarina Alexandra Feodorovna confessed to a friend. Fatal overdoses of this slow-acting hypnotic were not uncommon. Pioneering aviator Arthur Whitten Brown died of an accidental overdose.
