Chlordiazepoxide: Chlordiazepoxide, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo-diazepin-4-oxide (5.1.22), is also synthesized from 2-amino-5-chlorobenzophenone. This is reacted in the usual manner with hydroxylamine, forming 2-amino-5-chlorobenzophe-none oxide (5.1.20), which upon reaction with chloroacetic acid chloride in acetic acid easily cyclizes to 6-chloro-2-chloromethyl-4-phenylquinazolin-3-oxide (5.1.21). Reacting this with a primary amine, methylamine in particular, leads to an interesting rearrangement (with a ring expansion), and the reaction product turns out to be 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxide (5.1.22)—chlordiazepoxide. An analogous rearrangement with a ring expansion also proceeds upon reaction with alkaline or alcoxides; however, it should be noted that with dialkylamines, the reaction forms the expected substitution products, 2-dialkylaminomethyl derivatives of 6-chloro-4-phenylquinazolin-3-oxide. Chlordiazepoxide was the first representative of the benzo-diazepine series of anxiolytics to be introduced into medical practice [15-17].
Chlordiazepoxide is used for treating neurotic conditions such as relieving feelings of fear, worry, and stress. It exhibits soporific action on the CNS, causes muscle relaxation, and possesses anticonvulsant activity. It is frequently used after operational interventions. The most frequently used synonyms are elenium and librium.
Oxazepam: Oxazepam, 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-benzodiazepin-2-one (5.1.25), is synthesized in a similar manner as described above, which was discovered during the synthesis of chlordiazepoxide, but instead of using a primary amine, a simple, inorganic base was used as a nucleophile. In order to do this, 6-chloro-2-chloromethyl-4-phenylquina-zolin-3-oxide (5.1.21) undergoes treatment with sodium hydroxide, giving 7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-on-4-oxide (5.1.23). This undergoes an extremely curious acetoxylation reaction of the third position of the benzodiazepine ring, using acetic anhydride, and which reminiscents the Polonovski reaction, giving 7-chloro-1,3-dihydro-3-acetoxy-5-phenyl-2H-benzodiazepin-2-one (5.1.24). Subsequent hydrolysis of the product's acetyl group gives oxazepam (5.1.25) [18-24].
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