Comparative study on the preparation of C(3)‐hydroxy‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐ones

Abstract

C(3)‐Hydroxy‐1,4‐benzodiazepin‐2‐ones 1–3 have been prepared in high yields using a new, two step approach. In the first step, the 3‐deoxy‐precursors 4–6 were acetylated at C(3) using the redox‐system lead tetraacetate and iodine, or potassium iodide, in acetic acid. The intermediary acetates 9–11 were quantitatively hydrolyzed into 1–3 in non‐aqueous conditions, i.e. in a methanol‐methylene chloride solvent mixture in the presence of sodium methoxide. Another route to the title compounds has been improved as follows. The yields of C(3)‐bromination of compounds 4–6 has been significantly augmented in relation to the known methods using the strong trifluoroacetic acid in very dilute carbon tetrachloride solutions as a catalyst for NBS mediated bromination. The intermediary C(3)‐bromo derivatives have been acetoxylated in situ, and compounds 9–11 have been isolated in over 80% yield. These compounds were solvolyzed into 1–3 as described above. The third part of this paper describes the search for feasible reaction conditions in the synthesis of 3 according to a known method (Scheme 1.); optimization of the yields in all steps was performed.

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

“…The general synthesis of these derivatives is depicted in Scheme 22 via an oxidation followed by an acetylation step [108][109][110]. Alternatively, acetylation using lead (IV) acetate and potassium iodide in acetic acid is reported (Scheme 22, conditions e and f) without the isolation of the iodinated intermediate [111,112]. Alternatively, diazepam can also be obtained starting from 2-amino-5-chlorobenzophenone (compound 112 or structure 118 R 1 : Cl) with chloroacetyl chloride and hydroxylamine, followed by a methylation (Scheme 21) [105].…”

“…The general synthesis of these derivatives is depicted in Scheme 22 via an oxidation followed by an acetylation step [108][109][110]. Alternatively, acetylation using lead (IV) acetate and potassium iodide in acetic acid is reported (Scheme 22, conditions e and f) without the isolation of the iodinated intermediate [111,112].…”

Development of a Continuous Flow Synthesis of Lorazepam

“…Route A reportedly suffers from process irreproducibility issues and uses harsh oxidizing agents like persulfate. 9 Route B is not readily scalable, since the final 1,3-H shift transformation occurs under silica gel conditions and uses benzene as solvent, 10 while Routes C 11 and D 12 both require six steps to complete the synthesis. These studies indicate that there is a need for a robust and efficient synthetic route for lorazepam 5.…”