2H-l,4-benzodiazepines

CN 7-chloro-l-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one... 

Diazepam From a chemical point of view, diazepam, 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.2), is the most simple of all of the examined derivatives of l,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.1), is methylated by dimethylsulfate, which leads to the formation of diazepam (5.1.2). 

In similar studies, the reduction potentials of 1,2-benzothiazole derivatives in DMF were correlated to antimycotic activity [166], and those of 1,3,5,7-substituted-1,3-dihydro-2H-l, 4-benzodiazepin-2-ones and benzodiazepine-2-thiones in dimethylformamide (DMF)-water solutions were correlated to inhibition of orientation reactions and to protection from electric shock [167]. 

Chloro-5-phenyl-l-methyl-3-hydroxy-l,3-dihydro-2H-l,4-benzodiazepine-2-one Phenyl chlorocarbonate Dimethylamine... 

A suspension of 100 g of 7-chloro-5-phenyl-l-methyl-3-hydroxy-l,3-dihydro-2H-l,4-benzodiazepin-2-one in 700 ml of anhydrous pyridine, kept stirred between 0°C and +5°C, is slowly treated, during 20 to 30 minutes, with 54.5 ml phenyl chlorocarbonate. The temperature is gradually allowed to rise to 20°-25°C and stirring is maintained at this temperature during 24 hours. 

A suspension of 45 g 3-phenoxycarbonyloxy-l-methyl-7-chloro-5-phenyl-l,3-dihydro-2H-l,4benzodiazepin-2-one in 450 ml methanol is treated with stirring, with 43 ml of a solution of dimethylamine in methanol (containing 31 g dimethylamine in 100 ml). Stirring is maintained at 20°C to 25°C during 5 hours. The reaction mixture is filtered, and the filtrate is diluted with 450 ml water. The precipitate thus formed, is 3-(N,N-dimethylcarbamoyloxy)-l-methyl-7-chloro-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, which is collected on a filter, dried and recrystallized from ethyl acetate, and has a melting point of 173°C to 174°C. 

Chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepine-2-thione Formic acid hydrazide... 

A solution of 60 g of chromic anhydride in 40ml of water was added dropwise to a suspension of 60 g of 2-aminomethyl-l-methyl-5-chloro-3-(o-fluorophenyl)-indole hydrochloride in 600 ml of acetic acid. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1.1 liters of ether and 1 liter of water and then 800 ml of 28% ammonium hydroxide, in small portions. The ethereal layer separated, washed with water, dried, and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and 100 ml of 20% ethanolic hydrogen chloride was added to the solution and the mixture was cooled. The precipitate was collected by filtration to yield 46.5 g of l-methyl-7-chloro-5-(o-fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepine-2-one hydrochloride, melting point 218°C (decomposed). Recrystallization from ethanol raised the melting point to 218.5°C to 219°C (decomposed). 

A solution of 6.5 g (32 mmol) of 7-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione in 30 ml of dry dimethylformamide is treated with 4.3 g (38 mmol) of potassium t-butylate under an argon atmosphere. 

Prepare a solution of sodium methylate by dissolving 3.9 g of sodium metal in 500 ml of methanol. Add 39.0 g of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepine-2-one. Evaporate the reaction mixture to a residue and dissolve the residue in 170 ml of dimethylformamide. Add 30 g of 2,2,2-trifluoroethyl iodide and stir at room temperature for Vi hour, then heat to 60°C to 70°C for an additional 7 hours. Add 19 g of 2,2,2-trifluoroethyl iodide and resume the heating and stirring at 60°C to 70°C for an additional 16 hours. Filter off the solids and evaporate the filtrate to a residue in vacuo. Triturate the residue with water and extract with ethyl ether. Wash the ethereal extract with water, dry over anhydrous sodium sulfate and evaporate... 

To a slightly warm suspension of 3-acetoxy-7-chloro-5-(o-chlorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one thus obtained was added 4N sodium hydroxide solution with stirring. All the solid dissolved and soon a thick white solid precipitated out. The solid was filtered, washed well with water and recrystallized from ethanol. The product was isolated as a solvate with 1 mol of ethanol. When heated it loses the ethanol of solvation and melts at 166°C to 168°C. 

Acetoxy-7-chloro-l,3-dihydro-5-(o-chlorophenyl)-2H-l,4-benzodiazepin-2-one Sodium hydroxide... 

To a suspension of 3.4 g of 3-acetoxy-7-chloro-l,3-dihydro-5-(o-chlorophenyl)-2H-l,4-benzodiazepin-2-one in 80 ml of alcohol was added 6 ml of 4 N sodium hydroxide. After complete solution had taken place a solid precipitated that redissolved upon the addition of 80 ml of water. The solution was acidified with acetic acid to give white crystals. After recrystallization from alcohol the compound melted at 192°C to 194°C. 

Chemical Name l,3-Dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one Common Name -Structural Formula ... 

Chemical Name 7-Chloro-l,3-dihydro-3-hydroxy-5-phenyl-2H-l,4-benzodiazepin-2one... 

A) Suspend 10 g of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one 4-oxide in 150 ml of acetic anhydride and warm on a steam bath with stirring until all the solid has dissolved. Cool and filter off crystalline, analytically pure 3-acetoxy-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, melting point 242°C to 243°C. 

The chromatographic resolution of (R-S)-7-chloro-l,3-dihydro-3-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (III) is another example of the previous method that can be cited [21], Figure, 2. 

Another example of the chromatographic resolution of a starting mixture with relatively low chemical purity is shown in Figure 4, [21. The chromatographic profile that is obtained with CD detection reveals only two peaks, allowing a safe identification of the antipodes of (R) and (S)-7-chloro-1,3-dihydro-3-i-propyl-5-phenyl-2H- l,4-benzodiazepin-2-one, (R,S)-(IV). But the profile obtained with the UV absorbance detector provides evidence for at least four different peaks, two of which are partially overlapped. Thus the enantiomeric composition is more correctly determined by CD detection. 

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