Synthesis of imidazolidin‐4‐ones and their conversion into 1,4‐benzodiazepin‐2‐ones

Abstract

Abstractα‐Haloacetanilides Ia‐e react with hexamine in ethanol giving the bisimidazolidin‐4‐one derivatives IIa‐e, which hydrolize, in acidic media into the corresponding mono‐imidazolidin‐4‐ones IIIa‐e. The compounds IIa‐d were converted into 1,4‐benzodiazepin‐2‐ones, under different conditions and in the presence of a variety of agents. The yields were between 50 and 100%.

Development of a Continuous Flow Synthesis of Lorazepam

“…In prior batch syntheses of delorazepam 3, cyclization to form the 1,4-diazepine ring was performed with hexamethylene tetramine in a two-step process. 30 Additional conditions explored included the presence of NH 4 OAc 9 , NH 4 OH in methanol for 48 h, 31 hydrazine, 32 NH 3 in MeOH, 33 NaI/NH 3 in MeOH, 34 and NaN 3. 35 Our hypothesis was that the ammonium salt counter ion could play a crucial role in the cyclization as it can also act as a buffer for the reaction.…”

“…We next sought to identify the most efficient ammonia source for the second stage reaction. In prior batch syntheses of delorazepam 3 , cyclization to form the 1,4-diazepine ring was performed with hexamethylene tetramine in a two-step process . Additional conditions explored included the presence of NH 4 OAc 9 , NH 4 OH in methanol for 48 h, hydrazine, NH 3 in MeOH, NaI/NH 3 in MeOH, and NaN 3.…”