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Chapter 6
Synthesis of benzodiazepines
6.4 Synthetic methods for benzodiazepines derivatives
The most extensively used methods for preparing 1,4-benzodiazepines begins
with an ortho-aminobenzophenone (1). The first method involves two-step synthesis.
The first step involves treatment of the appropriate aminobenzophenone with
haloacetyl halide to afford the amide (2), followed by the addition of ammonia to first
displace the chlorine giving the glycinamide (3). Then cyclization by imine formation
will give the benzodiazepine (4). 54-55 The other method involves treating the o-aminoketone
with an amino acid ester hydrochloride in pyridine to yield (4) (Figure-14).
Generally, the first method gave a higher percent yield of clean product, while the
second method facilitated the conversion of o-aminoketones to benzodiazepines in
one step, with a variety of substituents. 54-56
Figure-14
Jin-Yuan Wang et al. 57 have developed a new strategy for the synthesis of 1,4-
benzodiazepine from Methyl1-arylaziridine-2-carboxylates with N-[2-Bromomethyl(phenyl)]trifluoroacetamides
(Figure-15). The reaction proceeds through the
N-benzylation and highly regioselective ring-opening reaction of aziridine by bromide
anion followed by Et 3 N mediated intramolecular nucleophilic displacement of the
bromide by the amide nitrogen.
R
Br
NH
O
CF 3
MeOOC
N
R'
1) CH 3 CN, reflux 11hrs
2) Et 3 N (2.0 eq.)
CH 3 CN, reflux, 12hrs
F 3 COC
R N
N
COOMe
R'
Figure-15
Department of Chemistry, Saurashtra University, Rajkot-360005 208