Preparation of Clonazepam and "Clonitrazolam"

Here follows a synthesis of Clonazepam (5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-one) and of the new designer benzodiazepine derivate "Clonitrazolam" (6-(2-chlorophenyl)-1-methyl-8-nitro- 4H-s-triazolo(4,3-a)-(1,4)-benzodiazepine).

1. 2-amino-2'-chloro-5-nitrobenzophenone

(see US-patent 3,215,737)

A mixture of 435 g (2.485 mol) 2-chlorobenzoyl chloride and 209 g (1.53 mol) anhydrous zinc chloride is heated up to 130-140 C, and in small portions, 166 g (1.2 mol) 4-nitroaniline is added over 30 min. After complete addition, the mixture is heated up to 200-205 C (use a metal bath of Wood's alloy to heat the flask) with stirring for 1 h . After cooling to 80 C, carefully a mixture of 298 mL water and 425 mL acetic acid is added with stirring, then 553 mL 96% sulfuric acid. The mixture is heated, refluxed and stirred for 4 h and cooled to 0 C. Ammonia solution (26%) - 62 mL is added together with ice, and after recooling to room temperature, the solid is extracted into six 250 mL portions of warm (60 C) toluene. The combined toluene extract is washed exhaustively with six 250 mL portions of warm (60 C) hydrochloric acid (3 N), with six 250 mL portions of warm (60 C) 50% sodium hydroxide solution, the organic layer is dried (sodium sulfate) and evaporated to dryness in vacuo. The residue is recrystallized from petroleum ether/benzene to yield about 60g (15-20%) 2-amino-2'-chloro-5-nitrobenzophenone, mp. 118-120°C.

2. 2-(bromoacetamido)-2'-chloro-5-nitrobenzophenone

(see Netherlands patent appl. 6,405,644, Chem. Abstr. 62/16157d-f)

To a solution of 100 g (0.36 mol) 2-amino-2'-chloro-5-nitrobenzophenone in 3 L benzene is added 77.8 g (0.385 mol) bromoacetyl bromide, and with a stream of dry air bubbling through the mixture, the reaction mixture is heated at 40 C for 2 h. Thereafter, the mixture is concentrated to dryness in vacuo, leaving about 143 g (quant.) almost pure 2-(bromoacetamido)-2'-chloro-5-nitrobenzophenone.

3. Clonazepam (5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-one)

(see swiss patent 580,087, workup: US patent 3,335,181)

The 143 g (0.36 mol) intermediate from step 2, 101 g hexamethylenetetramine (urotropine) and 36 mL 99 % formic acid are suspended/dissolved in 5 L absolute ethanol, the mixture is refluxed with stirring for 4 h, and then the mixture is concentrated in vacuo to dryness. The residue is dissolved in 2 L dichloromethane and 4 L water, the organic layer is seperated and mixed with 2 L ethanol. Over a 20 cm vigreux column, the dicloromethane is distilled off and the residual solution is cooled to 0 C for 24 h. The almost yellow-white crystalls of Clonazepam are vacuum-filtered off and washed with 0 C ethanol, after drying, about 90.9 g (80%) of Clonazepam are resulting, mp. 235-237°C.

4. 5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-thione

(see J Med. Chem. Vol. 14, p. 1078-1081 (1971) )

A mixture of 100 g Clonazepam (0.317 mol, 5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-one ), 77.4 g phosphorous pentasulfide (0.348 mol) and 2.5 L pyridine is refluxed under a nitrogen atmosphere for 30 min. After cooling and concentrating in vacuo, the residue is suspended in ice water and extracted exhaustively with dichloromethane. The organic extract is dried over potassium carbonate and evaporated to dryness in vacuo. The residue is recrystallized from a minimum amount of ethanol to yield about 69.4 g (66%) of 5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-thione, mp. 219-221°C (dec).

5. 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-s-triazolo(4,3-a)-(1,4)-benzodiazepine

(see J Med. Chem. Vol. 14, p. 1078-1081 (1971) )

A stirred mixture of 50 g 5-(2-chlorophenyl)-1,3-dihydro-7-nitrobenzo(1,4)-diazepin-2-thione (0.151 mol), 31.25 g acethydrazide (0.4 mol) and 2 L n-butanol is refluxed under nitrogen for 4 h, and concentrated in vacuo to dryness. The residue is suspended in water, the solid filtered off and recrystallized from a minimum amount of isopropanol to yield about 37.5 g (70%) of 6-(2-chlorophenyl)-1-methyl-8-nitro-4H-s-triazolo- (4,3-a)-(1,4)-benzodiazepine ("Clonitrazolam"), mp. 229-231°C.