Quinazolines and 1,4-Benzodiazepines. II.¹ The Rearrangement of 6-Chloro-2-chloromethyl-4-phenylquinazoline 3-Oxide into 2-Amino Derivatives of 7-Chloro-5-phenyl-3H-1,4-benzodiazepine 4-Oxide

The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: Half a century of anxiolytic drugs

“…Using this substance, the Hoffmann-LaRoche researcher developed 40 new compounds from the reaction of his key product, a haloalkane, with a number of secondary amines, selected to give them some structural similarity to the recently marketed tricyclic substances (Sternbach & Reeder, 1961a) However, when Lowell O. Randall, director of Pharmacological Research at Roche, studied the sedative, anticonvulsants and relaxant properties of these compounds, the results were negative (the first failure). Further chemical studies showed that the tricyclic system in the key intermediate product of synthesis was not benzoheptoxydiazine as previously believed, but was instead 3-oxido-quinazoline, and this appeared to be the reason for the lack of biological activity among the derivatives synthesised from the intermediate synthesis (the first error).…”

“…The explanation appeared when he found that in the final stage of the synthesis, he had used methylamine, a primary amine, by mistake, meaning that the reaction had taken a different form (transposition reaction with ring enlargement) from the one observed after using secondary amines (Sternbach & Reeder, 1961a) (the second twist of chance). This new tranquiliser, which was briefly known as methaminodiazepoxide, was patented by Sternbach on 15 May 1958, its name was then changed to chlordiazepoxide, and it was the first drug in a new family, known as the benzodiazepines (Fig.…”

Synthesis, antimicrobial and antifungal activities of novel 1H-1,4-diazepines containing pyrazolopyrimidinone moiety

“…A variety of reagent such as NaBH 4 , Al 2 O 3 -P 2 O 5 , MgO-POCl 3 , Yb(OTf) 3 and glacial acetic acid 12,13 and SiO 2 -Cl/wet SiO 2 14 and microwave irradiation 15 are used for the synthesis of 1H-1,4-diazepines. However, many of these methods involve the use of strong acids, high temperature conditions and extended reaction time and also entail several side reactions resulting in low yield in products.…”

Solid-State Characterization of Chlordiazepoxide Polymorphs

“…18 Chlordiazepoxide (100 g) was dissolved in hot ethanol (1800 mL). The solution was concentrated to 2 /3 volume by boiling and left to reach room temperature with stirring.…”