2.3- Dihydro-benzo diazepines

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. 

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]. 

Following the same rationale, the Cl sequence can also be applied to the synthesis of seven-membered heteroazepines. Thus, upon CIR of electron-deficient (hetero) aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of orf/io-phenylene diamines 50 or ortho-zmmo thiophenols 52, 2,4-di(hetero)aryl substituted 2,3-dihydro benzo[b][l,4]diazepines 90 or di(hetero)aryl substituted 2,3-dihydro benzo[h][l,4]thiazepines 91 can be obtained in a consecutive three-component reaction in moderate to good yields (Scheme 49) [242, 243]. 

Fahmy AM, Hassan KM, Khalaf AA, Ahmed RA (1987) Synthesis of some new P-lactams, 4-thiazolidinones and pyrazolines. Indian J Chem Sect B 26 884-887 Muller TJJ, Braun R, Ansorge M (2000) A novel three component one-pot pyrimidine synthesis based upon a coupling-isomerization sequence. Org Lett 2 1967-1970 Braun RU, Zeitler K, Muller TJJ (2000) A novel 1,5-benzoheteroazepine synthesis via a one-pot coupling-isomerization-cyclocondensation sequence. Org Lett 2 4181-4184 Braun RU, Muller TJJ (2004) One-pot syntheses of dihydro benzo[b][l, 4]thiazepines and -diazepines via coupling-isomerization-cyclocondensation sequences. Tetrahedron 60 9463-9469... 

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-... 

Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzo-diazepin-2-... 

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

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). 

Typical procedure. 7-Chloro-3-cyano-2,3-dihydro- 7-methyl-l-oxo-S-phenyl- 7 H- 7,4-benzo-diazepine 1451 [1102] A mixture of triphenylphosphine (104.0 g, 0.4 mol), tetra-chloromethane (350 mL), dioxane (400 mL), and the carboxamide 1450 (65.5 g, 0.2 mol) was stirred at 80 °C for 90 min, in the course of which the amide dissolved and the solution became orange. The solvent was then evaporated in vacuo and the residue was redissolved in dichloromethane. The organic solution was washed with water and then concentrated in vacuo. The resulting oil crystallized on trituration with a little diethyl ether. The cmde product, which still contained some triphenylphosphine oxide, was recrystallized from ethanol to afford 47 g (76%) of pure product 1451 mp 208-210 °C IR v ax = 2266 cm (CN). 

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

A soln. of 2-amino-5-chlorobenzamidoacetonitrile in tetrahydrofuran added drop-wise under Ng to a suspension of NaH in anhydrous tetrahydrofuran, refluxed 2 hrs., and stirred an additional hr. 2-amino-7-diloro-3,4-dihydro-5H-l,4-benzo-diazepin-5-one. Y 85%. F. e. with lower yields s. M. Julia, N. Hurion, and H. D. Tam, Chim. Ther. 5, 343 (1970). 

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