Polonovski Rearrangement Lorazepam

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Oxazepam is similar to chlordiazepoxide in terms of pharmacological properties; however, it has a somewhat less harsh effect, is less toxic, and exhibits a less expressed myorelaxant effect. It is often tolerated better by patients than other tranquilizers. It is used in neurosis, conditions of anxiety, fear, stress, trouble falling asleep, and psychovegatative disorders. The most common synonyms are nozepam and tazepam.

Lorazepam: Lorazepam, 7-chloro-4-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-ben-zodiazepin-2-one (5.1.31), is synthesized according to a scheme containing some of the same elements for the synthesis of chlordiazepoxide and oxazepam, and comes from 2-amino-2',5-dichlorobenzophenone. Reacting this with hydroxylamine gives (5.1.26), the reaction of which with chloracetyl chloride, and upon heterocyclization gives 6-chloro-2-chlormethyl-4-(2'-chlorophenyl)quinazolin-3-oxide (5.1.27). Reacting this with methylamine, as in the case of chlordiazepoxide, leads to rearrangement and a ring expansion, forming 7-chloro-2-methylamino-5-(2'-chlorphenyl)-3H-1,4-benzodiazepin-4-oxide (5.1.28). The resulting benzodiazepin-4-oxide undergoes acetylation by acetic anhydride at the secondary nitrogen atom, and is further hydrolyzed by hydrochloric acid into 7-chloro-5-(2'-chlorophenyl)-1,2-dihydro-3H-1,4-benzodiazepin-2-on-4-oxide (5.1.29). Reaction of this product with acetic anhydride leads to a Polonovski type rearrangement reaction, giving a 3-acetoxylated benzodiazepine, 7-chloro-1,3-dihydro-3-acetoxy-5-(2'-chlorphenyl)-2H-benzodiazepin-2-one (5.1.30), the hydrolysis of which forms the desired product lorazepam (5.1.31) [18,25-29].

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Indications for its use are the same as those of other tranquilizers as well as in the capacity of a drug for cardioneurosis, preoperational medical anesthesia, and as an adjuvant drug in endoscopic procedures. It differs somewhat in that it exhibits shorter-lasting action. The most common synonyms are ativan and tavor.

Chorazepate: Chorazepate, 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzo-diazepin-3-carboxylic acid (5.1.34), which is used in the form of a dipotassium salt, is synthesized by yet another interesting synthetic scheme. 2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenylmagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine (5.1.32). Reacting this with amino-malonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one (5.1.33), which upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt (5.1.34), chlorazepate [30-32].

Chlorazepate is among the long-acting tranquilizers used upon the same indications as other tranquilizers, and also as an adjuvant drug for epileptic attacks. The most common synonyms are tranxene, noctran, and others.

Alprazolam: Alprazolam, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodi-azepine (5.1.39), is a chemical analog of triazolam (4.2.4) that differs by the absence of a chlorine atom in the o-position of the 6-phenyl ring. The same scheme that was used to make triazolam can be used to make alprazolam, with the exception that it begins with 2-amino-5-chlorobenzophenone [33-35]. However, a non-standard way of making alprazolam has been suggested, which comes from 2,6-dichloro-4-phenylquinoline, the reaction of which with hydrazine gives 6-chloro-2-hydrazino-4-phenylquinoline (5.1.35). Boiling this with triethyl orthoacetate in xylene leads to the heterocyclization into a triazole derivative (5.1.36). The resulting product undergoes oxidative cleavage using sodium periodate and ruthenium dioxide in an acetone-water system to give 2-[4-(3'-methyl-1,2,4-tria-zolo)]-5-chlorobenzophenone (5.1.37). Oxymethylation of the last using formaldehyde and subsequent substitution of the resulting hydroxyl group by phosphorous tribromide, gives 2-[4-(3'-methyl-5'-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone (5.1.38). Substitution of the bromine atom with an amino group using ammonia and the spontaneous, intermolecular heterocyclization following that reaction gives alprazolam (5.1.39) [36-38].

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  • lukas
    How is lorazepam synthesised?
    8 hours ago

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