Benzo diazepin-2-ones

Removal of the solvent gave an oil which was taken up In ether and filtered through a pad of Woelm grade I alumina. The eluent was concentrated and the residue was crystallized from methylene chloride/hexane yielding 1-methyl-7-nitro-5-(2-fluorophenyl)-3H-1,4-benzo-diazepin-2(1 H)-one as pale yellow needles melting at 166° to 167°C. 

B) Preparation of 7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-6H-1,4-Bemodiazepin-5-one A mixture of 25.25 g (0.1 mol) of 4-acetyl-7-chloro-1,2,3,4-tetrahydro-1-methyl-5H-1,4-benzo-diazepin-5-one, 33.3 ml (0.1 mol) of 3 N sodium hydroxide and 350 ml of ethanol was heated under reflux for 15 minutes and then concentrated to dryness in vacuo. The residue was treated with 500 ml of water, collected and washed with ethanol to give 20.2 g... 

B) Add to a suspension of 34 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzo-diazepin-2-one in 80 ml of alcohol, 6 ml of 4N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1 4-benzodiazepin-2-one, melting point 203°Cto 204°C. 

An analogous reaction of (2-acylphenyl)acetic acids with hydrazine or substituted hydrazines in refluxing benzene, xylene or butanol with azeotropic removal of water gives 3//-2,3-benzo-diazepin-4(5//)-ones 3.128,129... 

The bromo derivative 16 reacts with phenylmagnesium bromide in diethyl ether, followed by workup with 5% aqueous hydrobromic acid, to give 2-methyl-4,5-diphenyl-2//-2,3-benzo-diazepin-l(5//)-one (17) in 55% yield.137 No further details were reported. 

The drug diazepam may serve as an illustrative example. Chemically, this compound is called 7-chloro-l,3-dihy-dro-1 -methyl-5-phenyl-2H-l, 4-benzo-diazepin-2-one, a term too unwieldy for everyday use. A simpler name is diazepam. This is not a legally protected name but a generic (nonproprietary) name. An INN (= international nonproprietary name) is a generic name that has been agreed upon by an international commission. 

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 phenyhnagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine (5.1.32). Reacting this with amino-malonic ester gives a heterocyclization product, 7-chloro-l,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]. 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

Clonazepam. Clonazepam, chemically 5-(2-chlorophenyl) -1,3-dihydro- 7-nitro-2ff-1,4-benzo-diazepin-2-one(4b), is closely related to nitrazepam (4e), differing only at position 5 with the o-chloro substituent. Only 0.5% of the original drug is recovered unchanged in the urine after 24 h, indicating extensive bio-... 

A) Diazepam (7-Chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzo-diazepin-2-one). 

Substituents, such as OH, SH, and NHj, can also participate in tautomeric equilibria, for example compare (13) with (14)-(16). The tautomerism of l,2-diazepin-4-ones has been thoroughly investigated by Moore et al. and the two keto tautomers (11) and (12) found to predominate in an equilibrium ratio of ca. 8 1, respectively (Equation (1)) <68JA1369, 73JOC2939>. 5 f-2,3-Benzo-diazepin-l-ones and benzodiazepine-1-thiones have also been established to exist in their oxo and thiono tautomeric forms <70BSF2237>. 

Titanium tetrachloride-tetrahydrofuran complex in tetrahydrofuran added during 20 min. to an ice-cooled mixture of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazepin-2-one and methylamine in dry tetrahydrofuran, allowed to react at room temp, with continued stirring, and the product isolated after 4 hrs. or when thin-... 

An intimate mixture of 2-nitro-N-methyl-N-phenacetylbenzamide and Fe-powder stirred 1 hr. at 90° with 0.5%-HCl -> 4-methyl-2-phenyl-3,4-dihydro-5H-l,4-benzo-diazepin-5-one. Y 85-90%. K. H. Weber, Arch. Pharm. 302, 584 (1969) 1,4-benzo-diazepines, review, s. A. V. Bogatskii and S. A. Andronati, Russ. Chem. Rev. 39, 1064 (1970) (Eng. transl.)... 

Na-methoxide added to a soln. of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazepin-2-one in anhydrous dimethylformamide, stirred and heated 0.5 hr. on a steam bath, cooled to 30, treated with l-bromo-3-chloropropane, and stirred 66 hrs. at 20° -> 7-chloro-l-(3-chloropropyl)-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one. Y 86%. L. H. Sternbach et al., J. Med. Ghem. 8, 815 (1965). 

A suspension of 2 - [1 - (2 - amino - 5 - chlorophenyl) -1 - phenylmethylamino] acetic acid in xylene refluxed with stirring under a Dean-Stark head until after 6 hrs. no more water separates 7-chloro-l,3,4,5-tetrahydro-5-phenyl-2H-l,4-benzo-diazepin-2-one (startg. m. f. 372). Y 81%. R. I. Fryer et al., J. Org. Ghem. 30, 1308 (1965) S,N-heterocyclics s. M. Uskokovi6 et al., J. Org. Ghem. 30, 3111. 

C15H10CIN3O3, 5-(2-Chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzo-diazepin-2-one, 45B, 270... 

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